NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Prostate Cancer
Version 1.2022 — September 10, 2021

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Table of Contents
Prostate Cancer Discussion

*Edward Schaeffer, MD, PhD/Chair ω Thomas A. Farrington ¥ George Netto, MD ≠

Robert H. Lurie Comprehensive Cancer Prostate Health Education Network (PHEN) O'Neal Comprehensive Cancer Center at UAB
Center of Northwestern University Xin Gao, MD † Þ David F. Penson, MD, MPH ω
*Sandy Srinivas, MD/Vice-Chair † ω Dana-Farber/Brigham and Women's Vanderbilt-Ingram Cancer Center
Stanford Cancer Institute Cancer Center | Massachusetts General Julio M. Pow-Sang, MD ω
Emmanuel S. Antonarakis, MD † Hospital Cancer Center Moffitt Cancer Center
The Sidney Kimmel Comprehensive Shilpa Gupta, MD † Robert Reiter, MD, MBA ω
Cancer Center at Johns Hopkins Case Comprehensive Cancer Center/University UCLA Jonsson Comprehensive Cancer Center
Andrew J. Armstrong, MD, ScM † Hospitals Seidman Cancer Center and
Cleveland Clinic Taussig Cancer Institute Mack Roach, III, MD §
Duke Cancer Institute UCSF Helen Diller Family
Heather H. Cheng, MD, PhD † Eric Mark Horwitz, MD § Comprehensive Cancer Center
Fred Hutchinson Cancer Research Center/ Fox Chase Cancer Center
Stan Rosenfeld ¥
Seattle Cancer Care Alliance Joseph E. Ippolito, MD, PhD ф University of California San Francisco
Anthony Victor D’Amico, MD, PhD § Siteman Cancer Center at Barnes- Patient Services Committee Chair
Dana-Farber/Brigham and Women’s Jewish Hospital and Washington
University School of Medicine Ahmad Shabsigh, MD ω
Cancer Center | Massachusetts The Ohio State University Comprehensive
General Hospital Cancer Center Michael R. Kuettel, MD, MBA, PhD § Cancer Center - James Cancer Hospital
Brian J. Davis, MD, PhD § Roswell Park Comprehensive Cancer Center and Solove Research Institute
Mayo Clinic Cancer Center Joshua M. Lang, MD, MS † Benjamin A. Teply, MD †
Neil Desai, MD, MHS § University of Wisconsin Carbone Cancer Center Fred & Pamela Buffett Cancer Center
UT Southwestern Simmons Rana McKay, MD † Jonathan Tward, MD, PhD §
Comprehensive Cancer Center UC San Diego Moores Cancer Center Huntsman Cancer Institute
Tanya Dorff, MD † Todd Morgan, MD ω at the University of Utah
City of Hope National Cancer Center University of Michigan Rogel Cancer Center Richard Valicenti, MD §
James A. Eastham, MD ω Sameer Nath, MD § UC Davis Comprehensive Cancer Center
Memorial Sloan Kettering Cancer Center University of Colorado Cancer Center

NCCN
ф Diagnostic/Interventional ¥ Patient advocate
§ Radiotherapy/Radiation oncology
Continue Deborah Freedman-Cass, PhD
radiology Ryan Berardi, MSc
Þ Internal medicine w Urology
† Medical oncology * Discussion Section Writing
Dorothy A. Shead, MS
≠ Pathology Committee NCCN Guidelines Panel Disclosures
Version 1.2022, 09/10/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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NCCN Guidelines Version 1.2022 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

NCCN Prostate Cancer Panel Members Principles of Life Expectancy Estimation (PROS-A)
Clinical Trials: NCCN believes
Summary of Guidelines Updates Principles of Genetics and Molecular/ Biomarker that the best management for any
Initial Prostate Cancer Diagnosis (PROS-1) Analysis (PROS-B)
patient with cancer is in a clinical
Initial Risk Stratification and Staging Workup for Principles of Risk Stratification (PROS-C) trial.
Clinically Localized Disease (PROS-2) Principles of Imaging (PROS-D) Participation in clinical trials is
Very-Low-Risk Group (PROS-3) Principles of Active Surveillance and Observation especially encouraged.
Low-Risk Group (PROS-4) (PROS-E) Find an NCCN Member Institution:
Favorable Intermediate-Risk Group (PROS-5) Principles of Radiation Therapy (PROS-F) https://www.nccn.org/home/
Principles of Surgery (PROS-G) member-institutions.
Unfavorable Intermediate-Risk Group (PROS-6)
High- or Very-High-Risk Group (PROS-7) Principles of Androgen Deprivation Therapy (PROS-H)
Regional Risk Group (PROS-8) Principles of Non-Hormonal Systemic Therapy NCCN Categories of
(PROS-I) Evidence and Consensus: All
Monitoring (PROS-9)
Staging (ST-1) recommendations are category 2A
Radical Prostatectomy PSA Persistence/Recurrence unless otherwise indicated.
(PROS-10)
See NCCN Categories of Evidence
Radiation Therapy Recurrence (PROS-11)
and Consensus.
Systemic Therapy for Castration-Naïve Prostate
Cancer (PROS-12)
Systemic Therapy for M0 Castration-Resistant NCCN Categories of Preference:
Prostate Cancer (CRPC) (PROS-13) All recommendations are
Systemic Therapy for M1 CRPC (PROS-14) considered appropriate.
Systemic Therapy for M1 CRPC: Adenocarcinoma See NCCN Categories of
(PROS-15) Preference.

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical
circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or
warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2021.

Version 1.2022, 09/10/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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NCCN Guidelines Version 1.2022 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Prostate Cancer from Version 2.2021 include:
General: Terminologies modified to be more inclusive of all sexual PROS-2A
and gender identities. • Footnote f modified: An ultrasound- or MRI- or DRE-targeted
PROS-1 lesion that is biopsied more than once and demonstrates cancer
• Initial Prostate Cancer Diagnosis and Workup: This page was (regardless of percentage core involvement or number of cores
extensively revised. involved) counts can be considered as a single positive core.
PROS-2 • Footnote g removed: Plain films, CT, MRI, or PET/CT or PET/MRI with
• Initial Risk Stratification and Staging Workup for Clinically Localized F-18 sodium fluoride PET/CT or PET/MRI, C-11 choline PET/CT or
Disease - This page was extensively revised. Columns for germline PET/MRI, or F-18 fluciclovine PET/CT or PET/MRI can be considered
testing and molecular biomarker analysis of tumor were removed for equivocal results on initial bone imaging scan. See PROS-D.
from this page and included in a new principles page. • Replaced footnote d with: Tumor-based molecular assays and
• Third column header modified: Imaging Additional Evaluation germline genetic testing are other tools that can assist with risk
• Very low risk group: stratification. See Principles of Genetics and Molecular/Biomarker
First bullet revised: cT1c Analysis (PROS-B) to determine if a patient is an appropriate
Bullet revised under Additional Evaluation: Consider confirmatory candidate for germline genetic testing, and see Principles of Risk
prostate biopsy ± mpMRI if not performed prior to biopsy to Stratification (PROS-C) to determine if a patient is an appropriate
establish candidacy for active surveillance (Also for Low risk candidate for tumor-based molecular assays.
group) • Footnote i removed: mpMRI is preferred over CT for pelvic ±
• Low risk group: abdominal abdominal/pelvic staging. See PROS-D.
First bullet modified: cT1–cT2a • Added footnote i: Bone imaging can be achieved by conventional
• Intermediate risk group: technetium-99m-MDP bone scan. Plain films, CT, MRI, or PET/CT or
Added (eg, <6 of 12 cores) PET/MRI with F-18 sodium fluoride, C-11 choline, F-18 fluciclovine,
Favorable, removed the following bullets from Additional Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for
Evaluation column: equivocal results on initial bone imaging. Soft tissue imaging of
◊ Bone imaging: not recommended for staging pelvis, abdomen, and chest can include chest CT and abdominal/
◊ Pelvic ± abdominal imaging: recommended if nomogram pelvic CT or abdominal/pelvic MRI. mpMRI is preferred over CT for
predicts >10% probability of pelvic lymph node involvement pelvic staging. Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat
◊ If regional or distant metastases are found, see PROS-8 PSMA PET/CT or PET/MRI can be considered for bone and soft
Modified: Consider confirmatory prostate biopsy ± mpMRI if tissue (full body) imaging. See Principles of Imaging (PROS-D).
not performed prior to biopsy to establish candidacy for those (Also for PROS-10, PROS-11A)
considering active surveillance • Added footnote j: Because of the increased sensitivity and
Unfavorable, added the following bullet to Additional Evaluation specificity of PSMA-PET tracers for detecting micrometastatic
column: Bone and soft tissue imaging (Also for High and Very High disease compared to conventional imaging (CT, MRI) at both initial
risk groups) staging and biochemical recurrence, the Panel does not feel that
• High risk group: conventional imaging is a necessary prerequisite to PSMA-PET
First bullet modified: cT3a OR and that PSMA-PET/CT or PSMA-PET/MRI can serve as an equally
• Very high risk group: effective, if not more effective front-line imaging tool for these
First bullet modified: cT3b–cT4 patients. (Also for PROS-9, -10, -11A, -12, -13)

Continued
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Prostate Cancer Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Prostate Cancer from Version 2.2021 include:
PROS-3, PROS-4, PROS-5, PROS-6, PROS-7 PROS-9
• Changed Observation to Monitoring, with consideration of early RT • Modified footnote ii: Document castrate levels of testosterone if on
for a detectable and rising PSA or PSA >0.1 ng/mL. ADT clinically indicated. Workup for progression should include
PROS-4 bone and soft tissue evaluation. Bone imaging can be achieved
• Removed: Active surveillance (preferred) by conventional technetium-99m-MDP bone scan. Plain films, CT,
PROS-5 MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline,
• Changed Consider mpMRI and/or prostate biopsy to confirm F-18 fluciclovine, Ga-68 PSMA-11, or F-18 piflufolastat PSMA can
candidacy for active surveillance to Consider confirmatory prostate be considered for equivocal results on initial bone imaging. Soft
biopsy with or without mpMRI and with or without molecular tumor tissue imaging of pelvis, abdomen, and chest can include chest CT
analysis to establish candidacy for active surveillance. and abdominal/pelvic CT or abdominal/pelvic MRI. Alternatively,
• Modified: EBRT or brachytherapy alone Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI
PROS-6 can be considered for bone and soft tissue (full body) imaging.
• Modified: Observation (preferred) See Principles of Imaging (PROS-D). bone imaging, chest CT, and
PROS-7 abdominal/pelvic CT with contrast or abdominal/pelvic MRI with and
• Initial therapy, changed format and added abiraterone option: without contrast. If there is no evidence of metastases, consider
EBRT + ADT (1.5–3 y; category 1) C-11 choline PET/CT or PET/MRI or F-18 fluciclovine PET/CT or
or PET/MRI for further soft tissue and bone evaluation or F-18 sodium
EBRT + ADT (2 y) + docetaxel for 6 cycles (for very-high-risk only) fluoride PET/CT or PET/MRI for further bone evaluation. The Panel
or remains unsure of what to do when M1 is suggested by these PET
EBRT + brachytherapy + ADT (1–3 y; category 1 for ADT) tracers but not on conventional imaging. (also on PROS-10 through
or PROS-13)
EBRT + ADT (2 y) + abiraterone (for very-high-risk only) • Removed footnote: The term "castration-naïve" is used to define
PROS-8 patients who are not on ADT at the time of progression. The NCCN
• Previous page, Regional and Metastatic Risk Group, was removed. Prostate Cancer Panel uses the term "castration-naïve" even when
• Regional risk group, added (Any T, N1, M0) to the heading. patients have had neoadjuvant, concurrent, or adjuvant ADT as part
• Added: RP + PLND with adjuvant therapy of radiation.
PROS-8A
• Added footnote: The fine-particle formulation of abiraterone can be
used instead of the standard form (category 2B; other recommended
option).
• Revised footnote v: Added a footnote linking to new Principles of
Risk Stratification page.
• Footnote z: replaced salvage therapy with local therapy.
• Revised footnote: Patients with pN1 disease who chose observation
should see PROS-10 for monitoring for initial definitive therapy
if PSA is undetectable. For patients with pN1 disease and PSA
persistence, see PROS-10.

Continued
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NCCN Guidelines Version 1.2022 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Prostate Cancer from Version 2.2021 include:
PROS-10 PROS-13
• Radical Prostatectomy PSA Persistence/Recurrence • Systemic Therapy for M0 Castration-Resistant Prostate Cancer:
Added: Bone and soft tissue imaging Revised: Conventional CRPC, imaging studies negative for distant
Removed the following bullets: metastases (Also on PROS-14)
◊ Bone imaging, Revised: Consider periodic disease assessment (PSA and
◊ Chest CT imaging) PSA increasing
◊ Abdominal/pelvic CT or abdominal/pelvic MRI Revised: Yes PSA increasing or radiographic evidence of
◊ C-11 choline or F-18 fluciclovine PET/CT or PET/MRI metastases
• Removed footnote: F-18 sodium fluoride or C-11 choline or F-18 Revised: No Stable PSA and no evidence of metastases
fluciclovine PET/CT or PET/MRI can be considered after bone scan Revised: Maintain current treatment and continue monitoring
for further evaluation when clinical suspicion of bone metastases is consider periodic disease assessment (PSA and imaging)
high. PROS-14
• Removed footnote: Histologic confirmation is recommended • Systemic Therapy for M1 CRPC
whenever feasible due to significant rates of false positivity. Revised second bullet: Tumor testing for MSI-H or dMMR and
PROS-11 for homologous recombination gene mutations (HRRm), if not
• Radiation Therapy Recurrence previously performed.
Revised: PSA persistence/recurrence or Positive DRE Removed bullet: Germline and tumor testing for homologous
Removed the following bullets: recombination gene mutations if not previously performed.
◊ Bone Imaging Added bullet: Consider tumor mutational burden (TMB) testing
◊ Prostate MRI First-line and subsequent treatment options:
Revised: Bone and chest CT soft tissue imaging Added: Cabazitaxel/carboplatin
Removed the following bullets: • Footnote added: Germline testing for HRRm is recommended if not
◊ Abdominal/pelvic imaging CT or abdominal/pelvic MRI performed previously. See Principles of Genetics and Molecular/
◊ C-11 choline or F-18 fluciclovine PET/CT or PET/MRI Biomarker Analysis (PROS-B).
PROS-12 PROS-15
• Systemic Therapy for Castration-Naive Prostate Cancer: • Systemic Therapy for M1 CRPC: Adenocarcinoma
Revised: Monitoring Observation (preferred) Prior novel hormone therapy/No prior docetaxel:
Revised: Consider periodic imaging for patients with M1 to ◊ Second bullet, third sub-bullet revised: Pembrolizumab for
monitor treatment response MSI-H, dMMR, or TMB ≥10 mut/Mb
• Footnote added: PSADT and Grade Group should be considered Prior docetaxel/no prior novel hormone therapy:
when deciding whether to begin ADT for patients with M0 disease. ◊ Second bullet, third sub-bullet revised: Pembrolizumab for
• Footnote added: Patients with life expectancy ≤5 years can consider MSI-H, dMMR, or TMB ≥10 mut/Mb
observation. See Principles of Active Surveillance and Observation Prior docetaxel and prior novel hormone therapy:
(PROS-E). ◊ Second bullet, third sub-bullet revised: Pembrolizumab for
• Footnote modified: The term "castration-naïve" is used to define MSI-H, dMMR, or TMB ≥ 10 mut/Mb
patients who have not been treated with ADT and those who are not
on ADT at the time of progression.

Continued
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Prostate Cancer Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Prostate Cancer from Version 2.2021 include:
PROS-15A Fifth bullet, third sub-bullet added: Ga-68 PSMA-11 or F-18
• Footnote removed: Patients with disease progression on a given piflufolastat PSMA PET/CT or PET/MRI (full body imaging) can be
therapy should not repeat that therapy, with the exception of considered as an alternative to bone scan.
docetaxel, which can be given as a rechallenge after progression Deleted: F-18 sodium fluoride PET/CT or PET/MRI may be used to
on a novel hormone therapy in the metastatic CRPC setting in men detect bone metastatic disease with greater sensitivity but less
who have not demonstrated definitive evidence of progression on specificity than standard bone scan imaging.
prior docetaxel therapy in the castration-naïve setting. PROS-D (3 of 3)
PROS-A • Positron Emission Tomography (PET)
• Principles of Life Expectancy Estimation Bullets were reordered and revised.
Fourth bullet modified: If using a life expectancy table, life First bullet added: PSMA-PET refers to a growing body of
expectancy can should then be adjusted using the clinician’s radiopharmaceuticals that target PSMA on the surface of prostate
assessment of overall health as follows cells. There are multiple PSMA radiopharmaceuticals at various
Fifth bullet modified: Examples of upper, middle, and lower stages of investigation. At this time, the NCCN Guidelines only
quartiles of life expectancy at selected ages are included 5-year recommend the currently FDA-approved PSMA agents, F-18
increments of age are reproduced in the NCCN Guidelines for piflufolastat (DCFPyL) and Ga-68 PSMA-11. See Table 2 in the
Older Adult Oncology for life expectancy estimation. Discussion section for more detail.
PROS-B Second bullet added: F-18 piflufolastat PSMA or Ga-68 PSMA-
• Principles of Genetics and Molecular/Biomarker Analysis: This 11 PET/CT or PET/MRI can be considered as an alternative to
section has been extensively revised. standard imaging of bone and soft tissue for initial staging, the
PROS-C detection of biochemically recurrent disease, and as workup for
• Principles of Risk Stratification: This section is new. progression with bone scan plus CT or MRI for the evaluation of
PROS-D (1 of 3) bone, pelvis, and abdomen.
• Bone Imaging: Fourth bullet added: Studies suggest that F-18 piflufolastat PSMA
Second, third, and fourth bullets modified: Bone scan imaging or Ga-68 PSMA-11 PET imaging have a higher sensitivity than C-11
PROS-D (2 of 3) choline or F-18 fluciclovine PET imaging, especially at very low
• Bone Imaging (continued) PSA levels.
Third bullet modified: Bone scans and soft tissue imaging (CT or Fifth bullet added: Because of the increased sensitivity and
MRI) in patients with metastatic prostate cancer or non-metastatic specificity of PSMA-PET tracers for detecting micrometastatic
progressive prostate cancer may be obtained regularly during disease compared to conventional imaging (CT, MRI) at both initial
systemic therapy to assess clinical benefit. staging and biochemical recurrence, the Panel does not feel that
Fifth bullet revised: PET imaging/CT for deletion of bone conventional imaging is a necessary prerequisite to PSMA-PET
metastatic disease in patients with M0 CRPC. and that PSMA-PET/CT or PSMA-PET/MRI can serve as an equally
Fifth bullet, second sub-bullet revised: Plain films, CT, MRI, PET/ effective, if not more effective front-line imaging tool for these
CT or PET/MRI with F-18 piflufolastat PSMA, Ga-68 PSMA-11, patients.
F-18 sodium fluoride, C-11 choline, or F-18 fluciclovine can be
considered for equivocal results on initial bone scan.

Continued
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NCCN Guidelines Version 1.2022 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Prostate Cancer from Version 2.2021 include:
Sixth bullet added: Histologic or radiographic confirmation of PROS-F (1 of 5)
involvement detected by PET imaging is recommended whenever • Definitive Radiation Therapy General Principles:
feasible due to the presence of false positives. Although false Third bullet removed: Brachytherapy boost, when added to EBRT
positives exist, literature suggests that these are outweighed plus ADT in patients men with NCCN intermediate- and high-risk
by the increase in true positives detected by PET relative prostate cancer, has demonstrated improved biochemical control
to conventional imaging. To reduce the false-positive rate, over EBRT plus ADT alone in randomized trials, but with higher
physicians should consider the intensity of PSMA-PET uptake toxicity.
and correlative CT findings in the interpretation of scans. Several Brachytherapy, added the following bullets:
reporting systems have been proposed but will not have been ◊ Interstitial implantation of prostate +/- proximal seminal vesicles
validated or widely used. with temporary (high dose-rate, HDR) or permanent (low dose-
Bullet removed: The use of PET/CT or PET/MRI imaging using rate, LDR) radioactive sources for monotherapy or as "boost"
tracers other than F-18 FDG for staging of small-volume recurrent when added to EBRT should be performed in practices with
or metastatic prostate cancer is a rapidly developing field wherein adequate training, experience, and quality assurance measures.
most of the data are derived from single-institution series or ◊ Patient selection should consider aspects of gland size,
registry studies. FDA clearance and reimbursement for some tests baseline urinary symptoms, and prior procedures (ie,
makes unlikely the conduct of clinical trials to evaluate their utility transurethral resection prostate) that may increase risk of
and impact upon oncologic outcome. adverse effects. Neoadjuvant ADT to shrink a gland to allow
Bullet removed: PET/CT or PET/MRI for detection of biochemically treatment should balance its additional toxicity with this benefit.
recurrent disease. ◊ Third bullet revised: Post-implant dosimetry must be performed
Bullet removed: Histologic confirmation is recommended for LDR implants to verify dosimetry. to document the quality of
whenever feasible due to significant rates of false positivity. the low dose-rate (LDR) implant.
PROS-E (1 of 2) ◊ Post-implant dosimetry must be performed Brachytherapy
• Principles of Active Surveillance and Observation: boost, when added to EBRT and ADT, improves biochemical
Third bullet revised: Active surveillance is preferred for patients control. To address historical trial data concern for increased
with very-low-risk prostate cancer and life expectancy ≥20 years toxicity incidence, careful patient selection and contemporary
and for men with low-risk prostate cancer and life expectancy ≥10 planning associated with lesser toxicity, such as use of
years. Observation is preferred for patients with low-risk prostate recognized organ at risk dose constraints, use of high-quality
cancer with life expectancy <10 years. ultrasound and other imaging, and prescription of dose as
Sixth bullet revised: Cancer progression (risk group tightly as possible to the target without excessive margins.
reclassification) may have occurred if: Higher grade cancer Brachytherapy, bullet removed: Patients with a very large prostate
Gleason Grade 4 or 5 cancer is found upon repeat prostate biopsy. or very small prostate, symptoms of bladder outlet obstruction
Seventh bullet revised: Patients with clinically localized prostate (high International Prostate Symptom Score [IPSS]), or a previous
cancers who are candidates for definitive treatment and Patients transurethral resection of the prostate (TURP) are more difficult to
who choose active surveillance should have regular follow-up. implant and may suffer increased risk of side effects. Neoadjuvant
Seventh bullet, ninth sub-bullet revised: A repeat prostate biopsy ADT may be used to shrink the prostate to an acceptable size;
should be considered no is not generally recommended more however, increased toxicity would be expected from ADT
often than annually to assess for disease progression unless and prostate size may not decline in some patients despite
clinically indicated. because PSA kinetics may not be as reliable neoadjuvant ADT. Potential toxicity of ADT must be balanced
for predicting progression. against the potential benefit of target reduction. Continued
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NCCN Guidelines Version 1.2022 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Prostate Cancer from Version 2.2021 include:
PROS-F (4 of 5) Third bullet revised: Decipher molecular assay is recommended to
• Post-Prostatectomy Radiation Therapy inform adjuvant treatment, if adverse features are found after RP.
First bullet modified: The panel recommends use of nomograms The panel recommends consultation with the American Society
and consideration of age and comorbidities, clinical and for Radiation Oncology (ASTRO)/American Urological Association
pathologic information, PSA levels, and PSADT, and Decipher (AUA) Guidelines.
molecular assay to individualize treatment discussion. Patients PROS-G
with high Decipher genomic classifier scores (GC >0.6) should • Pelvic Lymph Node Dissection:
be strongly considered for EBRT and addition of ADT when the First bullet revised: An extended PLND will discover metastases
opportunity for early EBRT has been missed. approximately twice as often as a limited PLND. Extended PLND
First bullet, first sub-bullet modified: EBRT with 2 years of anti- provides more complete staging and may cure some patients with
androgen therapy with 150 mg/day of bicalutamide demonstrated microscopic metastases; therefore, an extended PLND is preferred
improved overall and metastasis-free survival on a prospective when PLND is performed.
randomized trial (RTOG 9601) versus radiation alone in the salvage PROS-H (1 of 5)
setting. A secondary analysis of RTOG 9601 found that patients • ADT for Clinically Localized (N0,M0) Disease:
with PSA ≤ 0.6 ng/mL had no OS improvement with the addition of Sixth bullet added: Abiraterone can be added to EBRT and 2
the antiandrogen to EBRT. In addition, results of a retrospective years of ADT in patients with very-high-risk prostate cancer. In
analysis of RP specimens from patients in 9601 suggest that the STAMPEDE trial, the hazard ratios for OS with the addition
those with low PSA and a low Decipher score derived less benefit of abiraterone to EBRT and ADT in patients with node-negative
(development of distant metastases, OS) from bicalutamide than disease was 0.69 (95% CI, 0.49–0.96).
those with a high Decipher score. • ADT for Regional (N1,M0) Disease:
First bullet, second sub-bullet revised: EBRT with 6 months of Second bullet, third sub-bullet removed: Neither formulation of
ADT (LHRH agonist) improved biochemical or clinical progression abiraterone should be given following progression on the other
at 5 years on a prospective randomized trial (GETUG-16) versus formulation.
radiation alone in patients with rising PSA levels between 0.2 and PROS-H (2 of 5)
2.0 ng/mL after RP. • ADT for Metastatic Castration-Naïve Disease:
First bullet, third sub-bullet added The ongoing SPPORT trial Removed: ADT is the gold standard for men with metastatic
(NCT00567580) of patients with PSA levels between 0.1 and 2.0 prostate cancer.
ng/mL at least 6 weeks after RP has reported preliminary results Added: ADT with treatment intensification is preferred for most
on clinicaltrials.gov. The primary outcome measure of percentage patients with metastatic prostate cancer. ADT alone is appropriate
of participants free from progression (FFP) at 5 years was 70.3 for some patients.
(95% CI, 66.2–74.3) for those who received EBRT to the prostate Third bullet revised: Abiraterone should be given with concurrent
bed and 81.3 (95% CI, 77.9–84.6) for those who also received 4–6 steroid [see ADT for Regional (N1,M0) Disease]. Neither
months of ADT (LHRH agonist plus antiandrogen). formulation of abiraterone should be given following progression
on the other formulation.

Continued
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® ® ®
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Updates in Version 1.2022 of the NCCN Guidelines for Prostate Cancer from Version 2.2021 include:
PROS-H (3 of 5) PROS-I (1 of 3)
• Secondary Hormone Therapy for M0 or M1 CRPC: • Header modified: Principles of Non-Hormonal Systemic Therapy
Third bullet, third sub-bullet, first sub-bullet removed: Immunotherapy and Chemotherapy
Ketoconazole • Added new section: Non-Hormonal Systemic Therapy for Very-High-
Third bullet, third sub-bullet, fourth sub-bullet removed: Estrogens Risk Prostate Cancer
including diethylstilbestrol (DES) First bullet added: Docetaxel can be added to EBRT and 2 years
Fourth bullet revised: Abiraterone should be given with concurrent of ADT in patients with very-high-risk prostate cancer. In the
steroid, either prednisone 5 mg orally twice daily for the standard STAMPEDE trial, the hazard ratio for OS in 96 randomized patients
formulation or methylprednisolone 4 mg orally twice daily for the with nonmetastatic disease was 0.93 (95% CI, 0.60–1.43) with the
fine-particle formulation. Neither formulation of abiraterone should addition of docetaxel to EBRT and ADT.
be given following progression on the other formulation. • Modified: Non-Hormonal Systemic Therapy for M1 Castration-Naïve
Fifth bullet removed: Ketoconazole ± hydrocortisone should not Prostate Cancer
be used if the disease progressed on abiraterone. • Modified: Non-Hormonal Systemic Therapy for M1 CRPC
Sixth bullet removed: DES has cardiovascular and PROS-I (2 of 3)
thromboembolic side effects at any dose, but frequency is dose • Immunotherapy, third bullet modified: Pembrolizumab (for MSI-H,
and agent dependent. DES should be initiated at 1 mg/day and dMMR, or TMB ≥ 10 mut/Mb)
increased, if necessary, to achieve castrate levels of serum
testosterone (<50 ng/dL). Other estrogens delivered topically
or parenterally may have less frequent side effects but data are
limited.
PROS-H (4 of 5)
• Principles of Androgen Deprivation Therapy, seventh bullet
modified: Evidence-based guidance on the sequencing of agents in
either pre- or post-docetaxel remains limited unavailable.
PROS-H (5 of 5)
• Monitor/Surveillance, fifth bullet modified: Screening for and
intervention to prevent/treat diabetes and cardiovascular disease
are recommended in patients receiving ADT. These medical
conditions are common in older individuals and it remains
uncertain whether strategies for screening, prevention, and
treatment of diabetes and cardiovascular disease in patients
receiving ADT should differ from the general population.

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INITIAL PROSTATE CANCER DIAGNOSISa,b,c WORKUP

• Perform physical exam

• Perform digital rectal exam (DRE)
to confirm clinical stage
• Perform and/or collect prostate-
specific antigen (PSA) and
calculate PSA density and PSA See Initial Risk
Clinically localized doubling time (PSADT)
Stratification and Staging
prostate cancer (Any T, • Obtain and review diagnostic
prostate biopsies Workup for Clinically
N0, M0 or Any T, NX, MX)
• Estimate life expectancy (See Localized Disease (PROS-2)
Principles of Life Expectancy
Estimation [PROS-A])
• Inquire about known high-risk
germline mutationsc
• Obtain family historyc

See Regional Prostate Cancer

• Perform physical exam (PROS-8)
Regional prostate • Perform DRE to confirm clinical stage
cancer (Any T, N1, M0) • Perform and/or collect PSA and
calculate PSADT
• Estimate life expectancy (See
Metastatic prostate Principles of Life Expectancy See Metastatic Prostate Cancer
cancer (Any T, Any N, M1) Estimation [PROS-A]) (PROS-12)
• Inquire about known high-risk
germline mutationsc
• Obtain family historyc

a See NCCN Guidelines for Older Adult Oncology for tools to aid optimal b See NCCN Guidelines for Prostate Cancer Early Detection.
assessment and management of older adults. c See Principles of Genetics and Molecular/Biomarker Analysis (PROS-B).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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INITIAL RISK STRATIFICATION AND STAGING WORKUP FOR CLINICALLY LOCALIZED DISEASEd

Clinical/Pathologic Features
Risk Group Additional Evaluationg,h Initial Therapy
See Staging (ST-1)

Has all of the following:

• cT1c
• Grade Group 1
Very lowe • PSA <10 ng/mL • Consider confirmatory prostate biopsy ± mpMRI if not performed prior to See PROS-3
• Fewer than 3 prostate biopsy fragments/cores
f
positive, ≤50% biopsy to establish candidacy for active surveillance
cancer in each fragment/core
• PSA density <0.15 ng/mL/g

Has all of the following but does not qualify for very low risk:
e • cT1–cT2a
Low • Consider confirmatory prostate biopsy ± mpMRI if not performed prior to See PROS-4
• Grade Group 1
• PSA <10 ng/mL biopsy to establish candidacy for active surveillance

Has all of the following:

Has all of the following: • 1 IRF
• Consider confirmatory prostate biopsy ± mpMRI if not performed prior to
• No high-risk group Favorable • Grade Group 1 or 2
biopsy for those considering active surveillance See PROS-5
features intermediate • <50% biopsy cores
• No very-high-risk positive (eg, <6 of 12
group features cores)f
Intermediatee • Has one or more Has one or more of the
intermediate risk following:
factors (IRFs): • 2 or 3 IRFs
Unfavorable • Grade Group 3 Bone and soft tissue imagingi,j
cT2b–cT2c See PROS-6
intermediate • If regional or distant metastases are found, see PROS-8 or PROS-12
Grade Group 2 or 3 • ≥ 50% biopsy cores
PSA 10–20 ng/mL positive (eg, ≥ 6 of 12
cores)f

Has no very-high-risk features and has exactly one high-risk feature:

• cT3a OR Bone and soft tissue imagingi,j
High See PROS-7
• Grade Group 4 or Grade Group 5 OR • If regional or distant metastases are found, see PROS-8 or PROS-12
• PSA >20 ng/mL

Has at least one of the following:

• cT3b–cT4 Bone and soft tissue imagingi,j
Very high • Primary Gleason pattern 5 See PROS-7
• If regional or distant metastases are found, see PROS-8 or PROS-12
• 2 or 3 high-risk features
• >4 cores with Grade Group 4 or 5

See Footnotes for Initial Risk Stratification and Staging Workup for Clinically Localized Disease (PROS-2A).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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INITIAL RISK STRATIFICATION AND STAGING WORKUP FOR CLINICALLY LOCALIZED DISEASE

d Tumor-based molecular assays and germline genetic testing are other tools that can assist with risk stratification. See Principles of Genetics and Molecular/Biomarker
Analysis (PROS-B) to determine if a patient is an appropriate candidate for germline genetic testing, and see Principles of Risk Stratification (PROS-C) to determine if
a patient is an appropriate candidate for tumor-based molecular assays.
e Forasymptomatic patients in very-low-, low-, and intermediate-risk groups with life expectancy ≤5 years, no imaging or treatment is indicated until the patient becomes
symptomatic, at which time imaging can be performed and ADT should be given (See PROS-H).
f An ultrasound- or MRI- or DRE-targeted lesion that is biopsied more than once and demonstrates cancer (regardless of percentage core involvement or number of
cores involved) can be considered as a single positive core.
g See Principles of Imaging (PROS-D).
h Bone imaging should be performed for any patient with symptoms consistent with bone metastases.
i Bone imaging can be achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline,
F-18 fluciclovine, Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for equivocal results on initial bone imaging. Soft tissue imaging of the pelvis,
abdomen, and chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. mpMRI is preferred over CT for pelvic staging. Alternatively, Ga-68
PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI can be considered for bone and soft tissue (full body) imaging. See Principles of Imaging (PROS-D).
j Because of the increased sensitivity and specificity of prostate-specific membrane antigen (PSMA)-PET tracers for detecting micrometastatic disease compared to
conventional imaging (CT, MRI) at both initial staging and biochemical recurrence, the Panel does not feel that conventional imaging is a necessary prerequisite to
PSMA-PET and that PSMA-PET/CT or PSMA-PET/MRI can serve as an equally effective, if not more effective front-line imaging tool for these patients.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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VERY-LOW-RISK GROUP
EXPECTED INITIAL THERAPY ADJUVANT THERAPY
PATIENT
SURVIVALk
Active surveillance (preferred)m
• Consider confirmatory prostate biopsy with or without mpMRI to establish candidacy
Progressive diseaseu
for active surveillancen
See Initial Risk Stratification
• PSA no more often than every 6 mo unless clinically indicated
and Staging Workup for
• DRE no more often than every 12 mo unless clinically indicated
Clinically Localized Disease
• Repeat prostate biopsy no more often than every 12 mo unless clinically indicated
(PROS-2)
• Repeat mpMRI no more often than every 12 mo unless clinically indicated
>20 y EBRTo or brachytherapyo
Adverse feature(s):r,s
EBRTo ± ADTt
or
Monitoring, with consideration of early RT for a See Monitoring for Initial
Radical prostatectomy (RP)p Definitive Therapy (PROS-9)
detectable and rising PSA or PSA >0.1 ng/mL (See
PROS-9)

No adverse features
Active surveillancem
• Consider confirmatory prostate biopsy with or without mpMRI to establish candidacy Progressive diseaseu
for active surveillancen See Initial Risk
10–20 yl • PSA no more often than every 6 mo unless clinically indicated Stratification and Staging
• DRE no more often than every 12 mo unless clinically indicated Workup for Clinically
• Repeat prostate biopsy no more often than every 12 mo unless clinically indicated Localized Disease (PROS-2)
• Repeat mpMRI no more often than every 12 mo unless clinically indicated

<10 ye Observation q See Monitoring (PROS-9)

See Footnotes for Risk Groups (PROS-8A).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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LOW-RISK GROUP
EXPECTED INITIAL THERAPY ADJUVANT THERAPY
PATIENT
SURVIVALk
Active surveillancem
• Consider confirmatory prostate biopsy with or without mpMRI and with or without
Progressive diseaseu
molecular tumor analysisv to establish candidacy for active surveillancen
See Initial Risk Stratification
• PSA no more often than every 6 mo unless clinically indicated
and Staging Workup for
• DRE no more often than every 12 mo unless clinically indicated
Clinically Localized Disease
• Repeat prostate biopsy no more often than every 12 mo unless clinically
(PROS-2)
indicatedw
• Repeat mpMRI no more often than every 12 mo unless clinically indicated

≥10 y EBRTo or brachytherapyo

Adverse feature(s):r,s
EBRT o ± ADTt
or See Monitoring for Initial
Monitoring, with consideration of early RT for Definitive Therapy (PROS-9)
a detectable and rising PSA or PSA >0.1 ng/mL
RPp (See PROS-9)

No adverse features

<10 ye Observation q See Monitoring (PROS-9)

See Footnotes for Risk Groups (PROS-8A).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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FAVORABLE INTERMEDIATE-RISK GROUP

EXPECTED INITIAL THERAPY ADJUVANT THERAPY
PATIENT Active surveillancem
SURVIVALk • Consider confirmatory prostate biopsy with or without mpMRI and with or without
molecular tumor analysisv to establish candidacy for active surveillancen Progressive
• PSA no more often than every 6 mo unless clinically indicated diseaseu
• DRE no more often than every 12 mo unless clinically indicated See Initial Risk
• Repeat prostate biopsy no more often than every 12 mo unless clinically indicatedw Stratification and
• Repeat mpMRI no more often than every 12 mo unless clinically indicated Staging Workup for
Clinically Localized
Disease (PROS-2)
EBRTo or brachytherapyo
Adverse feature(s) and no lymph node
>10 y
metastases:r,s
EBRTo ± ADTt Undetectable PSA See Monitoring for
or after RP or PSA Initial Definitive
Monitoring, with consideration of early nadirx after RT Therapy (PROS-9)
RT for a detectable and rising PSA or PSA
>0.1 ng/mL (See PROS-9)
See Radical
RPp ± PLND if predicted Prostatectomy
No adverse features or lymph node PSA Persistence/
probability of lymph node
metastases Recurrence
metastasis ≥2%
(PROS-10)
Lymph node metastasis:aa PSA persistence/
ADTt,bb (category 1) ± EBRTo (category recurrencey,z
2B)
or See Radiation
Monitoring, with consideration of early Therapy
treatment for a detectable and rising PSA Recurrence
or PSA >0.1 ng/mL (See PROS-9) (PROS-11)
EBRTo or brachytherapy o

5–10 ye
See Monitoring
Observation (preferred)q (PROS-9)
See Footnotes for Risk Groups (PROS-8A).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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UNFAVORABLE INTERMEDIATE-RISK GROUP

EXPECTED INITIAL THERAPY ADJUVANT THERAPY
PATIENT
SURVIVALk
Adverse feature(s) and no lymph node metastases:r,s
EBRT o ± ADTt
or Undetectable PSA See Monitoring for
Monitoring, with consideration of early RT for a after RP or PSA Initial Definitive
detectable and rising PSA or PSA >0.1 ng/mL (See nadirx after RT Therapy (PROS-9)
PROS-9)
RPp ± PLND if predicted
probability of lymph No adverse features or lymph node metastases See Radical
node metastasis ≥2% Prostatectomy
PSA Persistence/
Lymph node metastasis:aa Recurrence
ADTt,bb (category 1) ± EBRT o (category 2B) (PROS-10)
>10 ycc or
Monitoring, with consideration of early treatment for PSA persistence/
a detectable and rising PSA or PSA >0.1 ng/mL (See recurrencey,z
PROS-9)
EBRTo + ADTt (4–6 mo) See Radiation
or Therapy
EBRTo + brachytherapyo ± ADTt (4–6 mo) Recurrence
(PROS-11)

5–10 ye

See Monitoring
Observation q
(PROS-9)

See Footnotes for Risk Groups (PROS-8A).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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HIGH- OR VERY-HIGH-RISK GROUP

EXPECTED INITIAL THERAPY ADJUVANT THERAPY
PATIENT
SURVIVALk EBRTo + ADTt (1.5–3 y; category 1)
or
EBRTo + brachytherapyo + ADTt (1–3 y; category 1 for ADT) See Monitoring
Undetectable
or for Initial
PSA after RP
EBRTo + ADTt (2 y) + docetaxel for 6 cycles (for very-high-risk only) Definitive
or PSA nadirx
or Therapy
after RT
EBRTo + ADTt (2 y) + abirateronedd (for very-high-risk only) (PROS-9)

>5 y or See Radical

Adverse feature(s) and no lymph node metastases:r,s
symptomaticcc Prostatectomy
EBRT o ± ADTt
or PSA
Monitoring, with consideration of early RT for Persistence/
detectable and rising PSA or PSA >0.1 ng/mL (See Recurrence
PROS-9) (PROS-10)

RPp + PLNDee No adverse features or lymph node metastases PSA persistence/

recurrencey,z
Lymph node metastasis:aa
ADTt,bb (category 1) ± EBRT o (category 2B) See Radiation
or Therapy
Monitoring, with consideration of early Recurrence
treatment for detectable and rising PSA or (PROS-11)
PSA >0.1 ng/mL (See PROS-9)

Observationq See Monitoring (PROS-9)

or
≤5 y and
ADTt,ff Best supportive care
asymptomatic
or
EBRTo,ff

See Footnotes for Risk Groups (PROS-8A).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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REGIONAL RISK GROUP (ANY T, N1, M0)

EXPECTED INITIAL THERAPY ADJUVANT THERAPY
PATIENT
SURVIVALk
Undetectable
EBRTo + ADTt (preferred) PSA after RP or See Monitoring
or PSA nadirx (PROS-9)
EBRTo + ADTt + after RT
abirateronedd,gg

ADTt ± abirateronedd,gg

>5 y or Adverse feature(s) and no lymph node metastases:r,s

symptomatic EBRT o ± ADTt
or See Radical
Monitoring, with consideration of early RT for a detectable Prostatectomy
and rising PSA or PSA >0.1 ng/mL (See PROS-9) PSA Persistence/
Recurrence
RPp + PLND No adverse features or lymph node metastases (PROS-10)

Lymph node metastases:aa

PSA persistence/
ADTt,bb (category 1) ± EBRT o (category 2B) recurrencey,z
or
Monitoring, with consideration of early treatment for a
detectable and rising PSA or PSA >0.1 ng/mL (See PROS-9) See Radiation
Therapy
Recurrence
Observationq (PROS-11)
≤5 y and or
asymptomatic ADTt Best supportive care

See Footnotes for Risk Groups (PROS-8A).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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FOOTNOTES
e For asymptomatic patients in very-low-, low-, and intermediate-risk groups with x PSA nadir is the lowest value reached after EBRT or brachytherapy.
life expectancy ≤5 years, no imaging or treatment is indicated until the patient y PSA persistence/recurrence after RP is defined as failure of PSA to fall to
becomes symptomatic, at which time imaging can be performed and ADT should undetectable levels (PSA persistence) or undetectable PSA after RP with a
be given (See PROS-H). subsequent detectable PSA that increases on 2 or more determinations (PSA
k See Principles of Life Expectancy Estimation (PROS-A). recurrence).
l The Panel remains concerned about the problems of overtreatment related z RTOG-ASTRO (Radiation Therapy Oncology Group - American Society for
to the increased diagnosis of early prostate cancer from PSA testing. See Therapeutic Radiology and Oncology) Phoenix Consensus: 1) PSA increase
NCCN Guidelines for Prostate Cancer Early Detection. Active surveillance is by 2 ng/mL or more above the nadir PSA is the standard definition for PSA
recommended for this subset of patients. recurrence after EBRT with or without HT; and 2) A recurrence evaluation should
m Active surveillance involves actively monitoring the course of disease with the be considered when PSA has been confirmed to be increasing after radiation
expectation to intervene with potentially curative therapy if the cancer progresses. even if the increase above nadir is not yet 2 ng/mL, especially in candidates for
local therapy who are young and healthy. Retaining a strict version of the ASTRO
See Principles of Active Surveillance and Observation (PROS-E).
definition allows comparison with a large existing body of literature. Rapid
n If higher grade and/or higher T stage is found, see PROS-2. increase of PSA may warrant evaluation (prostate biopsy) prior to meeting the
o See Principles of Radiation Therapy (PROS-F). Phoenix definition, especially in younger or healthier patients.
p See aa For patients with pN1 disease and PSA persistence, see PROS-10.
Principles of Surgery (PROS-G).
q Observation bb See monitoring for N1 on ADT (PROS-9).
involves monitoring the course of disease with the expectation
to deliver palliative therapy for the development of symptoms or a change in cc Activesurveillance of unfavorable intermediate and high-risk clinically localized
exam or PSA that suggests symptoms are imminent. See Principles of Active cancers is not recommended in patients with a life expectancy >10 years
Surveillance and Observation (PROS-E). (category 1).
r Adverse laboratory/pathologic features include: positive margin(s); seminal dd The fine-particle formulation of abiraterone can be used instead of the standard
vesicle invasion; extracapsular extension; or detectable PSA. form (category 2B; other recommended option).
s Decipher molecular assay is recommended if not previously performed to inform ee RP + PLND can be considered in younger, healthier patients without tumor
adjuvant treatment if adverse features are found post-RP. fixation to the pelvic sidewall.
t See Principles of Androgen Deprivation Therapy (PROS-H). ff ADT or EBRT may be considered in selected patients with high- or very-high-risk
u Criteria for progression are not well defined and require physician judgment; disease, where complications, such as hydronephrosis or metastasis, can be
however, a change in risk group strongly implies disease progression. See expected within 5 years.
Discussion. gg Abiraterone with ADT should be considered for a total of 2 years for those
v See Principles of Risk Stratification (PROS-C). patients with N1 disease who are treated with radiation to the prostate and
pelvic nodes. (See PROS-H).
w Repeat molecular tumor analysis is discouraged.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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MONITORING RECURRENCE See Radical

See NCCN Guidelines for Survivorship Prostatectomy PSA
Post-RP PSA persistence/recurrencey
Persistence/Recurrence
(PROS-10)
• PSA every 6–12 mo
for 5 y,hh then every
PSA recurrencez See Radiation
year
Initial definitive therapy Post-RT or Therapy Recurrence
• DRE every year, but
Positive DRE (PROS-11)
may be omitted if
PSA undetectable
Radiographic evidence of Biopsy of See Systemic Therapy
metastatic disease without metastatic for Castration-Naïve
PSA persistence/recurrence site Disease (PROS-12)
Systemic Therapy for
• Physical exam + PSA N1,M0 M0 CRPC (PROS-13)
N1 on ADT
every 3–6 mo
or Progressionj,ii,jj
• Imaging for symptoms
Localized on observation See Systemic Therapy for
or increasing PSAg M1 M1 CRPC (PROS-14)

g See Principles of Imaging (PROS-D). Retaining a strict version of the ASTRO definition allows comparison with a
j Because of the increased sensitivity and specificity of PSMA-PET tracers for large existing body of literature. Rapid increase of PSA may warrant evaluation
detecting micrometastatic disease compared to conventional imaging (CT, MRI) (prostate biopsy) prior to meeting the Phoenix definition, especially in younger or
at both initial staging and biochemical recurrence, the Panel does not feel that healthier patients.
conventional imaging is a necessary prerequisite to PSMA-PET and that PSMA- hh PSA as frequently as every 3 mo may be necessary to clarify disease status,
PET/CT or PSMA-PET/MRI can serve as an equally effective, if not more effective especially in high-risk patients.
front-line imaging tool for these patients. ii Document castrate levels of testosterone if clinically indicated. Workup for
y PSA persistence/recurrence after RP is defined as failure of PSA to fall to progression should include bone and soft tissue evaluation. Bone imaging can be
undetectable levels (PSA persistence) or undetectable PSA after RP with a achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI,
subsequent detectable PSA that increases on 2 or more determinations (PSA or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, F-18 fluciclovine,
recurrence). Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for equivocal
z RTOG-ASTRO (Radiation Therapy Oncology Group - American Society for results on initial bone imaging. Soft tissue imaging of pelvis, abdomen, and
Therapeutic Radiology and Oncology) Phoenix Consensus: 1) PSA increase by 2 chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI.
ng/mL or more above the nadir PSA is the standard definition for PSA recurrence Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI
after EBRT with or without HT; and 2) A recurrence evaluation should be can be considered for bone and soft tissue (full body) imaging. See Principles of
considered when PSA has been confirmed to be increasing after radiation even if Imaging (PROS-D).
the increase above nadir is not yet 2 ng/mL, especially in candidates for salvage jj Treatment for patients who progressed on observation of localized disease is
local therapy who are young and healthy. ADT. See Principles of Androgen Deprivation Therapy (PROS-H).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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RADICAL PROSTATECTOMY PSA PERSISTENCE/RECURRENCE

Studies negative for

EBRTo ± ADTt See Systemic Therapy
distant metastases
or Progressionj,ii for Castration-Naïve
or imaging not
Observationq Disease (PROS-12)
performed
• Risk stratificationkk
PSADT
Consider:
PSA persistence/ • Bone and soft tissue
recurrencey imagingi,j
• Prostate bed biopsy
(especially if imaging See Systemic Therapy
Studies positive for
suggests local recurrence) for Castration-Naïve
distant metastases
Disease (PROS-12)

i Bone imaging can be achieved by conventional technetium-99m-MDP bone

scan. Plain films, CT, MRI, or PET/CT or PET/MRI with F-18 sodium fluoride,
C-11 choline, F-18 fluciclovine, Ga-68 PSMA-11, or F-18 piflufolastat PSMA
can be considered for equivocal results on initial bone imaging. Soft tissue t See Principles of Androgen Deprivation Therapy (PROS-H).
imaging of pelvis, abdomen, and chest can include chest CT and abdominal/ y PSA persistence/recurrence after RP is defined as failure of PSA to fall to
pelvic CT or abdominal/pelvic MRI. mpMRI is preferred over CT for pelvic staging. undetectable levels (PSA persistence) or undetectable PSA after RP with a
Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI subsequent detectable PSA that increases on 2 or more determinations (PSA
can be considered for bone and soft tissue (full body) imaging. See Principles of recurrence).
Imaging (PROS-D). ii Document castrate levels of testosterone if clinically indicated. Workup for
j Because of the increased sensitivity and specificity of PSMA-PET tracers for progression should include bone and soft tissue evaluation. Bone imaging can be
detecting micrometastatic disease compared to conventional imaging (CT, MRI) achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI,
at both initial staging and biochemical recurrence, the Panel does not feel that or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, F-18 fluciclovine,
conventional imaging is a necessary prerequisite to PSMA-PET and that PSMA- Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for equivocal
PET/CT or PSMA-PET/MRI can serve as an equally effective, if not more effective results on initial bone imaging. Soft tissue imaging of pelvis, abdomen, and
front-line imaging tool for these patients. chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI.
o See Principles of Radiation Therapy (PROS-F). Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI
q Observation involves monitoring the course of disease with the expectation can be considered for bone and soft tissue (full body) imaging. See Principles of
to deliver palliative therapy for the development of symptoms or a change in Imaging (PROS-D).
exam or PSA that suggests symptoms are imminent. See Principles of Active kk PSADT
 can be calculated to inform nomogram use and counseling and/or
Surveillance and Observation (PROS-E). Decipher molecular assay (category 2B) can be considered to inform counseling.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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RADIATION THERAPY RECURRENCE

Observationq
or
RP + PLNDp
or
Brachytherapyo
Life or
expectancy Cryotherapy Progressionj,ii
>10 y or
TRUS biopsy
High-intensity
positive, studies
focused
negative
ultrasound (HIFU)
for distant See Systemic
(category 2B)
metastases Therapy for
Castration-Naïve
Life Disease (PROS-12)
expectancy
≤10 y or
• Risk stratificationll See Systemic
PSADT
TRUS biopsy Therapy for M0
PSA • Transrectal CRPC (PROS-13)
negative, Observationq
recurrencez ultrasound (TRUS) Progressionj,ii
studies negative or
or biopsy or
for distant ADTt
Positive DRE • Consider:
metastases
 Bone and soft See Systemic
tissue imagingi,j Therapy for M1
CRPC (PROS-14)

Studies positive
for distant
metastases

See footnotes (PROS-11A).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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FOOTNOTES
i Bone imaging can be achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline,
F-18 fluciclovine, Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for equivocal results on initial bone imaging. Soft tissue imaging of pelvis, abdomen,
and chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. mpMRI is preferred over CT for pelvic staging. Alternatively, Ga-68 PSMA-11 or
F-18 piflufolastat PSMA PET/CT or PET/MRI can be considered for bone and soft tissue (full body) imaging. See Principles of Imaging (PROS-D).
j Because of the increased sensitivity and specificity of PSMA-PET tracers for detecting micrometastatic disease compared to conventional imaging (CT, MRI) at both
initial staging and biochemical recurrence, the Panel does not feel that conventional imaging is a necessary prerequisite to PSMA-PET and that PSMA-PET/CT or
PSMA-PET/MRI can serve as an equally effective, if not more effective front-line imaging tool for these patients.
o See Principles of Radiation Therapy (PROS-F).
p See Principles of Surgery (PROS-G).
q Observation involves monitoring the course of disease with the expectation to deliver palliative therapy for the development of symptoms or a change in exam or PSA
that suggests symptoms are imminent. See Principles of Active Surveillance and Observation (PROS-E).
t See Principles of Androgen Deprivation Therapy (PROS-H).
z RTOG-ASTRO (Radiation Therapy Oncology Group - American Society for Therapeutic Radiology and Oncology) Phoenix Consensus: 1) PSA increase by 2 ng/mL
or more above the nadir PSA is the standard definition for PSA recurrence after EBRT with or without HT; and 2) A recurrence evaluation should be considered when
PSA has been confirmed to be increasing after radiation even if the increase above nadir is not yet 2 ng/mL, especially in candidates for salvage local therapy who are
young and healthy. Retaining a strict version of the ASTRO definition allows comparison with a large existing body of literature. Rapid increase of PSA may warrant
evaluation (prostate biopsy) prior to meeting the Phoenix definition, especially in younger or healthier patients.
ii Document castrate levels of testosterone if clinically indicated. Workup for progression should include bone and soft tissue evaluation. Bone imaging can be achieved
by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, F-18 fluciclovine, Ga-68 PSMA-
11, or F-18 piflufolastat PSMA can be considered for equivocal results on initial bone imaging. Soft tissue imaging of pelvis, abdomen, and chest can include chest CT
and abdominal/pelvic CT or abdominal/pelvic MRI. Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI can be considered for bone and soft
tissue (full body) imaging. See Principles of Imaging (PROS-D).
ll PSADT can be calculated to inform nomogram use and counseling.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 1.2022, 09/10/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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SYSTEMIC THERAPY FOR CASTRATION-NAÏVE PROSTATE CANCERmm

See
Monitoring (preferred) Studies
Systemic
M0nn,oo or negative
Therapy for
ADTt,pp for distant
• Physical exam + M0 CRPC
metastases
ADTt with one of the following: PSA every 3–6 mo (PROS-13)
• Preferred regimens: • Imaging for
Abiraterone (category 1)t,dd symptomsg
Apalutamide (category 1)t Progressionj,ii,xx
• Consider periodic
Docetaxel 75 mg/m2 for 6 cyclesvv (category 1)ww imaging to See
Enzalutamide (category 1)t Studies
M1qq,rr,ss,tt,uu monitor treatment Systemic
• EBRTo to the primary tumor for low-volume M1vv positive
responseg Therapy for
or for distant
M1 CRPC
ADTt,pp metastases
(PROS-14)
g See Principles of Imaging (PROS-D).
j Because of the increased sensitivity and specificity of PSMA-PET tracers for nn PSADT and Grade Group should be considered when deciding whether to begin
detecting micrometastatic disease compared to conventional imaging (CT, MRI) ADT for patients with M0 disease.
at both initial staging and biochemical recurrence, the Panel does not feel that oo Patients with a life expectancy ≤5 years can consider observation. See Principles
conventional imaging is a necessary prerequisite to PSMA-PET and that PSMA- of Active Surveillance and Observation (PROS-E).
PET/CT or PSMA-PET/MRI can serve as an equally effective, if not more effective pp Intermittent ADT can be considered for patients with M0 or M1 disease to reduce
front-line imaging tool for these patients. toxicity. See Principles of Androgen Deprivation Therapy (PROS-H).
o See Principles of Radiation Therapy (PROS-F). qq EBRT to sites of bone metastases can be considered if metastases are in
t See Principles of Androgen Deprivation Therapy (PROS-H). weight-bearing bones or if the patient is symptomatic.
dd The fine-particle formulation of abiraterone can be used instead of the standard rr ADT
 alone (see PROS-H) or observation are recommended for asymptomatic
form (category 2B; other recommended option). patients with metastatic disease and life expectancy ≤5 years.
ii Document castrate levels of testosterone if clinically indicated. Workup for ss Tumor
 and germline testing for homologous recombination gene mutations is
progression should include bone and soft tissue evaluation. Bone imaging can be recommended and tumor testing for microsatellite instability (MSI) or deficient
achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI, mismatch repair (dMMR) can be considered. See Principles of Genetics and
or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, F-18 fluciclovine, Molecular/Biomarker Analysis (PROS-B).
Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for equivocal tt SBRT to metastases can be considered in patients with oligometastatic
results on initial bone imaging. Soft tissue imaging of pelvis, abdomen, and progression where progression-free survival is the goal.
chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. uu Routine use of bone antiresorptive therapy is not recommended in the castration-
Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI naïve setting unless for elevated fracture risk (see PROS-H).
can be considered for bone and soft tissue (full body) imaging. See Principles of vv High-volume
 disease is differentiated from low-volume disease by visceral
Imaging (PROS-D). metastases and/or 4 or more bone metastases, with at least one metastasis
mm T  he term "castration-naïve" is used to define patients who have not been beyond the pelvis vertebral column. Patients with low-volume disease have less
treated with ADT and those who are not on ADT at the time of progression. certain benefit from early treatment with docetaxel combined with ADT.
The NCCN Prostate Cancer Panel uses the term "castration-naïve" even ww See Principles of Non-Hormonal Systemic Therapy (PROS-I).
when patients have had neoadjuvant, concurrent, or adjuvant ADT as part of xx Patients
 who were under monitoring for M0 disease should receive an
radiation therapy provided they have recovered testicular function. appropriate therapy for castration-naïve disease.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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SYSTEMIC THERAPY FOR M0 CASTRATION-RESISTANT PROSTATE CANCER (CRPC)yy

Change or
No maintain
metastases current
Monitoring PSA (M0) treatment
(preferred) increasing or and continue
PSADT
or radiographic monitoring
>10 mo
Other secondary evidence of Imagingj,ii
hormone therapyt metastases
Continue See Systemic
CRPC, ADTt to Consider Metastases Therapy for
imaging maintain periodic (M1) M1 CRPC
studies castrate disease (PROS-14)
negative serum Preferred regimens: assessment
for distant levels of • Apalutamidet (PSA and
metastases testosterone (category 1) imaging)g
(<50 ng/dL) • Darolutamidet
(category 1) Stable PSA and Maintain current treatment
PSADT
• Enzalutamidet no evidence of and consider periodic disease
≤10 mo
(category 1) metastases assessment (PSA and imaging)g
Other recommended
regimens:
• Other secondary
hormone therapyt

ii Document castrate levels of testosterone if clinically indicated. Workup for

g See Principles of Imaging (PROS-D). progression should include bone and soft tissue evaluation. Bone imaging can be
j Because of the increased sensitivity and specificity of PSMA-PET tracers for achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI,
detecting micrometastatic disease compared to conventional imaging (CT, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, F-18 fluciclovine,
MRI) at both initial staging and biochemical recurrence, the Panel does not feel Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for equivocal
that conventional imaging is a necessary prerequisite to PSMA-PET and that results on initial bone imaging. Soft tissue imaging of pelvis, abdomen, and
PSMA-PET/CT or PSMA-PET/MRI can serve as an equally effective, if not more chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI.
effective front-line imaging tool for these patients. Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI
q Observation involves monitoring the course of disease with the expectation can be considered for bone and soft tissue (full body) imaging. See Principles of
to deliver palliative therapy for the development of symptoms or a change in Imaging (PROS-D).
exam or PSA that suggests symptoms are imminent. See Principles of Active yy CRPC
 is prostate cancer that progresses clinically, radiographically, or
Surveillance and Observation (PROS-E). biochemically despite castrate levels of serum testosterone (<50 ng/dL). Scher
t See Principles of Androgen Deprivation Therapy (PROS-H). HI, et al. J Clin Oncol 2008;26:1148-1159.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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SYSTEMIC THERAPY FOR M1 CRPCyy

• Continue ADTt to maintain

• Metastatic lesion castrate levels of serum
biopsyzz testosterone (<50 ng/dL) Adenocarcinomazz See PROS-15
• Tumor testing for • Additional treatment
MSI-H or dMMR and options:
CRPC, imaging for homologous Bone antiresorptive
studies recombination gene therapy with denosumab
positive mutations (HRRm), (category 1, preferred)
for metastases if not previously or zoledronic acid
performedc,aaa if bone metastases First-line and subsequent treatment
• Consider tumor present optionsbbb:
mutational burden Palliative RTo for painful Small cell/ • Chemotherapyww,ccc
(TMB) testingc bone metastases neuroendocrine Cisplatin/etoposide
Best supportive care prostate cancer Carboplatin/etoposide
(NEPC)zz Docetaxel/carboplatin
Cabazitaxel/carboplatinddd
Best supportive care

c See Principles of Genetics and Molecular/Biomarker Analysis (PROS-B).

bbb Document castrate levels of testosterone if progression occurs on ADT. Workup
o See Principles of Radiation Therapy (PROS-F).
t See Principles of Androgen Deprivation Therapy (PROS-H). for progression should include chest CT, bone imaging, and abdominal/pelvic
ww See Principles of Non-Hormonal Systemic Therapy (PROS-I).. CT with contrast or abdominal/pelvic MRI with and without contrast. See
yy CRPC
 Principles of Imaging (PROS-D) and Discussion.
is prostate cancer that progresses clinically, radiographically, or ccc For
 additional small cell/NEPC therapy options, see NCCN Guidelines for Small
biochemically despite castrate levels of serum testosterone (<50 ng/dL). Scher Cell Lung Cancer.
HI, et al. J Clin Oncol 2008;26:1148-1159. ddd Cabazitaxel 20 mg/m² plus carboplatin AUC 4 mg/mL per min with growth
zz Histologic
 evidence of both adenocarcinoma and small cell carcinoma may
be present, in which case treatment can follow either pathway. Treat as factor support can be considered for fit patients with aggressive variant
adenocarcinoma if biopsy is not feasible or not performed. prostate cancer (visceral metastases, low PSA and bulky disease, high LDH,
aaa Germline testing for HRRm is recommended if not performed previously. See high carcinoembryonic antigen [CEA], lytic bone metastases, NEPC histology)
Principles of Genetics and Molecular/Biomarker Analysis (PROS-B). or unfavorable genomics (defects in at least 2 of PTEN, TP53, and RB1). Corn
PG, et al. Lancet Oncol 2019;20:1432-1443.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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SYSTEMIC THERAPY FOR M1 CRPC: ADENOCARCINOMAbbb,eee,fff

No prior docetaxel/no prior novel hormone therapyggg Prior novel hormone therapy/No prior docetaxelggg,mmm
• Preferred regimens • Preferred regimens
Abirateronet,hhh (category 1iii) Docetaxel (category 1)ww
Docetaxelww,jjj (category 1) Sipuleucel-Tww,kkk
Enzalutamidet (category 1) • Useful in certain circumstances
•Useful in certain circumstances Olaparib for HRRm (category 1)nnn
Sipuleucel-Tww,kkk (category 1) Cabazitaxel/carboplatinww,ddd
Radium-223lll for symptomatic bone metastases (category 1) Pembrolizumab for MSI-H, dMMR, or TMB ≥10 mut/Mbww
•Other recommended regimens Radium-223lll for symptomatic bone metastases (category 1)
Other secondary hormone therapyt Rucaparib for BRCAmooo
• Other recommended regimens
Abirateronet,hhh
Abiraterone + dexamethasonehhh,ppp
Enzalutamidet
Other secondary hormone therapyt
Prior docetaxel/no prior novel hormone therapyggg Prior docetaxel and prior novel hormone therapyggg,mmm
(All systemic therapies are category 2B if visceral metastases are
• Preferred regimens present)
Abirateronet,hhh (category 1) • Preferred regimens
Cabazitaxelww Cabazitaxelww (category 1iii)
Enzalutamidet (category 1) Docetaxel rechallengeww
• Useful in certain circumstances • Useful in certain circumstances
Mitoxantrone for palliation in symptomatic patients who Olaparib for HRRm (category 1iii)nnn
cannot tolerate other therapiesww Cabazitaxel/carboplatinww,ddd
Cabazitaxel/carboplatinww,ddd Pembrolizumab for MSI-H, dMMR, or TMB ≥10 mut/Mbww
Pembrolizumab for MSI-H, dMMR, or TMB ≥10 mut/Mbww Mitoxantrone for palliation in symptomatic patients who cannot
Radium-223lll for symptomatic bone metastases (category 1) tolerate other therapiesww
• Other recommended regimens Radium-223lll for symptomatic bone metastases (category 1iii)
Sipuleucel-Tww,kkk Rucaparib for BRCAmooo
Other secondary hormone therapyt • Other recommended regimens
Abirateronet,hhh
Enzalutamidet
Other secondary hormone therapyt

See Footnotes for Systemic Therapy M1 CRPC (PROS-15A).

Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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FOOTNOTES
t See Principles of Androgen Deprivation Therapy (PROS-H). kkk Sipuleucel-T is recommended only for asymptomatic or minimally symptomatic,
ww See Principles of Non-Hormonal Systemic Therapy (PROS-I).. no liver metastases, life expectancy >6 mo, and ECOG performance status
bbb Document
0–1. Benefit with sipuleucel-T has not been reported in patients with visceral
castrate levels of testosterone if progression occurs on ADT. Workup metastases and is not recommended if visceral metastases are present.
for progression should include chest CT, bone imaging, and abdominal/pelvic
Sipuleucel-T also is not recommended for patients with small cell/NEPC.
CT with contrast or abdominal/pelvic MRI with and without contrast. Consider
metastatic lesion biopsy. If small cell neuroendocrine is found, see PROS-15. lll Radium-223is not recommended for use in combination with docetaxel or any
See Principles of Imaging (PROS-D) and Discussion. other systemic therapy except ADT and should not be used in patients with
ddd Cabazitaxel 20 mg/m² plus carboplatin AUC 4 mg/mL per min with growth visceral metastases. Concomitant use of denosumab or zoledronic acid is
factor support can be considered for fit patients with aggressive variant recommended. See Principles of Radiation Therapy (PROS-F).
prostate cancer (visceral metastases, low PSA and bulky disease, high LDH, mmm Consider
 AR-V7 testing to help guide selection of therapy (See Discussion).
high CEA, lytic bone metastases, NEPC histology) or unfavorable genomics
nnn Olaparib is a treatment option for patients with mCRPC and a pathogenic
(defects in at least 2 of PTEN, TP53, and RB1). Corn PG, et al. Lancet Oncol
2019;20:1432-1443. mutation (germline and/or somatic) in a homologous recombination repair gene
(BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL,
eee Visceral metastases refers to liver, lung, adrenal, peritoneal, and brain PALB2, RAD51B, RAD51C, RAD51D, or RAD54L) who have been treated
metastases. Soft tissue/lymph node sites are not considered visceral previously with androgen receptor-directed therapy. Patients with PPP2R2A
metastases. mutations in the PROfound trial experienced an unfavorable risk-benefit profile.
fff Patients Therefore, olaparib is not recommended in patients with a PPP2R2A mutation.
can continue through all treatment options listed. Best supportive care
There may be heterogeneity of response to olaparib for non-BRCA mutations
is always an appropriate option.
based on which gene has a mutation. (See Discussion).
ggg Novel hormone therapies include abiraterone, enzalutamide, darolutamide, or ooo Rucaparib is a treatment option for patients with mCRPC and a pathogenic
apalutamide received for metastatic castration-naïve disease, M0 CRPC, or BRCA1 or BRCA2 mutation (germline and/or somatic) who have been treated
previous lines of therapy for M1 CRPC. with androgen receptor-directed therapy and a taxane-based chemotherapy.
hhh The fine-particle formulation of abiraterone can be used instead of the standard If the patient is not fit for chemotherapy, rucaparib can be considered even if
form (other recommended option). taxane-based therapy has not been given.
iii The ppp Switching from prednisone to dexamethasone 1 mg/day can be considered for
noted category applies only if no visceral metastases.
patients with disease progression on either formulation of abiraterone. Trials show
jjj Although most patients without symptoms are not treated with chemotherapy, the improved PSA responses and PFS and acceptable safety using this strategy.
survival benefit reported for docetaxel applies to those with or without symptoms. Romero-Laorden N, et al. Br J Cancer 2018;119:1052-1059 and Fenioux C, et al.
Docetaxel may be considered for patients with signs of rapid progression or BJU Int 2019;123:300-306.
visceral metastases despite lack of symptoms.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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PRINCIPLES OF LIFE EXPECTANCY ESTIMATION

• Life expectancy estimation is critical to informed decision-making in prostate cancer early detection and treatment.

• Estimation of life expectancy is possible for groups of patients but challenging for individuals.

• Life expectancy can be estimated using:

The Social Security Administration tables (www.ssa.gov/OACT/STATS/table4c6.html)
The WHO’s Life Tables by country (http://apps.who.int/gho/data/view.main.60000?lang=en)
The Memorial Sloan Kettering Male Life Expectancy tool (https://webcore.mskcc.org/survey/surveyform.aspx?preview=true&excelsurveylis
tid=4).

• If using a life expectancy table, life expectancy should be adjusted using the clinician’s assessment of overall health as follows:
Best quartile of health - add 50%
Worst quartile of health - subtract 50%
Middle two quartiles of health - no adjustment

• Example of upper, middle, and lower quartiles of life expectancy at selected ages are included in the NCCN Guidelines for Older Adult
Oncology for life expectancy estimation.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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PRINCIPLES OF GENETICS AND MOLECULAR/BIOMARKER ANALYSIS

GERMLINE TESTING

For details regarding the nuances of genetic counseling and testing, see Principles of Cancer Risk Assessment and Counseling (EVAL-A) in
the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic.

• Pre-test Considerations
The panel recommends inquiring about family and personal history of cancer, and known germline variants at time of initial diagnosis.
Criteria for germline testing (see PROS-B, 2 of 3) should be reviewed at time of initial diagnosis and, if relevant, at recurrence.
Germline testing should be considered in appropriate individuals where it is likely to impact the prostate cancer treatment and clinical trial
options, management of risk of other cancers, and/or potential risk of cancer in family members.
• Testing
If criteria are met (see PROS-B, 2 of 3), germline multigene testing that includes at least BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1,
MSH2, MSH6, and PMS2 is recommended.
Additional genes may be appropriate depending on clinical context. For example, HOXB13 is a prostate cancer risk gene that does not
have therapeutic implications in advanced disease, but testing may have utility for family counseling.

• Post-test Considerations
Post-test genetic counseling is strongly recommended if a germline mutation (pathogenic/likely pathogenic variant) is identified. Cascade
testing for relatives is critical to inform the risk for familial cancers in all relatives.
Post-test genetic counseling is recommended if positive family history but no pathogenic variant OR if only germline variants of unknown
significance (VUS) are identified. This is to ensure accurate understanding of family implications and review indications for additional
testing and/or follow-up (including clinical trials of reclassification).
Resources are available to review the available data supporting pathogenic consequences of specific variants (eg, https://www.ncbi.nlm.
nih.gov/clinvar/; https://brcaexchange.org/about/app).
Individuals should be counseled to inform providers of any updates to family cancer history.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-B
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PRINCIPLES OF GENETICS AND MOLECULAR/BIOMARKER ANALYSIS

Germline testing is recommended in patients with a personal history of prostate cancer in the following scenarios:
• By Prostate Cancer Stage or Risk Group (diagnosed at any age)
Metastatic, regional (node positive), very-high risk localized, high-risk localized prostate cancer
• By Family Historya and/or Ancestry
≥1 first-, second-, or third-degree relative with:
◊ breast cancer at age ≤50 y
◊ colorectal or endometrial cancer at age ≤50 y
◊ male breast cancer at any age
◊ ovarian cancer at any age
◊ exocrine pancreatic cancer at any age
◊ metastatic, regional, very-high-risk, high-risk prostate cancer at any age
≥1 first-degree relative (father or brother) with:
◊ prostate cancerb at age ≤60 y
≥2 first-, second-, or third-degree relatives with:
◊ breast cancer at any age
◊ prostate cancerb at any age
≥3 first- or second-degree relatives with:
◊ Lynch syndrome-related cancers, especially if diagnosed <50 y: colorectal, endometrial, gastric, ovarian, exocrine pancreas, upper
tract urothelial, glioblastoma, biliary tract, and small intestinal cancer
A known family history of familial cancer risk mutation (pathogenic/likely pathogenic variants), especially in: BRCA1, BRCA2, ATM,
PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2, EPCAM
Ashkenazi Jewish ancestry
• Personal history of breast cancer
Germline testing may be considered in patients with a personal history of prostate cancer in the following scenarios:
• By Prostate Cancer Tumor Characteristics (diagnosed at any age)
◊ intermediate-risk prostate cancer with intraductal/cribriform histologyc
• By prostate cancerb AND a prior personal history of any of the following cancers:
◊ exocrine pancreatic, colorectal, gastric, melanoma, pancreatic, upper tract urothelial, glioblastoma, biliary tract, and small intestinal

a Close blood relatives include first-, second-, and third-degree relatives on the same side of the family. See Pedigree: First-, Second-, and Third-Degree Relatives of
Proband (EVAL-B) in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic.
b Family history of prostate cancer should not include relatives with clinically localized Grade Group 1 disease.
c Acinar prostate adenocarcinoma with invasive cribriform pattern, intraductal carcinoma of prostate (IDC-P) or ductal adenocarcinoma component have increased
genomic instability, and germline testing may be considered.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-B
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PRINCIPLES OF GENETICS AND MOLECULAR/BIOMARKER ANALYSIS

SOMATIC TUMOR TESTING

• Pre-test Considerations
At present, tumor molecular and biomarker analysis may be used for treatment decision-making, including understanding eligibility for
biomarker-directed treatments, genetic counseling, early use of platinum chemotherapy, and eligibility for clinical trials. Clinical trials may
include established and/or candidate molecular biomarkers for eligibility.
Tumor molecular profiles may change with subsequent treatments and re-evaluation may be considered at time of cancer progression for
treatment decision-making.
Patients should be informed that tumor molecular analysis by DNA sequencing has the potential to uncover germline findings.
Confirmatory germline testing may be recommended (see Post-test Considerations, below, and see Tumor Testing in the Principles of
Cancer Risk Assessment and Counseling (EVAL-A) in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian,
and Pancreatic)
• Testing
Tumor testing for alterations in homologous recombination DNA repair genes, such as BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D,
CHEK2, and CDK12, is recommended in patients with metastatic prostate cancer. This testing can be considered in patients with regional
prostate cancer.
Tumor testing for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) is recommended in patients with metastatic
castration-resistant prostate cancer and may be considered in patients with regional or castration-naïve metastatic prostate cancer.
TMB testing may be considered in patients with metastatic castration-resistant prostate cancer.
• Tumor Specimen and Assay Considerations
The panel strongly recommends a metastatic biopsy for histologic and molecular evaluation. When unsafe or unfeasible, plasma ctDNA
assay is an option, preferably collected during biochemical (PSA) and/or radiographic progression in order to maximize diagnostic yield.
Caution is needed when interpreting ctDNA-only evaluation due to potential interference from clonal hematopoiesis of indeterminate
potential (CHIP), which can result in a false-positive biomarker signal.
DNA analysis for MSI and immunohistochemistry (IHC) for MMR are different assays measuring different biological effects caused by
dMMR function. If MSI is used, testing using an a next-generation sequencing (NGS) assay validated for prostate cancer is preferred.
• Post-test Considerations
Post-test genetic counseling is recommended if pathogenic/likely pathogenic variant (mutation) identified in any gene that has clinical
implications if also identified in germline (eg, BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2).
Post-test genetic counseling to assess for the possibility of Lynch syndrome is recommended if MSI-H or dMMR is found.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF RISK STRATIFICATION

• Current treatment recommendations for localized, locally advanced, post-radical prostatectomy (RP), and recurrent prostate cancer are
based on prognosis, which is estimated through risk stratification.
• NCCN and other risk classification schemas are prognostic and have not been shown to be predictive of benefit to a specific treatment.
• The 3-tier D’Amico or NCCN risk groups have been the most common risk groups reported in clinical trials. However, most trials enroll
patients across multiple NCCN risk groups with no evidence of treatment interaction by NCCN risk group. This lack of interaction may be due
to underpowering since few trials stratify by NCCN risk group prior to randomization.
• Thus, recommendations of when to offer conservative management, radical therapy, or use of short-term ADT (ST-ADT) or long-term ADT (LT-
ADT), are based on expert opinion and estimates of absolute benefit and harm from a given therapy in the context of NCCN risk groups.
• There are newer risk classification schemas that have been shown to outperform NCCN risk groups,1,2 as well as tools (imaging, gene
expression biomarkers, germline testing) that together improve risk stratification.
These tools are recommended when they will have the ability to change management (eg, active surveillance vs radical treatment, RT +/-
ADT).
Patients with low or favorable intermediate-risk disease and life expectancy ≥10 y may consider the use of the following tumor-based
molecular assays: Decipher, Oncotype DX Prostate, and Prolaris. Patients with unfavorable intermediate- and high-risk disease and life
expectancy ≥10 y may consider the use of Decipher and Prolaris tumor-based molecular assays. (See Table 2 on PROS-C, page 2 of 3)
Retrospective studies have shown that tumor-based molecular assays performed on prostate biopsy or RP specimens provide prognostic
information independent of NCCN or CAPRA risk groups. These include, but are not limited to, likelihood of death with conservative
management, likelihood of biochemical progression after RP or EBRT, and likelihood of developing metastasis after RP or salvage
radiotherapy.
For germline testing criteria, see PROS-B.
• These tools should not be ordered reflexively. Improved risk stratification can better identify patients who may derive greater or lesser
absolute benefit from a given treatment.

See References on page PROS-C, 3 of 3.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-C
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PRINCIPLES OF RISK STRATIFICATION

Table 1. Initial Risk Stratification for Clinically Localized Disease

Category Tool Predictive Prognostic Endpoint Trained For
NCCN No Yes BCR*
STAR-CAP 1 No Yes PCSM
Clinical 3
CAPRA No Yes BCR
MSKCC 4 No Yes BCR and PCSM
MRI No Yes -
Imaging
PET No Yes -
Decipher No Yes Metastasis
Prolaris No Yes Time to BCR and time to death from
Gene Expression Testing
prostate cancer
Oncotype DX Prostate No Yes Adverse pathology
Germline Testing BRCA2 No Yes -
*Very-low, low, favorable-intermediate, unfavorable-intermediate, high, very-high, and regional prostate cancer.

Table 2. Tumor-Based Molecular Assays Can be Considered in Patients with Life Expectancy ≥10y as follows:

Favorable Unfavorable
Very low risk Low risk High risk Very high risk
intermediate risk intermediate risk

Decipher No Yes Yes Yes Yes No

Prolaris No Yes Yes Yes Yes No

Oncotype DX Prostate No Yes Yes No No No

See References on page PROS-C, 3 of 3.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-C
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PRINCIPLES OF RISK STRATIFICATION

REFERENCES
1 Dess RT, Suresh K, Zelefsky MJ, et al. Development and validation of a clinical prognostic stage group system for nonmetastatic prostate cancer using disease-
specific mortality results from the international staging collaboration for cancer of the prostate. JAMA Oncol 2020;6:1912-1920.
2 Zelic R, Garmo H, Zugna D, et al. Predicting prostate cancer death with different pretreatment risk stratification tools: A head-to-head comparison in a nationwide
cohort study. Eur Urol 2020;77:180-188.
3 Cooperberg MR, Pasta DJ, Elkin EP, et al. The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable
preoperative predictor of disease recurrence after radical prostatectomy. J Urol 2005;173:1938-1942.
4 Graefen M, Karakiewicz PI, Cagiannos I, et al. International validation of a preoperative nomogram for prostate cancer recurrence after radical prostatectomy. J Clin
Oncol 2002;20:3206-3212.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-C
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PRINCIPLES OF IMAGING
Goals of Imaging Ultrasound
• Imaging is performed for the detection and characterization of disease • Ultrasound uses high-frequency sound waves to image small
to select treatment or guide change in management. regions of the body.
• Imaging techniques can evaluate anatomic or functional parameters. Standard ultrasound imaging provides anatomic information.
Anatomic imaging techniques include plain film radiographs, Vascular flow can be assessed using Doppler ultrasound
ultrasound, CT, and MRI. techniques.
Functional imaging techniques include radionuclide bone scan, • Endorectal ultrasound is used to guide transrectal biopsies of the
PET/CT, and advanced MRI techniques, such as spectroscopy and prostate. Endorectal ultrasound can be considered for patients
diffusion-weighted imaging (DWI). with suspected recurrence after RP to guide prostate bed biopsy.
Efficacy of Imaging • Advanced ultrasound techniques for imaging of the prostate and
• The utility of imaging for patients with early PSA persistence/ for differentiation between prostate cancer and prostatitis are
recurrence after RP depends on risk group prior to operation, under evaluation.
pathologic Gleason grade and stage, PSA, and PSADT after Bone Imaging
recurrence. Low- and intermediate-risk groups with low serum PSAs • The use of the term “bone scan” refers to the conventional
postoperatively have a very low risk of positive bone scans or CT technetium-99m-MDP bone scan in which technetium is taken up
scans. by bone that is turning over and imaged with a gamma camera
• Frequency of imaging should be based on individual risk, age, PSADT, using planar imaging or 3-D imaging with single-photon emission
Gleason score, and overall health. CT (SPECT).
• Conventional bone scans are rarely positive in asymptomatic patients Sites of increased uptake imply accelerated bone turnover and
with PSA <10 ng/mL. The relative risk for bone metastasis or death may indicate metastatic disease.
increases as PSADT shortens. Bone imaging should be performed Osseous metastatic disease may be diagnosed based on the
more frequently when PSADT ≤8 months, where there appears to be an overall pattern of activity, or in conjunction with anatomic
inflection point. imaging.
Plain Radiography • Bone imaging is indicated in the initial evaluation of patients at
• Plain radiography can be used to evaluate symptomatic regions in the high risk for skeletal metastases.
skeleton. However, conventional plain x-rays will not detect a bone • Bone imaging can be considered for the evaluation of the post-
lesion until nearly 50% of the mineral content of the bone is lost or prostatectomy patient when there is failure of PSA to fall to
gained. undetectable levels, or when there is undetectable PSA after RP
• CT or MRI may be more useful to assess fracture risk as these with a subsequent detectable PSA that increases on 2 or more
modalities permit more accurate assessment of cortical involvement subsequent determinations.
than plain films where osteoblastic lesions may obscure cortical • Bone imaging can be considered for the evaluation of patients
involvement. with an increasing PSA or positive DRE after RT if the patient is a
candidate for additional local therapy or systemic therapy.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF IMAGING
• Bone scans are helpful to monitor metastatic prostate cancer to • CT may be performed with intravenous contrast, and CT technique
determine the clinical benefit of systemic therapy. However, new should be optimized to maximize diagnostic utility while minimizing
lesions seen on an initial post-treatment bone scan, compared to the radiation dose.
pre-treatment baseline scan, may not indicate disease progression. • CT can be used for examination of the pelvis and/or abdomen for
• New lesions in the setting of a falling PSA or soft tissue response initial evaluation (see PROS-2) and as part of workup for recurrence
and in the absence of pain progression at that site may indicate or progression (see PROS-11 through PROS-15).
bone scan flare or an osteoblastic healing reaction. For this Magnetic Resonance Imaging
reason, a confirmatory bone scan 8–12 weeks later is warranted • The strengths of MRI include high soft tissue contrast and
to determine true progression from flare reaction. Additional new characterization, multiparametric image acquisition, multiplanar
lesions favor progression. Stable scans make continuation of imaging capability, and advanced computational methods to assess
treatment reasonable. Bone scan flare is common, particularly on function.
initiation of new hormonal therapy, and may be observed in nearly MRI can be performed with and without the administration of
half of patients treated with the newer agents, enzalutamide and intravenous contrast material.
abiraterone. Similar flare phenomena may exist with other imaging Resolution of MRI images in the pelvis can be augmented using an
modalities, such as CT or PET/CT imaging. endorectal coil.
• Bone scans and soft tissue imaging (CT or MRI) in patients with • Standard MRI techniques can be used for examination of the pelvis
metastatic or non-metastatic prostate cancer may be obtained and/or abdomen for initial evaluation (see PROS-2) and as part of
regularly during systemic therapy to assess clinical benefit. workup for recurrence or progression (see PROS-11 through PROS-
• Bone scans should be performed for symptoms and as often as 15).
every 6–12 mo to monitor ADT. The need for soft tissue images • MRI may be considered in patients after RP when PSA fails to fall
remains unclear. In CRPC, 8- to 12-week imaging intervals appear to undetectable levels or when an undetectable PSA becomes
reasonable. detectable and increases on 2 or more subsequent determinations,
• PET imaging for detection of bone metastatic disease or after RT for increasing PSA or positive DRE if the patient is a
Plain films, CT, MRI, PET/CT, or PET/MRI with F-18 piflufolastat candidate for additional local therapy. MRI-US fusion biopsy may
PSMA, Ga-68 PSMA-11, F-18 sodium fluoride, C-11 choline, or F-18 improve the detection of higher grade (Grade Group ≥2) cancers.
fluciclovine can be considered for equivocal results on initial bone • mpMRI can be used in the staging and characterization of prostate
scan. cancer. mpMRI images are defined as images acquired with at
Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI (full least one more sequence in addition to the anatomical T2-weighted
body imaging) can be considered as an alternative to bone scan. images, such as DWI or dynamic contrast-enhanced (DCE) images.
Computed Tomography • mpMRI may be used to better risk stratify patients who are
• CT provides a high level of anatomic detail, and may detect gross considering active surveillance. Additionally, mpMRI may detect
extracapsular disease, nodal metastatic disease, and/or visceral large and poorly differentiated prostate cancer (Grade Group ≥2)
metastatic disease. and detect extracapsular extension (T staging) and is preferred
• CT is generally not sufficient to evaluate the prostate gland. over CT for abdominal/pelvic staging. mpMRI has been shown to be
equivalent to CT scan for pelvic lymph node evaluation.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-D
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PRINCIPLES OF IMAGING
Positron Emission Tomography (PET) and interpretation of the utility of PET/CT or PET/MRI.
• PSMA-PET refers to a growing body of radiopharmaceuticals that • Table 2 in the Discussion section provides a summary of the main
target PSMA on the surface of prostate cells. There are multiple PET/CT or PET/MRI imaging tracers utilized for study in prostate
PSMA radiopharmaceuticals at various stages of investigation. cancer both before definitive therapy and at recurrence.
At this time, the NCCN Guidelines only recommend the currently • PET/CT or PET/MRI results may change treatment but may not
FDA-approved PSMA agents, F-18 piflufolastat (DCFPyL) and Ga-68 change oncologic outcome.
PSMA-11. See Table 2 in the Discussion section for more detail. • When the worst prognosis patients from one risk group move to
• F-18 piflufolastat PSMA or Ga-68 PSMA-11 PET/CT or PET/MRI can the higher risk group, the average outcome of both risk groups
be considered as an alternative to standard imaging of bone and soft will improve even if treatment has no impact on disease. This
tissue for initial staging, the detection of biochemically recurrent phenomenon is known as the Will Rogers effect, in which the
disease, and as workup for progression with bone scan plus CT or improved outcomes of both groups could be falsely attributed
MRI for the evaluation of bone, pelvis, and abdomen. to improvement in treatment, but would be due only to improved
• C-11 choline or F-18 fluciclovine PET/CT or PET/MRI may be used to risk group assignment. As an example, F-18 sodium fluoride PET/
detect small-volume recurrent disease in soft tissues and in bone. CT may categorize some patients as M1b who would have been
• Studies suggest that F-18 piflufolastat PSMA or Ga-68 PSMA-11 categorized previously as M0 using a bone scan (stage migration).
PET imaging have a higher sensitivity than C-11 choline or F-18 Absent any change in the effectiveness of therapy, the overall
fluciclovine PET imaging, especially at very low PSA levels. survival of both M1b and M0 groups would improve. The definition
• Because of the increased sensitivity and specificity of PSMA- of M0 and M1 disease for randomized clinical trials that added
PET tracers for detecting micrometastatic disease compared docetaxel or abiraterone to ADT was based on CT and conventional
to conventional imaging (CT, MRI) at both initial staging and radionuclide bone scans. Results suggest that overall survival of
biochemical recurrence, the Panel does not feel that conventional M1 disease is improved, whereas progression-free but not overall
imaging is a necessary prerequisite to PSMA-PET and that PSMA- survival of M0 disease is improved. Therefore, a subset of patients
PET/CT or PSMA-PET/MRI can serve as an equally effective, if not now diagnosed with M1 disease using F-18 sodium fluoride PET/
more effective front-line imaging tool for these patients. CT might not benefit from the more intensive therapy used in
• Histologic or radiographic confirmation of involvement detected by these trials and could achieve equivalent overall survival from less
PET imaging is recommended whenever feasible due to the presence intensive therapy aimed at M0 disease. Carefully designed clinical
of false positives. Although false positives exist, literature suggests trials using proper staging will be necessary to prove therapeutic
that these are outweighed by the increase in true positives detected benefit, rather than making assumptions compromised by stage
by PET relative to conventional imaging. To reduce the false-positive migration.
rate, physicians should consider the intensity of PSMA-PET uptake • F-18 fluorodeoxyglucose (FDG) PET/CT should not be used
and correlative CT findings in the interpretation of scans. Several routinely for staging prostate cancer since data are limited in
reporting sytems have been proposed but will not have been patients with prostate cancer.
validated or widely used.
• High variability among PET/CT or PET/MRI equipment, protocols,
interpretation, and institutions provides challenges for application

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-D
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PRINCIPLES OF ACTIVE SURVEILLANCE AND OBSERVATION

• The NCCN Prostate Cancer Panel and the NCCN Prostate Cancer • Patients who choose active surveillance should have regular follow-up.
Early Detection Panel (See NCCN Guidelines for Prostate Cancer Follow-up should be more rigorous in younger patients than in older
Early Detection) remain concerned about overdiagnosis and patients. Follow-up should include:
overtreatment of prostate cancer. The panel recommends that Consider confirmatory prostate biopsy with or without mpMRI and
patients and their physicians (ie, urologist, radiation oncologist, with or without molecular tumor analysis to establish candidacy for
medical oncologist, primary care physician) consider active active surveillance. Molecular tumor analysis also can be used to
surveillance based on careful consideration of the patient’s confirm candidacy in patients with low and favorable intermediate-risk
prostate cancer risk profile, age, and health. prostate cancer.
• The NCCN Guidelines for Prostate Cancer distinguish between Assess PSA no more often than every 6 months unless clinically
active surveillance and observation. Both involve no more often indicated.
than every-6-month monitoring but active surveillance may Perform DRE no more often than every 12 months unless clinically
involve surveillance prostate biopsies. Evidence of progression indicated.
will prompt conversion to potentially curative treatment in Repeat prostate biopsy no more often than every 12 months unless
active surveillance patients, whereas monitoring continues clinically indicated.
until symptoms develop or are imminent (ie, PSA >100 ng/mL Repeat mpMRI no more often than every 12 months unless clinically
or change in exam) in observation patients, who will then begin indicated.
palliative ADT. Needle biopsy of the prostate should be repeated within 6 months of
• Active surveillance is preferred for patients with very-low-risk diagnosis if initial biopsy was <10 cores or assessment discordant
prostate cancer and life expectancy ≥20 years. Observation is (eg, palpable tumor contralateral to side of positive biopsy).
preferred for patients with low-risk prostate cancer with life MRI-US fusion biopsy may improve the detection of higher grade
expectancy <10 years. See Risk Group Criteria (PROS-2). (Grade Group ≥2) cancers.
• Patients with favorable intermediate-risk prostate cancer (See A repeat prostate biopsy should be considered if there are prostate
Risk Group Criteria [PROS-2]) may be considered for active exam changes, MRI suggests more aggressive disease, or PSA
surveillance. See Discussion. increases, but no parameter is very reliable for detecting prostate
• Active surveillance involves actively monitoring the course of cancer progression.
disease with the expectation to intervene with curative intent if the A repeat prostate biopsy is not generally recommended more often
cancer progresses. than annually to assess for disease progression unless clinically
• Cancer progression (risk group reclassification) may have indicated.
occurred if: Repeat prostate biopsies are not indicated when life expectancy is
Higher grade cancer is found upon repeat prostate biopsy. less than 10 years or appropriate when patients are on observation.
Prostate cancer is found in a greater number of prostate PSADT appears unreliable for identification of progressive disease
biopsies or occupies a greater extent of prostate biopsy. that remains curable.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-E
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PRINCIPLES OF ACTIVE SURVEILLANCE AND OBSERVATION

• Advantages of active surveillance: • Advantages of observation:
About two thirds of those eligible for active surveillance may avoid Patients will avoid possible side effects of unnecessary definitive
or delay treatment. therapy and early initiation and/or continuous ADT.
Patients will avoid possible side effects of definitive therapy that • Disadvantages of observation:
may be unnecessary.
There will be a risk of urinary retention or pathologic fracture
Quality of life/normal activities will potentially be less affected. without prior symptoms or concerning PSA levels.
Risk of unnecessary treatment of small, indolent cancers will be
reduced.
• Disadvantages of active surveillance:
Although very low, there will be a chance of missed opportunity for
cure.
About one third of patients will require treatment, although
treatment delays do not seem to impact cure rate.
Periodic follow-up mpMRI and prostate biopsies may be necessary.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-E
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PRINCIPLES OF RADIATION THERAPY

Definitive Radiation Therapy General Principles • Biologically effective dose (BED) modeling with the linear-quadratic
• Highly conformal RT techniques should be used to treat localized equation may not be accurate for extremely hypofractionated
prostate cancer. (SBRT/stereotactic ablative radiotherapy [SABR]) radiation.
• Photon or proton EBRT are both effective at achieving highly • Brachytherapy:
conformal radiotherapy with acceptable and similar biochemical Interstitial implantation of prostate +/- proximal seminal vesicles
control and long-term side effect profiles (See Discussion). with temporary (high dose-rate, HDR) or permanent (low dose-rate,
• Ideally, the accuracy of treatment should be verified by daily LDR) radioactive sources for monotherapy or as "boost" when
prostate localization, with any of the following: techniques of added to EBRT should be performed in practices with adequate
image-guided RT (IGRT) using CT, ultrasound, implanted fiducials, training, experience, and quality assurance measures.
or electromagnetic targeting/tracking. Endorectal balloons may Patient selection should consider aspects of gland size, baseline
be used to improve prostate immobilization. Biocompatible and urinary symptoms, and prior procedures (ie, transurethral
biodegradable perirectal spacer materials may be implanted resection prostate) that may increase risk of adverse effects.
between the prostate and rectum in patients undergoing external Neoadjuvant ADT to shrink a gland to allow treatment should
radiotherapy with organ-confined prostate cancer in order to balance its additional toxicity with this benefit.
displace the rectum from high radiation dose regions. A randomized Post-implant dosimetry must be performed for LDR implants to
phase III trial demonstrated reduced rectal bleeding in patients verify dosimetry.
undergoing the procedure compared to controls. Retrospective data Brachytherapy boost, when added to EBRT and ADT, improves
also support its use in similar patients undergoing brachytherapy. biochemical control. To address historical trial data concerns
Patients with obvious rectal invasion or visible T3 and posterior for increased toxicity incidence, careful patient selection and
extension should not undergo perirectal spacer implantation. contemporary planning associated with lesser toxicity, such as
• Various fractionation and dose regimens can be considered use of recognized organ at risk dose constraints, use of high-
depending on the clinical scenario (See Table 1 on PROS-F 3 of 5). quality ultrasound and other imaging, and prescription of dose as
Dose escalation has been proven to achieve the best biochemical close as possible to the target without excessive margins should
control in patients with intermediate- and high-risk disease. be implemented.
• Stereotactic body RT (SBRT) is acceptable in practices with
appropriate technology, physics, and clinical expertise. SBRT for
metastases can be considered in the following circumstances:
In a patient with limited metastatic disease to the vertebra or
paravertebral region when ablation is the goal (eg, concern for
impending fracture or tumor encroachment on spinal nerves or
vertebra)
In a patient with oligometastatic progression where progression-
free survival is the goal
In a symptomatic patient where the lesion occurs in or immediately
adjacent to a previously irradiated treatment field.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Continued
PROS-F
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PRINCIPLES OF RADIATION THERAPY

Definitive Radiation Therapy by Risk Group ADT can be considered.
• Very low risk • Low-volume metastatic disease
Patients with NCCN very-low-risk prostate cancer are encouraged Radiation therapy to the prostate is an option in patients
to pursue active surveillance. with low-volume castration-naïve metastatic disease, without
• Low risk contraindications to radiotherapy. ADT is required unless
Patients with NCCN low-risk prostate cancer are encouraged to medically contraindicated.
pursue active surveillance. This recommendation is based on the STAMPEDE phase 3
Prophylactic lymph node radiation should NOT be performed randomized trial, which randomized 2,061 patients to standard
routinely. ADT or antiandrogen therapy should NOT be used systemic therapy with or without radiotherapy to the primary. The
routinely. overall cohort had a significant improvement from the addition of
• Favorable intermediate risk radiotherapy to the primary in failure-free survival, but not overall
Prophylactic lymph node radiation is not performed routinely, and survival. The prespecified low-volume subset had a significant
ADT or antiandrogen therapy is not used routinely. Prophylactic improvement in both failure-free survival and overall survival.
lymph node radiation and/or ADT use is reasonable if additional Minimizing toxicity is paramount when delivering radiation therapy
risk assessments suggest aggressive tumor behavior. to the primary in patients with metastatic disease.
• Unfavorable intermediate risk It remains uncertain whether treatment of regional nodes in
Prophylactic nodal radiation can be considered if additional risk addition to the primary improves outcomes; nodal treatment
assessments suggest aggressive tumor behavior. ADT should should be performed in the context of a clinical trial.
be used unless additional risk assessments suggest less- Dose escalation beyond biologically effective dose equivalents
aggressive tumor behavior or if medically contraindicated. The of the two-dose prescriptions used in STAMPEDE (55 Gy in 20
duration of ADT can be reduced when combined with EBRT and fractions or 6 Gy x 6 fractions) is not recommended given the
brachytherapy. Brachytherapy combined with ADT (without EBRT), known increase in toxicity from dose intensification without
or SBRT combined with ADT can be considered if delivering overall survival improvement in localized disease.
longer courses of EBRT would present medical or social hardship. Brachytherapy is not recommended outside of a clinical trial,
• High and very high risk as safety and efficacy have not been established in this patient
Prophylactic nodal radiation should be considered. ADT is population.
required unless medically contraindicated. Brachytherapy • High-volume metastatic disease
combined with ADT (without EBRT), or SBRT combined with ADT, Radiation therapy to the prostate should NOT be performed in
can be considered if delivering longer courses of EBRT would patients with high-volume metastatic disease outside the context
present a medical or social hardship. of a clinical trial unless for palliative intent.
• Regional disease This recommendation is based on two randomized trials, HORRAD
Nodal radiation should be performed. Clinically positive nodes and STAMPEDE, neither of which showed an improvement in
should be dose-escalated as dose-volume histogram parameters overall survival from the addition of radiotherapy to the primary
allow. ADT is required unless medically contraindicated, and the when combined with standard systemic therapy.
addition of abiraterone or fine-particle abiraterone (category 2B) to

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Continued
PROS-F
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PRINCIPLES OF RADIATION THERAPY

Table 1: Below are examples of regimens that have shown acceptable efficacy and toxicity. The optimal regimen for an individual patient warrants evaluation of comorbid conditions, voiding
symptoms and toxicity of therapy. Additional fractionation schemes may be used as long as sound oncologic principles and appropriate estimate of BED are considered.
See PROS-3, PROS-4, PROS-5, PROS-6, PROS-7, PROS-8, PROS-12, and PROS-H for other recommendations, including recommendations for neoadjuvant/concomitant/adjuvant ADT.

NCCN Risk Group

( indicates an appropriate regimen option if radiation therapy is given)
Regimen Preferred Dose/Fractionation
Very Low Favorable Unfavorable High and Low Volume
Regional N1
and Low Intermediate Intermediate Very High M1a

EBRT
3 Gy x 20 fx
Moderate Hypofractionation 2.7 Gy x 26 fx     
(Preferred) 2.5 Gy x 28 fx
2.75 Gy x 20 fx 
Conventional Fractionation 1.8–2 Gy x 37–45 fx     
7.25–8 Gy x 5 fx  
6.1 Gy x 7 fx  
Ultra-Hypofractionation
6 Gy x 6 fx 
Brachytherapy Monotherapy
LDR
Iodine 125 145 Gy
Palladium 103 125 Gy  
Cesium 131 115 Gy

HDR
13.5 Gy x 2 implants  
Iridium-192
9.5 Gy BID x 2 implants
EBRT and Brachytherapy (combined with 45–50.4 Gy x 25–28 fx or 37.5 Gy x 15 fx)
LDR
Iodine 125 110–115 Gy  
Palladium 103 90–100 Gy
Cesium 131 85 Gy
HDR 15 Gy x 1 fx  
Iridium-192 10.75 Gy x 2 fx
a High-volume disease is differentiated from low-volume disease by visceral metastases and/or 4 or more bone metastases, with at least one metastasis beyond the
pelvis vertebral column. Patients with low-volume disease have less certain benefit from early treatment with docetaxel combined with ADT.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Continued
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Salvage Brachytherapy agonist plus antiandrogen).
• Permanent LDR or temporary HDR brachytherapy is a treatment • The Panel recommends consultation with the American Society
option for pathologically confirmed local recurrence after EBRT or for Radiation Oncology (ASTRO)/American Urological Association
brachytherapy. Subjects should have restaging imaging according (AUA) Guidelines. Evidence supports offering adjuvant/salvage RT
to the NCCN high-risk stratification group to rule out regional nodal in most patients with adverse pathologic features or detectable PSA
or metastatic disease. Patients should be counseled that salvage and no evidence of disseminated disease.
brachytherapy significantly increases the probability of urologic, • Indications for adjuvant RT include pT3a disease, positive margin(s),
sexual, and bowel toxicity compared to primary brachytherapy. or seminal vesicle involvement. Adjuvant RT is usually given within
Post-Prostatectomy Radiation Therapy 1 year after RP and after operative side effects have improved/
• The panel recommends use of nomograms and consideration of age stabilized. Patients with positive surgical margins may benefit the
and comorbidities, clinical and pathologic information, PSA levels, most.
PSADT, and Decipher molecular assay to individualize treatment • Indications for salvage RT include an undetectable PSA
discussion. Patients with high Decipher genomic classifier scores that becomes subsequently detectable and increases on 2
(GC >0.6) should be strongly considered for EBRT and addition of measurements or a PSA that remains persistently detectable after
ADT when the opportunity for early EBRT has been missed. RP. Treatment is more effective when pre-treatment PSA is low and
EBRT with 2 years of 150 mg/day of bicalutamide demonstrated PSADT is long.
improved overall and metastasis-free survival on a prospective • The recommended prescribed doses for adjuvant/salvage post-
randomized trial (RTOG 9601) versus radiation alone in the salvage prostatectomy RT are 64–72 Gy in standard fractionation. Biopsy-
setting. A secondary analysis of RTOG 9601 found that patients proven gross recurrence may require higher doses.
with PSA ≤0.6 ng/mL had no OS improvement with the addition of • Nuclear medicine advanced imaging techniques can be useful
the antiandrogen to EBRT. In addition, results of a retrospective for localizing disease with PSA levels as low as 0.5 ng/mL (see
analysis of RP specimens from patients in 9601 suggest that Discussion).
those with low PSA and a low Decipher score derived less benefit • Nomograms, and tumor-based molecular assays, can be used
(development of distant metastases, OS) from bicalutamide than to prognosticate risk of metastasis and prostate cancer-specific
those with a high Decipher score. mortality in patients with adverse risk features after RP.
EBRT with 6 months of ADT (LHRH agonist) improved biochemical • Target volumes include the prostate bed and may include the whole
or clinical progression at 5 years on a prospective randomized pelvis according to physician discretion.
trial (GETUG-16) versus radiation alone in patients with rising PSA
levels between 0.2 and 2.0 ng/mL after RP.
The ongoing SPPORT trial (NCT00567580) of patients with PSA
levels between 0.1 and 2.0 ng/mL at least 6 weeks after RP has
reported preliminary results on clinicaltrials.gov. The primary
outcome measure of percentage of participants free from
progression (FFP) at 5 years was 70.3 (95% CI, 66.2–74.3) for
those who received EBRT to the prostate bed and 81.3 (95% CI,
77.9–84.6) for those who also received 4–6 months of ADT (LHRH
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Continued
PROS-F
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PRINCIPLES OF RADIATION THERAPY

Radiopharmaceutical Therapy Palliative Radiotherapy
• Radium-223 is an alpha-emitting radiopharmaceutical that has • 8 Gy as a single dose is as effective for pain palliation at any bony
been shown to extend survival in patients who have CRPC with site as longer courses of radiation, but re-treatment rates are higher.
symptomatic bone metastases, but no visceral metastases. • Widespread bone metastases can be palliated using strontium-89 or
Radium-223 alone has not been shown to extend survival in samarium-153 with or without focal external beam radiation.
patients with visceral metastases or bulky nodal disease (>3–4 • 30 Gy in 10 fractions or 37.5 Gy in 15 fractions may be used as
cm). Radium-223 differs from beta-emitting agents, such as alternative palliative dosing depending on clinical scenario (both
samarium-153 and strontium-89, which are palliative and have no category 2B).
survival advantage. Radium-223 causes double-strand DNA breaks
and has a short radius of activity. Grade 3–4 hematologic toxicity (ie,
2% neutropenia, 3% thrombocytopenia, 6% anemia) occurs at low
frequency.
• Radium-223 is administered intravenously once a month for 6
months by an appropriately licensed facility, usually in nuclear
medicine or RT departments.
• Prior to the initial dose, patients must have absolute neutrophil count
(ANC) ≥1.5 x 10⁹/L, platelet count ≥100 x 10⁹/L, and hemoglobin ≥10 g/
dL.
• Prior to subsequent doses, patients must have ANC ≥1 x 10⁹/L
and platelet count ≥50 x 10⁹/L (per label). Radium-223 should be
discontinued if a delay of 6–8 weeks does not result in the return of
blood counts to these levels.
• Non-hematologic side effects are generally mild, and include nausea,
diarrhea, and vomiting. These symptoms may occur because
radium-223 is eliminated predominantly by fecal excretion.
• Radium-223 is not intended to be used in combination with
chemotherapy due to the potential for additive myelosuppression,
except in a clinical trial.
• Radium-223 may increase fracture risk when given concomitantly
with abiraterone.
• Radium-223 is not recommended for use in combination with
docetaxel or any other systemic therapy except ADT.
• Concomitant use of denosumab or zoledronic acid is recommended;
it does not interfere with the beneficial effects of radium-223 on
survival.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-F
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PRINCIPLES OF SURGERY
Pelvic Lymph Node Dissection Radical Prostatectomy
• Extended pelvic lymph node dissection (PLND) provides more • RP is an appropriate therapy for any patient with clinically localized
complete staging and may cure some patients with microscopic prostate cancer that can be completely excised surgically, who has
metastases; therefore, an extended PLND is preferred when PLND is a life expectancy of ≥10 years, and who has no serious comorbid
performed. conditions that would contraindicate an elective operation.
• An extended PLND includes removal of all node-bearing tissue • High-volume surgeons in high-volume centers generally provide
from an area bound by the external iliac vein anteriorly, the pelvic better outcomes.
sidewall laterally, the bladder wall medially, the floor of the pelvis • Blood loss can be substantial with RP, but can be reduced by
posteriorly, Cooper's ligament distally, and the internal iliac artery using laparoscopic or robotic assistance or by careful control of
proximally. the dorsal vein complex and periprostatic vessels when performed
• A PLND can be excluded in patients with <2% predicated probability open.
of nodal metastases by nomograms, although some patients with • Urinary incontinence can be reduced by preservation of urethral
lymph node metastases will be missed. length beyond the apex of the prostate and avoiding damage to
• PLND can be performed using an open, laparoscopic, or robotic the distal sphincter mechanism. Bladder neck preservation may
technique. decrease the risk of incontinence. Anastomotic strictures increase
the risk of long-term incontinence.
• Recovery of erectile function is directly related to age at RP,
preoperative erectile function, and the degree of preservation of the
cavernous nerves. Replacement of resected nerves with nerve grafts
has not been shown to be beneficial. Early restoration of erections
may improve late recovery.

Salvage Radical Prostatectomy

• Salvage RP is an option for highly selected patients with local
recurrence after EBRT, brachytherapy, or cryotherapy in the
absence of metastases, but the morbidity (ie, incontinence, loss of
erection, anastomotic stricture) is high and the operation should be
performed by surgeons who are experienced with salvage RP.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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ADT for Clinically Localized (N0,M0) Disease degarelix with abiraterone
• Neoadjuvant ADT for RP is strongly discouraged outside of a clinical trial. ADT alone or with abiraterone (see below).
• ADT should not be used as monotherapy in clinically localized prostate • Abiraterone should be given with concurrent steroid:
cancer unless there is a contraindication to definitive local therapy such Prednisone 5 mg orally once daily for the standard formulation
as life expectancy ≤5 years and comorbidities. Under those circumstances, Methylprednisolone 4 mg orally twice daily for the fine-particle
ADT may be used [see ADT for Patients on Observation Who Require formulation (category 2B).
Treatment and Those with Life Expectancy ≤5 Years (PROS-H, 4 of 5)]. Abiraterone with ADT should be considered for a total of 2 years for those
• Giving ADT before, during, and/or after radiation (neoadjuvant, concurrent, patients with N1 disease who are treated with radiation to the prostate
and/or adjuvant ADT) prolongs survival in selected radiation-managed and pelvic nodes.
patients. Options are: • Options for ADT are:
LHRH agonist alone Orchiectomy
◊ Goserelin, histrelin, leuprolide, or triptorelin LHRH agonist alone
LHRH agonist (as above) plus first-generation antiandrogen ◊ Goserelin, histrelin, leuprolide, or triptorelin
◊ Nilutamide, flutamide, or bicalutamide LHRH agonist (as above) plus first-generation antiandrogen
LHRH antagonist ◊ Nilutamide, flutamide, or bicalutamide
◊ Degarelix, relugolix LHRH antagonist
LHRH agonist or degarelix with abiraterone (very high risk only) ◊ Degarelix, relugolix
LHRH agonist, LHRH agonist plus first-generation antiandrogen, or Orchiectomy plus abiraterone
degarelix with docetaxel (very high risk only) LHRH agonist (as above) plus abiraterone
• Studies of short-term (4–6 mo) and long-term (2–3 y) neoadjuvant, Degarelix plus abiraterone
concurrent, and/or adjuvant ADT all have used combined androgen Patients with regional disease and life expectancy <5 years who chose
blockade. Whether the addition of an antiandrogen is necessary requires ADT can receive LHRH agonist, LHRH antagonist, or orchiectomy.
further study. ADT for pN1 Disease
• The largest randomized trial to date using the antiandrogen bicalutamide • In one randomized trial, immediate and continuous use of ADT in patients
alone at high dose (150 mg) showed a delay in recurrence of disease but with positive nodes following RP resulted in significantly improved overall
no improvement in survival; however, longer follow-up is needed. survival compared to patients who received delayed ADT. Therefore,
• Abiraterone can be added to EBRT and 2 years of ADT in patients with such patients should be considered for immediate LHRH agonist, LHRH
very-high-risk prostate cancer. In the STAMPEDE trial, the hazard ratios for antagonist, or orchiectomy. EBRT may be added (category 2B), in which
OS with the addition of abiraterone to EBRT and ADT in patients with node- case the ADT options are as for neoadjuvant, concurrent, and/or adjuvant
negative disease was 0.69 (95% CI, 0.49–0.96). ADT for clinically localized disease (see above). Many of the side effects of
ADT for Regional (N1,M0) Disease continuous ADT are cumulative over time on ADT.
• Patients with N1,M0 prostate cancer and a life expectancy >5 years can be ADT for M0 PSA Persistence/Recurrence After RP or EBRT (ADT for M0
treated with: Castration-Naïve Disease)
EBRT and neoadjuvant, concurrent, and/or adjuvant ADT as for patients • The timing of ADT for patients whose only evidence of cancer after
with N0,M0 disease (see above) without abiraterone definitive treatment is an increasing PSA is influenced by PSA velocity,
EBRT and neoadjuvant, concurrent, and/or adjuvant LHRH agonist or patient anxiety, the short- and long-term side effects of ADT, and the

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-H
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underlying comorbidities of the patient. ADT for Metastatic Castration-Naïve Disease
• Most patients will have a good 15-year prognosis, but their prognosis is • ADT with treatment intensification is preferred for most patients with
best approximated by the absolute level of PSA, the rate of change in the metastatic prostate cancer. ADT alone is appropriate for some patients.
PSA level (PSADT), and the initial stage, grade, and PSA level at the time of • Treatment options for patients with M1 castration-naïve disease are:
definitive therapy. ADT alone (orchiectomy, LHRH agonist, LHRH agonist plus first
• Earlier ADT may be better than delayed ADT, although the definitions of generation antiandrogen, or LHRH antagonist)
early and late (what level of PSA) are controversial. Since the benefit of ◊ A first-generation antiandrogen must be given with LHRH agonist
early ADT is not clear, treatment should be individualized until definitive for ≥7 days to prevent testosterone flare if metastases are present in
studies are done. Patients with a shorter PSADT (or a rapid PSA velocity) weight-bearing bone)
and an otherwise long life expectancy should be encouraged to consider Orchiectomy plus docetaxel
ADT earlier. LHRH agonist alone plus docetaxel
• Some patients are candidates for salvage therapy after PSA persistence/ ◊ Goserelin, histrelin, leuprolide, or triptorelin
recurrence. See PROS-10 and PROS-11. ◊ A first-generation antiandrogen must be given with LHRH agonist
• Patients with prolonged PSADTs (>12 months) and who are older are for ≥7 days to prevent testosterone flare if metastases are present in
candidates for observation. weight-bearing bone)
• Patients who choose ADT should consider intermittent ADT. A phase 3 trial LHRH agonist (as above) plus first-generation antiandrogen plus
that compared intermittent to continuous ADT showed that intermittent docetaxel
ADT was not inferior to continuous ADT with respect to survival, and ◊ Nilutamide, flutamide, or bicalutamide
quality of life was better for the intermittent ADT arm. The 7% increase in Degarelix plus docetaxel
prostate cancer deaths in the intermittent ADT arm was balanced by more Orchiectomy plus abiraterone, enzalutamide, or apalutamide
non-prostate cancer deaths in the continuous ADT arm. An unplanned LHRH agonist (as above) plus abiraterone, enzalutamide, or apalutamide
subset analysis showed that patients with Grade Group 4 or 5 prostate Degarelix plus abiraterone, enzalutamide, or apalutamide
cancer in the continuous arm had a median overall survival that was 14 • Abiraterone should be given with concurrent steroid [see ADT for Regional
months longer (8 years) than those in the intermittent arm (6.8 years). (N1,M0) Disease].
• ADT options are:
• When EBRT to primary is given with ADT in low-volume M1, the options are
M0 RP PSA Persistence/Recurrence:
LHRH agonist, LHRH antagonist, and orchiectomy.
◊ EBRT +/- neoadjuvant, concurrent, and/or adjuvant ADT [See ADT for
• Two randomized phase 3 clinical trials of abiraterone with prednisone
Clinically Localized (N0,M0) Disease]
plus ADT in patients with castration-naïve metastatic prostate cancer
M0 EBRT PSA Recurrence, TRUS-biopsy negative or M0 PSA Recurrence
demonstrated improved overall survival over ADT alone. Adverse
after progression on salvage EBRT:
events were higher with abiraterone and prednisone but were generally
◊ Orchiectomy
mild in nature and were largely related to mineralocorticoid excess (ie,
◊ LHRH agonist alone
hypertension, hypokalemia, edema), hormonal effects (ie, fatigue, hot
– Goserelin, histrelin, leuprolide, or triptorelin
flushes), and liver toxicity. Cardiac events, severe hypertension, and liver
◊ LHRH agonist (as above) plus first-generation antiandrogen
toxicity were increased with abiraterone.
– Nilutamide, flutamide, or bicalutamide
• A double-blind randomized phase 3 clinical trial of apalutamide plus ADT
◊ LHRH antagonist
in patients with castration-naïve metastatic prostate cancer demonstrated
– Degarelix, relugolix

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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improved overall survival over ADT alone. Adverse events that were ◊ Fine-particle abiraterone + methylprednisolone (for M1 only)
more common with apalutamide than with placebo included rash, Other secondary hormone therapy (for M0 or M1)
hypothyroidism, and ischemic heart disease. ◊ First-generation antiandrogen (nilutamide, flutamide, or bicalutamide)
• An open-label randomized phase 3 clinical trial of enzalutamide plus ADT ◊ Corticosteroids (hydrocortisone, prednisone, or dexamethasone)
in patients with castration-naïve metastatic prostate cancer demonstrated ◊ Antiandrogen withdrawal
improved overall survival over ADT alone. In a separate double-blind ◊ Ketoconazole plus hydrocortisone
randomized phase 3 clinical trial, enzalutamide reduced the risk of • Abiraterone should be given with concurrent steroid, either prednisone 5
metastatic progression or death compared with placebo. Adverse events mg orally twice daily for the standard formulation or methylprednisolone 4
associated with enzalutamide included fatigue, seizures, and hypertension. mg orally twice daily for the fine-particle formulation.
• A phase 3 trial compared continuous ADT to intermittent ADT, but the • A phase 3 study of patients with M0 CRPC and a PSADT ≤10 months
study could not demonstrate non-inferiority for survival. However, quality- showed apalutamide (240 mg/day) improved the primary endpoint of
of-life measures for erectile function and mental health were better in the metastasis-free survival over placebo (40.5 months vs. 16.2 months). After
intermittent ADT arm after 3 months of ADT compared to the continuous a median follow-up of 52 months, final overall survival analysis showed an
ADT arm. improved median overall survival with apalutamide versus placebo (73.9
• In addition, three meta-analyses of randomized controlled trials failed to months vs. 59.9 months). Adverse events included rash (24% vs. 5.5%),
show a difference in survival between intermittent and continuous ADT. fracture (11% vs. 6.5%), and hypothyroidism (8% vs. 2%). Bone support
• Close monitoring of PSA and testosterone levels and possibly imaging should be used in patients receiving apalutamide.
is required when using intermittent ADT, especially during off-treatment • A phase 3 study of patients with M0 CRPC and a PSADT ≤10 months
periods, and patients may need to switch to continuous ADT upon signs of showed enzalutamide (160 mg/day) improved the primary endpoint of
disease progression. metastasis-free survival over placebo (36.6 months vs. 14.7 months).
Secondary Hormone Therapy for M0 or M1 CRPC Median overall survival was longer in the enzalutamide group than in the
• Androgen receptor activation and autocrine/paracrine androgen synthesis placebo group (67.0 months vs. 56.3 months). Adverse events included
are potential mechanisms of recurrence of prostate cancer during ADT falls and nonpathologic fractures (17% vs. 8%), hypertension (12% vs. 5%),
(CRPC). Thus, castrate levels of testosterone (<50 ng/dL) should be major adverse cardiovascular events (5% vs. 3%), and mental impairment
maintained by continuing LHRH agonist or degarelix while additional disorders (5% vs. 2%). Bone support should be used in patients receiving
therapies are applied. enzalutamide.
• Once the tumor becomes resistant to initial ADT, there are a variety of • A phase 3 study of patients with M0 CRPC and a PSADT ≤10 months
options that may afford clinical benefit. The available options are based on showed darolutamide (600 mg twice daily) improved the primary endpoint
whether the patient has evidence of metastases by conventional imaging, of metastasis-free survival over placebo (40.4 months vs. 18.4 months).
M0 CRPC vs. M1 CRPC, and whether or not the patient is symptomatic. Overall survival at 3 years was 83% (95% CI, 80–86) in the darolutamide
• Administration of secondary hormonal therapy can include: group compared with 77% (95% CI, 72–81) in the placebo group. Adverse
Second-generation antiandrogen events that occurred more frequently in the treatment arm included fatigue
◊ Apalutamide (for M0 and PSADT ≤10 months) (12.1% vs. 8.7%), pain in an extremity (5.8% vs. 3.2%), and rash (2.9% vs.
◊ Darolutamide (for M0 and PSADT ≤10 months) 0.9%). The incidence of fractures was similar between darolutamide and
◊ Enzalutamide (for M0 and PSADT ≤10 months or M1) placebo (4.2% vs. 3.6%).
Androgen metabolism inhibitor • In a randomized controlled trial in the setting of M1 CRPC prior to
◊ Abiraterone + prednisone (for M1 only) docetaxel chemotherapy, abiraterone, and low-dose prednisone (5 mg

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF ANDROGEN DEPRIVATION THERAPY

BID) compared to prednisone alone improved radiographic progression- ADT for Patients on Observation Who Require Treatment and Those with
free survival (rPFS), time to initiation of chemotherapy, time to onset or Life Expectancy ≤5 Years
worsening of pain, and time to deterioration of performance status. An • Treatment for patients who progressed on observation of localized disease
improvement in overall survival was demonstrated. Use of abiraterone is LHRH agonist or antagonist or orchiectomy.
and prednisone in this setting is a category 1 recommendation. The Optimal ADT
side effects of abiraterone that require ongoing monitoring include • Medical castration (ie, LHRH agonist or antagonist) and surgical castration
hypertension, hypokalemia, peripheral edema, atrial fibrillation, congestive (ie, bilateral orchiectomy) are equally effective.
heart failure, liver injury, and fatigue, as well as the known side effects of • Combined androgen blockade (medical or surgical castration combined
ADT and long-term corticosteroid use. with an antiandrogen) provides modest to no benefit over castration alone
• A phase 3 study of docetaxel-naïve patients with M1 CRPC showed that in patients with metastatic disease.
enzalutamide (160 mg daily) resulted in significant improvement in rPFS • Antiandrogen therapy should precede or be coadministered with LHRH
and overall survival. The use of enzalutamide in this setting is category 1. agonist and be continued in combination for at least 7 days for patients
The side effects of enzalutamide that require long-term monitoring include with overt metastases who are at risk of developing symptoms associated
fatigue, diarrhea, hot flashes, headache, and seizures (reported in 0.9% of with the flare in testosterone with initial LHRH agonist alone.
patients on enzalutamide). • Antiandrogen monotherapy appears to be less effective than medical or
• For symptomatic patients with M1 CRPC, all secondary hormone options surgical castration and is not recommended.
listed above are allowed, but initial use of docetaxel may be preferred. • No clinical data support the use of finasteride or dutasteride with combined
Both randomized trials of abiraterone and enzalutamide in the pre- androgen blockade.
docetaxel setting were conducted in patients who had no or minimal • Patients who do not achieve adequate suppression of serum testosterone
symptoms due to M1 CRPC. How these agents compare to docetaxel (<50 ng/dL) with medical or surgical castration can be considered
for pain palliation in this population of patients is not clear. Both drugs for additional hormonal manipulations (with antiandrogens, LHRH
have palliative effects in the post-docetaxel setting. Both abiraterone and antagonists, or steroids), although the clinical benefit remains uncertain.
enzalutamide are approved in this pre-docetaxel setting and have category Consider monitoring testosterone levels 12 weeks after first dose of
1 recommendations. Both drugs are suitable options for patients who are LHRH therapy, then upon increase in PSA. The optimal level of serum
not good candidates to receive docetaxel. testosterone to effect “castration” has yet to be determined.
• In the post-docetaxel M1 CRPC population, enzalutamide and abiraterone • Relugolix has not been adequately studied in combination with potent
plus prednisone have been shown to extend survival in randomized androgen receptor inhibitors such as enzalutamide, apalutamide,
controlled trials. Therefore, each agent has a category 1 recommendation. darolutamide, or abiraterone acetate, nor has it been studied in
• Two randomized clinical trials (STRIVE and TERRAIN) showed that 160 mg/ combination with docetaxel or cabazitaxel chemotherapy. Potential drug
day enzalutamide improved PFS compared to 50 mg/day bicalutamide in interactions include induction of cytochrome P450 enzymes and reduced
patients with treatment-naïve M1 CRPC and, therefore, enzalutamide may concentration and efficacy of relugolix with enzalutamide or apalutamide
be the preferred option in this setting. However, bicalutamide can still be and cardiac QTc interactions with abiraterone. Further studies of relugolix
considered in some patients, given the different side effect profiles of the dosing and drug interactions with commonly used agents in advanced
agents and the increased cost of enzalutamide. prostate cancer are needed to ensure patient safety and proper dosing.
• Evidence-based guidance on the sequencing of agents in either pre- or • Data are limited on long-term compliance of oral relugolix and the potential
post-docetaxel remains limited. effects on optimal ADT. Ongoing monitoring for sustained suppression
of testosterone (< 50ng/dL) can be considered, and relugolix may not be a

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF ANDROGEN DEPRIVATION THERAPY

preferred agent if patient compliance is uncertain. daily dietary intake of vitamin D will assist the nutritionist in making a
patient-specific recommendation for vitamin D supplementation. There are
Monitor/Surveillance
currently no guidelines on how often to monitor vitamin D levels. However,
• ADT has a variety of adverse effects, including hot flashes, loss of libido,
for those who require monitoring with DEXA scans, it makes sense to
erectile dysfunction, shrinkage of penis and testicles, loss of muscle
check the serum vitamin D level at the same time.
mass and strength, fatigue, anemia, breast enlargement and tenderness/
• Denosumab (60 mg SQ every 6 months), zoledronic acid (5 mg IV annually),
soreness, depression and mood swings, hair loss, osteoporosis, greater
and alendronate (70 mg PO weekly) increase bone mineral density, a
incidence of clinical fractures, obesity, insulin resistance, alterations
surrogate for fracture risk, during ADT for prostate cancer. Treatment
in lipids, and greater risk for diabetes and cardiovascular disease. The
with either denosumab, zoledronic acid, or alendronate sodium is
intensity and spectrum of these side effects vary greatly, and many are
recommended when the absolute fracture risk warrants drug therapy.
reversible or can be avoided or mitigated. For example, physical activity
• Screening for and intervention to prevent/treat diabetes and cardiovascular
can counter many of these symptoms and should be recommended
disease are recommended in patients receiving ADT. These medical
(see NCCN Guidelines for Survivorship). Use of statins also should be
conditions are common in older individuals and it remains uncertain
considered. Patients and their medical providers should be advised about
whether strategies for screening, prevention, and treatment of diabetes
these risks prior to treatment.
and cardiovascular disease in patients receiving ADT should differ from the
• Screening and treatment for osteoporosis are advised according to
general population.
guidelines for the general population from the National Osteoporosis
Foundation (www.nof.org). The National Osteoporosis Foundation guidelines
include recommendations for: 1) calcium (1000–1200 mg daily from food
and supplements) and vitamin D3 (400–1000 IU daily); and 2) additional
treatment for men aged ≥50 years with low bone mass (T-score between
-1.0 and -2.5, osteopenia) at the femoral neck, total hip, or lumbar spine by
dual-energy x-ray absorptiometry (DEXA) scan and a 10-year probability of
hip fracture ≥3% or a 10-year probability of a major osteoporosis-related
fracture ≥20%. Fracture risk can be assessed using FRAX®, the algorithm
released by WHO. ADT should be considered “secondary osteoporosis”
when using the FRAX® algorithm. Treatment options to increase bone
density, a surrogate for fracture risk in patients without metastases,
include denosumab (60 mg SQ every 6 months), zoledronic acid (5 mg IV
annually), and alendronate (70 mg PO weekly).
• A baseline DEXA scan should be obtained before starting therapy in
patients at increased risk for fracture based on FRAX® screening. A follow-
up DEXA scan after 1 year of therapy is recommended by the International
Society for Clinical Densitometry, although there is no consensus on the
optimal approach to monitoring the effectiveness of drug therapy. Use of
biochemical markers of bone turnover to monitor response to therapy is
not recommended. The serum level of 25-hydroxy vitamin D and average

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF NON-HORMONAL SYSTEMIC THERAPY

Non-Hormonal Systemic Therapy for Very-High-Risk Prostate Cancer chemotherapy treatment based on phase 3 clinical trial data for patients
• Docetaxel can be added to EBRT and 2 years of ADT in patients with very- with symptomatic mCRPC. Radium-223 has been studied in symptomatic
high-risk prostate cancer. In the STAMPEDE trial, the hazard ratio for OS patients who are not candidates for docetaxel-based regimens and resulted
in 96 randomized patients with nonmetastatic disease was 0.93 (95% CI, in improved overall survival. Abiraterone and enzalutamide have been
0.60–1.43) with the addition of docetaxel to EBRT and ADT. shown to extend survival in patients who progressed on docetaxel. (See
PROS-H). Mitoxantrone with prednisone may provide palliation but has not
Non-Hormonal Systemic Therapy for M1 Castration-Naïve Prostate Cancer been shown to extend survival.
• Patients with high-volume, ADT-naïve, metastatic disease should be • Only regimens utilizing docetaxel on an every-3-week schedule
considered for ADT (See PROS-H) and docetaxel based on the results of the demonstrated beneficial impact on survival. The duration of therapy should
ECOG 3805 (CHAARTED) trial. In this study, 790 patients were randomized be based on the assessment of benefit and toxicities. In the pivotal trials
to 6 cycles of docetaxel at 75 mg/m2 every 3 weeks with dexamethasone establishing survival advantage of docetaxel-based chemotherapy, patients
with ADT vs. ADT alone. In the majority subset of patients with high-volume received up to 10 cycles of treatment if no progression and no prohibitive
disease, defined as 4 or more bone metastases including one extra-axial toxicities were noted.
bone lesion or visceral metastases, a 17-month improvement in overall • Patients who are not candidates for docetaxel or who are intolerant of
docetaxel should be considered for cabazitaxel with concurrent steroid,
survival was observed (HR, 0.60; P = .0006). Improvements in PSA response,
based on recent results that suggest clinical activity of cabazitaxel
time to clinical progression, and time to recurrence were observed with in mCRPC. Cabazitaxel was associated with lower rates of peripheral
use of docetaxel. Toxicities of 6 cycles of docetaxel included fatigue, neuropathy than docetaxel, particularly at 20 mg/m2 (12% vs. 25%) and may
neuropathy, stomatitis, diarrhea, and neutropenia with or without fever. be appropriate in patients with pre-existing mild peripheral neuropathy.
The use of myeloid growth factors should follow the NCCN Guidelines Current data do not support greater efficacy of cabazitaxel over docetaxel.
for Hematopoietic Growth Factors, based on risk of neutropenic fever. • Increasing PSA should not be used as the sole criteria for progression.
Docetaxel should not be offered to patients with low-volume metastatic Assessment of response should incorporate clinical and radiographic
prostate cancer, since this subgroup was not shown to have improved criteria.
survival in either the ECOG study or a similar European (GETUG-AFU 15) • Cabazitaxel at 25 mg/m² with concurrent steroid has been shown in a
trial. randomized phase 3 study (TROPIC) to prolong overall survival, PFS, and
PSA and radiologic responses when compared with mitoxantrone with
Non-Hormonal Systemic Therapy for M1 CRPC prednisone and is FDA approved in the post-docetaxel second-line setting.
Chemotherapy Toxicity at this dose was significant and included febrile neutropenia,
• Docetaxel with concurrent steroid severe diarrhea, fatigue, nausea/vomiting, anemia, thrombocytopenia,
Concurrent steroids may include: dexamethasone on the day of sepsis, and renal failure. A recent trial, PROSELICA, compared cabazitaxel
chemotherapy or daily prednisone. 25 mg/m² every 3 weeks to 20 mg/m² every 3 weeks. Cabazitaxel 20 mg/
• Cabazitaxel with concurrent steroid m² had less toxicity; febrile neutropenia, diarrhea, and fatigue were
Concurrent steroids may include: dexamethasone on the day of less frequent. Cabazitaxel at 20 mg/m² had a significantly lower PSA
chemotherapy or daily prednisone. response rate but nonsignificantly lower radiographic response rate and
• Cabazitaxel/carboplatin with concurrent prednisone twice daily non-significantly shorter PFS and overall survival (13.4 months vs. 14.5
Concurrent steroids may include: dexamethasone on the day of months) compared to 25 mg/m². Cabazitaxel starting dose can be either 20
chemotherapy or daily prednisone. mg/m² or 25 mg/m² for patients with mCRPC who have progressed despite
• Mitoxantrone with prednisone prior docetaxel chemotherapy. Cabazitaxel 25 mg/m² with concurrent
• Every-3-week docetaxel with concurrent steroid is the preferred first-line steroid may be considered for healthy patients who wish to be more

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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aggressive. Growth factor support may be needed with either dose. Sipuleucel-T is only for asymptomatic or minimally symptomatic,
• Cabazitaxel at 25 mg/m2 with concurrent steroid improved radiographic PFS patients with no liver metastases, life expectancy >6 months, ECOG
and reduced the risk of death compared with abiraterone or enzalutamide in performance status 0–1.
patients with prior docetaxel treatment for mCRPC in the CARD study. Sipuleucel-T is not recommended for patients with small cell/NEPC.
• Cabazitaxel 20 mg/m² plus carboplatin AUC 4 mg/mL per minute with growth Sipuleucel-T has been shown in a phase 3 clinical trial to extend mean
factor support can be considered for fit patients with aggressive variant survival from 21.7 months in the control arm to 25.8 months in the
prostate cancer (ie, visceral metastases, low PSA and bulky disease, high treatment arm, which constitutes a 22% reduction in mortality risk.
LDH, high carcinoembryonic antigen [CEA], lytic bone metastases, NEPC Sipuleucel-T is well tolerated; common complications include chills,
histology) or unfavorable genomics (defects in at least 2 of PTEN, TP53, and pyrexia, and headache.
RB1). Corn PG, et al. Lancet Oncol 2019;20:1432-1443. • Pembrolizumab (for MSI-H, dMMR, or TMB ≥ 10 mut/Mb)
• Docetaxel retreatment can be attempted after progression on a novel Pembrolizumab is recommended only as subsequent systemic therapy
hormone therapy in patients with metastatic CRPC who have not for patients with metastatic CRPC who have progressed through prior
demonstrated definitive evidence of progression on prior docetaxel therapy
docetaxel and/or a novel hormone therapy.
in the castration-naïve setting.
• No chemotherapy regimen to date has demonstrated improved survival or Prevention of Skeletal-Related Events
quality of life after cabazitaxel, and trial participation should be encouraged. • In patients with CRPC who have bone metastases, denosumab and
• Treatment decisions around off-label chemotherapy use in the treatment- zoledronic acid have been shown to prevent disease-related skeletal
refractory CRPC should be individualized based on comorbidities and complications, which include fracture, spinal cord compression, or the
functional status and after informed consent. need for surgery or RT to bone.
• No benefits of combination approaches over sequential single-agent • When compared to zoledronic acid, denosumab was shown to be
therapies have been demonstrated, and toxicity is higher with combination superior in prevention of skeletal-related events.
regimens. See NCCN Guidelines for Hematopoietic Growth Factors for • A phase 3 clinical trial that assessed a role for zoledronic acid in patients
recommendations on growth factor support. beginning ADT for bone metastases was negative.
• Choice of agent may depend on underlying comorbidities, whether the
Targeted Therapy
patient has been treated with zoledronic acid previously, logistics, and/or
• Consider inclusion of olaparib in patients who have an HHR mutation and
cost considerations.
have progressed on prior treatment with androgen receptor-directed therapy
Denosumab (preferred) is given subcutaneously every 4 weeks.
regardless of prior docetaxel therapy.
Although renal monitoring is not required, denosumab is not
• Consider inclusion of rucaparib for patients with mCRPC and a pathogenic
recommended in patients with creatinine clearance <30 mL/min. When
BRCA1 or BRCA2 mutation (germline and/or somatic) who have been treated
creatinine clearance is <60 mL/min, the risk for severe hypocalcemia
with androgen receptor-directed therapy and a taxane-based chemotherapy.
increases. Even in patients with normal renal function, hypocalcemia
If the patient is not fit for chemotherapy, rucaparib can be considered even if
is seen twice as often with denosumab than zoledronic acid and all
taxane-based therapy has not been given.
patients on denosumab should be treated with vitamin D and calcium
Immunotherapy
• Patients with asymptomatic or minimally symptomatic mCRPC may consider
immunotherapy.
• Sipuleucel-T

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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with periodic monitoring of serum calcium levels.
Zoledronic acid is given intravenously every 3 to 4 weeks or
every 12 weeks. The dose is based on the serum creatinine
obtained just prior to each dose and must be adjusted for
impaired renal function. Zoledronic acid is not recommended for
creatinine clearance <30 mL/min.
• Osteonecrosis of the jaw (ONJ) is seen with both agents; risk is
increased in patients who have tooth extractions, poor dental
hygiene, or a dental appliance. Patients should be referred
for dental evaluation before starting either zoledronic acid or
denosumab. If invasive dental procedures are required, bone-
targeted therapy should be withheld until the dentist indicates that
the patient has healed completely from all dental procedure(s).
• The optimal duration of therapy for either denosumab or
zoledronic acid remains uncertain.
• The toxicity profile of denosumab when denosumab is used in
patients who have been treated with zoledronic acid remains
uncertain.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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American Joint Committee on Cancer (AJCC)

TNM Staging System For Prostate Cancer (8th ed., 2017)
Pathological T (pT)
Table 1. Definitions for T, N, M
Clinical T (cT) T Primary Tumor
T Primary Tumor T2 Organ confined
TX Primary tumor cannot be assessed T3 Extraprostatic extension
T0 No evidence of primary tumor T3a Extraprostatic extension (unilateral or bilateral) or microscopic
T1 Clinically inapparent tumor that is not palpable invasion of bladder neck
T1a Tumor incidental histologic finding in 5% or less of T3b Tumor invades seminal vesicle(s)
tissue resected T4 Tumor is fixed or invades adjacent structures other than seminal
T1b Tumor incidental histologic finding in more than 5% vesicles such as external sphincter, rectum, bladder, levator
of tissue resected muscles, and/or pelvic wall
Note: There is no pathological T1 classification.
T1c Tumor identified by needle biopsy found in one or both sides, 
Note: Positive surgical margin should be indicated by an R1 descriptor, indicating
but not palpable residual microscopic disease.
T2 Tumor is palpable and confined within prostate
T2a Tumor involves one-half of one side or less N Regional Lymph Nodes
T2b Tumor involves more than one-half of one side but NX Regional lymph nodes cannot be assessed
not both sides N0 No positive regional nodes
T2c Tumor involves both sides N1 Metastases in regional node(s)
T3 Extraprostatic tumor that is not fixed or does not invade
adjacent structures M Distant Metastasis
T3a Extraprostatic extension (unilateral or bilateral) M0 No distant metastasis
T3b Tumor invades seminal vesicle(s) M1 Distant metastasis
T4 Tumor is fixed or invades adjacent structures other M1a Nonregional lymph node(s)
than seminal vesicles such as external sphincter, rectum, M1b Bone(s)
bladder, levator muscles, and/or pelvic wall.
M1c Other site(s) with or without bone disease

Note: When more than one site of metastasis is present, the most advanced category
is used. M1c is most advanced.

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.

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Table 2. AJCC Prognostic Groups

Group T N M PSA (ng/mL) Grade Group Histopathologic Type
Stage I cT1a-c N0 M0 PSA <10 1 This classification applies to adenocarcinomas and squamous carcinomas,
cT2a N0 M0 PSA <10 1 but not to sarcoma or transitional cell (urothelial) carcinoma of the prostate.
Adjectives used to describe histologic variants of adenocarcinomas of
pT2 N0 M0 PSA <10 1 prostate include mucinous, signet ring cell, ductal, and neuroendocrine,
Stage IIA cT1a-c N0 M0 PSA ≥10 <20 1 including small cell carcinoma. There should be histologic confirmation of the
cT2a N0 M0 PSA ≥10 <20 1 disease.
pT2 N0 M0 PSA ≥10 <20 1 Definition of Histologic Grade Group (G)
cT2b N0 M0 PSA <20 1 Recently, the Gleason system has been compressed into so-called Grade
cT2c N0 M0 PSA <20 1 Groups.
Stage IIB T1-2 N0 M0 PSA <20 2
Grade Group Gleason Score Gleason Pattern
Stage IIC T1-2 N0 M0 PSA <20 3
1 ≤6 ≤3+3
T1-2 N0 M0 PSA <20 4
2 7 3+4
Stage IIIA T1-2 N0 M0 PSA ≥20 1-4
3 7 4+3
Stage IIIB T3-4 N0 M0 Any PSA 1-4
4 8 4+4, 3+5, 5+3
Stage IIIC Any T N0 M0 Any PSA 5
5 9 or 10 4+5, 5+4, 5+5
Stage IVA Any T N1 M0 Any PSA Any
Stage IVB Any T Any N M1 Any PSA Any
Note: W
 hen either PSA or Grade Group is not available, grouping should be
determined by T category and/or either PSA or Grade Group as available.

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.

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Table of Contents
Prostate Cancer Discussion

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

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Discussion This discussion corresponds to the NCCN Guidelines for Prostate Cancer. Last updated: November 17, 2020.

Table of Contents
Overview ...................................................................................................... MS-2 Workup for Progression .......................................................................... MS-33
Literature Search Criteria and Guidelines Update Methodology .................. MS-2 Post-Radical Prostatectomy Treatment ...................................................... MS-34
Initial Prostate Cancer Diagnosis ................................................................. MS-2 Adjuvant/Early Salvage Therapy for Adverse Features .......................... MS-34
Estimates of Life Expectancy ....................................................................... MS-3 Adjuvant Therapy for pN1 ....................................................................... MS-35
Prostate Cancer Genetics ............................................................................ MS-3 Biochemical Recurrence After Radical Prostatectomy ............................ MS-35
Homologous DNA Repair Genes ............................................................. MS-4 Post-Irradiation Recurrence........................................................................ MS-36
DNA Mismatch Repair Genes .................................................................. MS-4 Androgen Deprivation Therapy ................................................................... MS-37
Effect of Intraductal/Cribriform or Ductal Histology .................................. MS-5 ADT for Clinically Localized (N0M0) Disease ......................................... MS-38
Genetic Testing Recommendations ......................................................... MS-5 ADT for Regional Disease ...................................................................... MS-39
Risk Stratification for Clinically Localized Disease ....................................... MS-7 Palliative ADT ......................................................................................... MS-40
Nomograms ............................................................................................. MS-8 ADT for Castration-Naive Disease .......................................................... MS-40
Tumor Multigene Molecular Testing ......................................................... MS-9 Intermittent Versus Continuous ADT ...................................................... MS-45
Initial Clinical Assessment and Staging Evaluation .................................... MS-10 Adverse Effects of Traditional ADT ......................................................... MS-46
Imaging Techniques .................................................................................. MS-11 Progression to and Management of CRPC ................................................. MS-48
Multiparametric MRI ............................................................................... MS-11 Secondary Hormone Therapy for CRPC .................................................... MS-49
Nuclear Imaging ..................................................................................... MS-11 Abiraterone Acetate in M1 CRPC ........................................................... MS-50
Risks of Imaging .................................................................................... MS-12 Enzalutamide in M0 and M1 CRPC ........................................................ MS-51
Observation ............................................................................................... MS-14 Apalutamide in M0 CRPC ....................................................................... MS-52
Active Surveillance .................................................................................... MS-14 Darolutamide in M0 CRPC ..................................................................... MS-53
Rationale................................................................................................ MS-15 Other Secondary Hormone Therapies .................................................... MS-53
Patient Selection .................................................................................... MS-16 Chemotherapy, Immunotherapy, and Targeted Therapy ............................ MS-54
Confirmatory Testing .............................................................................. MS-18 Docetaxel ............................................................................................... MS-54
Active Surveillance Program .................................................................. MS-18 Cabazitaxel............................................................................................. MS-55
Reclassification Criteria ......................................................................... MS-19 Sipuleucel-T ........................................................................................... MS-57
Radical Prostatectomy ............................................................................... MS-20 Pembrolizumab ...................................................................................... MS-57
Operative Techniques and Adverse Effects ........................................... MS-21 Mitoxantrone ........................................................................................... MS-58
Pelvic Lymph Node Dissection ............................................................... MS-21 Treatment Options for Patients with DNA Repair Gene Mutations .......... MS-58
Radiation Therapy ..................................................................................... MS-22 Small Cell/Neuroendocrine Prostate Cancer .............................................. MS-60
External Beam Radiation Therapy ......................................................... MS-22 Bone Metastases ........................................................................................ MS-61
Stereotactic Body Radiation Therapy ..................................................... MS-25 Visceral Metastases ................................................................................... MS-62
Brachytherapy ........................................................................................ MS-26 Sequencing of Therapy in CRPC................................................................ MS-62
Proton Therapy ...................................................................................... MS-28 AR-V7 Testing ........................................................................................ MS-63
Radiation for Distant Metastases ........................................................... MS-30 Summary .................................................................................................... MS-64
Comparison of Treatment Options for Localized Disease .......................... MS-31 Table 1. Available Tissue-Based Tests for Prostate Cancer Risk
Other Local Therapies ............................................................................... MS-32 Stratification/Prognosis ............................................................................... MS-65
Disease Monitoring .................................................................................... MS-33 Table 2. Summary of Main PET Imaging Tracers Studied in Prostate Cancer *
Patients After Initial Definitive Therapy .................................................. MS-33 ................................................................................................................... MS-66
Patients with Castration-Naïve Disease on ADT .................................... MS-33 Table 3. Selected Active Surveillance Experiences in North America ........ MS-67
Patients with Localized Disease Under Observation .............................. MS-33 References ................................................................................................. MS-68

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Overview detection of potentially fatal prostate cancer (see the NCCN Guidelines for
An estimated 191,930 new cases of prostate cancer will be diagnosed in Prostate Cancer Early Detection, available at www.NCCN.org) should
the United States in 2020, accounting for over 21% of new cancer cases in decrease the risk of overdetection and overtreatment AND preserve the
men.1 The age-adjusted death rate from prostate cancer declined by 52% decrease in prostate cancer mortality.
from 1993 to 2017, but the death rate has become stable in recent years.1
Literature Search Criteria and Guidelines Update
Researchers estimate that prostate cancer will account for 10.4% of male
Methodology
cancer deaths in the United States in 2020, with an estimated 33,330
deaths. Over the past several years, the incidence of prostate cancer has Prior to the update of the NCCN Guidelines for Prostate Cancer, an
declined, likely in part as a result of decreased detection attributed to electronic search of the PubMed database was performed to obtain key
decreased rates of prostate-specific antigen (PSA) screening.2-4 The literature in prostate cancer published since the previous Guidelines
comparatively low death rate suggests that increased public awareness update, using the search term “prostate cancer.” The PubMed database
with earlier detection and treatment has affected mortality from this was chosen because it remains the most widely used resource for medical
prevalent cancer. literature and indexes peer-reviewed biomedical literature.21

Early detection can lead to overtreatment of prostate cancers that do not The search results were narrowed by selecting studies in humans
threaten life expectancy, which results in unnecessary side effects that published in English. Results were confined to the following article types:
impair quality of life (QOL) and increase health care expenditures. The Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized
U.S. Preventive Services Task Force (USPSTF) recommended against Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation
PSA testing in 2012.5 The incidence of metastatic disease has Studies.
increased.4,6 The rate of prostate cancer mortality, which had been in
The data from key PubMed articles as well as articles from additional
decline for 2 decades, has stabilized.4 Prostate cancer incidence and
sources deemed as relevant to these guidelines as discussed by the panel
deaths have increased in the past few years for the first time in recent
during the Guidelines update have been included in this version of the
history, with prostate cancer deaths increasing from an estimated 26,730
Discussion section. Recommendations for which high-level evidence is
in 2017 to 31,620 in 2019.7,8 Increases in the incidence of metastases at
lacking are based on the panel’s review of lower-level evidence and expert
presentation and prostate cancer deaths may be influenced by declines in
opinion.
the rates of prostate cancer early detection, biopsies, diagnosis of
localized prostate cancers, and radical prostatectomy that followed the The complete details of the Development and Update of the NCCN
2012 USPSTF recommendations.9-19 The USPSTF released updated Guidelines are available at www.NCCN.org.
recommendations in 2018 that include individualized, informed decision-
making regarding prostate cancer screening in men aged 55 to 69 years.20 Initial Prostate Cancer Diagnosis
These updated recommendations may allow for a more balanced Initial suspicion of prostate cancer is based on an abnormal digital rectal
approach to prostate cancer early detection. Better use of PSA for early exam (DRE) or an elevated PSA level. A separate NCCN Guidelines

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Prostate Cancer

Panel has written guidelines for prostate cancer early detection (see the lower quartile of health, a life expectancy of 8.8 years is assigned. Thus,
NCCN Guidelines for Prostate Early Detection, available at treatment recommendations could change dramatically using the NCCN
www.NCCN.org). Definitive diagnosis requires biopsies of the prostate, Guidelines if a 65-year-old man was judged to be in either poor or
usually performed by a urologist using a needle under transrectal excellent health.
ultrasound (TRUS) guidance. A pathologist assigns a Gleason primary
and secondary grade to the biopsy specimen. Clinical staging is based on Prostate Cancer Genetics
the TNM (tumor, node, metastasis) classification from the AJCC Staging Family history of prostate cancer raises the risk of prostate cancer.28-31 In
Manual, Eighth Edition.22 NCCN treatment recommendations are based on addition, prostate cancer has been associated with hereditary breast and
risk stratification that includes TNM staging rather than on AJCC ovarian cancer (HBOC) syndrome (due to germline mutations in
prognostic grouping. homologous DNA repair genes) and Lynch syndrome (resulting from
germline mutations in DNA mismatch repair genes).31-36 In fact,
Pathology synoptic reports (protocols) are useful for reporting results from approximately 11% of patients with prostate cancer and at least 1
examinations of surgical specimens; these reports assist pathologists in additional primary cancer carry germline mutations associated with
providing clinically useful and relevant information. The NCCN Guidelines increased cancer risk.37 Therefore, the panel recommends a thorough
Panel favors pathology synoptic reports from the College of American review of personal and family history for all patients with prostate
Pathologists (CAP) that comply with the Commission on Cancer (CoC) cancer.38,39
requirements.23
The newfound appreciation of the frequency of germline mutations has
Estimates of Life Expectancy implications for family genetic counseling, cancer risk syndromes, and
Estimates of life expectancy have emerged as a key determinant of assessment of personal risk for subsequent cancers. Some patients with
primary treatment, particularly when considering active surveillance or prostate cancer and their families may be at increased risk for breast and
observation. Life expectancy can be estimated for groups of men, but it is ovarian cancer, melanoma, and pancreatic cancer (HBOC); colorectal
difficult to extrapolate these estimates to an individual patient. Life cancers (Lynch syndrome); and other cancer types. Data also suggest that
expectancy can be estimated using the Minnesota Metropolitan Life patients with prostate cancer who have BRCA1/2 germline mutations have
Insurance Tables, the Social Security Administration Life Insurance increased risk of progression on local therapy and decreased overall
Tables,24 the WHO’s Life Tables by Country,25 or the Memorial Sloan survival (OS).40-42 This information should be discussed with such men if
Kettering Male Life Expectancy tool26 and adjusted for individual patients they are considering active surveillance. Finally, there are possible
by adding or subtracting 50% based on whether one believes the patient is treatment implications for patients with DNA repair defects (see Treatment
in the healthiest quartile or the unhealthiest quartile, respectively.27 As an Options for Patients with DNA Repair Gene Mutations, below).
example, the Social Security Administration Life Expectancy for a 65-year-
old American man is 17.7 years. If judged to be in the upper quartile of Prostate cancer is often associated with somatic mutations that occur in
health, a life expectancy of 26.5 years is assigned. If judged to be in the the tumor but not in the germline. An estimated 89% of metastatic

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castration-resistant prostate cancer (CRPC) tumors contain a potentially the chances of identifying a germline DNA repair gene mutation in men
actionable mutation, with only about 9% of these occurring in the with prostate cancer (OR, 1.89; 95% CI, 1.33–2.68; P = .003).52 In a study
germline.43 Both germline and tumor mutations are discussed herein. of an unselected cohort of 3607 patients with a personal history of prostate
cancer who had germline genetic testing based on clinician referral, 11.5%
Homologous DNA Repair Genes had germline mutations in BRCA2, CHEK2, ATM, BRCA1, or PALB2.53
Somatic mutations in DNA repair pathway genes occur in up to 19% of
localized prostate tumors and 23% of metastatic CRPC tumors, with most More than 2% of Ashkenazi Jews carry germline mutations in BRCA1 or
mutations found in BRCA2 and ATM.43,44 These tumor mutations are often BRCA2, and these carriers have a 16% chance (95% CI, 4%–30%) of
associated with germline mutations. For example, 42% of patients with developing prostate cancer by the age of 70.54 In a study of 251
metastatic CRPC and somatic mutations in BRCA2 were found to carry unselected Ashkenazi Jewish patients with prostate cancer, 5.2% had
the mutation in their germlines.43 In localized prostate cancer, that number germline mutations in BRCA1 and BRCA2, compared with 1.9% of control
was 60%.44 Ashkenazi Jewish men.55

Overall, germline DNA repair mutations have been reported with the Germline BRCA1 or BRCA2 mutations have been associated with an
lowest frequencies seen in men with lower-risk localized prostate cancer increased risk for prostate cancer in numerous reports.35,36,55-65 In
(1.6%–3.8%), higher frequencies in those with higher-risk localized particular, BRCA2 mutations have been associated with a 2- to 6-fold
disease (6%–8.9%), and the highest frequencies in those with metastatic increase in the risk for prostate cancer, whereas the association of BRCA1
disease (7.3%–16.2%).43,45-51 One study found that 11.8% of men with mutations and increased risks for prostate cancer are less
metastatic prostate cancer have germline mutations in 1 of 16 DNA repair consistent.35,36,55,57,59,64,66,67 In addition, limited data suggest that germline
genes: BRCA2 (5.3%), ATM (1.6%), CHEK2 (1.9%), BRCA1 (0.9%), mutations in ATM, PALB2, and CHEK2 increase the risk of prostate
RAD51D (0.4%), PALB2 (0.4%), ATR (0.3%), and NBN, PMS2, GEN1, cancer.68-71 Furthermore, prostate cancer in men with germline BRCA
MSH2, MSH6, RAD51C, MRE11A, BRIP1, or FAM175A.50 mutations appears to occur earlier, has a more aggressive phenotype, and
is associated with significantly reduced survival times than in non-carrier
An additional study showed that 9 of 125 men with high-risk, very-high- patients.41,42,66,72-76
risk, or metastatic prostate cancer (7.2%) had pathogenic germline
mutations in MUTYH (4), ATM (2), BRCA1 (1), BRCA2 (1), and BRIP1 DNA Mismatch Repair Genes
(1).47 In this study, the rate of metastatic disease among those with a Tumor mutations in MLH1, MSH2, MSH6, and PMS2 may result in tumor
mutation identified was high (28.6%, 2 of 7 men). Although having a microsatellite instability (MSI) and deficient mismatch repair (dMMR;
relative with breast cancer was associated with germline mutation detected by immunohistochemistry) and are sometimes associated with
identification (P = .035), only 45.5% of the mutation carriers in the study germline mutations and Lynch syndrome. Patients with Lynch syndrome
had mutations that were concordant with their personal and family history. may have an increased risk for prostate cancer. In particular, studies show
Another study also found that a family history of breast cancer increased

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an increased risk for prostate cancer in older patients with germline MSH2 MMR gene alterations than those with adenocarcinoma histology.85-87 In
mutations.77,78 addition, limited data suggest that germline homologous DNA repair gene
mutations may be more common in prostate tumors of ductal or intraductal
In a study of more than 15,000 patients with cancer treated at Memorial origin88,89 and that intraductal histology is common in germline BRCA2
Sloan Kettering Cancer Center who had their tumor and matched normal mutation carriers with prostate cancer.90 Overall, the panel believes that
DNA sequenced and tumor MSI status assessed, approximately 5% of the data connecting histology and the presence of genomic alterations are
1048 patients with prostate cancer had MSI-high (MSI-H) or MSI- stronger for intraductal than ductal histology at this time. Therefore,
indeterminate tumors, 5.6% of whom were found to have Lynch syndrome patients with presence of intraductal carcinoma on biopsy should have
(0.29% of patients with prostate cancer).32 In another prospective case germline testing as described below.
series, the tumors of 3.1% of 1033 patients with prostate cancer
demonstrated MSI-H/dMMR status, and 21.9% of these patients had Genetic Testing Recommendations
Lynch syndrome (0.68% of the total population).79 In a study of an Germline Testing Based on Family History, Histology, and Risk Groups
unselected cohort of 3607 patients with a personal history of prostate The panel recommends inquiring about family and personal history of
cancer who had germline genetic testing based on clinician referral, 1.7% cancer at time of initial diagnosis. Based on the data discussed above, the
had germline mutations in PMS2, MLH1, MSH2, or MSH6.53 panel recommends germline genetic testing, with or without pre-test
genetic counseling, for patients with prostate cancer and any of the
Effect of Intraductal/Cribriform or Ductal Histology
following.38,39:
Ductal prostate carcinomas are rare, accounting for approximately 1.3% of • A positive family history (see definition in the guidelines above)
prostate carcinomas.80 Intraductal prostate cancer may be more common, • High-risk, very-high-risk, regional, or metastatic prostate cancer,
especially in higher risk groups, and may be associated with a poor regardless of family history
prognosis.81 It is important to note that there is significant overlap in
• Ashkenazi Jewish ancestry
diagnostic criteria and that intraductal, ductal, and invasive cribriform
• Intraductal/cribriform histology
features may coexist in the same biopsy. By definition, intraductal
carcinoma includes cribriform proliferation of malignant cells as long as Germline testing, when performed, should include MLH1, MSH2, MSH6,
they remain confined to a preexisting gland that is surrounded by basal and PMS2 (for Lynch syndrome) and the homologous recombination
cells. These features are seen frequently with an adjacent invasive genes BRCA2, BRCA1, ATM, PALB2, and CHEK2. Cancer predisposition
cribriform component and would be missed without the use of basal cell next-generation sequencing (NGS) panel testing, at a minimum including
markers. BRCA2, BRCA1, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, and PMS2,
can be considered. Additional genes may be appropriate depending on
Limited data suggest that prostate tumors with ductal or intraductal
clinical context. For example, HOXB13 is a prostate cancer risk gene and,
histology have increased genomic instability.82-85 In particular, tumors with
whereas there are not currently clear therapeutic implications in the
these histologies may be more likely to harbor somatic and/or germline

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advanced disease setting, testing may be valuable for family 4. The Decipher molecular assay is recommended to inform adjuvant
counseling.91,92 treatment if adverse features are found post-radical prostatectomy,
and can be considered as part of counseling for risk stratification in
Genetic counseling resources and support is critical, and pre-test patients with PSA resistance/recurrence after radical
counseling is preferred when feasible, especially if family history is prostatectomy (category 2B). See Tumor Multigene Molecular
positive. Post-test genetic counseling is recommended if a germline Testing, below).
mutation (pathogenic variant) is identified. Cascade testing for relatives is
critical to inform the risk for familial cancers in male and female relatives. If If somatic mutations in BRCA2, BRCA1, ATM, CHEK2, or PALB2 are
no pathogenic variant mutations or only germline variants of unknown found and/or if there is a strong family history of cancer, the patient should
significance (VUS) are identified but family history is positive, genetic be referred for genetic counseling.
counseling is recommended to discuss possible participation in family
studies and variant reclassification studies. Resources are available to If MSI testing is performed, testing using an NGS assay validated for
check the known pathologic effects of genomic variants (eg, prostate cancer is preferred.93-95 If MSI-H or dMMR is found, the patient
https://brcaexchange.org/about/app; https://www.ncbi.nlm.nih.gov/clinvar/). should be referred for genetic counseling to assess for the possibility of
Information regarding germline mutations in patients with metastatic Lynch syndrome. MSI-H or dMMR indicate eligibility for pembrolizumab in
disease can be used to inform future treatments or to determine eligibility second and subsequent lines of treatment for CRPC (see Pembrolizumab,
for clinical trials. below).

Somatic Tumor Testing Based on Risk Groups Patients should be informed that somatic tumor sequencing has the
Tumor testing recommendations are as follows: potential to uncover germline findings. However, virtually none of the NGS
1. Tumor testing for somatic homologous recombination gene tests is designed or validated for germline assessment. Therefore, over-
mutations (eg, BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, interpretation of germline findings should be avoided. If a germline
CHEK2, CDK12) can be considered in patients with regional (N1) mutation is suspected, the patient should be recommended for genetic
prostate cancer and is recommended for those with metastatic counseling and follow-up dedicated germline testing.
disease.
2. Tumor testing for MSI or dMMR can be considered in patients with Additional Testing
regional or metastatic castration-naïve prostate cancer and is Tumors from a majority of patients with metastatic CRPC harbor mutations
recommended in the metastatic CRPC setting. in genes involved in the androgen receptor signaling pathway.43 AR-V7
3. Multigene molecular testing can be considered for patients with testing in circulating tumor cells (CTCs) can be considered to help guide
low, intermediate, and high-risk prostate cancer and life selection of therapy in the post-abiraterone/enzalutamide metastatic
expectancy ≥10 years (see Tumor Multigene Molecular Testing, CRPC setting (discussed in more detail below, under AR-V7 Testing).
below).

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Risk Stratification for Clinically Localized Disease • Grade Group 3: Gleason score 4+3=7; predominantly poorly
Optimal treatment of prostate cancer requires assessment of risk: How formed/fused/cribriform glands with lesser component of well-
likely is a given cancer to be confined to the prostate or spread to the formed glands
regional lymph nodes? How likely is the cancer to progress or metastasize o For cases with >95% poorly formed/fused/cribriform glands
after treatment? How likely is adjuvant or salvage radiation to control or lack of glands on a core or at radical prostatectomy, the
cancer after an unsuccessful radical prostatectomy? Prostate cancers are component of <5% well-formed glands is not factored into
best characterized by a DRE and radiographically determined clinical T the grade.
stage, Gleason score and extent of cancer in the biopsy specimen, and • Grade Group 4: Gleason score 4+4=8; 3+5=8; 5+3=8
serum PSA level. Imaging studies (ie, ultrasound, MRI) have been o Only poorly formed/fused/cribriform glands; or
investigated intensively but have yet to be accepted as essential adjuncts o Predominantly well-formed glands and lesser component
to staging. lacking glands (poorly formed/fused/cribriform glands can
be a more minor component); or
The NCCN Guidelines have, for many years, incorporated a risk o Predominantly lacking glands and lesser component of
stratification scheme that uses a minimum of stage, Gleason grade, and well-formed glands (poorly formed/fused/cribriform glands
PSA to assign patients to risk groups. These risk groups are used to select can be a more minor component)
the appropriate options that should be considered and to predict the • Grade Group 5: Gleason score 9–10; lack gland formation (or with
probability of biochemical recurrence after definitive local therapy.96 Risk necrosis) with or without poorly formed/fused/cribriform glands
group stratification has been published widely and validated, and provides o For cases with >95% poorly formed/fused/cribriform glands
a better basis for treatment recommendations than clinical stage alone.97,98 or lack of glands on a core or at radical prostatectomy, the
component of <5% well-formed glands is not factored into
A new prostate cancer grading system was developed during the 2014
the grade.
International Society of Urological Pathology (ISUP) Consensus
Conference.99 Several changes were made to the assignment of Gleason Many experts believe that ISUP Grade Groups will enable patients to
pattern based on pathology. The new system assigns Grade Groups from better understand their true risk level and thereby limit overtreatment. The
1 to 5, derived from the Gleason score. new Grade Group system was validated in two separate cohorts, one of
• Grade Group 1: Gleason score ≤6; only individual discrete well- >26,000 men and one of 5880 men, treated for prostate cancer with either
formed glands radical prostatectomy or radiation.100,101 Both studies found that Grade
• Grade Group 2: Gleason score 3+4=7; predominantly well-formed Groups predicted the risk of recurrence after primary treatment. For
glands with lesser component of poorly formed/fused/cribriform instance, in the larger study, the 5-year biochemical recurrence-free
glands progression probabilities after radical prostatectomy for Grade Groups 1
through 5 were 96% (95% CI, 95–96), 88% (95% CI, 85–89), 63% (95%
CI, 61–65), 48% (95% CI, 44–52), and 26% (95% CI, 23–30), respectively.

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The separation between Grade Groups was less pronounced in the metastasis. The authors used these factors to separate the patients into
radiation therapy (RT) cohort, likely because of increased use of unfavorable and favorable intermediate-risk groups and determined that
neoadjuvant/concurrent/adjuvant androgen deprivation therapy (ADT) in the unfavorable intermediate-risk group had worse PSA recurrence-free
the higher risk groups. In another study of the new ISUP Grade Group survival and higher rates of distant metastasis and prostate cancer-
system, all-cause mortality and prostate cancer-specific mortality were specific mortality than the favorable intermediate-risk group. The use of
higher in men in Grade Group 5 than in those in Grade Group 4.102 active surveillance in men with favorable intermediate-risk prostate cancer
Additional studies have supported the validity of this new system.103-108 is discussed below (see Active Surveillance in Favorable Intermediate
The NCCN Panel has accepted the new Grade Group system to inform Risk). The NCCN Panel has included the separation of intermediate risk
better treatment discussions compared to those using Gleason score. group into favorable and unfavorable subsets in their risk stratification
Patients remain divided into very-low-, low-, intermediate-, high-, and very- scheme.
high-risk groups.
Nomograms
The NCCN Guidelines Panel recognized that heterogeneity exists within The more clinically relevant information that is used in the calculation of
each risk group. For example, an analysis of 12,821 patients showed that time to PSA recurrence, the more accurate the result. A nomogram is a
men assigned to the intermediate-risk group by clinical stage (T2b–T2c) predictive instrument that takes a set of input data (variables) and makes
had a lower risk of recurrence than men categorized according to Gleason predictions about an outcome. Nomograms predict more accurately for the
score (7) or PSA level (10–20 ng/mL).109 A similar trend of superior individual patient than risk groups, because they combine the relevant
recurrence-free survival was observed in men placed in the high-risk prognostic variables. The Partin tables were the first to achieve
group by clinical stage (T3a) compared to those assigned by Gleason widespread use for counseling men with clinically localized prostate
score (8–10) or PSA level (>20 ng/mL), although it did not reach statistical cancer.115-118 The tables give the probability (95% CIs) that a patient with a
significance. Other studies have reported differences in outcomes in the certain clinical stage, Gleason score, and PSA will have a cancer of each
high-risk group depending on risk factors or primary Gleason pattern.110,111 pathologic stage. Nomograms can be used to inform treatment decision-
Evidence also shows heterogeneity in the low-risk group, with PSA levels making for men contemplating active surveillance,119-121 radical
and percent positive cores affecting pathologic findings after radical prostatectomy,122-125 neurovascular bundle preservation126-128 or omission
prostatectomy.112,113 of pelvic lymph node dissection (PLND) during radical prostatectomy,129-132
brachytherapy,122,133-135 or external beam RT (EBRT).122,136 Biochemical
In a retrospective study, 1024 patients with intermediate-risk prostate progression-free survival (PFS) can be reassessed postoperatively using
cancer were treated with radiation with or without neoadjuvant and age, diagnostic serum PSA, and pathologic grade and stage.122,137-139
concurrent ADT.114 Multivariate analysis revealed that primary Gleason Potential success of adjuvant or salvage RT after unsuccessful radical
pattern 4, number of positive biopsy cores ≥50%, and presence of >1 prostatectomy can be assessed using a nomogram.122,140
intermediate-risk factors (IRFs; ie, T2b-c, PSA 10–20 ng/mL, Gleason
score 7) were significant predictors of increased incidence of distant

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None of the current models predicts with perfect accuracy, and only some Retrospective case cohort studies have shown that these assays provide
of these models predict metastasis121,122,137,141,142 and cancer-specific prognostic information independent of NCCN or CAPRA risk groups,
death.123,125,143-145 Given the competing causes of mortality, many men who which include likelihood of death with conservative management,
sustain PSA recurrence will not live long enough to develop clinical likelihood of biochemical recurrence after radical prostatectomy or EBRT,
evidence of distant metastases or to die from prostate cancer. Those with likelihood of adverse pathologic features after radical prostatectomy, and
a short PSA doubling time (PSADT) are at greatest risk of death. Not all likelihood of developing metastasis after operation, definitive EBRT, or
PSA recurrences are clinically relevant; thus, PSADT may be a more salvage EBRT.147-159 Evaluation of diagnostic biopsy tissue from patients
useful measure of risk of death.146 The NCCN Guidelines Panel enrolled in the Canary PASS multicenter active surveillance cohort
recommends that NCCN risk groups be used to begin the discussion of suggested that results of a molecular assay were not associated with
options for the treatment of clinically localized prostate cancer and that adverse pathology either alone or in combination with clinical variables.160
nomograms be used to provide additional and more individualized
information. Clinical utility studies on the tissue-based molecular assays have also
been performed.161,162 One prospective, clinical utility study of 3966
Tumor Multigene Molecular Testing patients newly diagnosed with localized prostate cancer found that the
Personalized or precision medicine is a goal for many translational and rates of active surveillance increased with use of a tissue-based gene
clinical investigators. Molecular testing of a tumor offers the potential of expression classifier.161 Active surveillance rates were 46.2%, 75.9%, and
added insight into the “biologic behavior” of a cancer that could thereby aid 57.9% for those whose classifier results were above the specified
in the clinical decision-making. The NCCN Prostate Cancer Guidelines threshold, below the threshold, and those who did not undergo genomic
Panel strongly advocates for use of life expectancy estimation, testing, respectively (P < .001). The authors estimate that one additional
nomograms, and other clinical parameters such as PSA density as the patient may choose active surveillance for every nine men with favorable
foundations for augmented clinical decision-making. Whereas risk groups, risk prostate cancer who undergo genomic testing.
life expectancy estimates, and nomograms help inform decisions,
Another clinical utility study used two prospective registries of patients with
uncertainty about disease progression persists, and this is where the
prostate cancer post-radical prostatectomy (n = 3455).162 Results of
prognostic multigene molecular testing can have a role.
molecular testing with Decipher changed management recommendations
Several tissue-based molecular assays have been developed in an effort for 39% of patients. This study also evaluated clinical benefit in 102
to improve decision-making in newly diagnosed men considering active patients. Those who were classified as high-risk by the assay had
surveillance and in treated men considering adjuvant therapy or treatment significantly different 2-year PSA recurrence rates if they received
for recurrence. Uncertainty about the risk of disease progression can be adjuvant EBRT versus if they did not (3% vs. 25%; HR, 0.1; 95% CI, 0.0–
reduced if such molecular assays can provide accurate and reproducible 0.6; P = .013). No differences in 2-year PSA recurrence were observed
prognostic or predictive information beyond NCCN risk group assignment between those who did and did not receive adjuvant therapy in those
and currently available life expectancy tables and nomograms. classified as low or intermediate risk by the assay. Based on these results,

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the panel recommends that the Decipher molecular assay should be used Initial Clinical Assessment and Staging Evaluation
to inform adjuvant treatment if adverse features are found post-radical For patients with very-low-, low-, and intermediate-risk prostate cancer
prostatectomy. and a life expectancy of 5 years or less and without clinical symptoms,
further imaging and treatment should be delayed until symptoms develop,
Several of these assays are available, and four have received positive
at which time imaging can be performed and ADT should be given. Those
reviews by the Molecular Diagnostic Services Program (MolDX) and are
with a life expectancy less than or equal to 5 years who fall into the high-
likely to be covered by CMS (Centers for Medicare & Medicaid Services).
or very-high-risk categories should undergo bone imaging and, if indicated
Several other tests are under development, and the use of these assays is
by nomogram prediction of lymph node involvement, pelvic +/- abdominal
likely to increase in the coming years.
imaging.
Table 1 lists these tests in alphabetical order and provides an overview of
For symptomatic patients and/or those with a life expectancy of greater
each test, populations where each test independently predicts outcome,
than 5 years, bone imaging is appropriate for patients with unfavorable
and supporting references. These molecular biomarker tests have been
intermediate-risk prostate cancer and T2 disease with PSA over 10
developed with extensive industry support, guidance, and involvement,
ng/mL163; high- or very-high-risk disease;164 or symptomatic disease.
and have been marketed under the less rigorous FDA regulatory pathway
Conventional bone scan is recommended first, with subsequent plain
for biomarkers. Although full assessment of their clinical utility requires
films, CT, MRI, or F-18 sodium fluoride PET/CT or PET/MRI, C-11 choline
prospective randomized clinical trials, which are unlikely to be done, the
PET/CT or PET/MRI, or F-18 fluciclovine PET/CT or PET/MRI (see
panel believes that men with low or favorable intermediate disease and life
Nuclear Imaging, below) to address equivocal findings. Retrospective
expectancy greater than or equal to 10 years may consider the use of
evidence suggests that Gleason score and PSA levels are associated with
Decipher, Oncotype DX Prostate, Prolaris, or ProMark during initial risk
positive bone scan findings.164 The SEER database validation of NCCN’s
stratification. Patients with unfavorable intermediate- and high-risk disease
imaging recommendations found that only 0.14% of patients with bone
and life expectancy greater than or equal to 10 years may consider the
metastases would have been missed, whereas the negative predictive
use of Decipher or Prolaris. In addition, Decipher may be considered to
value (NPV) was 99.8%.165
inform adjuvant treatment if adverse features are found after radical
prostatectomy and during workup for radical prostatectomy PSA Pelvic +/- abdominal imaging is recommended for intermediate or higher
persistence or recurrence (category 2B for the latter setting). Future risk disease when a nomogram indicates a greater than 10% chance of
comparative effectiveness research may allow these tests and others like lymph node involvement, although staging studies may not be cost-
them to gain additional evidence regarding their utility for better risk effective until the chance of lymph node positivity reaches 45%.166
stratification of men with prostate cancer. Multivariate analysis of retrospective data on 643 men with newly
diagnosed prostate cancer who underwent staging CT found that PSA,
Gleason score, and clinical T stage were associated independently with a
positive finding (P < .05 for all).167 A validation of NCCN’s pelvic imaging

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recommendations using the SEER database found that only 0.3% to 0.4% biopsy cores, while reducing detection of low-grade and insignificant
of patients with positive lymph nodes are missed, depending on which cancers.170-172 Second, mpMRI aids in the detection of extracapsular
nomogram is used, whereas the NPV was 99.5%.165 Multiparametric MRI extension (T staging), with high NPVs in low-risk men.173 mpMRI results
(mpMRI) is preferred over CT for abdominal/pelvic staging (see may inform decision-making regarding nerve-sparing operation.174 Third,
Multiparametric MRI, below). Biopsy should be considered for further mpMRI has been shown to be equivalent to CT scan for staging of pelvic
evaluation of suspicious nodal findings. lymph nodes.175,176 Finally, mpMRI outperforms bone scan and targeted x-
rays for detection of bone metastases, with a sensitivity of 98% to 100%
Imaging Techniques and specificity of 98% to 100% (vs. sensitivity of 86% and specificity of
Imaging techniques are useful for staging and for detecting metastases 98%–100% for bone scan plus targeted x-rays).177
and tumor recurrence. Anatomic imaging techniques include radiographs,
ultrasound, CT, and MRI. Functional techniques include radionuclide bone Nuclear Imaging
scan (conventional Tc EDTMP scan), PET/CT, PET/MRI, and advanced The use of PET/CT or PET/MRI imaging using tracers other than F-18
MRI, such as spectroscopy and diffusion-weighted imaging (DWI). TRUS fluorodeoxyglucose (FDG) for staging of small-volume recurrent or
is the most common technique for anatomic visualization of the prostate. metastatic prostate cancer is a rapidly developing field wherein most of the
TRUS is used to guide transrectal biopsies, and can be considered for data are derived from single-institution series or registry studies.168 High
patients with biochemical recurrence after operation or radiation. More variability among equipment, protocols, interpretation, and institutions
details on each technique are outlined in the algorithm under Principles of provides challenges for application and interpretation of the utility of
Imaging. PET/CT or PET/MRI. Furthermore, FDA clearance and reimbursement for
some tests makes unlikely the conduct of clinical trials to evaluate their
Multiparametric MRI utility and impact upon oncologic outcome. Three PET tracers are FDA
The use of mpMRI in the staging and characterization of prostate cancer cleared for use in men with prostate cancer: C-11 choline, F-18 sodium
has increased in the last few years. To be considered “multiparametric,” fluoride, and F-18 fluciclovine.
MRI images must be acquired with at least one more sequence apart from
the anatomical T2-weighted one, such as DWIs or dynamic contrast- C-11 choline PET/CT or PET/MRI and F-18 fluciclovine PET/CT or
enhanced (DCE) images. Furthermore, a high-quality mpMRI requires a PET/MRI detect small-volume disease in bone and soft tissues.178,179 The
3.0 T magnet; the need for an endorectal coil remains controversial. reported sensitivity and specificity of C-11 choline PET/CT in restaging
patients with biochemical recurrence ranges from 32% to 93% and from
Evidence supports the implementation of mpMRI in several aspects of 40% to 93%, respectively.180-189 The reported sensitivity and specificity of
prostate cancer management.168 First, mpMRI helps detect larger and/or F-18 fluciclovine PET/CT ranges from 37% to 90% and from 40% to
more poorly differentiated cancers (ie, Grade Group ≥2).169 mpMRI has 100%, respectively.186,190,191 A prospective study compared F-18
been incorporated into MRI-TRUS fusion-targeted biopsy protocols, which fluciclovine and C-11 choline PET/CT scans in 89 patients, and agreement
has led to an increase in the diagnosis of high-grade cancers with fewer was 85%.186 The FALCON trial showed that results of F-18 fluciclovine

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PET/CT in 104 patients with biochemical recurrence after definitive patients with high-risk prostate cancer before curative-intent definitive
therapy resulted in a change in management for 64%.192 The panel treatment. The prospective, randomized, multicenter proPSMA study
believes that F-18 fluciclovine PET/CT or PET/MRI or C-11 choline found that PSMA PET/CT imaging was more accurate than conventional
PET/CT or PET/MRI may be used in men with biochemical recurrence imaging at the detection of positive pelvic nodes or distant metastatic
after primary treatment for further soft tissue and/or bone evaluation after disease.204
bone scan, chest CT, and abdominal/pelvic CT or abdominal/pelvic MRI.
Another investigational agent, F-18 fluorodihydrotestosterone (FDHT),
F-18 sodium fluoride PET/CT detects bone metastases with greater targets the androgen receptor and is not effective in the castration-naïve
sensitivity, but less specificity, than standard bone scan imaging, setting, but shows promise in CRPC, with sensitivity in the range of 63% to
reportedly in the range of 87% to 100% and 62% to 89%, respectively.193- 97%.205,206 Another investigational tracer, C-11 acetate, relies upon
196
F-18 sodium fluoride PET/CT was evaluated in men with biochemical increased levels of fatty acid synthetase reported in prostate cancer. C-11
relapse after prior local therapy.197 The positive detection rate of bone acetate performs similarly to C-11 choline but may have better specificity,
metastases not seen on CT and bone scan was 16.2%. except high-quality data remain unavailable.207

The panel believes that F-18 sodium fluoride, C-11 choline, and F-18 The panel notes that false-positive rates are high with nuclear imaging;
fluciclovine PET/CT or PET/MRI may be considered after bone scan for therefore, histologic confirmation is strongly recommended whenever
further evaluation of the bones when bone scan results are equivocal. A feasible. Moreover, these PET/CT and PET/MRI tests are expensive, and,
typical application is to resolve uncertainty when bone scan reveals a whereas results may change treatment,208 they may not change oncologic
single lesion and suspicion for diffuse metastases is high. The panel outcome. Earlier detection of bone metastatic disease, for instance, may
cautions, however, that earlier detection of bone metastatic disease may result in earlier use of newer and more expensive therapies, which may
result in earlier use of newer and more expensive therapies, which may not improve oncologic outcome or OS. The panel remains unsure of how
not improve oncologic outcome or OS. to treat patients when M1 is suggested by PET-based imaging but not by
conventional imaging.
Newer tracers are under development, but they are neither FDA cleared
nor readily available and are considered investigational at this time. For Table 2 summarizes the main PET imaging tracers studied in prostate
instance, gallium (Ga)-68 prostate-specific membrane antigen (PSMA) cancer. F-18 FDG PET should not be used routinely, because data are
may provide better detection of recurrences at lower PSA levels than limited in patients with prostate cancer and suggest that its sensitivity is
reported for FDA-approved imaging agents, and has comparable significantly lower than that seen with other tracers.197,209,210
sensitivity (76%–86%) and specificity (86%–100%).198-202 A prospective
head-to-head comparison of Ga-68 PSMA PET/CT and F-18 fluciclovine Risks of Imaging
PET/CT in 50 patients with biochemical recurrence after radical As with any medical procedure, imaging is not without risk. Some of these
prostatectomy found that PSMA had higher detection rates.203 The risks are concrete and tangible, while others are less clear. Risks
potential role of Ga-68 PSMA PET/CT has also been investigated in

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associated with imaging include exposure to ionizing radiation, adverse reactions can be life-threatening (bronchospasm or anaphylactoid). The
reaction to contrast media, false-positive scans, and overdetection. risk of severe reaction is low with non-ionic contrast materials.212 Both
iodinated CT contrast material and gadolinium-based MR contrast
Deterministic and stochastic are two types of effects from exposure to materials can affect renal function, particularly when renal function is
ionizing radiation by x-ray, CT, or PET/CT. Deterministic effects are those impaired. MR contrast materials also have been associated with systemic
that occur at a certain dose level, and include events such as cataracts nephrogenic sclerosis in patients with impaired renal function. Centers
and radiation burns. No effect is seen below the dose threshold. Medical performing imaging studies with contrast materials should have policies in
imaging is always performed almost below the threshold for deterministic place to address the use of contrast in these patients.
effects. Stochastic effects tend to occur late, increase in likelihood as dose
increases, and have no known lower “safe” limit. The major stochastic Every imaging test has limitations for sensitivity, specificity, and accuracy,
effect of concern in medical imaging is radiation-induced malignancy. which are modulated further by the expertise of the interpreting physician.
Unfortunately, no direct measurements are available to determine risk of Harm can arise from failure to detect a tumor or tumor recurrence (ie, false
cancer arising from one or more medical imaging events, so risks are negative), but harm to the patient and added expense to the medical
calculated using other models (such as from atomic bomb survivors). The system also can result from false-positive scans. Improper interpretation of
literature is conflicting with regard to the precise risk of secondary a benign finding as malignant can lead to significant patient anxiety,
malignancies in patients undergoing medical imaging procedures. There is additional and unnecessary imaging, and invasive procedures that carry
a small but finite risk of developing secondary malignancies as a result of their own risks for adverse outcomes.
medical imaging procedures, and the risk is greatest in young patients.
However, the absolute risk of fatal malignancy arising from a medical Accurate and medically relevant interpretation of imaging studies requires
imaging procedure is very low, and is difficult to detect given the familiarity and expertise in the imaging modality, attention to detail in
prevalence of cancer in the population and the multiple factors that image review, knowledge of tumor biology, and familiarity with treatment
contribute to oncogenesis.211 Efforts should be made to minimize dose options and algorithms. Challenging cases are best addressed through
from these procedures, which begin with judicious use of imaging only direct communication, either physician-to-physician or in a multidisciplinary
when justified by the clinical situation. Harm may arise from not imaging a tumor board setting.
patient, through disease non-detection, or from erroneous staging.
Medical imaging is a critical tool in the evaluation and management of
Many imaging studies make use of contrast material delivered by oral, patients with malignancy. However, as with any medical procedure,
intravenous, or rectal routes. The use of contrast material may improve imaging is not without risks to patients. Inappropriate use of imaging also
study performance, but reactions to contrast material may occur and they has been identified as a significant contributor to health care costs in the
should be used only when warranted. Some patients develop adverse United States and worldwide. Therefore, imaging should be performed
reactions to iodinated intravenous contrast material. Most reactions are only when medically appropriate, and in a manner that reduces risk (eg,
mild cutaneous reactions (eg, hives, itching) but occasionally severe minimizing radiation dose). An algorithmic approach to the use of imaging,

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such as by NCCN and the Appropriateness Criteria developed by the defer treatment and its potential side effects. Because these patients have
American College of Radiology,213 can assist in medical decision-making. a longer life expectancy, they should be followed closely and treatment
should start promptly should the cancer progress so as not to miss the
Observation chance for cure.
Observation involves monitoring the course of prostate cancer with the
expectation to deliver palliative therapy for development of symptoms or In one study, approximately two thirds of eligible men avoided treatment,
change in exam or PSA that suggests symptoms are imminent. and thus the possible associated side effects of treatment, after 5 years of
Observation thus differs from active surveillance. The goal of observation active surveillance.215 In another study, 55% of the population remained
is to maintain QOL by avoiding noncurative treatment when prostate untreated at 15 years.216 Although a proportion of men on active
cancer is unlikely to cause mortality or significant morbidity. The main surveillance will eventually undergo treatment, the delay does not appear
advantage of observation is avoidance of possible side effects of to impact cure rates, and several studies have shown that active
unnecessary definitive therapy or ADT. However, patients may develop surveillance is safe.215-219 In fact, a 2015 meta-analysis of 26 active
urinary retention or pathologic fracture without prior symptoms or surveillance cohort studies that included 7627 men identified only 8
increasing PSA level. prostate cancer deaths and 5 cases of metastasis.220

Observation is applicable to elderly or frail men with comorbidity that will Further, the ProtecT study, which randomized 1643 men with localized
likely out-compete prostate cancer for cause of death. Johansson and prostate cancer to active surveillance, radical prostatectomy, or RT, found
colleagues214 observed that only 13% of men developed metastases 15 no significant difference in the primary outcome of prostate cancer
years after diagnosis of T0–T2 disease and only 11% had died from mortality at a median of 10 years follow-up.221 Of 17 prostate cancer
prostate cancer. Because prostate cancer will not be treated for cure for deaths (1% of study participants), 8 were in the active surveillance group,
patients with shorter life expectancies, observation for as long as possible 5 were in the operation group, and 4 were in the radiation group (P = .48
is a reasonable option based on physician discretion. Monitoring should for the overall comparison). However, higher rates of disease progression
include PSA and physical exam no more often than every 6 months, but and metastases were seen in the active surveillance group.221,222
will not involve surveillance biopsies or radiographic imaging. When Approximately 23% of participants had Gleason scores 7–10, and 5 of 8
symptoms develop or are imminent, patients can begin palliative ADT. deaths in the active surveillance group were in this subset. Patient-
reported outcomes were compared among the 3 groups.223 The operation
Active Surveillance group experienced the greatest negative effect on sexual function and
urinary continence, whereas bowel function was worst in the radiation
Active surveillance (formerly referred to as watchful waiting, expectant
management, or deferred treatment) involves actively monitoring the group.
course of the disease with the expectation to deliver curative therapy if the
In addition, studies have shown that active surveillance does not adversely
cancer progresses. Unlike observation, active surveillance is mainly
impact psychological well-being or QOL.223-228 Possible disadvantages of
applicable to younger men with seemingly indolent cancer with the goal to

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active surveillance are listed in the Principles section of the algorithm and Rationale
include the possible necessity of follow-up prostate biopsies. The NCCN Guidelines Panel remains concerned about the problems of
overtreatment related to the increased frequency of diagnosis of prostate
The proportion of men with low-risk prostate cancer choosing active
cancer from widespread use of PSA for early detection or screening (see
surveillance in the Veterans Affairs Integrated Health Care System
the NCCN Guidelines for Prostate Cancer Early Detection, available at
increased from 2005 to 2015: from 4% to 39% of men younger than 65
www.NCCN.org).
years and from 3% to 41% of men 65 years or older.229 An analysis of the
SEER database found a similar trend, with the use of active surveillance in The debate about the need to diagnose and treat every man who has
men with low-risk prostate cancer increasing from 14.5% in 2010 to 42.1% prostate cancer is fueled by the high prevalence of prostate cancer upon
in 2015.230 An international, hospital-based, retrospective analysis of autopsy of the prostate236; the high frequency of positive prostate biopsies
greater than 115,000 men with low-risk prostate cancer reported that in men with normal DREs and serum PSA values237; the contrast between
active surveillance utilization increased, but the proportions were lower at the incidence and mortality rates of prostate cancer; and the need to treat
7% in 2010 and 20% in 2014.231 Ultimately, a recommendation for active an estimated 37 men with screen-detected prostate cancer238,239 or 100
surveillance must be based on careful individualized weighing of a number men with low-risk prostate cancer240 to prevent one death from the
of factors: life expectancy, general health condition, disease disease. The controversy regarding overtreatment of prostate cancer and
characteristics, potential side effects of treatment, and patient preference. the value of prostate cancer early detection233,238-243 has been further
informed by publication of the Goteborg study, a subset of the European
The panel believes there is an urgent need for further clinical research
Randomized Study of Screening for Prostate Cancer (ERSPC).244,245 Many
regarding the criteria for recommending active surveillance, the criteria for
believe that this study best approximates proper use of PSA for early
reclassification on active surveillance, and the schedule for active
detection because it was population-based and involved a 1:1
surveillance especially as it pertains to prostate biopsies, which pose an
randomization of 20,000 men who received PSA every 2 years and used
increasing burden. One such study is a prospective multi-institutional
thresholds for prostate biopsy of PSA >3 and >2.5 since 2005. The 14-
cohort study, which has been funded by the NCI.232 Nine hundred five
year follow-up reported in 2010 was longer than the European study as a
men, median age 63 years and median follow-up 28 months,
whole (9 years) and the Prostate, Lung, Colorectal, and Ovarian (PLCO)
demonstrated 19% conversion to therapy. Much should be learned about
trial (11.5 years). Prostate cancer was diagnosed in 12.7% of the
the criteria for selection of and progression on active surveillance as this
screened group compared to 8.2% of the control group. Prostate cancer
cohort and research effort mature. Literature suggests that as many as 7%
mortality was 0.5% in the screened group and 0.9% in the control group,
of men undergoing prostate biopsy will suffer an adverse event,233 and
which gave a 40% absolute cumulative risk reduction of prostate cancer
those who develop urinary tract infection are often fluoroquinolone-
death (compared to ERSPC 20% and PLCO 0%).244 Most impressively,
resistant.234 Radical prostatectomy may become technically challenging
40% of the patients were initially managed using active surveillance and
after multiple sets of biopsies, especially as it pertains to potency
28% were still on active surveillance at the time these results were
preservation.235
analyzed. To prevent a prostate cancer death, 12 men would need to be

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diagnosed and treated as opposed to the ERSPC as a whole where 37 Guidelines Panel was reached that insignificant prostate cancer,
men needed to be treated. Analysis of 18-year follow-up data from the especially when detected early using serum PSA, poses little threat to
Goteborg study reduced the number needed to be diagnosed to prevent 1 men with a life expectancy of less than 20 years. The confidence that
prostate cancer death to 10.246 Thus, early detection, when applied Americans with very-low-risk prostate cancer have a very small risk of
properly, should reduce prostate cancer mortality. However, that reduction prostate cancer death is enhanced by lead time bias introduced by PSA
comes at the expense of overtreatment that may occur in as many as 50% early detection that ranges from an estimated 12.3 years in a 55-year-old
of men treated for PSA-detected prostate cancer.247 man to 6 years in a 75-year-old man.249 At this time, the NCCN Panel
recommends active surveillance for all men with very-low-risk prostate
The best models of prostate cancer detection and progression estimate cancer and life expectancy less than 20 years and believes that it should
that 23% to 42% of all U.S. screen-detected cancers were overtreated248 be considered for men with very-low-risk prostate cancer and life
and that PSA detection was responsible for up to 12.3 years of lead-time expectancy greater than or equal to 20 years.
bias.249 The NCCN Guidelines Panel responded to these evolving data
with careful consideration of which men should be recommended active The panel recommends active surveillance for all men with low- and
surveillance. However, the NCCN Guidelines Panel recognizes the favorable intermediate-risk prostate cancer and life expectancy less than
uncertainty associated with the estimation of chance of competing causes 10 years and believes that it should be considered for men with low and
of death; the definition of very-low-, low-, and favorable intermediate-risk favorable intermediate risk and life expectancy greater than or equal to 10
prostate cancer; the ability to detect disease progression without years.
compromising chance of cure; and the chance and consequences of
Active Surveillance in Favorable Intermediate Risk
treatment side effects.
The literature on outcomes of active surveillance in men with intermediate-
Patient Selection risk prostate cancer is limited.255 In the PIVOT trial, men with clinically
Epstein and colleagues250 introduced clinical criteria to predict localized prostate cancer and a life expectancy greater than or equal to 10
pathologically “insignificant” prostate cancer. Insignificant prostate cancer years were randomized to radical prostatectomy or observation.256 Of the
is identified by: clinical stage T1c, biopsy Grade Group I, the presence of 120 participants with intermediate-risk disease who were randomized to
disease in fewer than 3 biopsy cores, ≤50% prostate cancer involvement observation, 13 died from prostate cancer, a non-significant difference
in any core, and PSA density <0.15 ng/mL/g. Despite the usefulness of compared with 6 prostate cancer deaths in 129 participants with
these criteria, physicians are cautioned against using these as the sole intermediate-risk disease in the radical prostatectomy arm (HR, 0.50; 95%
decision maker. Studies have shown that as many as 8% of cancers that CI, 0.21–1.21; P = .12). After longer follow-up (median 12.7 years), a small
qualified as insignificant using the Epstein criteria were not organ-confined difference was seen in all-cause mortality in those with intermediate-risk
based on postoperative findings.251,252 A new nomogram may be better.253 disease (absolute difference, 14.5 percentage points; 95% CI, 2.8–25.6),
Although many variations upon this definition have been proposed but not in those with low-risk disease (absolute difference, 0.7 percentage
(reviewed by Bastian and colleagues254), a consensus of the NCCN points; 95% CI, -10.5–11.8).257 Urinary incontinence and erectile and

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NCCN Guidelines Version 1.2022

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sexual dysfunction, however, were worse through 10 years in the radical islanders.264 Five-year survival for all stages combined was higher for
prostatectomy group. These results and the less-than-average health of white men than for black or Hispanic men, but survival for distant stage
men in the PIVOT study258 suggest that men with competing risks may disease was higher for black men than white men. In an analysis that
safely be offered active surveillance. spanned 2010 to 2012, African-American men had a higher lifetime risk of
developing (18.2% vs. 13.3%) and dying from (4.4% vs. 2.4%) prostate
Other prospective studies of active surveillance that included men with cancer compared to Caucasian-American men.265 In one study, the
intermediate-risk prostate cancer resulted in favorable prostate cancer- increase in prostate-cancer-specific mortality in African-American men
specific survival rates of 94% to 100% for the full cohorts.216,217,219 was limited to those with grade group 1.266 Multiple studies have shown
However, with extended follow-up, the Toronto group has demonstrated that African Americans with very-low-risk prostate cancer may harbor high-
inferior metastasis-free survival for men with intermediate-risk prostate grade (Grade Group ≥2) cancer that is not detected by pre-treatment
cancer (15-year metastasis-free survival for cases of Gleason 6 or less biopsies. Compared to Caucasian Americans matched on clinical
with PSA <10 ng/mL, 94%; Gleason 6 or less with PSA 10–20 ng/mL, parameters, African Americans have been reported to have a 1.7- to 2.3-
94%; Gleason 3+4 with PSA 20 ng/mL or less, 84%; and Gleason 4+3 fold higher change of pathologic upgrading.267,268 However, other studies
with PSA 20 ng/mL or less, 63%).259 have not seen different rates of upstaging or upgrading.269,270 For example,
in a retrospective study of 895 men in the SEARCH database, no
Overall, the panel interpreted these data to show that a subset of men with
significant differences were seen in the rates of pathologic upgrading,
intermediate-risk prostate cancer may be considered for active
upstaging, or biochemical recurrence between African American and
surveillance. However, the precise inclusion criteria and follow-up
Caucasian Americans.269
protocols need continued refinement. Men must understand that a
significant proportion of men clinically staged as having favorable Several studies have reported that, among men with low-risk prostate
intermediate-risk prostate cancer may have higher risk disease.260-263 cancer who are enrolled in active surveillance programs, African
Americans have higher risk of disease progression to higher Gleason
The panel believes that active surveillance may be considered for men
grade or volume cancer than Caucasian Americans.271-273 African
with favorable intermediate-risk prostate cancer, but should be
Americans in the low- to intermediate-risk categories also appear to suffer
approached with caution, include informed decision-making, and use close
from an increased risk of biochemical recurrence after treatment.274 In
monitoring for progression.
addition, African American men with low-risk or favorable intermediate-risk
Role of Race in Decisions Regarding Active Surveillance prostate cancer have an increase in all-cause mortality after treatment,
Race is emerging as an important factor to consider when contemplating mainly due to cardiovascular complications after ADT.275
active surveillance, particularly for African-American men. A CDC analysis
Reasons for these clinical disparities are under investigation and may
of population-based cancer registries found that from 2003 to 2017, the
include difference in tumor location within the prostate that may reflect
incidence of prostate cancer was higher in black men than in white men,
different prostate cancer subtypes related to differences in gene
Hispanic men, American Indian/Alaska natives, and Asian/Pacific

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NCCN Guidelines Version 1.2022

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expression.276-279 In addition, treatment disparities and access to health A repeat prostate biopsy within 6 months of diagnosis is indicated if the
care may play a significant role.280,281 In fact, results of some studies initial biopsy was less than 10 cores or if assessment results show
suggest that racial disparities in prostate cancer outcomes are minimized discordance. A repeat prostate biopsy should also be considered if the
when health care access is equal.282-285 Strategies to improve risk- prostate exam changes, if mpMRI (if done) suggests more aggressive
stratification for African Americans considering active surveillance may disease, or if PSA increases. Furthermore, a repeat prostate biopsy
include mpMRI in concert with targeted image-guided biopsies, which should be considered to assess for disease progression regardless of
have been reported to improve detection of clinically significant tumors in these changes, but no more often than every 12 months, because PSA
some men.286 kinetics may not be reliable for predicting progression. Repeat biopsy is
useful to determine whether higher Gleason grade exists, which may
Confirmatory Testing influence prognosis and hence the decision to continue active surveillance
Before starting on an active surveillance program, mpMRI and/or prostate or proceed to definitive local therapy.289 Many clinicians choose to wait 2
biopsy should be considered to confirm candidacy for active years for a biopsy if there are no signs of progression. Repeat biopsies are
surveillance.287 Men with PI-RADS 4 or 5 on mpMRI have an increased not indicated when life expectancy is less than 10 years or when men are
risk of biopsy progression during active surveillance.288 In patients with low on observation. mpMRI may be considered to exclude the presence of
and favorable intermediate risk, molecular tumor analysis can also be anterior cancer if the PSA level increases and systematic prostate biopsy
considered before deciding whether to pursue active surveillance. remains negative.290

One study examined the role of molecular tumor analysis for predicting Results of a study of 211 patients with Grade Group 1 prostate cancer
upgrading on surveillance biopsy or the presence of adverse pathology on who had initial and repeat mpMRIs and PSA monitoring suggest that a
eventual radical prostatectomy in patients in an active surveillance negative initial mpMRI predicts a low risk of Gleason upgrading by
cohort.160 In this study, results of the molecular testing did not significantly systematic biopsy.291 In addition, PSA velocity was significantly associated
improve risk stratification over the use of clinical variables alone. with subsequent progression in those with an initial negative mpMRI. In
contrast, those with high-risk visible lesions on mpMRI before initiation of
Active Surveillance Program active surveillance had an increased risk of progression. A meta-analysis
The current NCCN recommendations for the active surveillance program of 43 studies found the sensitivity and NPV for mpMRI to be 0.81 and
include PSA no more often than every 6 months unless clinically indicated; 0.78, respectively.292
DRE no more often than every 12 months unless clinically indicated;
repeat prostate biopsy no more often than every 12 months unless Early experience supports the utilization of mpMRI in biopsy protocols to
clinically indicated; and repeat mpMRI no more often than every 12 better risk stratify men under active surveillance.293-295 However, more
months unless clinically indicated. Repeat molecular tumor analysis is recent studies have shown that a significant proportion of high-grade
discouraged during active surveillance. cancers are detected with systematic biopsy and not targeted biopsy in
men on active surveillance.296-298

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Reclassification Criteria 1298 men (0.15%) in the Johns Hopkins study.218 However, it remains
Reliable parameters of prostate cancer progression await the results of uncertain whether treatment of all who progressed to Gleason pattern 4
ongoing clinical trials. PSADT is not considered reliable enough to be used was necessary. Studies remain in progress to identify the best trigger
alone to detect disease progression.299 If repeat biopsy shows Grade points when interventions with curative intent may still be successful.
Group ≥3 disease, or if tumor is found in a greater number of biopsy cores
The Toronto group published findings on three patients who died of
or in a higher percentage of a given biopsy core, cancer progression may
prostate cancer in their experience with 450 men on active surveillance.302
have occurred.
These three deaths led them to revise their criteria for offering men active
Each of the major active surveillance series has used different criteria for surveillance, because each of these three men probably had metastatic
reclassification.216,218,300-304 Reclassification criteria were met by 23% of disease at the time of entry on active surveillance. The 450 men were
men with a median follow-up of 7 years in the Toronto experience,302 36% followed for a median of 6.8 years; OS was 78.6% and prostate cancer-
of men with a median follow-up of 5 years in the Johns Hopkins specific survival was 97.2%.302 Of the 30% (n = 145) of men who
experience,218 and 16% of men with a median follow-up of 3.5 years in the progressed, 8% had an increase in Gleason grade, 14% had a PSADT
University of California, San Francisco (UCSF) experience301 (Table 3). less than 3 years, 1% developed a prostate nodule, and 3% were treated
Uncertainty regarding reclassification criteria and the desire to avoid because of anxiety. One hundred thirty-five of these 145 men were
missing an opportunity for cure drove several reports that dealt with the treated: 35 by radical prostatectomy, 90 by EBRT with or without ADT, and
validity of commonly used reclassification criteria. The Toronto group 10 with ADT alone. Follow-up is available for 110 of these men, and 5-
demonstrated that a PSA trigger point of PSADT less than 3 years could year biochemical PFS is 62% for those undergoing radical prostatectomy
not be improved upon by using a PSA threshold of 10 or 20, PSADT and 43% for those undergoing radiation. Longer-term follow-up of this
calculated in various ways, or PSA velocity greater than 2 ng/mL/y.305 The cohort was reported in 2015.216 The 10- and 15-year actuarial cause-
Johns Hopkins group used biopsy-demonstrated reclassification to specific survival rates for the entire cohort were 98.1% and 94.3%,
Gleason pattern 4 or 5 or increased tumor volume on biopsy as their respectively. Only 15 of 993 (1.5%) patients had died of prostate cancer,
criteria for reclassification. Of 290 men on an annual prostate biopsy an additional 13 men (1.3%) had developed metastatic disease, and only
program, 35% demonstrated reclassification at a median follow-up of 2.9 36.5% of the cohort had received treatment by 10 years. In an analysis of
years.306 Neither PSADT (area under the curve [AUC], 0.59) nor PSA 592 patients enrolled in this cohort who had 1 or more repeat prostate
velocity (AUC, 0.61) was associated with prostate biopsy reclassification. biopsies, 31.3% of cases were upgraded. Fifteen percent of upgraded
Both groups have concluded that PSA kinetics cannot replace regular cases were upgraded to Gleason ≥8, and 62% of total upgraded cases
prostate biopsy, although treatment of most men who demonstrate proceeded to active treatment.307 Another analysis of this cohort revealed
reclassification on prostate biopsy prevents evaluation of biopsy that metastatic disease developed in 13 of 133 men with Gleason 7
reclassification as a criterion for treatment or reduction of survival. disease (9.8%) and 17 of 847 men with Gleason ≤6 disease (2.0%).308
Treatment of all men who developed Gleason pattern 4 on annual prostate PSADT and the number of positive scores were also predictors of
biopsies has thus far resulted in only 2 prostate cancer deaths among increased risk for the development of metastatic disease.

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In comparison, among 192 men on active surveillance who underwent absolute difference of 11%.313 Overall, 8 men needed to be treated to
delayed treatment at a median of 2 years after diagnosis in the Johns avert one death; that number fell to 4 for men younger than 65 years of
Hopkins experience, 5-year biochemical PFS was 96% for those who age. Longer follow-up results were also reported, in which the cumulative
underwent radical prostatectomy and 75% for those who underwent incidence of death from prostate cancer was 19.6% and 31.3% in the
radiation.304 The two groups were similar by pathologic Gleason grade, radical prostatectomy and watchful waiting groups, respectively, at 23
pathologic stage, and margin positivity. All men treated by radical years, with a mean increase of 2.9 years of life in the radical
prostatectomy after progression on active surveillance had freedom from prostatectomy group.314 The results of this trial offer high-quality evidence
biochemical progression at a median follow-up of 37.5 months, compared to support radical prostatectomy as a treatment option for clinically
to 97% of men in the primary radical prostatectomy group at a median localized prostate cancer.
follow-up of 35.5 months. A later publication from this group showed that
23 of 287 men who were treated after active surveillance (8%) Some patients at high or very high risk may benefit from radical
experienced biochemical recurrence, and the rate was independent of the prostatectomy. In an analysis of 842 men with Gleason scores 8 to 10 at
type of treatment.218 Several studies have shown that delayed radical biopsy who underwent radical prostatectomy, predictors of unfavorable
prostatectomy does not increase the rates of adverse pathology.232,309-311 outcome included PSA level over 10 ng/mL, clinical stage T2b or higher,
Gleason score 9 or 10, higher number of biopsy cores with high-grade
Radical Prostatectomy cancer, and over 50% core involvement.315 Patients without these
Radical prostatectomy is appropriate for any patient whose cancer characteristics showed higher 10-year biochemical-free and disease-
appears clinically localized to the prostate. However, because of potential specific survival after radical prostatectomy compared to those with
perioperative morbidity, radical prostatectomy should be reserved for unfavorable findings (31% vs. 4% and 75% vs. 52%, respectively). Radical
patients whose life expectancy is 10 years or more. Stephenson and prostatectomy is an option for men with high-risk disease and in select
colleagues125 reported a low 15-year prostate cancer-specific mortality of patients with very-high-risk disease.
12% in patients who underwent radical prostatectomy (5% for patients with
Radical prostatectomy is a salvage option for patients experiencing
low-risk disease), although it is unclear whether the favorable prognosis is
biochemical recurrence after primary EBRT, but morbidity (incontinence,
due to the effectiveness of the procedure or the low lethality of cancers
erectile dysfunction, and bladder neck contracture) remains significantly
detected in the PSA era.
higher than when radical prostatectomy is used as initial therapy.316,317
Radical prostatectomy was compared to watchful waiting in a randomized Overall and cancer-specific 10-year survival ranged from 54% to 89% and
trial of 695 patients with early-stage prostate cancer (mostly T2).312,313 With 70% to 83%, respectively.316 Patient selection is important, and salvage
a median follow-up of 12.8 years, those assigned to the radical prostatectomy should only be performed by highly experienced surgeons.
prostatectomy group had significant improvements in disease-specific
survival, OS, and risk of metastasis and local progression.312 The
reduction in mortality was confirmed at 18 years of follow-up, with an

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NCCN Guidelines Version 1.2022

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Operative Techniques and Adverse Effects postoperative management and additional cancer therapies were not
Long-term cancer control has been achieved in most patients with both the standardized between the groups.328
retropubic and the perineal approaches to radical prostatectomy; high-
An analysis of the Prostate Cancer Outcomes Study on 1655 men with
volume surgeons in high-volume centers generally achieve superior
localized prostate cancer compared long-term functional outcomes after
outcomes.318,319 Laparoscopic and robot-assisted radical prostatectomy
radical prostatectomy or EBRT.330 At 2 and 5 years, patients who
are commonly used and are considered comparable to conventional
underwent radical prostatectomy reported higher rates of urinary
approaches in experienced hands.320-322 In a cohort study using SEER
incontinence and erectile dysfunction but lower rates of bowel urgency.
Medicare-linked data on 8837 patients, minimally invasive compared to
However, no significant difference was observed at 15 years. In a large
open radical prostatectomy was associated with shorter length of hospital
retrospective cohort study involving 32,465 patients, those who received
stay, less need for blood transfusions, and fewer surgical complications,
EBRT had a lower 5-year incidence of urologic procedures than those who
but rates of incontinence and erectile dysfunction were higher.323 A second
underwent radical prostatectomy, but higher incidence for hospital
large study reported no difference in overall complications, readmission,
admissions, rectal or anal procedures, open surgical procedures, and
and additional cancer therapies between open and robot-assisted radical
secondary malignancies.331
prostatectomy, although the robotic approach was associated with higher
rates of genitourinary complications and lower rates of blood Return of urinary continence after radical prostatectomy may be improved
transfusion.324 Oncologic outcome of a robotic versus open approach was by preserving the urethra beyond the prostatic apex and by avoiding
similar when assessed by use of additional therapies323 or rate of positive damage to the distal sphincter mechanism. Bladder neck preservation
surgical margins,325 although longer follow-up is necessary. A meta- may allow more rapid recovery of urinary control.332 Anastomotic strictures
analysis on 19 observational studies (n = 3893) reported less blood loss that increase the risk of long-term incontinence are less frequent with
and lower transfusion rates with minimally invasive techniques than with modern surgical techniques. Recovery of erectile function is related
open operation.325 Risk of positive surgical margins was the same. Two directly to the degree of preservation of the cavernous nerves, age at
more recent meta-analyses showed a statistically significant advantage in surgery, and preoperative erectile function. Improvement in urinary and
favor of a robotic approach compared to an open approach in 12-month sexual function has been reported with nerve-sparing techniques.333,334
urinary continence326 and potency recovery.327 Early results from a Replacement of resected nerves with nerve grafts does not appear to be
randomized controlled phase 3 study comparing robot-assisted effective for patients undergoing wide resection of the neurovascular
laparoscopic radical prostatectomy and open radical retropubic bundles.335 The ability of mpMRI to detect extracapsular extension can aid
prostatectomy in 326 men were published in 2016.328,329 Urinary function in decision-making in nerve-sparing surgery.174
and sexual function scores and rates of postoperative complications did
not differ significantly between the groups at 6, 12, and 24 months after Pelvic Lymph Node Dissection
surgery. Rates of positive surgical margins were similar, based on a The decision to perform PLND should be guided by the probability of nodal
superiority test (10% in the open group vs. 15% in the robotic group). metastases. The NCCN Guidelines Panel chose 2% as the cutoff for
Assessment of oncologic outcomes from this trial will be limited because
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NCCN Guidelines Version 1.2022

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PLND because this avoids 47.7% of PLNDs at a cost of missing 12.1% of cost of proton therapy was almost double that of IMRT, and SBRT was
positive pelvic lymph nodes.130 A more recent analysis of 26,713 patients slightly less expensive.346
in the SEER database treated with radical prostatectomy and PLND
between 2010 and 2013 found that the 2% nomogram threshold would The panel believes that highly conformal RT (CRT) techniques should be
avoid 22.3% of PLNDs at a cost of missing 3.0% of positive pelvic lymph used to treat localized prostate cancer. Photon and proton beam radiation
nodes.336 The panel recommends use of a nomogram developed at are both effective at achieving highly CRT with acceptable and similar
Memorial Sloan Kettering Cancer Center that uses pretreatment PSA, biochemical control and long-term side effect profiles. Radiation
clinical stage, and Gleason sum to predict the risk of pelvic lymph node techniques are discussed in more detail below.
metastases.130
External Beam Radiation Therapy
PLND should be performed using an extended technique.337,338 An Over the past several decades, EBRT techniques have evolved to allow
extended PLND includes removal of all node-bearing tissue from an area higher doses of radiation to be administered safely. Three-dimensional
bounded by the external iliac vein anteriorly, the pelvic side wall laterally, (3D) CRT (3D-CRT) uses computer software to integrate CT images of the
the bladder wall medially, the floor of the pelvis posteriorly, Cooper’s patients’ internal anatomy in the treatment position, which allows higher
ligament distally, and the internal iliac artery proximally. Removal of more cumulative doses to be delivered with lower risk of late effects.141,347-349
lymph nodes using the extended technique has been associated with The second-generation 3D technique, intensity-modulated RT (IMRT), has
increased likelihood of finding lymph node metastases, thereby providing been used increasingly in practice.350 IMRT reduced the risk of
more complete staging.339-341 A survival advantage with more extensive gastrointestinal toxicities and rates of salvage therapy compared to 3D-
lymphadenectomy has been suggested by several studies, possibly due to CRT in some but not all older retrospective and population-based studies,
elimination of microscopic metastases,340,342-344 although definitive proof of although treatment cost is increased.351-354
oncologic benefit is lacking.345 PLND can be performed safely
laparoscopically, robotically, or as an open procedure, and complication More recently, moderately hypofractionated image-guided IMRT regimens
rates should be similar among the three approaches. (2.4–4 Gy per fraction over 4–6 weeks) have been tested in randomized
trials, and their efficacy has been similar or non-inferior to conventionally
Radiation Therapy fractionated IMRT, with one trial showing fewer treatment failures with a
RT techniques used in prostate cancer include EBRT, proton radiation, moderately fractionated regimen.355-364 Toxicity was similar between
and brachytherapy. EBRT techniques include IMRT and hypofractionated, moderately hypofractionated and conventional regimens in
image-guided SBRT. An analysis that included propensity-score matching some355,359,362,363 but not all of the trials.357,360,361 In addition, efficacy results
of patients showed that, among younger men with prostate cancer, SBRT varied among the trials, with some showing noninferiority or similar
and IMRT had similar toxicity profiles whereas proton radiation was efficacy and others showing that hypofractionation may be less effective
associated with reduced urinary toxicity and increased bowel toxicity. The than conventional fractionation schemes. These safety and efficacy
differences are likely a result of differences in fractionation schedules.365 In

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NCCN Guidelines Version 1.2022

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addition, results of a large cohort study showed no differences in quality of prostate (with or without seminal vesicles) is appropriate for patients with
life or urinary or bowel function between those that received low-risk cancers. Intermediate-risk and high-risk patients should receive
hypofractionated versus conventional regimens.366 Overall, the panel doses of up to 81.0 Gy.351,375,376
believes that hypofractionated IMRT techniques, which are more
convenient for patients, can be considered as an alternative to Data suggested that EBRT and radical prostatectomy were effective for
conventionally fractionated regimens when clinically indicated. The panel the treatment of localized prostate cancer.377 EBRT of the primary prostate
lists fractionation schemes that have shown acceptable efficacy and cancer shows several distinct advantages over radical prostatectomy.
toxicity on PROS-E page 3 of 5 in the algorithm above. An EBRT avoids complications associated with operation, such as bleeding
ASTRO/ASCO/AUA evidence-based guideline regarding the use of and transfusion-related effects, and risks associated with anesthesia, such
hypofractionated radiation in men with localized prostate cancer concluded as myocardial infarction and pulmonary embolus. 3D-CRT and IMRT
that moderately fractionated regimens are justified for routine use in this techniques are widely available and are possible for patients over a wide
setting and provides more detail on the topic.367 range of ages. EBRT has a low risk of urinary incontinence and stricture
and a good chance of short-term preservation of erectile function.378
Daily prostate localization using image-guided RT (IGRT) is essential with
either 3D-CRT or IMRT for target margin reduction and treatment The disadvantages of EBRT include a treatment course of 8 to 9 weeks.
accuracy. Imaging techniques, such as ultrasound, implanted fiducials, Up to 50% of patients have some temporary bladder or bowel symptoms
electromagnetic targeting and tracking, or endorectal balloon, can improve during treatment. There is a low but definite risk of protracted rectal
cure rates and decrease complications. symptoms from radiation proctitis, and the risk of erectile dysfunction
increases over time.378,379 The risk of late rectal complications following RT
These techniques have permitted safer dose escalation, and results of is related to the volume of the rectum receiving doses of radiation close to
randomized trials have suggested that dose escalation is associated with or exceeding the radiation dose required to control the primary tumor.
improved biochemical outcomes.368-373 Kuban and colleagues371 published
an analysis of their dose-escalation trial of 301 patients with stage T1b to Biomaterials have been developed, tested, and FDA approved to serve as
T3 prostate cancer. Freedom from biochemical or clinical recurrence was spacer materials when inserted between the rectum and prostate.380,381 In
higher in the group randomized to 78 Gy compared to 70 Gy (78% vs. a randomized phase 3 multicenter clinical trial of patients undergoing
59%, P = .004) at a median follow-up of 8.7 years. The difference was image-guided intensity-modulated RT (IG-IMRT), with the risk of late (3-
even greater among patients with diagnostic PSA >10 ng/mL (78% vs. year) common terminology criteria for adverse events (CTCAE) grade 2 or
39%, P = .001). An analysis of the National Cancer Database found that higher, physician-recorded rectal complications declined from 5.7% to 0%
dose escalation (75.6–90 Gy) resulted in a dose-dependent improvement in the control versus hydrogel spacer group.382 The hydrogel spacer group
in OS for men with intermediate- or high-risk prostate cancer.374 In light of had a significant reduction in bowel QOL decline. No significant
these findings, the conventional 70 Gy dose is no longer considered differences in adverse events were noted in those receiving hydrogel
adequate. A dose of 75.6 to 79.2 Gy in conventional fractions to the placement versus controls. Results of a secondary analysis of this trial
suggest that use of a perirectal spacer may decrease the sexual side

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effects of radiation.383 Spacer implantation, however, is quite expensive 8.4 years, the escalated dose reduced biochemical recurrences, but
and may be associated with rare complications such as rectum perforation increased late toxicity and had no effect on OS.
and urethral damage.384,385 Overall, the panel believes that biocompatible
EBRT for Patients with High-Risk or Very-High-Risk Disease
and biodegradable perirectal spacer materials may be implanted between
the prostate and rectum in patients undergoing external radiotherapy with EBRT has demonstrated efficacy in patients with high risk and very high
organ-confined prostate cancer in order to displace the rectum from high risk prostate cancer. One study randomized 415 patients to EBRT alone or
radiation dose regions. A randomized phase III trial demonstrated reduced EBRT plus 3-year ADT.389 In another study (RTOG 8531), 977 patients
rectal bleeding in patients undergoing the procedure compared to controls. with T3 disease treated with EBRT were randomized to adjuvant ADT or
Retrospective data also support its use in similar patients undergoing ADT at relapse.390 Two other randomized phase 3 trials evaluated long-
brachytherapy. Patients with obvious rectal invasion or visible T3 and term ADT with or without radiation in a population of patients who mostly
posterior extension should not undergo perirectal spacer implantation. had T3 disease.391-394 In all four studies, the combination group showed
improved disease-specific survival and OS compared to single-modality
If the cancer recurs, salvage radical prostatectomy is associated with a treatment. Patients with a PSA nadir >0.5 ng/mL after radiation and 6
higher risk of complications than primary radical prostatectomy.386 months of ADT have an adjusted hazard ratio (HR) for all-cause mortality
Contraindications to EBRT include prior pelvic irradiation, active of 1.72 (95% CI, 1.17–2.52; P = .01) compared with patients who received
inflammatory disease of the rectum, or a permanent indwelling Foley radiation only.395 Prophylactic nodal radiation should be considered in this
catheter. Relative contraindications include very low bladder capacity, population. 396-398
chronic moderate or severe diarrhea, bladder outlet obstruction requiring a
EBRT for Node-Positive Disease
suprapubic catheter, and inactive ulcerative colitis.
EBRT with neoadjuvant, concurrent, and/or adjuvant ADT is the preferred
EBRT for Early Disease option for patients with clinical N1 disease. Abiraterone can be added. In
EBRT is one of the principal treatment options for clinically localized addition, ADT alone or with abiraterone are options. In each case, the use
prostate cancer. The NCCN Guidelines Panel consensus was that modern of the fine-particle formulation of abiraterone is a category 2B
EBRT and surgical series show similar PFS in patients with low-risk recommendation.
disease treated with radical prostatectomy or EBRT. In a study of 3546
patients treated with brachytherapy plus EBRT, disease-free survival For adjuvant therapy for node-positive disease after radical prostatectomy,
(DFS) remained steady at 73% between 15 and 25 years of follow-up.387 see Adjuvant Therapy for pN1, below.
The panel lists several acceptable dosing schemas in the guidelines. The EBRT to the Primary Tumor in Low-Volume M1 Disease
NRG Oncology/RTOG 0126 randomized clinical trial compared 79.2 Gy Patients with newly diagnosed, low-volume metastatic prostate cancer can
(44 fractions) and 70.2 Gy (39 fractions), both in 1.8 Gy fractions, in 1499
be considered for ADT with EBRT to the primary tumor based on results
men with intermediate-risk prostate cancer.388 After a median follow-up of from the randomized controlled phase 3 STAMPEDE trial.399 In this
multicenter, international study, 2061 patients were randomized to lifelong

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ADT with or without EBRT to the primary tumor (either 55 Gy in 20 daily Stereotactic body RT (SBRT) is a technique that delivers highly conformal,
fractions over 4 weeks or 36 Gy in 6 weekly fractions over 6 weeks). The high-dose radiation in five or fewer treatment fractions, which are safe to
primary outcome of OS by intention-to-treat analysis was not met (HR, administer only with precise, image-guided delivery.407 Single-institution
0.92; 95% CI, 0.80–1.06; P = .266), but EBRT improved the secondary series with median follow-up as long as 6 years report excellent
outcome of failure-free survival (FFS; HR, 0.76; 95% CI, 0.68–0.84; P < biochemical PFS and similar early toxicity (bladder, rectal, and QOL)
.0001). In a pre-planned subset analysis, outcomes of patients with high compared to standard radiation techniques.406-412 According to a pooled
metastatic burden (defined as visceral metastases; ≥4 bone metastases analysis of phase 2 trials, the 5-year biochemical relapse-free survival is
with ≥1 outside the vertebral bodies or pelvis; or both) and those with low 95%, 84%, and 81% for patients with low-, intermediate-, and high-risk
metastatic burden (all others) were determined. EBRT improved OS disease, respectively.413 A study of individual patient data from a cohort of
(adjusted HR, 0.68; 95% CI, 0.52–0.90), prostate cancer-specific survival 2142 patients with low or intermediate-risk prostate cancer from 10 single
(adjusted HR, 0.65; 95% CI, 0.47–0.90), FFS (adjusted HR, 0.59; 95% CI, institution phase 2 trials and 2 multi-institutional phase 2 trials found that
0.49–0.72), and PFS (adjusted HR, 0.78; 95% CI, 0.63–0.98) in patients the 7-year cumulative rates of biochemical recurrence were 4.5%, 8.6%,
with low metastatic burden, but not in patients with high metastatic burden. and 14.9% for low-risk disease, favorable intermediate risk disease, and
Randomized clinical trials are ongoing to better test the value of removal unfavorable intermediate risk disease, respectively.414 Severe acute
or radiation of the primary tumor in patients with low metastatic burden toxicity was rare, at 0.6% for grade 3 or higher genitourinary toxic events
who are beginning ADT.400-404 and 0.09% for grade 3 or higher gastrointestinal toxic events. Late (7-year
cumulative incidence) toxicity rates were 2.4% and 0.4% for grade 3 or
The panel recommends against EBRT to the primary tumor in the case of higher genitourinary toxic events and gastrointestinal toxic events,
high-volume M1 disease based on the HORRAD and STAMPEDE respectively.
trials.399,405 No improvement in OS was seen from the addition of EBRT to
the primary when combined with standard systemic therapy in patients SBRT may be associated with more toxicity than moderately fractionated
with high-volume M1 disease in either trial. IMRT. One retrospective study of 4005 patients reported higher
genitourinary toxicity at 24 months after SBRT than IMRT (44% vs. 36%; P
Stereotactic Body Radiation Therapy = .001).415 Another phase 2 trial found increased toxicity with doses >47.5
The relatively slow proliferation rate of prostate cancer is reflected in a low Gy delivered in 5 fractions.416 An analysis using the SEER database also
α/β ratio,406 most commonly reported between 1 and 4. These values are reported that SBRT was more toxic than IMRT.417
similar to that for the rectal mucosa. Because the α/β ratio for prostate
cancer is similar to or lower than the surrounding tissues responsible for Several phase 3 trials have been initiated comparing conventional
most of the toxicity reported with radiation, appropriately designed regimens to SBRT.418-420 Preliminary results show that the genitourinary
radiation treatment fields and schedules using extremely hypofractionated and bowel toxicity is similar with the two techniques. In addition, the
regimens should result in similar cancer control rates without increased HYPO-RT-PC trial demonstrated non-inferiority of 42.7 Gy in seven
risk of late toxicity.

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fractions to 78.0 Gy in 39 fractions with respect to FFS in patients with progressive erectile dysfunction over several years. IMRT causes less
intermediate-to-high risk prostate cancer.420 acute and late genitourinary toxicity and similar freedom from biochemical
recurrence compared with iodine-125 or palladium-103 permanent seed
SBRT/extremely hypofractionated image-guided IMRT regimens (6.5 Gy implants.425,426 Current brachytherapy techniques attempt to improve the
per fraction or greater) can be considered as an alternative to radioactive seed placement and radiation dose distribution.
conventionally fractionated regimens at clinics with appropriate
technology, physics, and clinical expertise. Longer follow-up and There are currently two methods for prostate brachytherapy: low dose-rate
prospective multi-institutional data are required to evaluate longer-term (LDR) and high dose-rate (HDR). LDR brachytherapy consists of
results, especially because late toxicity theoretically could be worse in placement of permanent seed implants in the prostate. The short range of
hypofractionated regimens compared to conventional fractionation (1.8– the radiation emitted from these low-energy sources allows delivery of
2.0 Gy per fraction). adequate dose levels to the cancer within the prostate, with excessive
irradiation of the bladder and rectum avoided. Post-implant dosimetry
Brachytherapy should be performed to document the quality of an LDR implant.427 HDR
Brachytherapy involves placing radioactive sources into the prostate brachytherapy, which involves temporary insertion of a radiation source, is
tissue. Brachytherapy has been used traditionally for low-risk cases a newer approach.
because earlier studies found it less effective than EBRT for high-risk
disease.98,421 However, increasing evidence suggests that technical Two groups have observed a lower risk of urinary frequency, urgency, and
advancements in brachytherapy may provide a role for contemporary rectal pain with HDR brachytherapy compared with LDR brachytherapy
brachytherapy in high-risk localized and locally advanced prostate (permanent seed implant).428,429 Vargas and colleagues430 reported that
cancer.422,423 HDR brachytherapy results in a lower risk of erectile dysfunction than LDR
brachytherapy. Commonly prescribed doses for LDR and HDR
The advantage of brachytherapy is that the treatment is completed in 1 brachytherapy are listed in the guidelines.
day with little time lost from normal activities. In appropriate patients, the
cancer-control rates appear comparable to radical prostatectomy (over For patients with very large or very small prostates, symptoms of bladder
90%) for low-risk prostate cancer with medium-term follow-up.424 In outlet obstruction (high International Prostate Symptom Score), or a
addition, the risk of incontinence is minimal in patients without a previous previous TURP, seed implantation may be more difficult. These patients
transurethral resection of the prostate (TURP), and erectile function is also have an increased risk of side effects. Neoadjuvant ADT may be used
preserved in the short term.379 Disadvantages of brachytherapy include the to shrink the prostate to an acceptable size; however, increased toxicity is
requirement for general anesthesia and the risk of acute urinary retention. expected from ADT, and prostate size may not decline in some men. The
Irritative voiding symptoms may persist for as long as 1 year after potential toxicity of ADT must be weighed against the possible benefit of
implantation. The risk of incontinence is greater after TURP because of target reduction.
acute retention and bladder neck contractures, and many patients develop

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Ideally, the accuracy of brachytherapy treatment should be verified by Brachytherapy Boost

daily prostate localization with techniques of IGRT: CT, ultrasound, LDR or HDR brachytherapy can be added as a boost to EBRT plus ADT in
implanted fiducials, or electromagnetic targeting/tracking. Endorectal men with unfavorable intermediate-, high-, or very-high-risk prostate
balloons may be used to improve prostate immobilization. Perirectal cancer being treated with curative intent. Combining EBRT and
spacer materials (discussed under External Beam Radiation Therapy, brachytherapy allows dose escalation while minimizing acute or late
above) may be employed when the previously mentioned techniques are toxicity in patients with high-risk localized or locally advanced cancer.438-441
insufficient to improve oncologic cure rates and/or reduce side effects due This combination has demonstrated improved biochemical control over
to anatomic geometry or other patient-related factors (eg, medication EBRT plus ADT alone in randomized trials, but with higher toxicity.442-444
usage, comorbid conditions). Patients with obvious rectal invasion or An analysis of a cohort of 12,745 patients with high-risk disease found that
visible T3 and posterior extension should not undergo perirectal spacer treatment with brachytherapy (HR, 0.66; 95% CI, 0.49–0.86) or
implantation. brachytherapy plus EBRT (HR, 0.77; 95% CI, 0.66–0.90) lowered disease-
specific mortality compared to EBRT alone.445
Brachytherapy Alone for Localized Disease
Brachytherapy alone is an option for patients with very low, low, or The randomized ASCENDE-RT trial compared two methods of dose
favorable intermediate-risk prostate cancer, depending on life expectancy. escalation in 398 men with intermediate- or high-risk prostate cancer:
Patients with high-risk cancers are generally considered poor candidates dose-escalated EBRT boost to 78 Gy or LDR brachytherapy boost.446 All
for brachytherapy alone. Either LDR or HDR brachytherapy can be used in men were initially treated with 12 months of ADT and pelvic EBRT to 46
this setting. Gy. An intention-to-treat analysis found that the primary endpoint of
biochemical PFS was 89% versus 84% at 5 years; 86% versus 75% at 7
Retrospective analyses show that LDR or HDR brachytherapy alone can years; and 83% versus 62% at 9 years for the LDR versus EBRT boost
be effective and well tolerated in this population.431-435 A phase 2 trial in arms (log-rank P < .001). Toxicity was higher in the brachytherapy arm,
300 patients with intermediate-risk prostate cancer also found LDR with the cumulative incidence of grade 3 genitourinary events at 5 years of
brachytherapy alone to be safe and effective.436 However, randomized 18.4% for brachytherapy boost and 5.2% for EBRT boost (P < .001).447 A
controlled trials comparing brachytherapy to radical prostatectomy or trend for increased gastrointestinal toxicity with brachytherapy boost was
EBRT in this population are limited. In a single-center trial, 165 patients also seen (cumulative incidence of grade 3 events at 5 years, 8.1% vs.
with low-risk prostate cancer were randomized to LDR brachytherapy with 3.2%; P = .12). However, at 6-year follow-up, health-related QOL was
iodine-125 seeds or radical prostatectomy. The 2-year biochemical FFS similar between the groups in most domains, except that physical and
rates were similar between the groups at 96.1% after brachytherapy and urinary function scales were significantly lower in the LDR arm.448
97.4% after radical prostatectomy (P = .35).437 At 6-month follow-up, Whereas the toxicity is increased with the use of brachytherapy boost, this
continence was better in the brachytherapy group whereas potency was and other randomized controlled trials have failed to show an improvement
better in the radical prostatectomy group. in overall or cancer-specific survival.449

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Addition of ADT (2 or 3 years) to brachytherapy and EBRT is common for survival rates of 68.5%, 81.5%, and 90.3%, respectively, at 5 years.458
patients at high risk of recurrence. The outcome of trimodality treatment is Toxicities were mostly grade 1 and 2 and included gastrointestinal toxicity
excellent, with 9-year PFS and disease-specific survival reaching 87% and and urethral strictures, and one case of Grade 3 urinary incontinence. In
91%, respectively.450,451 However, it remains unclear whether the ADT another prospective phase 2 trial, the primary endpoint of grade ≥3 late
component contributes to outcome improvement. D’Amico and colleagues treatment-related gastrointestinal and genitourinary adverse events at 9 to
studied a cohort of 1342 patients with PSA over 20 ng/mL and clinical 24 months post salvage brachytherapy was below the unacceptable
T3/T4 and/or Gleason score 8 to 10 disease.452 Addition of either EBRT or threshold, at 14%.459
ADT to brachytherapy did not confer an advantage over brachytherapy
alone. The use of all three modalities reduced prostate cancer-specific Data on the use of brachytherapy after permanent brachytherapy are
mortality compared to brachytherapy alone (adjusted HR, 0.32; 95% CI, limited, but the panel agrees that it can be considered for carefully
0.14–0.73). Other analyses did not find an improvement in recurrence rate selected patients. Decisions regarding the use of brachytherapy in the
when ADT was added to brachytherapy and EBRT.453,454 recurrent-disease setting should consider comorbidities, extent of disease,
and potential complications. Brachytherapy in this setting is best
A large, multicenter, retrospective cohort analysis that included 1809 men performed at high-volume centers.
with Gleason score 9–10 prostate cancer found that multimodality therapy
with EBRT, brachytherapy, and ADT was associated with improved Proton Therapy
prostate cancer-specific mortality and longer time to distant metastasis Proton beam RT has been used to treat patients with cancer since the
than either radical prostatectomy or EBRT with ADT.455 In addition, an 1950s. Proponents of proton therapy argue that this form of RT could have
analysis of outcomes of almost 43,000 men with high-risk prostate cancer advantages over x-ray (photon)-based radiation in certain clinical
in the National Cancer Database found that mortality was similar in men circumstances. Proton therapy and x-ray–based therapies like IMRT can
treated with EBRT, brachytherapy, and ADT versus those treated with deliver highly conformal doses to the prostate. Proton-based therapies will
radical prostatectomy, but was worse in those treated with EBRT and deliver less radiation dose to some of the surrounding normal tissues like
ADT.456 muscle, bone, vessels, and fat not immediately adjacent to the prostate.
These tissues do not routinely contribute to the morbidity of prostate
Salvage Brachytherapy radiation and are relatively resilient to radiation injury; therefore, the
Brachytherapy can be considered in men with biochemical recurrence benefit of decreased dose to these types of normal, non-critical tissues
after EBRT. In a retrospective study of 24 men who had EBRT as primary has not been apparent. The critical normal structures adjacent to the
therapy and permanent brachytherapy after biochemical recurrence, the prostate that can create prostate cancer treatment morbidity include the
cancer-free and biochemical relapse-free survival rates were 96% and bladder, rectum, neurovascular bundles, and occasionally small bowel.
88%, respectively, after a median follow-up of 30 months.457 Results of a
phase 2 study of salvage HDR brachytherapy after EBRT included The weight of the current evidence about prostate cancer treatment
relapse-free survival, distant metastases-free survival, and cause-specific morbidity supports the notion that the volume of the rectum and bladder

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that receives radiobiologically high doses of radiation near the prescription performed using SEER-Medicare claims data for the following long-term
radiation dose accounts for the likelihood of long-term treatment morbidity, endpoints: gastrointestinal morbidity, urinary incontinence, non-
as opposed to higher volume, lower dose exposures. Numerous incontinence urinary morbidity, sexual dysfunction, and hip fractures.464
dosimetric studies have been performed trying to compare x-ray–based With follow-up as mature as 80 months and using both propensity scoring
IMRT plans to proton therapy plans to illustrate how one or the other type and instrumental variable analysis, the authors concluded that men
of treatment can be used to spare the bladder or rectum from higher dose receiving IMRT therapy had statistically significantly lower gastrointestinal
parts of the exposure. These studies suffer from the biases and talents of morbidity than patients receiving proton therapy, whereas rates of urinary
the investigators who plan and create computer models of dose deposition incontinence, non-incontinence urinary morbidity, sexual dysfunction, hip
for one therapy or the other.460 Although dosimetric studies in-silico can fractures, and additional cancer therapies were statistically
suggest that the right treatment planning can make an IMRT plan beat a indistinguishable between the cohorts. However, firm conclusions
proton therapy plan and vice versa, they do not accurately predict clinically regarding differences in toxicity or effectiveness of proton and photon
meaningful endpoints. therapy cannot be drawn because of the limitations inherent in
retrospective/observational studies.
Comparative effectiveness studies have been published in an attempt to
compare toxicity and oncologic outcomes between proton and photon The costs associated with proton beam facility construction and proton
therapies. Two comparisons between men treated with proton therapy or beam treatment are high compared to the expense of building and using
EBRT report similar early toxicity rates.461,462 A prospective QOL the more common photon linear accelerator-based practice.462 The
comparison of patient-reported outcomes using the EPIC instrument American Society for Radiation Oncology (ASTRO) evaluated proton
between IMRT (204 patients) and proton therapy (1234 patients) therapy and created a model policy to support the society’s position on
concluded that “No differences were observed in summary score changes payment coverage for proton beam therapy in 2014.465 This model policy
for bowel, urinary incontinence, urinary irritative/obstructive, and sexual was updated in 2017 and recommends coverage of proton therapy for the
domains between the 2 cohorts” after up to 2 years of follow-up.463 A treatment of non-metastatic prostate cancer if the patient is enrolled in
Medicare analysis of 421 men treated with proton therapy and a matched either an institutional review board (IRB)-approved study or a multi-
cohort of 842 men treated with IMRT showed less genitourinary toxicity at institutional registry that adheres to Medicare requirements for Coverage
6 months for protons, although the difference disappeared after 1 year.462 with Evidence Development (CED). The policy states: “In the treatment of
No other significant differences were seen between the groups. In prostate cancer, the use of [proton beam therapy] is evolving as the
contrast, a single-center report of prospectively collected QOL data comparative efficacy evidence is still being developed. In order for an
revealed significant problems with incontinence, bowel dysfunction, and informed consensus on the role of [proton beam therapy] for prostate
impotence at 3 months, 12 months, and >2 years after treatment with cancer to be reached, it is essential to collect further data, especially to
proton therapy.461 In that report, only 28% of men with normal erectile understand how the effectiveness of proton therapy compares to other RT
function maintained it after therapy. The largest retrospective comparative modalities such as IMRT and brachytherapy. There is a need for more
effectiveness analysis to date comparing IMRT to proton therapy was well-designed registries and studies with sizable comparator cohorts to

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help accelerate data collection. Proton beam therapy for primary treatment The panel notes that 8 Gy as a single dose is as effective for pain
of prostate cancer should only be performed within the context of a palliation at any bony site as longer courses of radiation, but re-treatment
prospective clinical trial or registry.” rates are higher. Other regimens (ie, 30 Gy in 10 fractions or 37.5 Gy in 15
fractions) may be used as alternative palliative dosing depending on
A prospective phase 2 clinical trial enrolled 184 patients with low or clinical scenario (both category 2B).
intermediate-risk prostate cancer who received 70 Gy of hypofractionated
proton therapy in 28 fractions.466 The 4-year rate of biochemical-clinical Radiation to metastases has also been studied in the oligometastatic
FFS was 93.5% (95% CI, 89%–98%). Grade ≥2 acute GI and urologic setting. The ORIOLE phase 2 randomized trial randomized 54 patients
toxicity rates were 3.8% and 12.5%, respectively. Late GI and urologic with recurrent castration-naïve prostate cancer and 1 to 3 metastases to
toxicity rates 7.6% and 13.6%, respectively, at 4 years. receive SABR or observation at a 2:1 ratio.471 The primary outcome
measure was progression at 6 months by increasing PSA, progression
The NCCN Panel believes no clear evidence supports a benefit or detected by conventional imaging, symptomatic progression, initiation of
decrement to proton therapy over IMRT for either treatment efficacy or ADT for any reason, or death. Progression at 6 months was lower in
long-term toxicity. Conventionally fractionated prostate proton therapy can patients in the SABR arm than in the observation arm (19% vs. 61%; P =
be considered a reasonable alternative to x-ray–based regimens at clinics .005). The secondary endpoint of PFS was also improved in the patients
with appropriate technology, physics, and clinical expertise. who received SABR (not reached vs. 5.8 months; HR, 0.30; 95% CI, 0.11–
0.81; P = .002). The panel considers this approach to be experimental at
Radiation for Distant Metastases
this time.
EBRT is an effective means of palliating isolated bone metastases from
prostate cancer. Studies have confirmed the common practice in Canada Radium-223 and Other Radiopharmaceuticals
and Europe of managing prostate cancer with bone metastases with a In May 2013, the U.S. Food and Drug Administration (FDA) approved
short course of radiation to the bone. A short course of 8 Gy x 1 is as radium-223 dichloride, an alpha particle-emitting radioactive agent. This
effective as, and less costly than, 30 Gy in 10 fractions.467 In a randomized first-in-class radiopharmaceutical was approved for treatment of metastatic
trial of 898 patients with bone metastases, grade 2–4 acute toxicity was CRPC in patients with symptomatic bone metastases and no known
observed less often in the 8-Gy arm (10%) than the 30-Gy arm (17%) (P = visceral metastatic disease. Approval was based on clinical data from a
.002); however, the retreatment rate was higher in the 8-Gy group (18%) multicenter, phase 3, randomized trial (ALSYMPCA) that included 921
than in the 30-Gy group (9%) (P < .001).468 In another study of 425 men with symptomatic CRPC, two or more bone metastases, and no
patients with painful bone metastases, a single dose of 8 Gy was non- known visceral disease.472 Fifty-seven percent of the patients received
inferior to 20 Gy in multiple fractions in terms of overall pain response to prior docetaxel and all patients received best supportive care. Patients
treatment.469 The SCORAD randomized trial failed to show non-inferiority were randomized in a 2:1 ratio to 6 monthly radium-223 intravenous
for ambulatory status of single-fraction 8-Gy EBRT to 20 Gy in 5 injections or placebo. Compared to placebo, radium-223 significantly
fractions.470 improved OS (median 14.9 months vs. 11.3 months; HR, 0.70; 95% CI,

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0.058–0.83; P < .001) and prolonged time to first skeletal-related event are no longer candidates for effective chemotherapy.478 Because many
(SRE) (median 15.6 months vs. 9.8 months). Preplanned subset analyses patients have multifocal bone pain, systemic targeted treatment of skeletal
showed that the survival benefit of radium-223 was maintained regardless metastases offers the potential of pain relief with minimal side effects.
of prior docetaxel use.473 Intention-to-treat analyses from ALSYMPCA Unlike the alpha-emitting agent radium-223, beta emitters confer no
showed that radium-223 also may reduce the risk of symptomatic SREs.474 survival advantage and are palliative. Beta-emitting radiopharmaceuticals
Grade 3/4 hematologic toxicity was low (3% neutropenia, 6% developed for the treatment of painful bone metastases most commonly
thrombocytopenia, and 13% anemia), likely due to the short range of used for prostate cancer include strontium-89 (89Sr) or samarium-153
radioactivity.472 Fecal elimination of the agent led to generally mild non- (153Sm).479,480 The risk of bone marrow suppression, which might
hematologic side effects, which included nausea, diarrhea, and vomiting. influence the ability to provide additional systemic chemotherapy, should
Radium-223 was associated with improved or slower decline of QOL in be considered before this therapy is initiated.
ALSYMPCA.475
Comparison of Treatment Options for Localized Disease
The multicenter, international, double-blind, placebo-controlled, phase 3 Several large prospective, population/cohort-based studies have
ERA 223 trial randomized bone-metastatic patients with chemotherapy- compared the outcomes of patients with localized prostate cancer treated
naïve CRPC to abiraterone with or without radium-223.476 The patients with EBRT, brachytherapy, radical prostatectomy, observation, and/or
were asymptomatic or mildly symptomatic. The primary endpoint of active surveillance. Barocas et al compared radical prostatectomy, EBRT,
symptomatic skeletal event-free survival in the intention-to-treat population and active surveillance in 2550 men and found that, after 3 years, radical
was not met. In fact, the addition of radium-223 to abiraterone was prostatectomy was associated with a greater decrease in urinary and
associated with an increased frequency of bone fractures compared with sexual function than either EBRT or active surveillance.481 Active
placebo. The panel therefore does not recommend this combination. surveillance, however, was associated with an increase in urinary irritative
symptoms. Health-related QOL measures including bowel and hormonal
Radium-223 is a category 1 option to treat symptomatic bone metastases
function were similar among the groups, as was disease-specific survival.
without visceral metastases. Hematologic evaluation should be performed
according to the FDA label before treatment initiation and before each Chen et al compared radical prostatectomy, EBRT, and brachytherapy
subsequent dose.477 Radium-223 given in combination with chemotherapy against active surveillance in 1141 men.482 As in the Barocas study,
(such as docetaxel) outside of a clinical trial has the potential for additive radical prostatectomy was associated with greater declines in sexual and
myelosuppression.477 It is not recommended for use in combination with urinary function than other treatments at 3 months. In this study, EBRT
docetaxel or any other systemic therapy except ADT. It should not be used was associated with worse short-term bowel function, and both EBRT and
in patients with visceral metastases, and it should be given with brachytherapy were associated with worsened urinary obstructive and
concomitant denosumab or zoledronic acid. irritative symptoms. By 2 years, however, differences among the groups
compared with active surveillance were insignificant. Results of a
Beta-emitting radiopharmaceuticals are an effective and appropriate
systematic review showed similar findings to these studies.483
option for patients with widespread metastatic disease, particularly if they

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Another study examined patient-reported outcomes in greater than 2000 lower 8-year biochemical progression-free rate compared to EBRT in a
patients with localized prostate cancer managed by radical prostatectomy, small trial of 62 patients, although disease-specific survival and OS were
brachytherapy, EBRT with or without ADT, or active surveillance.484 By 5 similar.489
years, most functional differences were minimal between management
approaches. However, radical prostatectomy was associated with worse Cryosurgery has been assessed in patients with recurrent disease after
incontinence in the full cohort and with worse sexual function in those with RT.490-492 In one registry-based study of 91 patients, the biochemical DFS
unfavorable intermediate-, high-, or very-high-risk disease than those rates at 1, 3, and 5 years were 95.3%, 72.4%, and 46.5%, respectively.
managed with EBRT and ADT. Adverse events included urinary retention (6.6%), incontinence (5.5%),
and rectourethral fistula (3.3%).492
Other Local Therapies
HIFU has been studied for treatment of initial disease.493,494 A prospective
Many therapies have been investigated for the treatment of localized
multi-institutional study used HIFU in 111 patients with localized prostate
prostate cancer in the initial disease and recurrent settings, with the goals
cancer.493 The radical treatment-free survival rate was 89% at 2 years, and
of reducing side effects and matching the cancer control of other
continence and erectile functions were preserved in 97% and 78% of
therapies. Cryotherapy or other local therapies are not recommended as
patients, respectively, at 12 months. Morbidity was acceptable, with a
routine primary therapy for localized prostate cancer due to lack of long-
grade III complication rate of 13%. In another prospective multi-
term data comparing these treatments to radiation or radical
institutional study, 625 men with localized prostate cancer were treated
prostatectomy. At this time, the panel recommends only cryosurgery and
with HIFU.495 Eighty-four percent of the cohort had intermediate- or high-
high-intensity focused ultrasound (HIFU; category 2B) as local therapy
risk disease. The primary endpoint of FFS was 88% at 5 years (95% CI,
options for RT recurrence in the absence of metastatic disease.
85%–91%). Pad-free urinary continence was reported by 98% of
Cryosurgery, also known as cryotherapy or cryoablation, is an evolving participants. Other case series studies have seen similar results.496,497
minimally invasive therapy that damages tumor tissue through local
HIFU also has been studied for treatment of radiation recurrence.498-504
freezing. In the initial disease setting, the reported 5-year biochemical
Analysis of a prospective registry of men treated with HIFU for radiation
disease-free rate after cryotherapy ranged from 65% to 92% in patients
recurrence revealed median biochemical recurrence-free survival at 63
with low-risk disease using different definitions of biochemical
months, 5-year OS of 88%, and cancer-specific survival of 94%.505
recurrence.485 A report suggests that cryotherapy and radical
Morbidity was acceptable, with a grade III/IV complication rate of 3.6%.
prostatectomy give similar oncologic results for unilateral prostate
Analysis of a separate prospective registry showed that 48% of men who
cancer.486 A study by Donnelly and colleagues487 randomly assigned 244
received HIFU following radiotherapy failure were able to avoid ADT at a
men with T2 or T3 disease to either cryotherapy or EBRT. All patients
median follow-up of 64 months.506
received neoadjuvant ADT. There was no difference in 3-year OS or DFS.
Patients who received cryotherapy reported poorer sexual function.488 For Other emerging local therapies, such as focal laser ablation and vascular-
patients with locally advanced cancer, cryoablation was associated with targeted photodynamic (VTP) therapy have also been studied.507,508 The

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multicenter, open-label, phase 3, randomized controlled CLIN1001 and a DRE is recommended annually. The clinician may opt to omit the
PCM301 trial compared VTP therapy (IV padeliporfin, optical fibers DRE if PSA levels remain undetectable.
inserted into the prostate, and subsequent laser activation) to active
surveillance in 413 men with low-risk prostate cancer.509 After a median Patients with Castration-Naïve Disease on ADT
follow-up of 24 months, 28% of participants in the VTP arm had disease The intensity of clinical monitoring for patients on ADT for castration-naïve
progression compared with 58% in the active surveillance arm (adjusted disease is determined by the response to initial ADT, EBRT, or both.
HR, 0.34; 95% CI, 0.24–0.46; P < .0001). Negative prostate biopsy results Follow-up evaluation of these patients should include history and physical
were more prevalent in the VTP group (49% vs. 14%; adjusted RR, 3.67; examination and PSA measurement every 3 to 6 months based on clinical
95% CI, 2.53–5.33; P < .0001). The most common serious adverse event judgment. Imaging should be performed for symptoms or increasing PSA.
in the VTP group was urinary retention (3 of 206 patients), which resolved The relative risk for bone metastasis or death increases as PSADT falls; a
within 2 months in all cases. major inflection point appears at PSADT of 8 months. Bone imaging
should be performed more frequently in these men.511
Disease Monitoring
Please refer to the NCCN Guidelines for Survivorship (available at Patients with Localized Disease Under Observation
www.NCCN.org) for recommendations regarding common consequences Patients with localized disease on observation follow the same monitoring
of cancer and cancer treatment (eg, cardiovascular disease risk recommendations as patients with castration-naïve disease who are on
assessment; anxiety, depression, trauma, and distress; hormone-related ADT, except that the physical exam and PSA measurement should only
symptoms; sexual dysfunction) and on the promotion of physical activity, be done every 6 months.
weight management, and proper immunizations in survivors.
Workup for Progression
Patients After Initial Definitive Therapy Castrate levels of testosterone should be documented if patients with
For patients initially treated with intent to cure, serum PSA levels should advanced disease on ADT show signs of progression, with adjustment of
be measured every 6 to 12 months for the first 5 years and then annually. ADT as necessary. If serum testosterone levels are <50 ng/dL, the patient
PSA testing every 3 months may be better for men at high risk of should undergo disease workup with bone imaging, chest CT, and an
recurrence. When prostate cancer recurred after radical prostatectomy, abdominal/pelvic CT or abdominal/pelvic MRI with and without contrast.512
Pound and colleagues found that 45% of patients experienced recurrence C-11 choline PET/CT or PET/MRI or F-18 fluciclovine PET/CT or PET/MRI
within the first 2 years, 77% within the first 5 years, and 96% by 10 can be considered for further soft tissue and bone evaluation, and F-18
years.510 Local recurrence may result in substantial morbidity and can, in sodium fluoride PET/CT or PET/MRI can be considered for further bone
rare cases, occur in the absence of a PSA elevation. Therefore, annual evaluation for patients without known metastatic disease (see Nuclear
DRE is appropriate to monitor for prostate cancer recurrence and to detect Imaging, above). The panel remains unsure what to do when M1 is
colorectal cancer. Similarly, after RT, the monitoring of serum PSA levels suggested by next-generation (PET-based) imaging but not on
is recommended every 6 months for the first 5 years and then annually

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NCCN Guidelines Version 1.2022

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conventional imaging. PET imaging is not recommended when prostatectomy. Patients were randomized to receive either adjuvant EBRT
metastases are already documented by conventional imaging. or usual care, and follow-up has reached a median of 12.6 years.517 The
initial study report revealed that adjuvant EBRT reduced the risk of PSA
ASCO has published guidelines on the optimal imaging strategies for relapse and disease recurrence.518 An update reported improved 10-year
patients with advanced prostate cancer.513 ASCO recommendations are biochemical FFS for patients with high-risk disease (seminal vesicle
generally consistent with those provided here. positive) receiving post-prostatectomy adjuvant radiation compared to
observation (36% vs. 12%; P = .001).519
Post-Radical Prostatectomy Treatment
Most patients who have undergone radical prostatectomy are cured of Another randomized trial conducted by EORTC compared post-
prostate cancer. However, some men will have adverse pathologic prostatectomy observation and adjuvant EBRT in 1005 patients.520 All
features, positive lymph nodes, or biochemical persistence or recurrence. patients had extraprostatic disease and/or positive surgical margins. The
Some men have detectable PSA after radical prostatectomy due to benign 5-year biochemical PFS significantly improved with EBRT compared to
prostate tissue in the prostate fossa. They have low stable PSAs and a observation for patients with positive surgical margins (78% vs. 49%), but
very low risk of prostate cancer progression.514,515 Serial PSA benefit was not seen for patients with negative surgical margins.
measurements can be helpful for stratifying men at highest risk of
progression and metastases. Several additional randomized trials have compared adjuvant radiation
with early salvage radiation for biochemical recurrence in patients with
Selecting men appropriately for adjuvant or salvage radiation is difficult. adverse features after radical prostatectomy. In the RADICALS-RT trial,
1396 patients were followed for a median 4.9 years and no differences
Adjuvant/Early Salvage Therapy for Adverse Features were seen in 5-year biochemical PFS and freedom from non-protocol
Adjuvant radiation with or without ADT can be given to men with PSA hormone therapy.521 However, urinary incontinence and grade 3–4 urethral
persistence (failure of PSA to fall to undetectable levels) or adverse strictures were more frequent in the adjuvant therapy group. The GETUG-
pathologic features (ie, positive margins, seminal vesicle invasion, AFU 17 trial and the TROG 08.03/ANZUP RAVES trial were both
extracapsular extension) who do not have lymph node metastases. terminated early for unexpectedly low event rates, but similarly found no
Positive surgical margins are unfavorable, especially if diffuse (>10-mm evidence of oncologic benefit with increased risk of genitourinary toxicity
margin involvement or ≥3 sites of positivity) or associated with persistent and erectile dysfunction when adjuvant therapy was used.522,523 Another
serum levels of PSA. The defined target volumes include the prostate randomized trial, however, saw an improvement in 10-year survival for
bed.516 Observation after radical prostatectomy is also appropriate. biochemical recurrence with the use of adjuvant therapy (HR, 0.26; 95%
CI, 0.14–0.48; P < .001).524
Published trials provide high-level evidence that can be used to counsel
patients more appropriately regarding the use of adjuvant therapy. Systematic reviews also come to conflicting conclusions on the utility of
Thompson and colleagues reported the results of SWOG 8794, which immediate post-prostatectomy radiation in patients with adverse
enrolled 425 men with extraprostatic cancer found at radical features.525,526

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Overall, the panel believes that adjuvant or early salvage EBRT after determinations (PSA recurrence); or 3) the occasional case with persistent
recuperation from operation may be beneficial in men with one or more but low PSA levels attributed to slow PSA metabolism or residual benign
adverse laboratory or pathologic features, which include positive surgical tissue. Consensus has not defined a threshold level of PSA below which
margin, seminal vesicle invasion, and/or extracapsular extension as noted PSA is truly “undetectable.”514 Group 3 does not require further evaluation
in the guideline by the American Urological Association (AUA) and until PSA increases, but the workup for 1 and 2 must include an evaluation
ASTRO.527 for distant metastases.

The value of whole pelvic irradiation in this setting is unclear due to a lack Several retrospective studies have assessed the prognostic value of
of benefit in PFS in two trials (RTOG 9413 and GETUG 01)397,398,528,529; various combinations of pretreatment PSA levels, Gleason scores,
whole pelvic radiation may be appropriate for selected patients. PSADT, and the presence or absence of positive surgical margins.536-540 A
large retrospective review of 501 patients who received salvage radiation
Adjuvant Therapy for pN1 for detectable and increasing PSA after radical prostatectomy539 showed
Adjuvant therapy can also be given to men with positive lymph nodes that the predictors of progression were Gleason score 8 to 10, pre-EBRT
found during or after radical prostatectomy. Several management options PSA level >2 ng/mL, seminal vesicle invasion, negative surgical margins,
should be considered. ADT is a category 1 option, as discussed above and PSADT ≤10 months. However, prediction of systemic disease versus
(see Adjuvant ADT for Lymph Node Metastases after RP).530 Another local recurrence and hence responsiveness to postoperative radiation has
option is observation. Retrospective data show that initial observation may proven unfeasible for individual patients using clinical and pathologic
be safe in some men with N1 disease at radical prostatectomy, because criteria.541 Delivery of adjuvant or salvage EBRT becomes both therapeutic
28% of a cohort of 369 patients remained free from biochemical and diagnostic—PSA response indicates local persistence/recurrence.
recurrence at 10 years.531 A third option is the addition of pelvic EBRT to Delayed biochemical recurrence requires restaging, and a nomogram122,542
ADT (category 2B). This last recommendation is based on retrospective may prove useful to predict response, but it has not been validated.
studies and a National Cancer Database analysis that demonstrated
improved biochemical recurrence-free survival, cancer-specific survival, The utility of imaging for men with an early biochemical recurrence after
and all-cause survival with post-prostatectomy EBRT and ADT compared radical prostatectomy depends on disease risk before operation and
to adjuvant ADT alone in patients with lymph node metastases.532-535 pathologic stage, Gleason grade, PSA, and PSADT after recurrence.
Patients with low- and intermediate-risk disease and low postoperative
Biochemical Recurrence After Radical Prostatectomy serum PSA levels have a very low risk of positive bone scans or CT
Men who suffer biochemical recurrence after radical prostatectomy fall into scans.543,544 In a series of 414 bone scans performed in 230 men with
three groups: 1) those whose PSA level fails to fall to undetectable levels biochemical recurrence after radical prostatectomy, the rate of a positive
after radical prostatectomy (persistent disease); 2) those who achieve an bone scan for men with PSA >10 ng/mL was only 4%.545
undetectable PSA after radical prostatectomy with a subsequent
The specific staging tests depend on the clinical history, but should include
detectable PSA level that increases on two or more subsequent laboratory
a calculation of PSADT to inform nomogram use and counseling. In

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addition, bone imaging; chest CT; abdominal/pelvic CT or months and those with PSADT greater than or equal to 6 months.548 Most
abdominal/pelvic MRI; C-11 choline PET/CT or PET/MRI or F-18 men with prolonged PSADT may be observed safely.549
fluciclovine PET/CT or PET/MRI; and prostate bed biopsy may be useful.
The Decipher molecular assay can be considered for prognostication after Six months of concurrent/adjuvant ADT can be coadministered with
radical prostatectomy (category 2B). A meta-analysis of five studies with salvage radiation based on the results of GETUG-16.550,551 A luteinizing
855 patients and median follow-up of 8 years found that the 10-year hormone-releasing hormone (LHRH) agonist should be used. Two years
cumulative incidence metastases rates for men classified as low, instead of 6 months of ADT can be considered in addition to radiation for
intermediate, and high risk by Decipher after radical prostatectomy were men with persistent PSA after radical prostatectomy or for PSA levels that
5.5%, 15.0%, and 26.7%, respectively (P < .001).546 exceed 1.0 ng/mL at the time of initiation of salvage therapy, based on
results of RTOG 9601.552 For 2 years of ADT, level 1 evidence supports
Bone imaging is appropriate when patients develop symptoms or when 150 mg bicalutamide daily but an LHRH agonist could be considered as
PSA levels are increasing rapidly. In one study, the probability of a positive an alternative.552
bone scan for a patient not on ADT after radical prostatectomy was less
than 5% unless the PSA increased to 40 to 45 ng/mL.547 A TRUS biopsy ADT alone becomes the salvage treatment when there is proven or high
may be helpful when imaging suggests local recurrence. suspicion for distant metastases. Pelvic radiation is not recommended but
may be given to the site of metastasis if in weight-bearing bones or if the
Patients with PSA recurrence (undetectable PSA that increases on two or patient is symptomatic. Observation remains acceptable for selected
more measurements) after radical prostatectomy may be observed or patients, with ADT delayed until symptoms develop or PSA levels suggest
undergo primary salvage EBRT with or without ADT if distant metastases that symptoms are imminent. In all cases, the form of primary or
are not detected. secondary systemic therapy should be based on the hormonal status of
the patient.
Large retrospective cohort studies support the use of EBRT in the setting
of biochemical recurrence, because it is associated with decreased all- Post-Irradiation Recurrence
cause mortality and increased prostate cancer-specific survival.541,548 The The 2006 Phoenix definition was revised by ASTRO and the RTOG in
recommended post-radical prostatectomy EBRT dose is 64 to 72 Gy and Phoenix: 1) PSA rise by 2 ng/mL or more above the nadir PSA is the
may be increased for gross recurrence that has been proven by biopsy. standard definition for biochemical recurrence after EBRT with or without
The target volume includes the prostate bed and may include the whole hormonal therapy; and 2) A recurrence evaluation should be considered
pelvis in selected patients.516 Treatment is most effective when pre- when PSA has been confirmed to be increasing after radiation even if the
treatment PSA level is below 0.5 ng/mL.542 Paradoxically, salvage EBRT rise above nadir is not yet 2 ng/mL, especially in candidates for salvage
was shown to be most beneficial when the PSADT time was less than 6 local therapy who are young and healthy.553 Retaining a strict version of
months in a cohort analysis of 635 men,541 although another study of 519 the ASTRO definition allows comparison with a large existing body of
men reported mortality reduction for both men with PSADT less than 6 literature. Rapid increase of PSA may warrant evaluation (prostate biopsy)

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prior to meeting the Phoenix definition, especially in younger or healthier Negative TRUS biopsy after post-radiation biochemical recurrence poses
men. clinical uncertainties. Observation, ADT, and enrolling in clinical trials are
viable options.
Further workup is indicated in patients who are considered candidates for
local therapy. These patients include those with original clinical stage T1– Patients with radiographic evidence of distant metastases should proceed
2, life expectancy greater than 10 years, and current PSA less than 10 to ADT for castration-naïve disease. Patients who were not initially
ng/mL.554 Workup typically includes PSADT calculation, bone imaging, candidates for local therapy should be treated with ADT or observed.
TRUS biopsy, and prostate MRI; in addition, a chest CT, an
abdominal/pelvic CT or abdominal/pelvic MRI, C-11 choline PET/CT or Androgen Deprivation Therapy
PET/MRI, or F-18 fluciclovine PET/CT or PET/MRI can be considered. ADT is administered as primary systemic therapy for regional or advanced
disease and as neoadjuvant/concomitant/adjuvant therapy in combination
Local radiation recurrences are most responsive to salvage therapy when
with radiation in localized or locally advanced prostate cancers.
PSA levels at the time of treatment are low (<5 ng/mL). Biopsy should be
encouraged at the time of radiation biochemical recurrence if staging In the community, ADT has been commonly used as primary therapy for
workup does not reveal metastatic disease. Prostate biopsy in the setting early-stage, low-risk disease, especially in the elderly. This practice has
of suspected local recurrence after radiation should be considered, been challenged by a large cohort study of 66,717 elderly men with T1–T2
including biopsy at the junction of the seminal vesicle and prostate, tumors.558 No 15-year survival benefit was found in patients receiving ADT
because this is a common site of recurrence. compared to observation alone. Similarly, another cohort study of 15,170
men diagnosed with clinically localized prostate cancer who were not
Options for primary salvage therapy for those with positive biopsy but low
treated with curative intent therapy reported no survival benefit from
suspicion of metastases to distant organs include observation or radical
primary ADT after adjusting for demographic and clinical variables.559
prostatectomy with PLND in selected cases by highly experienced
Placing patients with early prostate cancer on ADT should not be routine
surgeons. Salvage radical prostatectomy can result in long-term disease
practice.
control, but is often associated with impotence and urinary incontinence.555
Other options for localized interventions include cryotherapy,556 HIFU Antiandrogen monotherapy (bicalutamide) after completion of primary
(category 2B),498-501,505,506 and brachytherapy (reviewed by Allen and treatment was investigated as an adjuvant therapy in patients with
colleagues557 and discussed in Salvage Brachytherapy). Treatment, localized or locally advanced prostate cancer, but results did not support
however, needs to be individualized based on the patient's risk of its use in this setting.560,561
progression, the likelihood of success, and the risks involved with salvage
therapy. Castrate levels of serum testosterone (<50 ng/dL; <1.7 nmol/L) should be
achieved with ADT, because low nadir serum testosterone levels were
shown to be associated with improved cause-specific survival in the PR-7
study.562 Patients who do not achieve adequate suppression of serum

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NCCN Guidelines Version 1.2022

Prostate Cancer

testosterone (<50 ng/dL) with medical or surgical castration can be DFS compared with radiation alone in intermediate-risk (75% of study
considered for additional hormonal manipulations (with estrogen, population) and high-risk men.567 A secondary analysis of the RTOG 9408
antiandrogens, LHRH antagonists, or steroids), although the clinical trial showed that the benefit of ADT given with EBRT in patients
benefit remains uncertain. Monitoring testosterone levels 12 weeks after intermediate-risk prostate cancer was limited to those in the unfavorable
first dose of LHRH therapy and upon increase in PSA should be subset.568
considered.
RTOG 9910 and RTOG 9902 reinforced two important principles
ADT for Clinically Localized (N0M0) Disease concerning the optimal duration of ADT and use of systemic
ADT should not be used as monotherapy in clinically localized prostate chemotherapy in conjunction with EBRT.569,570 RTOG 9910 is a phase 3
cancer unless there is a contraindication to definitive local therapy, such randomized trial targeting men with intermediate-risk prostate cancer that
as life expectancy less than 5 years and comorbidities. Under those compared 4 months to 9 months of ADT. RTOG 9408 had previously
circumstances, ADT may be an acceptable alternative if the disease is shown that 4 months of ADT combined with EBRT improved survival in
high or very high risk (see Palliative ADT, below). men with intermediate-risk disease compared to EBRT alone.565
Consistent with earlier studies, RTOG 9910 demonstrated that there is no
In the clinically localized setting, ADT using an LHRH agonist—alone or reason to extend ADT beyond 4 months when given in conjunction with
with a first-generation antiandrogen—or an LHRH antagonist can be used EBRT in men with intermediate-risk disease.
as a neoadjuvant, concurrent, and/or adjuvant to EBRT in patients with
unfavorable intermediate-, high-, or very-high-risk prostate cancer, as RTOG 9902 compared long-term ADT and EBRT with and without
described in more detail below. paclitaxel, estramustine, and etoposide (TEE) chemotherapy in men with
locally advanced, high-risk prostate cancer.571 In the randomized cohort of
ADT used as neoadjuvant treatment before radical prostatectomy is 397 patients with a median follow-up of 9.2 years, results demonstrated no
strongly discouraged outside of a clinical trial. significant difference in ADT+EBRT versus ADT+EBRT+TEE in OS (65%
vs. 63%; P = .81), biochemical recurrence (58% vs. 54%; P = .82), distant
Neoadjuvant, Concurrent, and/or Adjuvant ADT with EBRT for
metastases (16% vs. 14%; P = .42), or DFS (22% vs. 26%; P = .61), but a
Intermediate-Risk Disease
substantial increase in toxicity (3.9% vs. 0% treatment-related deaths),
The addition of short-term ADT to radiation improved overall and cancer-
which resulted in early closure of the trial.571 Thus, the fact that 6 months
specific survival in three randomized trials containing 20% to 60% of men
of ADT improved survival compared to EBRT alone does not mean it is
with intermediate-risk prostate cancer (Trans Tasman Radiation Oncology
better than 4 months of ADT, and the fact that systemic chemotherapy is
Group [TROG] 9601, Dana Farber Cancer Institute [DFCI] 95096, and
effective in one setting (high-volume metastatic disease or CRPC) should
Radiation Therapy Oncology Group [RTOG] 9408).552,563-565 Only a cancer-
not lead to the assumption that it will be beneficial in other settings (eg,
specific survival benefit was noted in a fourth trial that recruited mostly
high-risk localized disease).572,573
high-risk men (RTOG 8610).566 Results of the EORTC 22991 trial showed
that the addition of 6 months of ADT significantly improved biochemical

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At this time, the panel recommends 4 to 6 months of ADT when EBRT is discontinued ADT within 5 years.578 Two randomized, phase 3 trials
given to patients as initial treatment of unfavorable intermediate risk showed 1.5 years of ADT was not inferior to 3 years of ADT.579,580
prostate cancer. If brachytherapy is added to EBRT in this setting, then 4
to 6 months of ADT is optional. A meta-analysis of data from 992 patients enrolled in 6 randomized
controlled trials showed that a longer duration of ADT with EBRT benefited
Neoadjuvant, Concurrent, and/or Adjuvant ADT with EBRT for High-Risk or men with Grade Group 4 or 5 prostate cancer.581
Very-High-Risk Disease
ADT combined with EBRT is an effective primary treatment for patients at Neoadjuvant, Concurrent, and/or Adjuvant ADT with EBRT for Recurrent
high risk or very high risk, as discussed in the Radiation Therapy section, Disease
above. Combination therapy was consistently associated with improved Men who develop PSA recurrence after radical prostatectomy without
disease-specific survival and OS compared to single-modality treatment in evidence of metastases can receive pelvic EBRT with
randomized phase 3 studies.389,390,392,393 neoadjuvant/concurrent/adjuvant ADT (see ADT for M0 Biochemical
Recurrence, below).
Increasing evidence favors long-term over short-term
neoadjuvant/concurrent/adjuvant ADT for patients with high- and very- ADT for Regional Disease
high-risk disease. The RTOG 9202 trial included 1521 patients with T2c- Primary ADT for Lymph Node Metastases
T4 prostate cancer who received 4 months of ADT before and during Men initially diagnosed with node-positive disease who have a life
EBRT.574 They were randomized to no further treatment or an additional 2 expectancy greater than 5 years can be treated with primary ADT. Primary
years of ADT. At 10 years, the long-term group was superior for all ADT options are orchiectomy, an LHRH agonist, an LHRH agonist with a
endpoints except OS. A subgroup analysis of patients with a Gleason first-generation antiandrogen, or an LHRH antagonist (category 2B); or
score of 8 to 10 found an advantage in OS for long-term ADT at 10 years orchiectomy, LHRH agonist, or LHRH antagonist with abiraterone. Another
(32% vs. 45%, P = .0061). At a median follow-up of 19.6 years, long-term option for these men is EBRT with 2 to 3 years of
ADT was superior for all endpoints including OS in the entire cohort (12% neoadjuvant/concurrent/adjuvant ADT (category 1, see Neoadjuvant,
relative reduction; P = .03).575 Concurrent, and/or Adjuvant ADT with EBRT for Regional Disease,
below). Abiraterone acetate (abiraterone) can be added to either
The EORTC 22961 trial also showed superior survival when 2.5 years of treatment, although abiraterone should not be coadministered with an
ADT were added to EBRT given with 6 months of ADT in 970 patients, antiandrogen (see Abiraterone Acetate in Castration-Naïve Prostate
most of whom had T2c–T3, N0 disease.576 The DART01/05 GICOR trial Cancer, below).
also reported similar results in men with high-risk disease.577 In a
secondary analysis of RTOG 8531, which mandated lifelong ADT for The EORTC 30846 trial randomized 234 treatment-naïve patients with
patients with locally advanced prostate cancer treated with EBRT, those node-positive prostate cancer to immediate versus delayed ADT.582 At 13
who adhered to the protocol had better survival than those who years median follow-up, the authors reported similar survival between the
two arms, although the study was not powered to show non-inferiority.

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Neoadjuvant, Concurrent, and/or Adjuvant ADT with EBRT for Regional based study of 731 men showed no benefit. Furthermore, a meta-analysis
Disease resulted in a recommendation against ADT for pathologic lymph node
Men initially diagnosed with pelvic lymph node-positive disease who have metastatic prostate cancer in the ASCO guidelines.585 In addition, a cohort
a life expectancy greater than 5 years can be treated with EBRT with 2 to analysis of 731 men with positive nodes failed to demonstrate a survival
3 years of neoadjuvant/concurrent/adjuvant ADT (category 1) with or benefit of ADT initiated within 4 months of radical prostatectomy compared
without abiraterone. Alternatively, they can receive primary ADT without to observation.584 At this time, the panel recommends that patients with
EBRT with or without abiraterone (see Primary ADT for Lymph Node lymph node metastases found at radical prostatectomy should be
Metastases, above and Abiraterone Acetate in Castration-Naïve Prostate considered for immediate ADT (category 1) with or without EBRT
Cancer, below). Neoadjuvant/concurrent/adjuvant ADT options are an (category 2B), but that observation is also an option for these patients.
LHRH agonist, an LHRH agonist with a first-generation antiandrogen, or
an LHRH antagonist. Abiraterone should not be coadministered with an Palliative ADT
antiandrogen. Palliative ADT can be given to men with a life expectancy of less than or
equal to 5 years who have high-risk, very-high-risk, regional, or metastatic
The role of adjuvant ADT after radical prostatectomy is restricted to cases
prostate cancer. Palliative ADT also can be given to patients with disease
where positive pelvic lymph nodes are found, although reports in this area
progression during observation, usually when symptoms develop or when
reveal mixed findings. Messing and colleagues randomly assigned 98
changes in PSA levels suggest that symptoms are imminent. The options
patients who were found to have positive lymph nodes at the time of
in this setting are orchiectomy, LHRH agonist, or LHRH antagonist
radical prostatectomy to immediate continuous ADT or observation.530 In
(category 2B for LHRH antagonist).
the immediate ADT arm of 47 patients, 30 remained alive, 29 of whom
were prostate cancer recurrence-free and 26 of whom were PSA ADT for Castration-Naive Disease
recurrence-free after a median follow-up of 11.9 years (range, 9.7–14.5
The term “castration-naive" is used to define patients who are not on ADT
years for survivors).530,583 Those receiving immediate ADT also had a
at the time of progression. The NCCN Prostate Cancer Panel uses the
significant improvement in OS (HR, 1.84; 95% CI, 1.01–3.35).
term "castration-naive" even when patients have had neoadjuvant,
However, these results differ from a SEER Medicare, population-based concurrent, and/or adjuvant ADT as part of RT provided they have
test of ADT published subsequently.584 The SEER Medicare-based study recovered testicular function. Options for patients with castration-naïve
of men who underwent radical prostatectomy and had positive lymph disease who require ADT depend on the presence of distant metastases,
nodes used propensity matching to compare men who received ADT and can be found in full in the Guidelines above.
within 120 days to those who were observed. The groups had similar
ADT for castration-naïve prostate cancer can be accomplished using
median and range of follow-up for survivors, but OS and prostate cancer-
bilateral orchiectomy, an LHRH agonist or antagonist, or an LHRH agonist
specific survival were similar. The Messing study occurred prior to the
plus a first-generation antiandrogen. As discussed below, abiraterone or
PSA era, but the studies are similar in almost all other respects. The
docetaxel can be added to orchiectomy, LHRH agonist, or LHRH
Messing study showed almost unbelievable benefit, and the population-

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NCCN Guidelines Version 1.2022

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antagonist for M1 disease. For patients with M0 disease, observation is treated with LHRH antagonist.593 The heart and T lymphocytes have
preferred over ADT. receptors for LHRH. Therefore, LHRH agonists may affect cardiac
contractility, vascular plaque stability, and inflammation.594
LHRH agonists and LHRH antagonists appear equally effective in patients
with advanced prostate cancer.586 A new LHRH antagonist, relugolix, has been studied as ADT in patients
with advanced prostate cancer in the randomized phase 3 HERO trial.595
Medical or surgical castration combined with an antiandrogen is known as In this study, 622 patients received relugolix (120 mg orally once daily)
combined androgen blockade. No prospective randomized studies have and 308 received leuprolide (injections every 3 months) for 48 weeks. The
demonstrated a survival advantage with combined androgen blockade primary endpoint, sustained castrate levels of testosterone (<50 ng per
over the serial use of an LHRH agonist and an antiandrogen.585 Meta- deciliter) through 48 weeks, showed noninferiority and superiority of
analysis data suggest that bicalutamide may provide an incremental relugolix over leuprolide (96.7%; 95% CI, 94.9–97.9 vs. 88.8% [95% CI,
relative improvement in OS by 5% to 20% over LHRH agonist 84.6–91.8]; P < .001 for superiority). The secondary endpoint of castrate
monotherapy.587,588 However, others have concluded that more complete levels of testosterone on day 4 was also improved in the relugolix arm
disruption of the androgen axis (with finasteride, dutasteride, or (56% vs. 0%). Furthermore, the incidence of major adverse cardiovascular
antiandrogen added to medical or surgical castration) provides little if any events was 2.9% in the relugolix arm and 6.2% in the leuprolide arm (HR,
benefit over castration alone.589,590 Combined androgen blockade therapy 0.46; 95% CI, 0.24–0.88). Relugolix is not yet approved by the FDA.
adds to cost and side effects, and prospective randomized evidence that
combined androgen blockade is more efficacious than ADT is lacking. Patients should be queried about adverse effects related to ADT.
Intermittent ADT should be used for those who experience significant side
Antiandrogen monotherapy appears to be less effective than medical or effects of ADT (see Intermittent Versus Continuous ADT, below).
surgical castration and is not recommended for primary ADT. Furthermore,
dutasteride plus bicalutamide showed no benefit over bicalutamide alone ADT for M0 Biochemical Recurrence
in patients with locally advanced or metastatic prostate cancer.591 Controversy remains about the timing and duration of ADT when local
therapy has failed. Many believe that early ADT is best, but cancer control
Recent evidence suggests that orchiectomy may be safer than an LHRH must be balanced against side effects. Early ADT is associated with
agonist. Four hundred twenty-nine men with metastatic prostate cancer increased side effects and the potential development of the metabolic
who underwent orchiectomy were compared to 2866 men who received syndrome.
LHRH agonist between 1995 and 2009. Orchiectomy was associated with
lower risk of fracture, peripheral arterial disease, and cardiac-related Patients with an increasing PSA level and with no symptomatic or clinical
complications, although risk was similar for diabetes, deep vein evidence of cancer after definitive treatment present a therapeutic
thrombosis, pulmonary embolism, and cognitive disorders.592 Post-hoc dilemma regarding the role of ADT. Some of these patients will ultimately
analysis of a randomized trial of LHRH antagonist versus LHRH agonist die of their cancer. Timing of ADT for patients whose only evidence of
found lower risk of cardiac events in patients with existing cardiac disease cancer is increasing PSA is influenced by PSA velocity (PSADT), patient

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NCCN Guidelines Version 1.2022

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and physician anxiety, the short-term and long-term side effects of ADT, Primary ADT for M1 Castration-Naïve Prostate Cancer
and underlying comorbidities of the patient. Early ADT is acceptable, but ADT is the gold standard for initial treatment of patients with metastatic
an alternative is close observation until progression of cancer, at which disease at presentation.585 A PSA value ≤4 ng/mL after 7 months of ADT
time appropriate therapeutic options may be considered. Earlier ADT may is associated with improved survival of patients newly diagnosed with
be better than delayed therapy, although the definitions of early and late metastatic prostate cancer.598
(ie, what level of PSA) remain controversial. The multicenter phase 3
TROG 03.06/VCOG PR 01-03 [TOAD] trial randomized 293 men with PSA ADT options for M1 castration-naïve disease are:
relapse after operation or radiation (n = 261) or who were not considered • Orchiectomy ± docetaxel
for curative treatment (n = 32) to immediate ADT or ADT delayed by a • LHRH agonist alone ± docetaxel
recommended interval of greater than or equal to 2 years.596 Five-year OS • LHRH agonist plus first-generation antiandrogen ± docetaxel
was improved in the immediate therapy arm compared with the delayed • LHRH antagonist ± docetaxel
therapy arm (91.2% vs. 86.4%; log-rank P = .047). No significant • Orchiectomy plus abiraterone, apalutamide, or enzalutamide
differences were seen in the secondary endpoint of global health-related • LHRH agonist plus abiraterone, apalutamide, or enzalutamide
QOL at 2 years.597 In addition, there were no differences over 5 years in • LHRH antagonist plus abiraterone, apalutamide, or enzalutamide
global QOL, physical functioning, role or emotional functioning, insomnia,
fatigue, dyspnea, or feeling less masculine. However, sexual activity was In patients with overt metastases in weight-bearing bone who are at risk of
lower and the hormone-treatment-related symptoms score was higher in developing symptoms associated with the flare in testosterone with initial
the immediate ADT group compared with the delayed ADT group. Most LHRH agonist alone, antiandrogen therapy should precede or be
clinical trials in this patient population require PSA level ≥0.5 mg/dL (after coadministered with LHRH agonist for at least 7 days to diminish ligand
radical prostatectomy) or “nadir + 2” (after radiation) for enrollment. binding to the androgen receptor.599,600 LHRH antagonists rapidly and
directly inhibit the release of androgens, unlike LHRH agonists that initially
The panel believes that the benefit of early ADT is uncertain and must be stimulate LHRH receptors prior to hypogonadism. Therefore, no initial flare
balanced against the risk of ADT side effects. Patients with an elevated is associated with these agents and coadministration of antiandrogen is
PSA and/or a shorter PSADT (rapid PSA velocity) and an otherwise long unnecessary.
life expectancy should be encouraged to consider ADT earlier. Men who
opt for ADT should consider the intermittent approach. The timing of ADT The data supporting the addition of abiraterone, apalutamide,
initiation should be individualized according to PSA velocity, patient enzalutamide, or docetaxel to ADT in this setting are discussed below.
anxiety, and potential side effects. Patients with shorter PSADT or rapid These are all category 1, preferred options; the fine-particle formulation of
PSA velocity and long life expectancy may be encouraged to consider abiraterone (discussed in Abiraterone Acetate in M1 CRPC, below) can be
early ADT. Men with prolonged PSADTs who are older are excellent added to ADT as a category 2B option. ADT (LHRH agonist, LHRH
candidates for observation. antagonist, or orchiectomy) with EBRT to the primary tumor for low-

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volume metastatic disease is discussed in EBRT to the Primary Tumor in were rare but slightly increased with abiraterone. The overall
Low-Volume M1 Disease, above. discontinuation rate due to side effects was 12%. Patient-reported
outcomes were improved with the addition of abiraterone, with
Abiraterone Acetate in Castration-Naïve Prostate Cancer
improvements in pain intensity progression, fatigue, functional decline,
In February 2018, the FDA approved abiraterone in combination with prostate cancer-related symptoms, and overall health-related QOL.605 A
prednisone for metastatic castration-naïve prostate cancer.601,602 This limitation of this trial is that only 27% of placebo-treated men received
approval was based on two randomized phase 3 clinical trials of abiraterone or enzalutamide at progression, and only 52% of these men
abiraterone and low-dose prednisone plus ADT that were reported in men received any life-prolonging therapy.603
with newly diagnosed metastatic prostate cancer or high-risk or node-
positive disease (STAMPEDE and LATITUDE) that demonstrated A second randomized trial (STAMPEDE) of 1917 men with castration-
improved OS over ADT alone.603 In LATITUDE, 1199 men with high-risk, naïve prostate cancer demonstrated similar OS benefits.606 However,
metastatic, castration-naïve prostate cancer were randomized to unlike LATITUDE, STAMPEDE eligibility permitted men with high-risk N0
abiraterone with prednisone 5 mg once daily or matching placebos. High- M0 disease (2 of 3 high-risk factors: stage T3/4, PSA >40, or Gleason
risk disease was defined as at least two of the following: Gleason score 8– score 8–10; n = 509), or N1 M0 disease (pelvic nodal metastases; n =
10, ≥3 bone metastases, and visceral metastases.603 Efficacy was 369) in addition to M1 patients, who made up the majority of patients (n =
demonstrated at the first interim analysis, and the trial was unblinded. The 941). The majority of men were newly diagnosed, while a minority of men
primary endpoint of OS was met, and favored abiraterone (HR, 0.62; 95% had recurrent, high-risk, or metastatic disease after local therapy (n = 98).
CI, 0.51–0.76; P < .0001). Estimated 3-year OS rates improved from 49% Thus, STAMPEDE was a heterogeneous mix of patients with high-risk,
to 66% at 30 months follow-up. Secondary endpoints were improved and non-metastatic, node-positive, or M1 disease. In M1 patients, treatment
included delayed castration-resistant radiographic progression (from with abiraterone plus prednisone was continued until progression. In
median 14.8–33.2 months), PSA progression (7.4–33.2 months), time to patients with N1 or M0 disease, 2 years of abiraterone plus prednisolone
pain progression, and initiation of chemotherapy. After the first interim was used if curative-intent EBRT was utilized. OS was improved in the
analysis, 72 patients crossed over from placebo to abiraterone. Final OS overall population (HR, 0.63; 95% CI, 0.5–0.76; P < .0001) and in the M1
analysis of LATITUDE after a median follow-up of 51.8 months showed and N1 subsets, without any heterogeneity of treatment effect by
median OS was significantly longer in the abiraterone group than in the metastatic status. The survival benefit of abiraterone was larger in men
placebo group (53.3 months vs. 36.5 months; HR, 0.66; 95% CI, 0.56– less than 70 years of age than in older men (HR, 0.94 vs. HR, 0.51). Older
0.78; P < .0001).604 men also suffered increased toxicities, which suggests heterogeneity in
clinical benefits by age and comorbidity. The secondary endpoint of FFS,
Adverse events were higher with abiraterone and prednisone but were which included PSA recurrence, was improved overall (HR, 0.29; P <
generally mild in nature and largely related to mineralocorticoid excess (ie, .0001) and in all subgroups regardless of M1 (HR, 0.31), N1 (HR, 0.29), or
hypertension, hypokalemia, edema), hormonal effects (ie, fatigue, hot M0 (HR, 0.21) status. No heterogeneity for FFS was observed based on
flushes), and liver toxicity.603 Cardiac events, such as atrial fibrillation, subgroups or by age. In this trial, subsequent life-prolonging therapy was

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NCCN Guidelines Version 1.2022

Prostate Cancer

received by 58% of men in the control group, which included 22% who Apalutamide in Castration-Naïve Prostate Cancer
received abiraterone and 26% who received enzalutamide. Thus, these The double-blind phase 3 TITAN clinical trial randomized 1052 patients
data reflect a survival advantage of initial abiraterone in newly diagnosed with metastatic, castration-naïve prostate cancer to ADT with apalutamide
men compared with deferring therapy to the CRPC setting. (240 mg/day) or placebo.608 Participants were stratified by Gleason score
at diagnosis, geographic region, and previous docetaxel treatment. The
Adverse events in STAMPEDE were similar to that reported in LATITUDE, median follow-up was 22.7 months. Both primary endpoints were met:
but were increased in older men, with higher incidences of grade 3–5 radiographic PFS (68.2% vs. 47.5% at 24 months; HR for radiographic
adverse events with abiraterone (47% vs. 33%) and 9 versus 3 treatment- progression or death, 0.48; 95% CI, 0.39–0.60; P < .001) and OS (82.4%
related deaths. Severe hypertension or cardiac disorders were noted in vs. 73.5% at 24 months; HR for death, 0.67; 95% CI, 0.51–0.89; P = .005).
10% of men and grade 3–5 liver toxicity in 7%, which illustrates the need Adverse events that were more common with apalutamide than with
for blood pressure and renal and hepatic function monitoring. placebo included rash, hypothyroidism, and ischemic heart disease.
Health-related QOL was maintained during treatment.609
Taken together, these data led the NCCN Panel to recommend
abiraterone with 5-mg once-daily prednisone as a treatment option with Apalutamide is a category 1 option for patients with M1 castration-naïve
ADT for men with newly diagnosed, M1, castration-naïve prostate cancer prostate cancer. The FDA approved this indication in September of
(category 1). Alternatively, the fine-particle formulation of abiraterone can 2019.610
be used (category 2B; see Abiraterone Acetate in M1 CRPC, below). For
men undergoing curative-intent treatment for N1 disease, abiraterone can Enzalutamide in Castration-Naïve Prostate Cancer
be added to EBRT with 2 to 3 years of neoadjuvant/concurrent/adjuvant The open-label randomized phase 3 ENZAMET clinical trial compared
ADT or can be given with ADT for castration-naïve disease (without enzalutamide (160 mg/day) plus ADT with ADT alone in 1125 men with
EBRT). The fine-particle formulation of abiraterone is an option (category metastatic castration-naïve prostate cancer.611 Stratification was by
2B; see Abiraterone Acetate in M1 CRPC, below). However, there was volume of disease, planned use of early docetaxel, planned use of bone
insufficient survival, FFS data, and follow-up available to recommend anti-resorptive therapy, comorbidity score, and trial site. The primary
abiraterone for men with high-risk or very-high-risk N0 M0 prostate cancer. endpoint of OS was met at the first interim analysis with median follow-up
Further follow-up and dedicated ongoing clinical trials are needed in this of 34 months (HR for death, 0.67; 95% CI, 0.52–0.86; P = .002).
curative-intent RT population. Enzalutamide also improved secondary endpoints, such as PFS using
PSA levels and clinical PFS.
Abiraterone can be given at 250 mg/day and administered following a low-
fat breakfast, as an alternative to the dose of 1000 mg/day after an In the double-blind randomized phase 3 ARCHES clinical, 1150 men with
overnight fast (see Abiraterone Acetate in M1 CRPC, below).607 The cost metastatic castration-naïve prostate cancer were randomized to receive
savings may reduce financial toxicity and improve compliance. ADT with either enzalutamide (160 mg/day) or placebo. Participants were
stratified by disease volume and prior docetaxel use. The primary endpoint
was radiographic PFS, which was improved in the enzalutamide group

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after a median follow-up of 14.4 months (19.0 months vs. not reached; deaths in the continuous ADT arm. Physical function, fatigue, urinary
HR, 0.39; 95% CI, 0.30–0.50; P < .001).612 problems, hot flashes, libido, and erectile dysfunction showed modest
improvement in the intermittent ADT group. The test population was
The safety of enzalutamide in these trials was similar to that seen in heterogenous, so it remains unclear which of these asymptomatic patients
previous trials in the castration-resistant setting. Adverse events benefitted from treatment. It is possible that many of these patients could
associated with enzalutamide in these trials included fatigue, seizures, and have delayed ADT without harm. The test population had a low disease
hypertension.611,612 burden and 59% of deaths in the trial were not related to prostate cancer.
Follow-up longer than 6.9 years may be required for disease-specific
Enzalutamide is a category 1 option for patients with M1 castration-naïve
deaths to out-balance deaths by other causes.
prostate cancer.
An unplanned Cox regression analysis of the trial showed that men with
Intermittent Versus Continuous ADT
Gleason sum greater than 7 in the continuous ADT arm had a median
ADT is associated with substantial side effects, which generally increase survival (8 years) that was 14 months longer than those with the same
with the duration of treatment. Intermittent ADT is an approach based on Gleason sum in the intermittent ADT arm (6.8 years).615 In this situation,
the premise that cycles of androgen deprivation followed by re-exposure patients should be given the option to weigh the effects of ADT on QOL
may delay “androgen independence,” reduce treatment morbidity, and against a possible impact on survival, although pathology was not centrally
improve QOL.613,614 Some men who have no ADT-related morbidity may reviewed and the study was not powered to detect small differences in
find the uncertainty of intermittent ADT not worthwhile. Intermittent ADT survival based on Gleason sum.616
requires close monitoring of PSA and testosterone levels, especially
during off-treatment periods, and patients may need to switch to The multinational European ICELAND trial randomized 702 participants
continuous therapy upon signs of disease progression. with locally advanced or biochemically recurrent prostate cancer to
continuous or intermittent ADT.617 Clinical outcomes, which included time
Intermittent ADT in Non-Metastatic Disease
to PSA progression, PSA PFS, OS, mean PSA levels over time, QOL, and
The Canadian-led PR.7 trial was a phase 3 trial of intermittent versus adverse events, were similar between the arms.
continuous ADT in patients with non-metastatic prostate cancer who
experienced biochemical recurrence after primary or salvage EBRT.615 A 2015 meta-analysis identified 6 randomized controlled trials comparing
One thousand three hundred eighty-six patients with PSA >3 ng/mL were continuous with intermittent ADT in men with locally advanced prostate
randomly assigned to intermittent ADT or continuous ADT. At a median cancer and found no difference in mortality and progression and an
follow-up of 6.9 years, the intermittent approach was non-inferior to advantage of the intermittent approach in terms of QOL and adverse
continuous ADT with respect to OS (8.8 vs. 9.1 years, respectively; HR, effects.618
1.02; 95% CI, 0.86–1.21). More patients died from prostate cancer in the
intermittent ADT arm (120 of 690 patients) than in the continuous ADT arm
(94 of 696 patients), but this was balanced by more non-prostate cancer

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Intermittent ADT in Metastatic Disease by 36%, heart failure by 38%, and pathologic fracture by 48%, compared
619
Hussain and colleagues conducted the SWOG (Southwest Oncology with continuous ADT.621 Furthermore, several meta-analyses of
Group) 9346 trial to compare intermittent and continuous ADT in patients randomized controlled trials reported no difference in survival between
with metastatic disease. After 7 months of induction ADT, 1535 patients intermittent ADT and continuous ADT.622-624 Another recent analysis
whose PSA dropped to 4 ng/mL or below (thereby demonstrating concluded that the non-inferiority of intermittent to continuous ADT in
androgen sensitivity) were randomized to intermittent or continuous ADT. terms of survival has not been clearly demonstrated.625 Still, the
At a median follow-up of 9.8 years, median survival was 5.1 years for the intermittent approach leads to marked improvement in QOL compared to
intermittent ADT arm and 5.8 years for the continuous ADT arm. The HR the continuous approach in most studies, and the panel believes that
for death with intermittent ADT was 1.10 with a 90% CI between 0.99 and intermittent ADT should be strongly considered.
1.23, which exceeded the pre-specified upper boundary of 1.20 for non-
inferiority. The authors stated that the survival results were inconclusive, A more personalized approach could be to treat all patients with metastatic
and that a 20% greater mortality risk with the intermittent approach cannot disease with ADT. After 7 months of ADT, patients can be assigned a risk
be ruled out. The study demonstrated better erectile function and mental category based on the PSA value at that time point598: low risk is defined
health in patients receiving intermittent ADT at 3 months, but the by a PSA less than 0.2 ng/mL (median survival of 75 months);
difference became insignificant thereafter, most likely due to intermediate risk is defined by a PSA between 0.2 and 4.0 ng/mL (median
contamination of assessments of those on the intermittent arm who may survival of 44 months), and high risk is defined by a PSA higher than 4.0
have returned to ADT at the pre-specified time points. A secondary ng/mL (median survival of 13 months). Those patients who have few or no
analysis of SWOG 9346 showed that intermittent ADT did not reduce symptoms related to ADT after 7 months of therapy will not benefit from
endocrine, bone, or cognitive events, whereas it increased the incidence intermittent ADT in terms of QOL, and therefore continuous ADT is
of ischemic and thrombotic events.620 reasonable because it is easier to administer.616 However, for those
patients with significant side effects impacting QOL, intermittent ADT
In a post-hoc stratification analysis of the trial, patients with minimal should be considered for those with low or intermediate risk after a
disease had a median survival of 5.4 years when receiving intermittent discussion about the impact on survival. A final consideration is based on
ADT versus 6.9 years when receiving continuous ADT (HR, 1.19; 95% CI, a subgroup analysis of S9346 that suggested that those who initially
0.98–1.43).619 The median survival was 4.9 years in the intermittent ADT present with pain have better survival on continuous therapy than
arm compared to 4.4 years in the continuous ADT arm for patients with intermittent therapy.
extensive disease (HR, 1.02; 95% CI, 0.85–1.22). These subgroup
analyses are hypothesis-generating. Adverse Effects of Traditional ADT
ADT has a variety of adverse effects including hot flashes, vasomotor
A population-based analysis that included 9772 patients with advanced instability, loss of libido, erectile dysfunction, shrinkage of penis and
prostate cancer aged greater than or equal to 66 years showed that testicles, loss of muscle mass and strength, fatigue, anemia, breast
intermittent ADT reduced the risks of total serious cardiovascular events enlargement and tenderness/soreness, depression and mood swings, hair

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loss, osteoporosis, greater incidence of clinical fractures, obesity, insulin approximately 2% to 3% per year during initial therapy. Most studies have
resistance, alterations in lipids, and greater risk for diabetes, acute kidney reported that bone mineral density continues to decline steadily during
injury, and cardiovascular disease.626-628 The intensity and spectrum of long-term therapy. ADT significantly decreases muscle mass,642 and
these side effects varies greatly. In general, the side effects of continuous treatment-related sarcopenia appears to contribute to frailty and increased
ADT increase with the duration of treatment. In addition, some forms of risk of falls in older men.
ADT may result in lower risk than others. For example, relugolix was
associated with a lower risk of major adverse cardiovascular events than The NCCN Guidelines Panel recommends screening and treatment for
leuprolide in the phase 3 HERO study (also see ADT for Castration-Naïve osteoporosis according to guidelines for the general population from the
Disease, above).595 National Osteoporosis Foundation.643 A baseline bone mineral density
study should be considered for the patients on ADT. The National
Recent evidence suggests that a link between ADT and cognitive decline, Osteoporosis Foundation guidelines include: 1) calcium (1000–1200 mg
dementia, or future Alzheimer’s disease may exist, although data are daily from food and supplements) and vitamin D3 (400–1000 IU daily); and
inconsistent, the risk is low, and the link remains to be proven.629-634 2) additional treatment for men aged greater than or equal to 50 years with
low bone mass (T-score between -1.0 and -2.5, osteopenia) at the femoral
Patients and their medical providers should be advised about these risks neck, total hip, or lumbar spine by dual-energy x-ray absorptiometry
prior to treatment. Many side effects of ADT are reversible or can be (DEXA) scan and a 10-year probability of hip fracture greater than or equal
avoided or mitigated. For example, physical activity can counter many of to 3% or a 10-year probability of a major osteoporosis-related fracture
these symptoms and should be recommended (see NCCN Guidelines for greater than or equal to 20%. Fracture risk can be assessed using the
Survivorship, available at www.NCCN.org). Use of statins also should be algorithm FRAX®, recently released by WHO.644 ADT should be
considered. considered “secondary osteoporosis” using the FRAX® algorithm.
Bone Health During ADT
Earlier randomized controlled trials demonstrated that bisphosphonates
Medical or surgical ADT is associated with greater risk for osteoporosis increase bone mineral density, a surrogate for fracture risk, during ADT.645-
and clinical fractures. In large population-based studies, for example, ADT 647
In 2011, the FDA approved denosumab as a treatment to prevent bone
was associated with a 21% to 54% relative increase in fracture risk.635-637 loss and fractures during ADT. Denosumab binds to and inhibits the
Longer treatment duration conferred greater fracture risk. Age and
receptor activator of NF-B ligand (RANKL) to blunt osteoclast function
comorbidity also were associated with higher fracture incidence. In a
and delay generalized bone resorption and local bone destruction.
population-based cohort of 3295 patients, surgical castration was
Approval was based on a phase 3 study that randomized 1468 patients
associated with a significantly lower risk of fractures than medical
with non-metastatic prostate cancer undergoing ADT to either biannual
castration using a GnRH agonist (HR, 0.77; 95% CI, 0.62–0.94;
denosumab or placebo. At 24 months, denosumab increased bone
P = .01).594 ADT increases bone turnover and decreases bone mineral
mineral density by 6.7% and reduced fractures (1.5% vs. 3.9%) compared
density,638-641 a surrogate for fracture risk in patients with non-metastatic
to placebo.648 Denosumab also was approved for prevention of SREs in
disease. Bone mineral density of the hip and spine decreases by

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patients with bone metastasis (see Chemotherapy, Immunotherapy, and cardiovascular disease (history of myocardial ischemia, coronary artery
Targeted Therapy). disease, myocardial infarction, cerebrovascular accident, angina pectoris,
or coronary artery bypass) compared with agonists.593 Men with a recent
Currently, treatment with denosumab (60 mg every 6 months), zoledronic history of cardiovascular disease appear to have higher risk,661 and
acid (5 mg IV annually), or alendronate (70 mg PO weekly) is increased physical activity may decrease the symptoms and
recommended when the absolute fracture risk warrants drug therapy. A cardiovascular side effects of men treated with ADT.662
baseline DEXA scan before start of therapy and a follow-up DEXA scan
after one year of therapy is recommended by the International Society for Several mechanisms may contribute to greater risk for diabetes and
Clinical Densitometry to monitor response. Use of biochemical markers of cardiovascular disease during ADT. ADT increases fat mass and
bone turnover is not recommended. There are no existing guidelines on decreases lean body mass.642,663,664 ADT with a GnRH agonist increases
the optimal frequency of vitamin D testing, but vitamin D levels can be fasting plasma insulin levels665,666 and decreases insulin sensitivity.667 ADT
measured when DEXA scans are obtained. also increases serum levels of cholesterol and triglycerides.665,668

Diabetes and Cardiovascular Disease Cardiovascular disease and diabetes are leading causes of morbidity and
In a landmark population-based study, ADT was associated with higher mortality in the general population. Based on the observed adverse
incidence of diabetes and cardiovascular disease.649 After controlling for metabolic effects of ADT and the association between ADT and higher
other variables, which included age and comorbidity, ADT with a GnRH incidence of diabetes and cardiovascular disease, screening for and
agonist was associated with increased risk for new diabetes (HR, 1.44; P intervention to prevent/treat diabetes and cardiovascular disease are
< .001), coronary artery disease (HR, 1.16; P < .001), and myocardial recommended for men receiving ADT. Whether strategies for screening,
infarction (HR, 1.11; P = .03). Studies that evaluated the potential prevention, and treatment of diabetes and cardiovascular disease in men
relationship between ADT and cardiovascular mortality have produced receiving ADT should differ from those of the general population remains
mixed results.566,649-656 In a Danish cohort of 31,571 patients with prostate uncertain.
cancer, medical castration was associated with an increased risk for
myocardial infarction (HR, 1.31; 95% CI, 1.16–1.49) and stroke (HR, 1.19; Progression to and Management of CRPC
95% CI, 1.06–1.35) whereas surgical castration was not.657 Other Most men with advanced disease eventually stop responding to traditional
population-based studies resulted in similar findings.594,658 However, a ADT and are categorized as castration-resistant (also known as
Taiwan National Health Insurance Research Database analysis found no castration-recurrent). CRPC is prostate cancer that progresses clinically,
difference in ischemic events with LHRH agonist therapy or radiographically, or biochemically despite castrate levels of serum
orchiectomy.659 A French database study showed the cardiovascular risk testosterone (<50 ng/dL).669 Patients whose disease progresses to CRPC
to be similar in men taking LHRH agonists and antagonists.660 However, during primary ADT should receive a laboratory assessment to assure a
some data suggest that LHRH antagonists might be associated with a castrate level of testosterone (<50 ng/dL; <1.7 nmol/L). Imaging tests may
lower risk of cardiac events within 1 year in men with preexisting be indicated to monitor for signs of distant metastases. Factors affecting

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NCCN Guidelines Version 1.2022

Prostate Cancer

the frequency of imaging include individual risk, age, overall patient health, who have not demonstrated definitive evidence of progression on prior
PSA velocity, and Gleason grade. docetaxel therapy.

For men who develop CRPC, ADT with an LHRH agonist or antagonist The decision to initiate therapy in the second and subsequent lines CRPC
should be continued to maintain castrate serum levels of testosterone setting should be based on the available high-level evidence of safety,
(<50 ng/dL). efficacy, and tolerability of these agents and the application of this
evidence to an individual patient. Prior exposures to therapeutic agents
Patients with CRPC and no signs of distant metastasis on conventional should be considered. There are not much data to inform the optimal
imaging studies (M0) can consider observation with continued ADT if sequence for delivery of these agents in men with metastatic CRPC (see
PSADT is greater than 10 months (preferred), because these patients will Sequencing of Therapy in CRPC, below). Choice of therapy is based
have a relatively indolent disease history.670 Secondary hormone therapy largely on clinical considerations, which include patient preferences, prior
with continued ADT is an option mainly for patients with shorter PSADT treatment, presence or absence of visceral disease, symptoms, and
(≤10 months) as described below, because the androgen receptor may potential side effects.
remain active.
NCCN recommends that patients being treated for CRPC be closely
For patients who develop metastatic CRPC, metastatic lesion biopsy is monitored with radiologic imaging (ie, CT, bone imaging), PSA tests, and
recommended, as is MSI/MMR testing, if not previously performed. If MSI- clinical exams for evidence of progression. Therapy should be continued
H or dMMR is found, referral to genetic counseling should be made to until clinical progression or intolerability in cases where PSA or bone
assess for the possibility of Lynch syndrome. These patients should also imaging changes may indicate flare rather than true clinical
have germline and tumor testing to check for mutations in homologous progression.672,673 The sequential use of these agents is reasonable in a
recombination genes (ie, BRCA1, BRCA2, ATM, PALB2, FANCA) if not patient who remains a candidate for further systemic therapy. Clinical trial
done previously.671 This information may be used for genetic counseling, and best supportive care are additional options.
early use of platinum chemotherapy, use of PARP inhibitors, or eligibility
for clinical trials. Secondary Hormone Therapy for CRPC
Research has shown enhancement of autocrine and/or paracrine
ADT is continued in patients with metastatic CRPC while additional
androgen synthesis in the tumor microenvironment of men receiving
therapies, including secondary hormone therapies, chemotherapies,
ADT.674,675 Androgen signaling consequent to non-gonadal sources of
immunotherapies, radiopharmaceuticals, and/or targeted therapies, are
androgen in CRPC refutes earlier beliefs that CRPC was resistant to
sequentially applied, as discussed in the sections that follow, and should
further hormone therapies. The development of novel hormonal agents
receive best supportive care. Patients with disease progression on a given
demonstrating efficacy in the non-metastatic and metastatic CRPC setting
therapy should not repeat that therapy, with the exception of docetaxel,
dramatically changed the paradigm of CRPC treatment.
which can be given as a rechallenge in the second- or subsequent-line
metastatic CRPC setting if given in the castration-naive setting in patients

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Abiraterone Acetate in M1 CRPC The most common adverse reactions with abiraterone/prednisone (>5%)
In April 2011, the FDA approved the androgen synthesis inhibitor, were fatigue (39%); back or joint discomfort (28%–32%); peripheral
abiraterone, in combination with low-dose prednisone, for the treatment of edema (28%); diarrhea, nausea, or constipation (22%); hypokalemia
men with metastatic CRPC who have received prior chemotherapy (17%); hypophosphatemia (24%); atrial fibrillation (4%); muscle discomfort
containing docetaxel. (14%); hot flushes (22%); urinary tract infection; cough; hypertension
(22%, severe hypertension in 4%); urinary frequency and nocturia;
FDA approval in the post-docetaxel, metastatic CRPC setting was based dyspepsia; or upper respiratory tract infection. The most common adverse
on the results of a phase 3, randomized, placebo-controlled trial (COU-AA- drug reactions that resulted in drug discontinuation were increased
301) in men with metastatic CRPC previously treated with docetaxel- aspartate aminotransferase and/or alanine aminotransferase (11%–12%),
containing regimens.676,677 Patients were randomized to receive either or cardiac disorders (19%, serious in 6%).
abiraterone 1000 mg orally once daily (n = 797) or placebo once daily (n =
398), and both arms received daily prednisone. In the final analysis, In May 2018, the FDA approved a novel, fine-particle formulation of
median survival was 15.8 versus 11.2 months in the abiraterone and abiraterone, in combination with methylprednisolone, for the treatment of
placebo arm, respectively (HR, 0.74; 95% CI, 0.64–0.86; P < .0001).677 patients with metastatic CRPC.681,682 In studies of healthy men, this
Time to radiographic progression, PSA decline, and pain palliation also formulation at 500 mg was shown to be bioequivalent to 1000 mg of the
were improved by abiraterone.677,678 originator formulation.683,684 In a phase 2 therapeutic equivalence study, 53
men with metastatic CRPC who were not treated previously with
FDA approval in the pre-docetaxel setting occurred on December 10, abiraterone, enzalutamide, radium-223, or chemotherapy (docetaxel for
2012, and was based on the randomized phase 3 COU-AA-302 trial of metastatic CRPC completed ≥1 year prior to enrollment was allowed) were
abiraterone and prednisone (n = 546) versus prednisone alone (n = 542) randomized to 500 mg daily of the new, fine-particle formulation plus 4 mg
in men with asymptomatic or minimally symptomatic, metastatic CRPC.679 methylprednisolone orally twice daily or to 1000 mg of the originator
Most men in this trial were not taking narcotics for cancer pain and none formulation daily plus 5 mg prednisone orally twice daily.685
had visceral metastatic disease or prior ketoconazole exposure. The Bioequivalence of these doses was confirmed based on serum
coprimary endpoint of radiographic PFS was improved by treatment from testosterone levels, PSA response, and abiraterone pharmacokinetics.
8.3 to 16.5 months (HR, 0.53; P < .001). OS was improved at final The rates of total and grade 3/4 adverse events were similar between the
analysis with a median follow-up of 49.2 months (34.7 months vs. 30.3 arms, with musculoskeletal and connective tissue disorders occurring
months; HR, 0.81; 95% CI, 0.70–0.93; P = .003).680 Key secondary more frequently in the originator-treated patients (37.9% vs. 12.5%). The
endpoints of time to symptomatic deterioration, time to chemotherapy panel believes that the fine-particle formulation of abiraterone can be used
initiation, time to pain progression, and PSA PFS improved significantly instead of the original formulation of abiraterone in the treatment of men
with abiraterone treatment, and PSA declines (62% vs. 24% with >50% with metastatic CRPC (category 2A), but switching from one formulation to
decline) and radiographic responses (36% vs. 16% RECIST responses) the other upon disease progression should not be undertaken. Abiraterone
were more common.

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with either steroid should not be given following progression on unpredictably; side effects should be monitored and standard dosing
abiraterone with the other steroid. (1000 mg on empty stomach) utilized if excess toxicity is observed on
modified dosing (250 mg with food).
Based on the studies described here, abiraterone is a category 1,
preferred option in first-line therapy for metastatic CRPC, regardless of Enzalutamide in M0 and M1 CRPC
previous docetaxel therapy, in the second-line setting following docetaxel, On August 31, 2012, the FDA approved enzalutamide, a next-generation
and in subsequent line therapy in the absence of visceral metastases. The antiandrogen, for treatment of men with metastatic CRPC who had
fine-particle formulation of abiraterone is listed under other recommended received prior docetaxel chemotherapy. Approval was based on the
options in these settings, as is the standard formulation in second-line results of the randomized, phase 3, placebo-controlled trial
after first-line enzalutamide. (AFFIRM).686,687 AFFIRM randomized 1199 men to enzalutamide or
placebo in a 2:1 ratio and the primary endpoint was OS. Median survival
Abiraterone should be given with concurrent steroid (either oral
was improved with enzalutamide from 13.6 to 18.4 months (HR, 0.63; P <
prednisone 5 mg twice daily or oral methylprednisolone 4 mg twice daily,
.001). Survival was improved in all subgroups analyzed. Secondary
depending on which formulation is given) to abrogate signs of
endpoints also were improved significantly, which included the proportion
mineralocorticoid excess that can result from treatment. These signs
of men with >50% PSA decline (54% vs. 2%), radiographic response (29%
include hypertension, hypokalemia, and peripheral edema. Thus,
vs. 4%), radiographic PFS (8.3 vs. 2.9 months), and time to first SRE (16.7
monitoring of liver function, potassium and phosphate levels, and blood
vs. 13.3 months). QOL measured using validated surveys was improved
pressure readings on a monthly basis is warranted during abiraterone
with enzalutamide compared to placebo. Adverse events were mild, and
therapy. Symptom-directed assessment for cardiac disease also is
included fatigue (34% vs. 29%), diarrhea (21% vs. 18%), hot flushes (20%
warranted, particularly in patients with pre-existing cardiovascular disease.
vs. 10%), headache (12% vs. 6%), and seizures (0.6% vs. 0%). The
A randomized phase 2 non-inferiority study of 75 patients with M1 CRPC incidence of cardiac disorders did not differ between the arms.
compared 1000 mg/day abiraterone after an overnight fast with 250 Enzalutamide is dosed at 160 mg daily. Patients in the AFFIRM study
mg/day after a low-fat breakfast.607 The primary endpoint was log change were maintained on GnRH agonist/antagonist therapy and could receive
in PSA, with secondary endpoints of PSA response (≥50%) and PFS. The bone supportive care medications. The seizure risk in the enzalutamide
primary endpoint favored the low-dose arm (log change in PSA, -1.59 vs. - FDA label was 0.9% versus 0.6% in the manuscript.686,688
1.19), as did the PSA response rate (58% vs. 50%), with an equal PFS of
Another phase 3 trial studied enzalutamide in the pre-chemotherapy
9 months in both arms. Noninferiority of the low dose was established
setting. The PREVAIL study randomly assigned 1717 patients with
according to the predefined criteria. Therefore, abiraterone can be given at
chemotherapy-naïve metastatic prostate cancer to daily enzalutamide or
250 mg/day administered following a low-fat breakfast, as an alternative to
placebo.689,690 The study was stopped early due to benefits shown in the
the dose of 1000 mg/day after an overnight fast in patients who will not
treatment arm. Compared to the placebo group, the enzalutamide group
take or cannot afford the standard dose. The cost savings may reduce
showed improved median PFS (20.0 months vs. 5.4 months) and median
financial toxicity and improve compliance. Food impacts absorption

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NCCN Guidelines Version 1.2022

Prostate Cancer

OS (35.3 months vs. 31.3 months). Improvements in all secondary agents and randomized 2:1 to enzalutamide (160 mg/day) plus ADT or
endpoints were also observed (eg, the time until chemotherapy initiation or placebo plus ADT. Enzalutamide improved the primary endpoint of
first SRE). metastasis-free survival over placebo (36.6 months vs. 14.7 months; HR
for metastasis or death, 0.29; 95% CI, 0.24–0.35; P < .0001). Median OS
Two randomized clinical trials have reported that enzalutamide may be was longer in the enzalutamide group than in the placebo group (67.0
superior to bicalutamide for cancer control in metastatic CRPC. The months vs. 56.3 months; HR for death, 0.73; 95% CI, 0.61–0.89; P =
TERRAIN study randomized 375 men with treatment-naïve, metastatic 0.001).694 Adverse events included fatigue (33% vs. 14%), hypertension
CRPC to 160 mg/day enzalutamide or 50 mg/day bicalutamide in a 1:1 (12% vs. 5%), major adverse cardiovascular events (5% vs. 3%), and
manner.691 The enzalutamide group had significantly better PFS (defined mental impairment disorders (5% vs. 2%). Patient-reported outcomes from
as PSA progression, soft tissue progression, or development of additional PROSPER indicate that enzalutamide delayed pain progression, symptom
bony metastases) compared to the bicalutamide group (median time to worsening, and decrease in functional status, compared with placebo.695
progression, 15.7 vs. 5.8 months; HR, 0.44; 95% CI, 0.34–0.57).
The FDA expanded approval for enzalutamide to include men with non-
The STRIVE trial randomized 396 men with M0 or M1 treatment-naïve metastatic CRPC on July 13, 2018,688,696 and the panel believes that
CRPC to 160 mg/day enzalutamide or 50 mg/day bicalutamide in a 1:1 patients with M0 CRPC can be offered enzalutamide, if PSADT is less
manner.692 The primary endpoint in this study was PFS, defined as either than or equal to 10 months (category 1, preferred).
PSA progression, radiographic progression of disease, or death from any
cause. Enzalutamide reduced the risk of progression or death by 76% Patients receiving enzalutamide have no restrictions for food intake and
compared to bicalutamide (HR, 0.24; 95% CI, 0.18–0.32). These studies concurrent prednisone is permitted but not required.686
demonstrated that enzalutamide extended PFS better than bicalutamide in
men choosing an antiandrogen for secondary hormonal therapy treatment Apalutamide in M0 CRPC
of CRPC. Bicalutamide can still be considered in some patients, given the The FDA approved apalutamide for treatment of patients with non-
different side-effect profiles of the agents and the increased cost of metastatic CRPC on February 14, 2018.610 This approval was based on
enzalutamide. the phase 3 SPARTAN trial of 1207 patients with M0 CRPC and PSADT
less than or equal to 10 months.697 Participants were stratified according to
Thus, enzalutamide represents a category 1, preferred treatment option PSADT (>6 months vs. ≤6 months), use of bone-sparing agents, and the
for men in both the pre-docetaxel and post-docetaxel metastatic CRPC presence of metastatic pelvic lymph nodes (N0 vs. N1). After median
setting. follow-up of 20.3 months, apalutamide at 240 mg/day with ADT improved
the primary endpoint of metastasis-free survival over placebo with ADT
The randomized, double-blind, placebo-controlled phase 3 PROSPER trial
(40.5 months vs. 16.2 months; HR for metastasis or death, 0.28; 95% CI,
assessed the use of enzalutamide in 1401 men with non-metastatic
0.23–0.35; P < .001). Adverse events included rash (24% vs. 5.5%),
CRPC.693 Men with PSADT less than or equal to 10 months were stratified
fracture (11% vs. 6.5%), and hypothyroidism (8% vs. 2%). Patients with
according to PSADT (<6 months vs. ≥6 months) and use of bone-sparing

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M0 CRPC can be offered apalutamide, if PSADT is less than or equal to frequently in the treatment arm included fatigue (12.1% vs. 8.7%), pain in
10 months (category 1). In a prespecified exploratory analysis of an extremity (5.8% vs. 3.2%), and rash (2.9% vs. 0.9%). The incidence of
SPARTAN, health-related QOL was maintained in both the apalutamide fractures was similar between darolutamide and placebo (4.2% vs.
and placebo groups.698 3.6%).701

After a median follow-up of 52 months, final OS analysis showed that Darolutamide is a category 1, preferred option for patients with M0 CRPC
participants in SPARTAN experienced an improved median OS with if PSADT is less than or equal to 10 months.
apalutamide versus placebo (73.9 months vs. 59.9 months; HR, 0.78; 95%
CI, 0.64–0.96; P = .016).699 This longer OS reached prespecified statistical Other Secondary Hormone Therapies
significance, even though 19% of participants crossed over from placebo Other options for secondary hormone therapy include a first-generation
to apalutamide. antiandrogen, antiandrogen withdrawal, ketoconazole (adrenal enzyme
inhibitor) with or without hydrocortisone, corticosteroid, or estrogens
Apalutamide is a category 1, preferred option for patients with M0 CRPC if including diethylstilbestrol (DES).703,704 However, none of these strategies
PSADT is less than or equal to 10 months. has yet been shown to prolong survival in randomized clinical trials.

Darolutamide in M0 CRPC DES can produce safe chemical castration in many men. Gynecomastia
The FDA approved darolutamide for treatment of patients with non- and cardiovascular side effects occur with increasing frequency with
metastatic CRPC on July 30, 2019.700 The phase 3 ARAMIS study increasing dose. Side effects are rare, and survival appears equivalent to
randomized 1509 patients with M0 CRPC and PSADT less than or equal that of other means of ADT at a 1-mg daily dose. The mechanism of action
to 10 months 2:1 to darolutamide (600 mg twice daily) or placebo.701 of DES remains uncertain because a 1-mg dose does not render some
Participants were stratified according to PSADT (>6 months vs. ≤6 men castrate, and DES produces responses when used in CRPC.705
months) and the use of osteoclast-targeted agents. The median follow-up
time was 17.9 months. Darolutamide improved the primary endpoint of Transdermal estradiol may provide similar cancer control with fewer side
metastasis-free survival compared to placebo (40.4 months vs. 18.4 effects.706 The ongoing PATCH clinical trial demonstrated similar rates of
months; HR for metastasis or death, 0.41; 95% CI, 0.34–0.50; P < .001). castrate levels of testosterone, PSA response, and side effects in 85 men
treated with LHRH agonist and 168 men treated with 100 mcg/24 hours
Patients in the placebo group of ARAMIS crossed over to darolutamide (n estrogen patches twice weekly.707 QOL outcomes and the experience of
= 170) or received other life-prolonging therapy (n = 137). Final analysis vasomotor symptoms were better at 6 months in the transdermal group
occurred after a median follow-up time of 29.0 months. The risk of death compared with the agonist group, but rates of significant gynecomastia
was 31% lower in the darolutamide group than in the placebo group (HR were higher in the transdermal group (37% vs. 5%).708 The PATCH trial
for death, 0.69; 95% CI, 0.53–0.88; P = .003).702 OS at 3 years was 83% continues enrollment in order to assess survival (NCT00303784).
(95% CI, 80–86) in the darolutamide group compared with 77% (95% CI,
72–81) in the placebo group. Adverse events that occurred more

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NCCN Guidelines Version 1.2022

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Ketoconazole with or without hydrocortisone is another option, but it 2-week docetaxel; febrile neutropenia rate was 4% versus 14% and other
should not be used if the disease progressed on abiraterone; both drugs toxicities and overall QOL were similar.
inhibit CYP17A1.
Docetaxel is the traditional mainstay of treatment for symptomatic
Patients whose disease progresses on combined androgen blockade can metastatic CRPC. Docetaxel is not commonly used for asymptomatic
have the antiandrogen discontinued.709,710 patients in this setting, but may be considered when the patient shows
signs of rapid progression or visceral metastases despite lack of
Chemotherapy, Immunotherapy, and Targeted Therapy symptoms. Treatment with greater than or equal to 8 cycles of docetaxel
Recent research has expanded the therapeutic options for patients with may be associated with better OS than fewer cycles in the metastatic
metastatic CRPC depending on the presence or absence of symptoms. CRPC setting, but prospective trials are necessary to test 6 versus 10
cycles of docetaxel in the metastatic castration-naïve and CRPC
Docetaxel settings.714 Retrospective analysis from the GETUG-AFU 15 trial suggests
Two randomized phase 3 studies evaluated docetaxel-based regimens in that docetaxel only benefits some patients with CRPC who received
symptomatic or rapidly progressive CRPC (TAX 327 and SWOG docetaxel in the castration-naïve setting.715
9916).573,711,712 TAX 327 compared docetaxel (every 3 weeks or weekly)
plus prednisone to mitoxantrone plus prednisone in 1006 men.711 Every-3- Thus, docetaxel is a category 1 preferred option for first-line treatment of
week docetaxel resulted in higher median OS than mitoxantrone (18.9 vs. metastatic CRPC and in second-line post abiraterone or enzalutamide.
16.5 months; P = .009). This survival benefit was maintained at extended The panel believes that docetaxel can be given as a rechallenge in the
follow-up.712 The SWOG 9916 study also showed improved survival with second- or subsequent-line metastatic CRPC setting if given in the
docetaxel when combined with estramustine compared to mitoxantrone castration-naive setting.
plus prednisone.573
Docetaxel is also included as an upfront option for men with castration-
Docetaxel is FDA-approved for metastatic CRPC. The standard regimen is naïve prostate cancer and distant metastases based on results from two
every 3 weeks. An alternative to every-3-week docetaxel is a biweekly phase 3 trials (ECOG 3805/CHAARTED and STAMPEDE).716,717
regimen of 50 mg/m2. This regimen is based on a large randomized phase CHAARTED randomized 790 men with metastatic, castration-naïve
2 trial of 346 men with metastatic CRPC randomized to either every-2- prostate cancer to docetaxel (75 mg/m2 IV q3 weeks x 6 doses) plus ADT
week docetaxel or every-3-week docetaxel, each with maintenance of or ADT alone.717 After a median follow-up of 53.7 months, the patients in
ADT and prednisone.713 Men treated with the every-2-week regimen the combination arm experienced a longer OS than those in the ADT arm
survived an average of 19.5 months compared to 17.0 months with the (57.6 months vs. 47.2 months; HR, 0.72; 95% CI, 0.59–0.89; P = .002).718
every-3-week regimen (P = .015). Time-to-progression and PSA decline Subgroup analysis showed that the survival benefit was more pronounced
rate favored every-2-week therapy. Tolerability was improved with every- in the 65% of participants with high-volume disease (HR, 0.63; 95% CI,
0.50–0.79; P < .001). Men with low-volume disease in CHAARTED did not

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derive a survival benefit from the inclusion of docetaxel (HR, 1.04; 95% CI, was 89% (95% CI, 84%–92%) for ADT/EBRT and 93% (95% CI, 90%–
0.70–1.55; P = .86). 96%) for ADT/EBRT/docetaxel (HR, 0.69; 90% CI, 0.49–0.97; one-sided P
= .03). Improvements were also seen in DFS and the rate of distant
The STAMPEDE trial, a multi-arm, multi-stage phase 3 trial, included metastasis. The panel does not recommend the addition of docetaxel to
patients with both M0 and M1 castration-naïve prostate cancer.716 The ADT plus EBRT in patients with high risk prostate cancer, however, at this
results in the M1 population essentially confirmed the survival advantage time.
of adding docetaxel (75 mg/m2 IV q3 weeks x 6 doses) to ADT seen in the
CHAARTED trial. In STAMPEDE, extent of disease was not evaluated in The direct randomized comparison of docetaxel with ADT and abiraterone
the 1087 men with metastatic disease, but the median OS for all patients with ADT in STAMPEDE showed that the two treatment options resulted in
with M1 disease was 5.4 years in the ADT-plus-docetaxel arm versus 3.6 similar efficacy and safety outcomes in patients with metastatic castration-
years in the ADT-only arm (a difference of 1.8 years between groups naïve prostate cancer.726
compared with a 1.1-year difference in CHAARTED). The results of the
STAMPEDE trial seem to confirm the results of the CHAARTED trial. Cabazitaxel
In June 2010, the FDA approved cabazitaxel, a semi-synthetic taxane
Men with low-volume metastatic disease can be offered early treatment derivative, for men with metastatic CRPC previously treated with a
with docetaxel combined with ADT; however, they have less certain docetaxel-containing regimen. An international randomized phase 3 trial
benefit from treatment than men with higher-volume disease, as this (TROPIC) randomized 755 men with progressive metastatic CRPC to
subgroup did not have definitively improved survival outcomes in the receive cabazitaxel 25 mg/m2 or mitoxantrone 12 mg/m2, each with daily
ECOG CHAARTED study or a similar European trial (GETUG-AFU prednisone.727 A 2.4-month improvement in OS was demonstrated with
15).717,719,720 Meta-analyses of randomized controlled trials also concluded cabazitaxel compared to mitoxantrone (HR, 0.72; P < .0001). The
that docetaxel provides a significant OS benefit in this setting, with no improvement in survival was balanced against a higher toxic death rate
evidence that the benefit was dependent on the volume of disease.721-723 with cabazitaxel (4.9% vs. 1.9%), which was due, in large part, to
differences in rates of sepsis and renal failure. Febrile neutropenia was
Some data suggest that the use of docetaxel in combination with ADT and
observed in 7.5% of cabazitaxel-treated men versus 1.3% of
EBRT may benefit fit men with high- and very-high-risk localized disease.
mitoxantrone-treated men. The incidences of severe diarrhea (6%), fatigue
The GETUG 12 trial, which randomized 413 men with high- or very-high
(5%), nausea/vomiting (2%), anemia (11%), and thrombocytopenia (4%)
risk prostate cancer to IMRT and ADT or ADT, docetaxel, and
also were higher in cabazitaxel-treated men, which indicated the need for
estramustine.724 After a median follow-up of 8.8 years, 8-year relapse-free
vigilance and treatment or prophylaxis in this setting to prevent febrile
survival was 62% in the combination therapy arm and 50% in the ADT-
neutropenia. The survival benefit was sustained at an updated analysis
only arm (adjusted HR, 0.71; 95% CI, 0.54–0.94; P = .017). The
with a median follow-up of 25.5 months.728 Furthermore, results of a post-
multicenter, phase 3 NRG Oncology RTOG 0521 trial randomized 563
hoc analysis of this trial suggested that the occurrence of grade ≥3
patients with high- or very-high-risk prostate cancer ADT plus EBRT with
or without docetaxel.725 After median follow-up of 5.7 years, 4-year OS

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neutropenia after cabazitaxel treatment was associated with docetaxel therapy. Docetaxel rechallenge can be considered in patients
improvements in both PFS and OS.729 who received docetaxel with ADT in the metastatic castration-naïve
setting.
The phase 3 open-label, multinational, non-inferiority PROSELICA study
compared 20 mg/m2 cabazitaxel with 25 mg/m2 cabazitaxel in 1200 The multicenter CARD study was a randomized, open-label clinical trial
patients with metastatic CRPC who progressed on docetaxel.730 The lower that compared cabazitaxel with either abiraterone or enzalutamide in 255
dose was found to be noninferior to the higher dose for median OS (13.4 patients with metastatic CRPC who had previously received docetaxel and
months [95% CI, 12.19–14.88] vs. 14.5 months [95% CI, 13.47–15.28]), either abiraterone or enzalutamide.732 Cabazitaxel at 25 mg/m2 with
and grade 3/4 adverse events were decreased (39.7% vs. 54.5%). In concurrent steroid improved the primary endpoint of radiographic PFS (8.0
particular, grade ≥3 neutropenia rates were 41.8% and 73.3% for the vs. 3.7 months; HR, 0.54; P < .0001) and reduced the risk of death (13.6
lower and higher dose groups, respectively. Cabazitaxel at 20 mg/m2 vs. 11.0 months; HR, 0.64; P = .008) compared with abiraterone or
every 3 weeks, with or without growth factor support, is now standard of enzalutamide in these patients. Cabazitaxel was also associated with an
care for fit patients. Cabazitaxel at 25 mg/m2 may be considered for increased rate of pain response and delayed time to pain progression and
healthy men who wish to be more aggressive. SREs.733 Therefore, cabazitaxel is included in these Guidelines as a
category 1, preferred option after progression occurs on docetaxel in
Recent results from the phase 3 FIRSTANA study suggested that patients with metastatic CRPC.
cabazitaxel has clinical activity in patients with chemotherapy-naïve
mCRPC.731 Median OS, the primary endpoint, was similar between 20 Cabazitaxel should be given with concurrent steroids (daily prednisone or
mg/m2 cabazitaxel, 25 mg/m2 cabazitaxel, and 75 mg/m2 docetaxel (24.5 dexamethasone on the day of chemotherapy). Physicians should follow
months, 25.2 months, and 24.3 months, respectively). Cabazitaxel was current guidelines for prophylactic white blood cell growth factor use,
associated with lower rates of peripheral sensory neuropathy than particularly in this heavily pre-treated, high-risk population. In addition,
docetaxel, particularly at 20 mg/m2 (12% vs. 25%). Therefore, patients supportive care should include antiemetics (prophylactic antihistamines,
who are not candidates for docetaxel, who are intolerant of docetaxel, or H2 antagonists, and corticosteroids prophylaxis) and symptom-directed
who have pre-existing mild peripheral neuropathy should be considered antidiarrheal agents. Cabazitaxel was tested in patients with hepatic
for cabazitaxel.731 dysfunction in a small, phase I, dose-escalation study.734 Cabazitaxel was
tolerated in patients with mild to moderate hepatic impairment. However,
The NCCN Guidelines Panel included cabazitaxel as an option for second- cabazitaxel should not be used in patients with severe hepatic dysfunction.
line therapy after progression on docetaxel for patients with symptomatic Cabazitaxel should be stopped upon clinical disease progression or
metastatic CRPC. This recommendation is category 1 based on intolerance.
randomized phase 3 study data (see Cabazitaxel, above).727,731 NCCN
panelists agreed that docetaxel rechallenge may be useful in some
patients (category 2A instead of category 1 in this setting), especially in
those who have not shown definitive evidence of progression on prior

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Sipuleucel-T recommended for patients with small cell/neuroendocrine prostate cancer.

In April 2010, sipuleucel-T became the first in a new class of cancer The panel prefers that sipuleucel-T be used as initial therapy for
immunotherapeutic agents to be approved by the FDA. This autologous asymptomatic or minimally symptomatic patients with metastatic CRPC,
cancer “vaccine” involves collection of the white blood cell fraction- so that disease burden is lower and immune function is potentially more
containing, antigen-presenting cells from each patient; exposure of the intact. However, it is also an option for second-line treatment. Patients
cells to the prostatic acid phosphatase-granulocyte macrophage colony- should have good performance level (ECOG 0-1), estimated life
stimulating factor (PAP-GM-CSF recombinant fusion protein); and expectancy greater than 6 months, and no liver metastases. Clinicians and
subsequent reinfusion of the cells. The pivotal study was a phase 3, patients should be aware that the usual markers of benefit (decline in PSA
multicenter, randomized, double-blind trial (D9902B).735 Five hundred and improvement in bone or CT scans) are not seen. Therefore, benefit to
twelve patients with minimally symptomatic or asymptomatic metastatic the individual patient cannot be ascertained using currently available
CRPC were randomized 2:1 to receive sipuleucel-T or placebo. Eighteen testing.
point 2 percent of patients had received prior chemotherapy, which
Treatment subsequent to sipuleucel-T treatment should proceed as
included docetaxel; eligibility requirements included no chemotherapy for 3
clinically indicated, particularly if symptoms develop.
months and no steroids for 1 month prior to enrollment. Median survival in
the vaccine arm was 25.8 months compared to 21.7 months in the control Pembrolizumab
arm. In a subset analysis, both those who did and those who did not
The FDA approved the use of pembrolizumab, an anti-PD1 antibody, for
receive prior chemotherapy benefited from sipuleucel-T treatment.
treatment of patients with “unresectable or metastatic MSI-high (MSI-H) or
Sipuleucel-T treatment resulted in a 22% reduction in mortality risk (HR,
mismatch repair (MMR)-deficient solid tumors who have progressed on
0.78; 95% CI, 0.61–0.98; P = .03). Common complications included mild
prior treatment and who have no satisfactory alternative treatment options”
to moderate chills (54.1%), pyrexia (29.3%), and headache (16.0%), which
on May 23, 2017.737 The indication has since been expanded to include
usually were transient.
several cancer types, but not prostate cancer specifically.738 The
A prospective registry of men with metastatic CRPC, PROCEED, enrolled recommended adult dose of pembrolizumab for this indication is 200 mg
1976 patients from 2011 to 2017, who were followed for a median of 46.6 intravenously once every 3 weeks.
months.736 The safety and tolerability of sipuleucel-T were consistent with
FDA-accelerated approval was based on the treatment of 149 patients
previous findings, and the median OS was 30.7 months (95% CI, 28.6–
across five clinical studies involving MSI-H or MMR-deficient (dMMR)
32.2 months).
colorectal (n = 90) or non-colorectal (n = 59) cancer for an objective
Sipuleucel-T is a category 1, preferred option for certain patients with response rate of 40% (59/149).737 All patients received greater than or
metastatic CRPC in first-line of therapy. Benefit of sipuleucel-T has not equal to 1 prior regimen. Among the non-colorectal cohorts, two patients
been reported in patients with visceral metastases and is not had metastatic CRPC: one achieved a partial objective response, and the
recommended if visceral metastases are present. Sipuleucel-T is also not other achieved stable disease for greater than 9 months.

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A growing number of additional patients with metastatic CRPC treated with endpoint of ORR in cohorts 1 and 2 was 5% (95% CI, 2%–11%) in cohort
pembrolizumab have been reported.79,739-743 In an early study, 10 patients 1 and 3% (95% CI, <1%–11%) in cohort 2. Responses were durable
with CRPC and non-visceral metastases (bone = 7; lymph nodes = 2; (range, 1.9 – ≥ 21.8 months).
bone and liver = 1) who had disease progression on enzalutamide were
treated with pembrolizumab and enzalutamide.739 Some of the patients The most common adverse events from pembrolizumab are fatigue,
also had experienced disease progression on additional therapies pruritus, diarrhea, anorexia, constipation, nausea, rash, fever, cough,
(docetaxel for castration-naïve disease, abiraterone, and/or sipuleucel-T). dyspnea, and musculoskeletal pain. Pembrolizumab also may be
Three of the 10 patients showed a near complete PSA response. Two of associated with immune-mediated side effects, which include colitis,
these three patients had radiographically measurable disease and hepatitis, endocrinopathies, pneumonitis, or nephritis.
achieved a partial radiographic response (including a response in liver
Based on the available data, the panel supports the use of pembrolizumab
metastases). Of the remaining patients, three showed stable disease, and
in patients with MSI-H or dMMR metastatic CRPC whose disease has
four displayed no evidence of clinical benefit. Genetic analysis of biopsy
progressed through at least one line of systemic therapy for M1 CRPC
tissue from two PSA responders and two PSA non-responders revealed
(category 2B). The prevalence of MMR deficiency in metastatic CPRC is
that one responder had an MSI-H tumor, whereas the other responder and
estimated at 2% to 5%,43,740 and testing for MSI-H or dMMR can be
the non-responders did not. The nonrandomized phase Ib KEYNOTE-028
performed using DNA testing or immunohistochemistry. If tumor MSI-H or
trial included 23 patients with advanced, progressive prostate cancer, of
dMMR is identified, the panel recommends referral to genetic counseling
whom 74% had received greater than or equal to two previous therapies
for consideration of germline testing for Lynch syndrome.
for metastatic disease.741 The objective response rate by investigator
review was 17.4% (95% CI, 5.0%–38.8%), with four confirmed partial Mitoxantrone
responses. Eight patients (34.8%) had stable disease. Treatment-related
Two randomized trials assessed the role of mitoxantrone in patients with
adverse events occurred in 61% of patients after a median follow-up of
metastatic CRPC.745,746 Although there was no improvement in OS,
7.9 months; 17% of the cohort experienced grade 3/4 events (ie, grade 4
palliative responses and improvements in quality of life were seen with
lipase increase, grade 3 peripheral neuropathy, grade 3 asthenia, grade 3
mitoxantrone.
fatigue).
Mitoxantrone can be used for palliation in symptomatic patients with
KEYNOTE-199 was a multi-cohort, open-label phase II study in 258
metastatic CRPC who cannot tolerate other therapies.
patients with metastatic CRPC and prior treatment with docetaxel and at
least one novel hormonal therapy that assessed pembrolizumab in Treatment Options for Patients with DNA Repair Gene Mutations
patients regardless of MSI status.744 Cohorts 1 and 2 included patients
Early studies suggest germline and somatic mutations in homologous
with PD-L1-positive (n = 133) and PD-L1-negative (n = 66) prostate
recombination repair (HRR) genes (eg, BRCA1, BRCA2, ATM, PALB2,
cancer, respectively. Cohort 3 included those with bone-predominant
FANCA, RAD51D, CHEK2) may be predictive of the clinical benefit of
disease with positive or negative PD-L1 expression (n = 59). The primary
poly-ADP ribose polymerase (PARP) inhibitors.747-749 PARP inhibitors are

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oral agents that exert their activity through the concept of synthetic study population encompassing cohorts A+B (HR, 0.49; 95% CI, 0.38–
lethality.750 At present, two PARP inhibitors are approved by the FDA for 0.63; P < .001).
use in prostate cancer (see Olaparib and see Rucaparib, below).751,752
In addition, final OS analysis of PROfound showed that OS was improved
DNA repair defects have also been reported to be predictive for sensitivity with olaparib versus abiraterone/enzalutamide in cohort A (HR, 0.69; 95%
to platinum agents in CRPC and other cancers.753-756 Platinum agents CI, 0.50–0.97; P = .02), despite the fact that 86 of 131 patients (66%)
have shown some activity in patients with CRPC without molecular crossed over to olaparib after disease progression in the control arm.762
selection.757 Studies of platinum agents in patients with CRPC that have
DNA repair gene mutations are needed. As a result of the favorable efficacy data from the PROfound trial, the FDA
approved olaparib (300 mg twice daily) in May 2020 for use in patients
In addition, a recent study suggested that patients with metastatic CRPC with mCRPC and deleterious or suspected deleterious germline or somatic
and germline mutations in DNA repair genes may have better outcomes if HRR gene mutations in at least one of 14 genes (BRCA1, BRCA2, ATM,
treated with abiraterone or enzalutamide than with taxanes.51 However, it BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B,
should be noted that the response of patients with metastatic CRPC and RAD51C, RAD51D, or RAD54L) and who had previously received
HRR gene mutations to standard therapies is similar to the response of treatment with enzalutamide or abiraterone.751 PPP2R2A was excluded
patients without mutations.758,759 due to preliminary evidence of inferior activity of olaparib in this subset.

Olaparib Since prior taxane therapy was not mandated in the PROfound study,
Preliminary clinical data using olaparib suggested favorable activity of this olaparib use might be reasonable in mCRPC patients both before or after
agent in patients with HRR gene mutations, but not in those without HRR docetaxel treatment. Adverse events that may occur with olaparib
mutations.748,749,760 The phase 3 PROfound study was a randomized trial treatment include anemia (including that requiring transfusion), fatigue,
evaluating olaparib 300 mg twice daily versus physician’s choice of nausea or vomiting, anorexia, weight loss, diarrhea, thrombocytopenia,
abiraterone or enzalutamide in patients with mCRPC and progression on creatinine elevation, cough, and dyspnea. Rare but serious side effects
at least one novel hormonal agent (abiraterone or enzalutamide) and up to may include thromboembolic events (including pulmonary emboli), drug-
one prior taxane agent (permitted but not required).761 Patients had to induced pneumonitis, and a theoretical risk of myelodysplasia or acute
have a somatic or germline HRR gene mutation, and were allocated to myeloid leukemia.761
one of two cohorts: cohort A comprised patients with BRCA1/2 or ATM
mutations, and cohort B comprised patients with a mutation in at least one The panel recommends olaparib as an option for men with metastatic
of 12 other HRR genes (BARD1, BRIP1, CDK12, CHEK1, CHEK2, CRPC, previous abiraterone or enzalutamide, and a HRRm in: 1) second-
FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L). line after first-line abiraterone or enzalutamide regardless of prior
The primary endpoint of improving radiographic PFS with olaparib versus docetaxel therapy [category 1]; 2) in second-line after docetaxel [category
abiraterone/enzalutamide was met in cohort A (HR, 0.34; 95% CI, 0.25– 2B]; and 3) in subsequent lines of therapy [category 1]. The HRR genes to
0.47; P < .001), and radiographic PFS was also superior in the entire be considered for use of olaparib are BRCA1, BRCA2, ATM, BARD1,

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BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, fit for chemotherapy. Furthermore, rucaparib should not be used in
RAD51D and RAD54L. Patients with PPP2R2A mutations in the patients with HRR gene mutations other than BRCA1/2.764 Adverse events
PROfound trial experienced an unfavorable risk-benefit profile; therefore, that may occur with rucaparib include anemia (including that requiring
olaparib is not recommended in patients with a PPP2R2A mutations. transfusion), fatigue, asthenia, nausea or vomiting, anorexia, weight loss,
diarrhea or constipation, thrombocytopenia, increased creatinine,
Any commercially available analytically and clinically validated somatic increased liver transaminases, and rash. Rare but serious side effects of
tumor and ctDNA assays and germline assays can be used to identify rucaparib include a theoretical risk of myelodysplasia or acute myeloid
patients for treatment. Careful monitoring of complete blood counts and leukemia, as well as fetal teratogenicity.763,764 Full FDA approval of
hepatic and renal function, along with type and screens and potential rucaparib is contingent upon a favorable efficacy and safety profile of this
transfusion support and/or dose reductions as needed for severe anemia drug in the phase 3 TRITON3 study (NCT02975934), a randomized trial of
or intolerance are recommended during olaparib therapy. rucaparib versus physician’s choice of therapy (abiraterone, enzalutamide,
or docetaxel) in patients with mCRPC and a germline or somatic BRCA1/2
Rucaparib
or ATM mutation who have previously received a novel hormonal agent
Rucaparib is a second PARP inhibitor approved for use in patients with
but no chemotherapy for mCRPC. The results of this trial are awaited.
mCRPC.752 This agent received accelerated FDA approval in May 2020
based on the preliminary favorable data from the TRITON2 clinical trial. In The panel recommends rucaparib as an option for men with metastatic
that open-label single-arm phase 2 trial, patients with mCRPC harboring a CRPC and a BRCA1 or BRCA2 mutation in second-line after first-line
deleterious or suspected deleterious germline or somatic BRCA1 or abiraterone or enzalutamide, in second-line after docetaxel, and in
BRCA2 mutation, who had previously received therapy with a novel subsequent lines of therapy. If the patient is not fit for chemotherapy,
hormonal agent plus one taxane chemotherapy, were treated with rucaparib can be considered even if taxane-based therapy has not been
rucaparib 600 mg twice daily.763 The primary endpoint of TRITON2 was given.
the objective response rate in patients with measurable disease, and was
43.5% (95% CI, 31.0%–56.7%) in this BRCA1/2-mutated population. The preferred method of selecting patients for rucaparib treatment is
Median radiographic PFS, a key secondary endpoint, was 9.0 months somatic analysis of BRCA1 and BRCA2 using a circulating tumor DNA
(95% CI, 8.3–13.5 months).763 The FDA indication for rucaparib (600 mg sample. As with olaparib, careful monitoring of complete blood counts and
twice daily) is for use in patients with mCRPC and deleterious or hepatic and renal function, along with type and screens and potential
suspected deleterious germline or somatic BRCA1 or BRCA2 mutations, transfusion support and/or dose reductions as needed for severe anemia
and who had previously received treatment with both a novel hormonal or intolerance are recommended during treatment with rucaparib.
agent (enzalutamide or abiraterone) as well as one taxane-containing
chemotherapy. Based on this information, the panel does not generally Small Cell/Neuroendocrine Prostate Cancer
recommend the use of rucaparib in BRCA1/2-mutated mCRPC patients De novo small cell carcinoma in untreated prostate cancers occurs rarely
who have not previously received a taxane agent unless the patient is not and is very aggressive.765 Treatment-associated small cell/neuroendocrine

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prostate cancer that occurs in men with metastatic CRPC is more (33% vs. 44%; P = .02). An update at 24 months also revealed an
common.766 In a multi-institution prospective series of 202 consecutive increase in the median time to first SRE (488 days vs. 321 days; P =
patients with metastatic CRPC, all of whom underwent metastatic .01).773 No significant differences were found in OS. Other
biopsies, small cell/neuroendocrine histology was present in 17%.766 bisphosphonates have not been shown to be effective for prevention of
Patients with small cell/neuroendocrine tumors and prior abiraterone disease-related skeletal complications. Earlier use of zoledronic acid in
and/or enzalutamide had a shorter OS when compared with those with men with castration-sensitive prostate cancer and bone metastases is not
adenocarcinoma and prior abiraterone and/or enzalutamide (HR, 2.02; associated with lower risk for SREs, and in general should not be used for
95% CI, 1.07–3.82). Genomic analysis showed that DNA repair mutations SRE prevention until the development of metastatic CRPC.774
and small cell/neuroendocrine histology were almost mutually exclusive.
The randomized TRAPEZE trial used a 2 X 2 factorial design to compare
Small cell/neuroendocrine carcinoma of the prostate should be considered clinical PFS (pain progression, SREs, or death) as the primary outcome in
in patients who no longer respond to ADT and test positive for metastases. 757 men with bone metastatic CRPC treated with docetaxel alone or with
These relatively rare tumors are associated with low PSA levels despite zoledronic acid, 89Sr, or both.775 The bone-directed therapies had no
large metastatic burden and visceral disease.767 Those with initial Grade statistically significant effect on the primary outcome or on OS in
Group 5 are especially at risk. Biopsy of accessible metastatic lesions unadjusted analysis. However, adjusted analysis revealed a small effect
should be considered to identify patients with small cell/neuroendocrine for 89Sr on clinical PFS (HR, 0.85; 95% CI, 0.73–0.99; P = .03). For
histomorphologic features in patients with visceral metastases.768 secondary outcomes, zoledronic acid improved the SRE-free interval (HR,
0.78; 95% CI, 0.65–0.95; P = .01) and decreased the total SREs (424 vs.
These cases may be managed by cytotoxic chemotherapy (ie, 605) compared with docetaxel alone.
cisplatin/etoposide, carboplatin/etoposide, docetaxel/carboplatin).769,770
Atezolizumab/carboplatin/etoposide is another option (category 3), based Denosumab was compared to zoledronic acid in a randomized, double-
on extrapolation of results from the IMpower133 trial in small-cell lung blind, placebo-controlled study in men with CRPC.776 The absolute
cancer.771 Physicians should consult the NCCN Guidelines for Small Cell incidence of SREs was similar in the two groups; however, the median
Lung Cancer (available at www.NCCN.org), because the behavior of small time to first SRE was delayed by 3.6 months by denosumab compared to
cell/neuroendocrine carcinoma of the prostate is similar to that of small cell zoledronic acid (20.7 vs. 17.1 months; P = .0002 for non-inferiority, P =
carcinoma of the lung. .008 for superiority). The rates of important SREs with denosumab were
similar to zoledronic acid and included spinal cord compression (3% vs.
Bone Metastases 4%), need for radiation (19% vs. 21%), and pathologic fracture (14% vs.
In a multicenter study, 643 men with CRPC and asymptomatic or 15%).
minimally symptomatic bone metastases were randomized to intravenous
zoledronic acid every 3 weeks or placebo.772 At 15 months, fewer men in Treatment-related toxicities reported for zoledronic acid and denosumab
the zoledronic acid 4-mg group than men in the placebo group had SREs were similar and included hypocalcemia (more common with denosumab
13% vs. 6%), arthralgias, and osteonecrosis of the jaw (ONJ, 1%–2%

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incidence). Most, but not all, patients who develop ONJ have preexisting calcium monitoring is required for denosumab and recommended for
dental problems.777 zoledronic acid, with repletion as needed.

Therefore, denosumab every 4 weeks (category 1) or zoledronic acid Radium-223 is a category 1 option to treat symptomatic bone metastases
every 3 to 4 weeks is recommended for men with CRPC and bone without visceral metastases, and the use of palliative, systemic radiation
metastases to prevent or delay disease-associated SREs. SREs include with either 89Sr or 153Sm (see Radium-223 and Other
pathologic fractures, spinal cord compression, operation, or EBRT to Radiopharmaceuticals, above).
bone. The optimal duration of zoledronic acid or denosumab in men with
CRPC and bone metastases remains unclear. A multi-institutional, open- Clinical research continues on the prevention or delay of disease spread
label, randomized trial in 1822 patients with bone-metastatic prostate to bone. A phase 3 randomized trial of 1432 patients with non-metastatic
cancer, breast cancer, or multiple myeloma found that zoledronic acid CRPC at high risk of bone involvement showed that denosumab delayed
every 12 weeks was non-inferior to zoledronic acid every 4 weeks.778 In bone metastasis by 4 months compared to placebo.782 OS was not
the every-12-weeks and every-4-weeks arms, 28.6% and 29.5% improved, and the FDA did not approve this indication for denosumab.
experienced at least 1 SRE within 2 years of randomization, respectively.
Visceral Metastases
Oral hygiene, baseline dental evaluation for high-risk individuals, and The panel defines visceral metastases as those occurring in the liver, lung,
avoidance of invasive dental surgery during therapy are recommended to adrenal gland, peritoneum, or brain. Soft tissue/lymph node sites are not
reduce the risk of ONJ.779 If invasive dental surgery is necessary, therapy considered visceral metastases. First-line abiraterone is category 2A in
should be deferred until the dentist confirms that the patient has healed these patients. In general, there are less data on treatment of patients with
completely from the dental procedure. Supplemental calcium and vitamin CRPC and visceral metastases than for those without visceral metastases.
D are recommended to prevent hypocalcemia in patients receiving either This is especially true in third and subsequent lines of therapy.
denosumab or zoledronic acid.
Sequencing of Therapy in CRPC
Monitoring of creatinine clearance is required to guide dosing of zoledronic No chemotherapy regimen has demonstrated improved survival or QOL
acid. Zoledronic acid should be dose reduced in men with impaired renal after cabazitaxel, although several systemic agents other than
function (estimated creatinine clearance 30–60 mL/min), and held for mitoxantrone have shown palliative and radiographic response benefits in
creatinine clearance <30 mL/min.780 Denosumab may be administered to clinical trials (ie, carboplatin, cyclophosphamide, doxorubicin, vinorelbine,
men with impaired renal function or even men on hemodialysis; however,
carboplatin/etoposide, docetaxel/carboplatin, gemcitabine/oxaliplatin,
the risk for severe hypocalcemia and hypophosphatemia is greater, and paclitaxel/carboplatin783-792). Prednisone or dexamethasone at low doses
the dose, schedule, and safety of denosumab have not yet been defined. may provide palliative benefits in the chemotherapy-refractory setting.793
A single study of 55 patients with creatinine clearance <30 mL/min or on No survival benefit for combination regimens over sequential single-agent
hemodialysis evaluated the use of 60-mg-dose denosumab.781 regimens has been demonstrated, and toxicity is higher with combination
Hypocalcemia should be corrected before starting denosumab, and serum

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regimens. Treatment with these agents could be considered after an A blinded, correlative study at three cancer centers assessed the
informed discussion between the physician and an individual patient about correlation between AR-V7 results before second-line treatment and OS in
treatment goals and risks/side effects and alternatives, which must include men with metastatic CRPC.803 Approximately half of the validation cohort
best supportive care. Participation in a clinical trial is encouraged. received taxane therapy in first line, whereas half received an androgen
receptor signaling inhibitor. In a high-risk subset of this cohort, patients
No randomized trials that compare taxane chemotherapies versus novel negative for AR-V7 had superior OS if they were treated with an androgen
hormonal therapies in patients who previously had abiraterone or receptor signaling inhibitor than if they were treated with a taxane (median
enzalutamide have been reported, and some data suggest cross- OS, 19.8 vs. 12.8 months; HR, 1.67; 95% CI, 1.00–2.81; P = .05).
resistance between abiraterone and enzalutamide.794-797 One molecular
biomarker that may aid appropriate selection of therapy after progression PROPHECY was a prospective multicenter validation study, which
on abiraterone or enzalutamide is the presence of androgen receptor enrolled 118 men with metastatic CRPC who were starting abiraterone or
splice variant 7 (AR-V7) in CTCs (See AR-V7 Testing, below).798 Results enzalutamide.804 The primary endpoint was to validate the prognostic
of a randomized, open-label, phase 2, crossover trial suggest that the significance of baseline AR-V7 in CTCs on radiographic or clinical PFS.
sequence of abiraterone followed by enzalutamide is more efficacious Secondary endpoints included OS. Prior exposure to enzalutamide or
than the reverse.799 abiraterone was permitted if the alternative hormonal therapy was
planned. After adjusting for CTC number and clinical prognostic factors,
AR-V7 Testing the detection of AR-V7 was associated with a shorter PFS (HR, 1.9 [P =
Lack of response of men with metastatic CRPC to abiraterone and .032] or 2.4 [P = .020], depending on the test used) and OS (HR, 4.2 [95%
enzalutamide was associated with detection of AR-V7 mRNA in CTCs CI, 2.1–8.5] or 3.5 [95% CI, 1.6–8.1], depending on the test used).
using an RNA-based polymerase chain reaction (PCR) assay.800 AR-V7
presence did not preclude clinical benefit from taxane chemotherapies These clinical experiences suggest that AR-V7 assays may be a useful
(docetaxel and cabazitaxel).801 Men with AR-V7–positive CTCs exhibited predictor of abiraterone and enzalutamide resistance in men with
superior PFS with taxanes compared to novel hormonal therapies metastatic CRPC with or without progression on prior enzalutamide or
(abiraterone and enzalutamide); the two classes of agents resulted in abiraterone. The prevalence of AR-V7 positivity is only 3% in patients prior
comparable PFS in men with AR-V7–negative CTCs. A confirmatory study to treatment with enzalutamide, abiraterone, and taxanes,802 so the panel
used a different CTC assay that detected nuclear-localized AR-V7 protein believes AR-V7 detection would not be useful to inform treatment
using immunofluorescence. Men with AR-V7–positive CTCs had superior decisions before these treatments are given. On the other hand, the
OS with taxanes versus abiraterone or enzalutamide, whereas OS was not prevalence of AR-V7 positivity is higher after progression on abiraterone
different between the two classes of agents among patients with AR-V7– or enzalutamide (19%–39%800), but data have already shown that
negative CTCs.802 abiraterone/enzalutamide crossover therapy is rarely effective and taxanes
are more effective in this setting. The panel recommends that use of AR-

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Prostate Cancer

V7 tests can be considered to help guide selection of therapy in the post-

abiraterone/enzalutamide metastatic CRPC setting.

Summary
The intention of these guidelines is to provide a framework on which to
base treatment decisions. Prostate cancer is a complex disease, with
many controversial aspects of management and with a dearth of sound
data to support many treatment recommendations. Several variables
(including adjusted life expectancy, disease characteristics, predicted
outcomes, and patient preferences) must be considered by the patient and
physician to tailor prostate cancer therapy for the individual patient.

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Prostate Cancer

Table 1. Available Tissue-Based Tests for Prostate Cancer Risk Stratification/Prognosis

Populations Outcome(s) Reported Selected Molecular Diagnostic Services Program (MolDX)
Test Platform
Studied (Test independently predicts) References Recommendations
Decipher Whole-transcriptome Post radical prostatectomy • Metastasis 152,155,156,279 Cover post-biopsy for NCCN very-low-, low-risk,
1.4M RNA (RP), adverse pathology/high- • Prostate cancer-specific mortality ,546,805-817 favorable intermediate, and unfavorable intermediate
expression (46,050 risk features risk prostate cancer in patients with at least 10 years
• Postoperative radiation sensitivity (PORTOS)
genes and noncoding life expectancy who have not received treatment for
RNA) oligonucleotide Post RP, biochemical • Metastasis prostate cancer and are candidates for active
microarray optimized recurrence/PSA persistence • Prostate cancer-specific mortality surveillance or definitive therapy
for FFPE tissue • PORTOS
Post RP, adjuvant, or salvage • Metastasis Cover post-RP for 1) pT2 with positive margins; 2)
radiation any pT3 disease; 3) rising PSA (above nadir)
• Prostate cancer-specific mortality
• PORTOS
Biopsy, localized prostate • Non-organ confined (pT3) or grade group 3
cancer post RP or EBRT disease at RP
• Lymph node metastasis
• Biochemical failure/recurrence Metastasis
• Prostate cancer-specific mortality
• Grade Group ≥4 disease at RP
M0 CRPC • Metastasis-free survival
Ki-67 IHC Biopsy, conservatively • Prostate cancer-specific mortality 818-821 Not recommended
managed (active surveillance)
Biopsy, low- to intermediate- • Non-organ-confined pT3 or Grade Group ≥4
risk treated with RP disease on RP
Oncotype Quantitative RT-PCR Biopsy, low- to high-risk • Metastases 154,822-826 Cover post-biopsy for NCCN very-low-, low-risk, and
DX for 12 prostate treated with RP • Prostate cancer-specific mortality favorable intermediate-risk prostate cancer in patients
Prostate cancer-related genes with at least 10 years life expectancy who have not
• Grade Group ≥3 and/or pT3+ disease at RP
and 5 housekeeping received treatment for prostate cancer and are
controls candidates for active surveillance or definitive therapy
Prolaris Quantitative RT-PCR Biopsy, conservatively • Prostate cancer-specific mortality 147-150,827-829 Cover post-biopsy for NCCN very-low-, low-risk, and
for 31 cell cycle- managed (active surveillance) favorable intermediate-risk prostate cancer in patients
related genes and 15 Biopsy, localized prostate • Biochemical recurrence with at least 10 years life expectancy who have not
housekeeping cancer • Metastasis received treatment for prostate cancer and are
controls candidates for active surveillance or definitive therapy
Biopsy, intermediate-risk • Biochemical recurrence
treated with EBRT
RP, node-negative localized • Biochemical recurrence
prostate cancer
Biopsy, Gleason grade 3+3 or • Non–organ-confined pT3 or Grade Group ≥3
3+4 on RP
ProMark Multiplex TURP, conservatively • Prostate cancer-specific mortality 830 Cover post-biopsy for NCCN very-low- and low-risk
immunofluorescent managed (active surveillance) prostate cancer in patients with at least 10 years life
staining of 8 proteins expectancy who have not received treatment for
prostate cancer and are candidates for active
surveillance or definitive therapy
PTEN Fluorescence in situ Biopsy, Grade Group 1 • Upgrading to Grade Group ≥3 on RP 831-835 Not recommended
hybridization or IHC RP, high-risk localized disease • Biochemical recurrence

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Prostate Cancer

Table 2. Summary of Main PET Imaging Tracers Studied in Prostate Cancer*

Tracer Half- Cyclotron Mechanism Excretion Sensitivity Specificity FDA Status Panel Recommendation
life of Action (%)* (%)*
(min)

C-11 choline 20 Onsite Cell Hepatic 32–93 40–93 • Cleared • May be used for detection
membrane of biochemically recurrent
synthesis small-volume disease in
soft tissues

• May be used after bone

scan for further evaluation
of equivocal findings

F-18 110 Regional Amino acid Renal 37–90 40–100 • Cleared • May be used for detection
fluciclovine transport of biochemically recurrent
small-volume disease in
soft tissues

• May be used after bone

scan for further evaluation
of equivocal findings

F-18 NaF 110 Regional Adsorption Hepatic 87–100 62–89 • Cleared • May be used after bone
within bone scan for further evaluation
matrix of equivocal findings

C-11 20 Onsite Lipid Lung 59–69 83–98 • Not cleared • May be used in clinical
acetate synthesis trial or registry

Ga-68 68 Generator PSMA Renal 76–86 86–100 • Not cleared • May be used in clinical
PSMA (no analog trial or registry
cyclotron)

* Interpret with caution; few studies used biopsy/surgery as gold standard; see Nuclear Imaging, above, for references.

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Prostate Cancer

Table 3. Selected Active Surveillance Experiences in North America

Center Toronto216,302,308 Johns UCSF301 UCSF (newer Canary PASS232
Hopkins218,300,303,3 cohort)836
04

No. patients 993 1298 321 810 905

Median age (y) 68 66 63 62 63

Median follow-up (months) 77 60 43 60 28

Overall survival 80% (10-y) 93% (10-y) 98% (10-y) 98% (5-y) -

Cancer-specific survival 98% (10-y) 99.9% (10-y) 100% (5-y) - -

Conversion to treatment 36.5% (10-y) 50% (10-y) 24% (3-y) 40% (5-y) 19% (28-mo)

Reason for treatment (% of entire cohort)

Gleason grade change 9.5% 15.1% 38% - -

PSA increase 11.7%* - 26%† - -

Positive lymph node - 0.4% - - -

Personal choice -1.6% 8% 8% - -

* PSA doubling time <3 years

†
PSA velocity >0.75 ng/mL/year

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Prostate Cancer

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NCCN Guidelines Version 1.2022

Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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545. Dotan ZA, Bianco FJ, Jr., Rabbani F, et al. Pattern of prostate- 552. Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without
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Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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674. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis 681. Package Insert. YONSA® (abiraterone acetate) tablets, for oral use.
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Prostate Cancer

688. Package Insert. XTANDI® (enzalutamide) capsules, for oral use. blind, phase 3 trial. Lancet Oncol 2019. Available at:
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Prostate Cancer

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Prostate Cancer

717. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy 724. Fizazi K, Faivre L, Lesaunier F, et al. Androgen deprivation therapy
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Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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