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NCCN Guidelines for Patients

available at www.nccn.org/patients

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

)

Prostate Cancer

Version 2.2021 — February 17, 2021

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NCCN

Deborah Freedman-Cass, PhD

Dorothy A. Shead, MS

NCCN Guidelines Panel Disclosures

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Diagnostic/Interventional

radiology

Internal medicine

†

Medical oncology

≠

Pathology

Patient advocate

Radiotherapy/Radiation oncology

Urology

Discussion Section Writing

Committee

*Edward Schaeer, MD, PhD/Chair ω

Robert H. Lurie Comprehensive Cancer

Center of Northwestern University

*Sandy Srinivas, MD/Vice-Chair † ω

Stanford Cancer Institute

Emmanuel S. Antonarakis, MD †

The Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

Andrew J. Armstrong, MD †

Duke Cancer Institute

Justin E. Bekelman, MD §

Abramson Cancer Center

at the University of Pennsylvania

Heather Cheng, MD, PhD †

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

Anthony Victor D’Amico, MD, PhD §

Dana-Farber/Brigham and Women’s

Cancer Center | Massachusetts

General Hospital Cancer Center

Brian J. Davis, MD, PhD §

Mayo Clinic Cancer Center

Neil Desai, MD, MHS §

UT Southwestern Simmons

Comprehensive Cancer Center

Tanya Dor, MD †

City of Hope National Cancer Center

James A. Eastham, MD ω

Memorial Sloan Kettering Cancer Center

Thomas A. Farrington ¥

Prostate Health Education Network (PHEN)

Xin Gao, MD † Þ

Dana-Farber/Brigham and Women's

Cancer Center | Massachusetts General

Hospital Cancer Center

Eric Mark Horwitz, MD §

Fox Chase Cancer Center

Joseph E. Ippolito, MD, PhD ф

Siteman Cancer Center at Barnes-

Jewish Hospital and Washington

University School of Medicine

Michael R. Kuettel, MD, MBA, PhD §

Roswell Park Comprehensive Cancer Center

Joshua M. Lang, MD †

University of Wisconsin Carbone Cancer Center

Rana McKay, MD †

UC San Diego Moores Cancer Center

Jesse McKenney, MD ≠

Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer Center

and Cleveland Clinic Taussig Cancer Institute

George Netto, MD ≠

O'Neal Comprehensive Cancer Center at UAB

David F. Penson, MD, MPH ω

Vanderbilt-Ingram Cancer Center

Julio M. Pow-Sang, MD ω

Mott Cancer Center

Robert Reiter, MD ω

UCLA Jonsson Comprehensive Cancer Center

Sylvia Richey, MD †

St. Jude Children’s Research Hospital/The

University of Tennessee Health Science Center

Mack Roach, III, MD §

UCSF Helen Diller Family

Comprehensive Cancer Center

Stan Rosenfeld ¥

University of California San Francisco

Patient Services Committee Chair

Ahmad Shabsigh, MD ω

The Ohio State University Comprehensive

Cancer Center - James Cancer Hospital

and Solove Research Institute

Daniel E. Spratt, MD §

University of Michigan

Rogel Cancer Center

Benjamin A. Teply, MD

Fred & Pamela Buett Cancer Center

Jonathan Tward, MD, PhD §

Huntsman Cancer Institute

at the University of Utah

NCCN Guidelines Version 2.2021

Prostate Cancer

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NCCN Guidelines Index

Table of Contents

Discussion

Clinical Trials: NCCN believes that

the best management for any patient

with cancer is in a clinical trial.

Participation in clinical trials is

especially encouraged.

To nd clinical trials online at NCCN

Member Institutions, click here: nccn.

org/clinical_trials/member_institutions.

aspx.

NCCN Categories of Evidence and

Consensus: All recommendations

are category 2A unless otherwise

indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

NCCN Prostate Cancer Panel Members

Summary of Guidelines Updates

Initial Prostate Cancer Diagnosis (PROS-1)

Initial Risk Stratication and Staging Workup for

Clinically Localized Disease (PROS-2)

Very-Low-Risk Group (PROS-3)

Low-Risk Group (PROS-4)

Favorable Intermediate-Risk Group (PROS-5)

Unfavorable Intermediate-Risk Group (PROS-6)

High- or Very-High-Risk Group (PROS-7)

Genetic and Molecular Biomarker Analysis for

Advanced Prostate Cancer (PROS-8)

Regional Risk Group (PROS-9)

Monitoring (PROS-10)

Radical Prostatectomy PSA Persistence/Recurrence

(PROS-11)

Radiation Therapy Recurrence (PROS-12)

Systemic Therapy for Castration-Naïve Prostate

Cancer (PROS-13)

Systemic Therapy for M0 Castration-Resistant

Prostate Cancer (CRPC) (PROS-14)

Systemic Therapy for M1 CRPC (PROS-15)

Systemic Therapy for M1 CRPC: Adenocarcinoma

(PROS-16)

Principles of Life Expectancy Estimation (PROS-A)

Principles of Genetics (PROS-B)

Principles of Imaging (PROS-C)

Principles of Active Surveillance and Observation

(PROS-D)

Principles of Radiation Therapy (PROS-E)

Principles of Surgery (PROS-F)

Principles of Androgen Deprivation Therapy (PROS-G)

Principles of Immunotherapy and Chemotherapy

(PROS-H)

Staging (ST-1)

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

NCCN Guidelines Version 2.2021

Prostate Cancer

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NCCN Guidelines Index

Table of Contents

Discussion

Updates in Version 2.2021 of the NCCN Guidelines for Prostate Cancer from Version 1.2021 include:

UPDATES

Continued

PROS-14

• Added a footnote to Continue ADT, See Principles of ADT.

PROS-G, page 1 of 5

• ADT for clinically localized (N0, M0) disease, Giving ADT before,

during, and/or after radiation (neoadjuvant/concurrent/adjuvant),

added relugolix.

• ADT for regional (N1, M0) disease:

Modied: EBRT and neoadjuvant, concurrent, and/or adjuvant

LHRH agonist or LHRH antagonist

degarelix with abiraterone.

Modied: Options for ADT alone or with abiraterone

are.

Modied: LHRH antagonist, Degarelix (category 2B)

or relugolix

Modied: Degarelix LHRH antagonist (as above)

plus abiraterone

• ADT for pN1 disease, removed (category 2B for LHRH antagonist)

PROS-G, page 2 of 5

• ADT for M0 PSA persistence/recurrence after RP or EBRT, M0 EBRT

PSA Persistence/Recurrence, TRUS-biopsy negative or M0 PSA

Persistence/Recurrence after progression on salvage EBRT: added

relugolix

• ADT for metastatic castration-naïve disease:

 ADT options were separated for clarity

Modied: LHRH antagonist

Degarelix plus docetaxel

Modied: LHRH antagonist (as above)

Degarelix plus abiraterone,

enzalutamide, or apalutamide

PROS-G, page 3 of 5

• Secondary hormone therapy for M0 or M1 CRPC:

Modied: Androgen receptor activation and autocrine/paracrine

androgen synthesis are potential mechanisms of recurrence

of prostate cancer during ADT (CRPC). Thus, castrate levels of

testosterone (<50 ng/dL) should be maintained by continuing LHRH

agonist or degarelix antagonist

while additional therapies are

applied.

PROS-G, page 4 of 5

• ADT for Patients on Observation Who Require Treatment and Those

with Life Expectancy ≤5 Years

Modied: Treatment for patients who progressed on observation of

localized disease is LHRH agonist or antagonist (category 2B for

LHRH antagonist) or orchiectomy.

• Optimal ADT

Modied: Medical castration (ie, LHRH agonist or antagonist)

(medical castration)

and surgical castration (ie, bilateral

orchiectomy) (surgical castration)

are equally eective.

PROS-G, page 5 of 5

• Optimal ADT

Added:

◊ Relugolix has not been adequately studied in combination with

potent androgen receptors inhibitors such as enzalutamide,

apalutamide, darolutamide, or abiraterone acetate, nor has

it been studied in combination with docetaxel or cabazitaxel

chemotherapy. Potential drug interactions include induction

of cytochrome P450 enzymes and reduced concentration and

ecacy of relugolix with enzalutamide or apalutamide and

cardiac QTc interactions with abiraterone. Further studies of

relugolix dosing and drug interactions with commonly used

agents in advanced prostate cancer are needed to ensure patient

safety and proper dosing.

◊ Data are limited on long-term compliance of oral relugolix and

the potential eects on optimal ADT. Ongoing monitoring for

sustained suppression of testosterone (less than 50ng/dL) can be

considered, and relugolix may not be a preferred agent if patient

compliance is uncertain.

NCCN Guidelines Version 2.2021

Prostate Cancer

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NCCN Guidelines Index

Table of Contents

Discussion

Updates in Version 1.2021 of the NCCN Guidelines for Prostate Cancer from Version 3.2020 include:

UPDATES

Continued

PROS-1

• Presence of intraductal/cribriform histology, added if intermediate-

risk prostate cancer.

• No intraductal/cribiform histology if intermediate-risk prostate

cancer

PROS-2

• Very-low-, low-, and favorable intermediate-risk groups, under

imaging column, replaced Not indicated

with Consider conrmatory

prostate biopsy ± mpMRI to establish candidacy for active

surveillance.

• Very-low- and low-risk groups, under germline testing column,

removed "or intraductal/cribiform histology."

• High-risk group, under clinical/pathologic features, changed at least

one to exactly one high-risk feature.

• High- and very-high-risk groups, under imaging column, removed

"if nomogram predicts >10% probability of pelvic lymph node

involvement."

PROS-2A

• Footnote d: added ...at which time imaging can be performed and

ADT should be given.

• Footnote j: removed "ProMark."

PROS-3

• Changed Consider mpMRI and/or prostate biopsy to conrm

candidacy for active surveillance to "Consider conrmatory

prostate biopsy with or without mpMRI to establish candidacy for

active surveillance."

• Expected patient survival, changed

greater than or equal to symbol to

greater than symbol. (also applies to PROS-5)

PROS-4 and PROS-5

• Changed Consider mpMRI and/or prostate biopsy to conrm

candidacy for active surveillance to Consider conrmatory prostate

biopsy with or without mpMRI and with or without molecular tumor

analysis

to establish candidacy for active surveillance.

PROS-5 and PROS-6

• Changed <10 y to 5–10 y.

PROS-7

• Removed category 1 from docetaxel: EBRT + ADT (1.5–3 y; category

1) ± docetaxel (category 1;

for very high risk only)

• Bottom branch, added: Best supportive care.

PROS-7A

• Modied footnote s: Decipher molecular assay is recommended if

not previously performed to inform adjuvant treatment if adverse

features are found post-RP.

PROS-8

• Metastatic risk group, removed the following footnote from this

page: ADT alone (see PROS-G) or observation is recommended for

asymptomatic patients with metastatic disease and life expectancy

≤5 years.

PROS-9

• Regional risk group, added (Any T, N1, M0) to the heading.

• Removed "ne-particle formulation of abiraterone" from the

algorithm and included a new footnote: The ne-particle formulation

of abiraterone can be used instead of the standard form (category

2B; other recommended option)."

• Added a new footnote: Abiraterone with ADT should be considered

for a total of 2 years for those men with N1 disease who are treated

with radiation to the prostate and pelvic nodes. (See PROS-G).

PROS-10

• Changed "Progression to metastatic disease without PSA

persistence/recurrence" to "Radiographic evidence of metastatic

disease without PSA persistence/recurrence," followed by biopsy.

• Modied footnote hh: Document castrate levels of testosterone if on

ADT. Workup for progression should include bone imaging, chest

CT, and abdominal/pelvic CT with contrast or abdominal/pelvic MRI

with and without contrast. If there is no evidence of metastases,

consider C-11 choline PET/CT or PET/MRI or F-18 uciclovine PET/

CT or PET/MRI for further soft tissue and bone evaluation or F-18

sodium uoride PET/CT or PET/MRI for further bone evaluation.

The Panel remains unsure of what to do when M1 is suggested by

these PET tracers next-generation imaging

but not on conventional

imaging. See Principles of Imaging (PROS-C) and Discussion.

• Removed footnotes from this page:

The term "castration-na

ïve" is used to dene patients who are not

on ADT at the time of progression. The NCCN Prostate Cancer

Panel uses the term "castration-naïve" even when patients have

had neoadjuvant, concurrent, or adjuvant ADT as part of radiation.

NCCN Guidelines Version 2.2021

Prostate Cancer

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NCCN Guidelines Index

Table of Contents

Discussion

therapy provided they have recovered testicular function.

 Castration-resistant prostate cancer (CRPC) is prostate cancer that

progresses clinically, radiographically, or biochemically despite

castrate levels of serum testosterone (<50 ng/dL). Scher HI, Halabi

S, Tannock I, et al. Design and end points of clinical trials for

patients with progressive prostate cancer and castrate levels of

testosterone: recommendations of the Prostate Cancer Clinical

Trials Working Group. J Clin Oncol 2008;26:1148-1159.

PROS-12

• Removed branching arrows for "Candidate" and "Non-candidate for

local therapy" before risk stratication and imaging.

• Added branching arrows for Life expectancy >10 y and Life

expectancy ≤10 y before treatment for patients with positive TRUS

biopsy and studies negative for distant metastases.

PROS-13

• Added the following footnotes:

The ne-particle formulation of abiraterone can be used instead of

the standard form (category 2B; other recommended option).

Routine use of bone antiresorptive therapy is not recommended in

the castration-naïve setting unless for elevated fracture risk (see

PROS-G).

SBRT to metastases can be considered in patients with

oligometastatic progression where progression-free survival is the

goal.

• Revised footnote: Tumor and germline testing for MSI-H or dMMR

and germline tumor testing for homologous recombination gene

mutations is recommended and tumor testing for MSI-H and dMMR

can be considered. See Principles of Genetics (PROS-B).

• Revised footnote: EBRT to sites of bone metastases can be

considered if metastases are in weight-bearing bones or if the

patient is symptomatic.

• Revised: Consider periodic imaging for patients with M1 to monitor

treatment response. Imaging for symptoms or increasing PSA

PROS-15

• Small cell/neuroendocrine prostate cancer, removed atezolizumab/

carboplatin/etoposide (category 3) as a rst-line and subsequent

treatment option.

• Modied footnote zz: Document castrate levels of testosterone if

progression occurs on ADT. Workup for progression should include

chest CT, bone imaging, and abdominal/pelvic CT with contrast or

abdominal/pelvic MRI with and without contrast.

PROS-16

• This page has been reformatted and extensively revised.

PROS-16A

• Added footnote: Novel hormone therapies include abiraterone,

enzalutamide, darolutamide, or apalutamide received for metastatic

castration-naïve disease, M0 CRPC, or previous lines of therapy for

M1 CRPC.

• Added footnote: Cabazitaxel 20 mg/m

plus carboplatin AUC 4

mg/mL per min with growth factor support can be considered

for t patients with aggressive variant prostate cancer (visceral

metastases, low PSA and bulky disease, high LDH, high CEA,

lytic bone metastases, NEPC histology) or unfavorable genomics

(defects in at least 2 of PTEN, TP53, and RB1). Corn PG, et al. Lancet

Oncol 2019;20(10):1432-1443.

• Added footnote: The ne-particle formulation of abiraterone can be

used instead of the standard form (other recommended option).

• Added footnote: Switching from prednisone to dexamethasone 1

mg/day can be considered for patients with disease progression

on either formulation of abiraterone. Trials show improved PSA

responses and PFS and acceptable safety using this strategy.

Romero-Laorden N, et al. Br J Cancer 2018;119(9):1052-1059 and

Fenioux C, et al. BJU Int 2019;123(2):300-306.

• Removed: de Wit R, de Bono J, Sternberg C, et al. Cabazitaxel

versus abiraterone or enzalutamide in metastatic prostate cancer. N

Engl J Med 2019; 381:2506-2518.

• Changed footnote: Patients with disease progression on a given

therapy should not repeat that therapy, with the exception of

docetaxel, which can be given as a rechallenge after progression

on a novel hormone therapy in the second- or subsequent line

metastatic CRPC setting if given

in men who have not demonstrated

denitive evidence of progression on prior docetaxel therapy in the

castration-na

ïve setting.

• Changed footnote: Sipuleucel-T is recommended only for

asymptomatic or minimally symptomatic, no liver metastases, life

expectancy >6 mo, and ECOG performance status 0–1.

Benet

Updates in Version 1.2021 of the NCCN Guidelines for Prostate Cancer from Version 3.2020 include:

UPDATES

Continued

NCCN Guidelines Version 2.2021

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Discussion

UPDATES

Continued

with sipuleucel-T has not been reported in patients with visceral

metastases and is not recommended if visceral metastases are

present. Sipuleucel-T also is not recommended for patients with

small cell/neuroendocrine prostate cancer.

• Changed footnote: Olaparib is a treatment option for patients with

mCRPC and a pathogenic mutation (germline and/or somatic)

in a homologous recombination repair gene (BRCA1, BRCA2,

ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2,

RAD51B, RAD51C, RAD51D, or RAD54L), who have been treated

with androgen receptor-directed therapy. Patients with PPP2R2A

mutations in the PROfound trial experienced an unfavorable risk-

benet prole. Therefore, olaparib is not recommended in patients

with a PPP2R2A mutation. There may be heterogeneity of response

to olaparib for non-BRCA mutations based on which gene has a

mutation.

PROS-B (2 of 2)

• Modifed bullet by adding rucaparib: At present, this information may

be used for genetic counseling, early use of platinum chemotherapy,

olaparib or rucaparib, and/or eligibility for clinical trials (eg, PARP

inhibitors). Clinical trials may include additional candidate DNA

repair genes under investigation as molecular biomarkers.

• Added bullet: The panel strongly advocates a metastatic biopsy

for histologic and molecular evaluation. When this is not possible,

plasma ctDNA assay is an option, preferably at time of biochemical

(PSA) or radiographic progression in order to maximize yield.

PROS-C (1 of 3)

• Modied: Endorectal ultrasound can be considered for patients with

suspected recurrence after RP to guide prostate bed biopsy.

PROS-C (2 of 3)

• Removed: Earlier detection of bone metastatic disease may result in

earlier use of newer and more expensive therapies, which may not

improve oncologic outcomes or overall survival.

• Modied: CT may be performed with and without oral and

intravenous contrast, and CT technique should be optimized to

maximize diagnostic utility while minimizing radiation dose.

PROS-C (3 of 3)

• Removed: (next-generation imaging).

PROS-D (1 of 2)

• Added: Consider conrmatory prostate biopsy with or without

mpMRI and with or without molecular tumor analysis to establish

candidacy for active surveillance.

• Removed: Consider mpMRI and/or prostate biopsy to conrm

candidacy for active surveillance.

PROS-D (2 of 2)

• Modied: About 2/3 of men eligible for active surveillance will

may

avoid or delay treatment.

PROS-E (1 of 5)

• Added the following:

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 eld.

PROS-E (4 of 5)

• Modied: Indications for adjuvant RT include pT3a disease, positive

margin(s), or seminal vesicle involvement.

PROS-G (1 of 5)

• Modied: ADT should not be used as monotherapy in clinically

localized prostate cancer unless there is a contraindication to

denitive local therapy such as life expectancy ≤5 years and

comorbidities. Under those circumstances, ADT may be used

[see ADT for Patients on Observation Who Require Treatment and

Those with Life Expectancy ≤5 Years (PROS-G, 4 of 5)]. (luteinizing

hormone-releasing hormone [LHRH] agonist, LHRH antagonist

[category 2B], or orchiectomy) may be an acceptable alternative if

the disease is high or very high risk.

• ADT for Regional (N1,M0) Disease, added:

EBRT and neoadjuvant, concurrent, and/or adjuvant LHRH agonist

or LHRH antagonist with abiraterone.

Abiraterone with ADT should be considered for a total of 2 years

for those men with N1 disease who are treated with radiation to the

Updates in Version 1.2021 of the NCCN Guidelines for Prostate Cancer from Version 3.2020 include:

NCCN Guidelines Version 2.2021

Prostate Cancer

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Discussion

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Prostate Cancer from Version 3.2020 include:

prostate and pelvic nodes.

PROS-G (3 of 5)

• Modied: A phase 3 study of patients with M0 CRPC and a PSADT

≤10 mo showed apalutamide (240 mg/day) improved the primary

endpoint of metastasis-free survival over placebo (40.5 months vs.

16.2 months). No signicant dierence was seen in overall survival

at the rst interim analysis. After a median follow-up of 52 months,

nal overall survival analysis showed an improved median overall

survival with apalutamide versus placebo (73.9 months vs. 59.9

months). Adverse events included rash (24% vs. 5.5%), fracture

(11% vs. 6.5%), and hypothyroidism (8% vs. 2%). Bone support

should be used in patients receiving apalutamide.

• Modied: A phase 3 study of patients with M0 CRPC and a PSADT

≤10 mo showed enzalutamide (160 mg/day) improved the primary

endpoint of metastasis-free survival over placebo (36.6 months vs.

14.7 months). No signicant dierence was seen in overall survival

at the rst interim analysis. Median overall survival was longer

in the in the enzalutamide group than in the placebo group (67.0

months vs. 56.3 months).

PROS-G (4 of 5)

• Modied: A phase 3 study of patients with M0 CRPC and a PSADT

≤10 mo showed darolutamide (600 mg twice daily) improved the

primary endpoint of metastasis-free survival over placebo (40.4

months vs. 18.4 months). An improvement in overall survival was

seen at the rst interim analysis (HR for death, 0.71; 95% CI, 0.50–

0.99; P = .045), although these data are immature (median survival

was not reached in eitherarm). Overall survival at 3 years was 83%

(95% CI, 80–86) in the darolutamide group compared with 77% (95%

CI, 72–81) in the placebo group. Adverse events that occurred more

frequently in the treatment arm included fatigue (12.1% vs. 8.7%),

pain in an extremity (5.8% vs. 3.2%), and rash (2.9% vs. 0.9%).

The incidence of fractures was similar between darolutamide and

placebo (4.2% vs. 3.6%).

PROS-H (1 of 3)

• Systemic therapy for M1 CRPC, added Cabazitaxel/carboplatin with

concurrent prednisone twice daily.

PROS-H (2 of 3)

• Added Cabazitaxel 20 mg/m

plus carboplatin AUC 4 mg/mL per

min with growth factor support can be considered for t patients

with aggressive variant prostate cancer (visceral metastases, low

PSA and bulky disease, high LDH, high CEA, lytic bone metastases,

NEPC histology) or unfavorable genomics (defects in at least 2 of

PTEN, TP53, and RB1). Corn PG, et al. Lancet Oncol 2019;20:1432-

1443.

• Modied: Docetaxel retreatment can be attempted in second or

subsequent lines of therapy for mCRPC after progression on a

novel hormone therapy in men with metastatic CRPC who have not

demonstrated denitive evidence of progression on prior docetaxel

therapy in the castration-naïve setting.

• Added: Targeted Therapy

Modied: Consider inclusion of olaparib in men who have an HRR

mutation and have progressed on prior treatment with androgen

receptor-directed therapy enzalutamide and/or abiraterone

regardless of prior docetaxel therapy.

Added: Consider inclusion of rucaparib for patients with mCRPC

and a pathogenic BRCA1 or BRCA2 mutation (germline and/or

somatic) who have been treated with androgen receptor-directed

therapy and a taxane-based chemotherapy. If the patient is not t

for chemotherapy, rucaparib can be considered even if taxane-

based therapy has not been given.

• Modied:

Only as subsequent systemic therapy for patients with

metastatic CRPC who have progressed through prior docetaxel and/or a

novel hormone therapy. at least one line of systemic therapy for M1 CRPC.

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Discussion

INITIAL PROSTATE CANCER DIAGNOSIS

a,b,c

• Perform digital rectal exam

(DRE) to conrm clinical

stage

• Perform and/or collect

prostate specic antigen

(PSA) and calculate PSA

density and PSA doubling

time (PSADT)

• Obtain and review diagnostic

prostate biopsies

• Estimate life expectancy (See

Principles of Life Expectancy

Estimation [PROS-A])

• Inquire about known high-

risk germline mutations

• Obtain family history

PROS-1

Family history of high-risk

germline mutations (eg,

BRCA1/2, Lynch mutation)

and/or

Family history is suspicious

and/or

Presence of intraductal/

cribriform histology in

intermediate-risk prostate

cancer

Germline

testing,

preferably with

pre-test genetic

counseling

Family history is

unknown or not

signicant

and

No intraductal/

cribriform histology

if intermediate-risk

prostate cancer

Consider germline

testing based on

clinical features

Germline

mutation

not

identied

Germline

mutation

identied

Genetic

counseling

See Initial Risk

Stratication and

Staging Workup

for Clinically

Localized Disease

(PROS-2)

See NCCN Guidelines for Older Adult Oncology for tools to aid optimal

assessment and management of older adults.

See NCCN Guidelines for Prostate Cancer Early Detection.

See Principles of Genetics (PROS-B).

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Prostate Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

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Discussion

INITIAL RISK STRATIFICATION AND STAGING WORKUP FOR CLINICALLY LOCALIZED DISEASE

PROS-2

Risk Group Clinical/Pathologic Features Imaging

f,g

Germline

Testing

Molecular/

Biomarker

Analysis of

Tumor

Initial

Therapy

Very low

Has all of the following:

• T1c

• Grade Group 1

• PSA <10 ng/mL

• Fewer than 3 prostate biopsy fragments/cores positive,

≤50% cancer in each fragment/core

• PSA density <0.15 ng/mL/g

• Consider conrmatory prostate biopsy ± mpMRI to

establish candidacy for active surveillance

Recommended

if family history

positive

See PROS-1

Not indicated

See PROS-3

Low

Has all of the following but does not qualify for very low risk:

• T1–T2a

• Grade Group 1

• PSA <10 ng/mL

• Consider conrmatory prostate biopsy ± mpMRI to

establish candidacy for active surveillance

Recommended

if family history

positive

See PROS-1

Consider if life

expectancy

≥10 y

See PROS-4

Intermediate

Has all of the following:

• No high-risk group

features

• No very-high-risk

group features

• Has one or more

intermediate risk

factors (IRF):

T2b–T2c

Grade Group 2 or 3

PSA 10–20 ng/mL

Favorable

intermediate

Has all of the

following:

• 1 IRF

• Grade Group 1

or 2

• <50% biopsy

cores positive

• Consider conrmatory prostate biopsy ± mpMRI to

establish candidacy for active surveillance

• Bone imaging

: not recommended for staging

• Pelvic ± abdominal imaging

: recommended if

nomogram predicts >10% probability of pelvic lymph

node involvement

• If regional or distant metastases are found, see PROS-8

Recommended

if family history

positive or

intraductal/

cribriform

histology

See PROS-1

Consider if life

expectancy

≥10 y

See PROS-5

Unfavorable

intermediate

Has one or more of

the following:

• 2 or 3 IRFs

• Grade Group 3

• ≥ 50% biopsy

cores positive

• Bone imaging

: recommended if T2 and PSA >10 ng/mL

• Pelvic ± abdominal imaging

: recommended if

nomogram predicts >10% probability of pelvic lymph

node involvement

• If regional or distant metastases are found, see PROS-8

Recommended

if family history

positive or

intraductal/

cribriform

histology

See PROS-1

Consider if life

expectancy

≥10 y

See PROS-6

High

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

feature:

• T3a OR

• Grade Group 4 or Grade Group 5 OR

• PSA >20 ng/mL

• Bone imaging

: recommended

• Pelvic ± abdominal imaging

: recommended

• If regional or distant metastases are found, see PROS-8

Recommended

Consider if life

expectancy

≥10 y

See PROS-7

Very high

Has at least one of the following:

• T3b–T4

• Primary Gleason pattern 5

• 2 or 3 high-risk features

• >4 cores with Grade Group 4 or 5

• Bone imaging

: recommended

• Pelvic ± abdominal imaging

: recommended

• If regional or distant metastases are found, see PROS-8

Recommended

Not routinely

recommended

See PROS-7

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

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Discussion

PROS-2A

See Principles of Genetics (PROS-B).

For asymptomatic 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-G).

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) counts as a single positive core.

See Principles of Imaging (PROS-C).

Bone imaging should be performed for any patient with symptoms consistent with bone metastases.

Plain films, CT, MRI, F-18 sodium fluoride PET/CT or PET/MRI, C-11 choline PET/CT or PET/MRI, or F-18 fluciclovine PET/CT or PET/MRI can be considered for

equivocal results on initial bone scan. See PROS-C.

mpMRI is preferred over CT for abdominal/pelvic staging. See PROS-C.

Men 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. Men with unfavorable intermediate- and high-risk disease and life expectancy ≥10 y may consider the use of Decipher and

Prolaris tumor-based molecular assays. Retrospective studies have shown that molecular assays performed on prostate biopsy or radical prostatectomy (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 external beam therapy, and likelihood of developing metastasis after RP or salvage radiotherapy. See

Discussion.

INITIAL RISK STRATIFICATION AND STAGING WORKUP FOR CLINICALLY LOCALIZED DISEASE

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

PROS-3

VERY-LOW-RISK GROUP

EXPECTED

PATIENT

SURVIVAL

INITIAL THERAPY ADJUVANT THERAPY

EBRT

or brachytherapy

Radical prostatectomy (RP)

>20 y

Adverse feature(s):

r,s

EBRT

± ADT

Observation

See Monitoring for Initial

Denitive Therapy (PROS-10)

Progressive disease

See Initial Risk Stratication

and Staging Workup for

Clinically Localized Disease

(PROS-2)

No adverse features

Active surveillance (preferred)

• Consider conrmatory prostate biopsy with or without mpMRI to establish candidacy

for active surveillance

• PSA no more often than every 6 mo unless clinically indicated

• DRE no more often than every 12 mo unless clinically indicated

• Repeat prostate biopsy no more often than every 12 mo unless clinically indicated

• Repeat mpMRI no more often than every 12 mo unless clinically indicated

Observation

10–20 y

<10 y

Progressive disease

See Initial Risk

Stratication and Staging

Workup for Clinically

Localized Disease (PROS-2)

Active surveillance

• Consider conrmatory prostate biopsy with or without mpMRI to establish candidacy

for active surveillance

• PSA no more often than every 6 mo unless clinically indicated

• DRE no more often than every 12 mo unless clinically indicated

• Repeat prostate biopsy no more often than every 12 mo unless clinically indicated

• Repeat mpMRI no more often than every 12 mo unless clinically indicated

See Footnotes for Risk Groups (PROS-7A).

See Monitoring (PROS-10)

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

≥10 y

PROS-4

LOW-RISK GROUP

EXPECTED

PATIENT

SURVIVAL

INITIAL THERAPY ADJUVANT THERAPY

EBRT

or brachytherapy

Adverse feature(s):

r,s

EBRT

± ADT

Observation

No adverse features

Active surveillance (preferred)

• Consider conrmatory prostate biopsy with or without mpMRI and with or without

molecular tumor analysis

to establish candidacy for active surveillance

• PSA no more often than every 6 mo unless clinically indicated

• DRE no more often than every 12 mo unless clinically indicated

• Repeat prostate biopsy no more often than every 12 mo unless clinically indicated

• Repeat mpMRI no more often than every 12 mo unless clinically indicated

Progressive disease

See Initial Risk Stratication

and Staging Workup for

Clinically Localized Disease

(PROS-2)

Observation

<10 y

See Footnotes for Risk Groups (PROS-7A).

See Monitoring for Initial

Denitive Therapy (PROS-10)

See Monitoring (PROS-10)

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

PROS-5

>10 y

FAVORABLE INTERMEDIATE-RISK GROUP

EXPECTED

PATIENT

SURVIVAL

INITIAL THERAPY ADJUVANT THERAPY

± PLND if predicted

probability of lymph node

metastasis ≥2%

Adverse feature(s) and no

lymph node metastases:

r,s

EBRT

± ADT

Observation

Lymph node metastasis:

ADT

t,z

(category 1) ± EBRT

(category 2B)

Observation

q,aa

No adverse features or

lymph node metastases

EBRT

or brachytherapy alone

Undetectable PSA

after RP or PSA

nadir

after RT

PSA persistence/

recurrence

x,y

See Radical

Prostatectomy PSA

Persistence/Recurrence

(PROS-11)

See Radiation Therapy

Recurrence (PROS-12)

EBRT

or brachytherapy alone

Observation (preferred)

Active surveillance

• Consider conrmatory prostate biopsy with or without mpMRI and with or without

molecular tumor analysis

to establish candidacy for active surveillance

• PSA no more often than every 6 mo unless clinically indicated

• DRE no more often than every 12 mo unless clinically indicated

• Repeat prostate biopsy no more often than every 12 mo unless clinically indicated

• Repeat mpMRI no more often than every 12 mo unless clinically indicated

Progressive disease

See Initial Risk

Stratication and

Staging Workup for

Clinically Localized

Disease (PROS-2)

See Monitoring

(PROS-10)

See Footnotes for Risk Groups (PROS-7A).

See Monitoring for

Initial Denitive

Therapy (PROS-10)

5–10 y

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Discussion

PROS-6

>10 y

± PLND if predicted

probability of lymph

node metastasis ≥2%

Adverse feature(s) and no lymph node metastases:

r,s

EBRT

± ADT

Observation

Lymph node metastasis:

ADT

t,z

(category 1) ± EBRT

(category 2B)

Observation

q,aa

No adverse features or lymph node metastases

Undetectable PSA

after RP or PSA

nadir

after RT

PSA persistence/

recurrence

x,y

See Radical

Prostatectomy

PSA Persistence/

Recurrence

(PROS-11)

See Radiation

Therapy

Recurrence

(PROS-12)

Observation (preferred)

EBRT

+ ADT

(4–6 mo)

EBRT

+ brachytherapy

± ADT

(4–6 mo)

UNFAVORABLE INTERMEDIATE-RISK GROUP

EXPECTED

PATIENT

SURVIVAL

INITIAL THERAPY ADJUVANT THERAPY

See Monitoring

(PROS-10)

See Footnotes for Risk Groups (PROS-7A).

See Monitoring for

Initial Denitive

Therapy (PROS-10)

5–10 y

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Discussion

HIGH- OR VERY-HIGH-RISK GROUP

EBRT

+ brachytherapy

+ ADT

(1–3 y; category 1 for ADT)

Undetectable

PSA after RP

or PSA nadir

after RT

PSA persistence/

recurrence

x,y

EBRT

+ ADT

(1.5–3 y; category 1)

± docetaxel (for very high risk only)

+ PLND

PROS-7

>5 y or

symptomatic

EXPECTED

PATIENT

SURVIVAL

INITIAL THERAPY ADJUVANT THERAPY

Adverse feature(s) and no lymph node metastases:

r,s

EBRT

± ADT

Observation

Lymph node metastasis:

ADT

t,z

(category 1) ± EBRT

(category 2B)

Observation

q,aa

No adverse features or lymph node metastases

See Monitoring

for Initial

Denitive

Therapy

(PROS-10)

See Radiation

Therapy

Recurrence

(PROS-13)

Observation

ADT

t,dd

EBRT

o,dd

≤5 y and

asymptomatic

See Radical

Prostatectomy

PSA

Persistence/

Recurrence

(PROS-11)

See Monitoring (PROS-10)

See Footnotes for Risk Groups (PROS-7A).

Best supportive care

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Discussion

For asymptomatic 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-G).

Men 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. Men with unfavorable intermediate- and

high-risk disease and life expectancy ≥10 y may consider the use of Decipher

and Prolaris tumor-based molecular assays. Retrospective studies have shown

that 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 external beam therapy, and

likelihood of developing metastasis after RP or salvage radiotherapy. See

Discussion.

See Principles of Life Expectancy Estimation (PROS-A).

The Panel remains concerned about the problems of overtreatment related

to the increased diagnosis of early prostate cancer from PSA testing. See

NCCN Guidelines for Prostate Cancer Early Detection. Active surveilance is

recommended for this subset of patients.

Active surveillance involves actively monitoring the course of disease with the

expectation to intervene with potentially curative therapy if the cancer progresses.

See Principles of Active Surveillance and Observation (PROS-D).

If higher grade and/or higher T stage is found, see PROS-2.

See Principles of Radiation Therapy (PROS-E).

See Principles of Surgery (PROS-F).

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-D).

Adverse laboratory/pathologic features include: positive margin(s); seminal vesicle

invasion; extracapsular extension; or detectable PSA.

Decipher molecular assay is recommended if not previously performed to inform

adjuvant treatment if adverse features are found post-RP.

See Principles of Androgen Deprivation Therapy (PROS-G).

Criteria for progression are not well defined and require physician judgment;

however, a change in risk group strongly implies disease progression. See

Discussion.

Repeat molecular tumor analysis is discouraged.

PSA nadir is the lowest value reached after EBRT or brachytherapy.

PSA persistence/recurrence after RP is defined as failure of PSA to fall to

undetectable levels (PSA persistence) or undetectable PSA after RP with a

subsequent detectable PSA that increases on 2 or more determinations (PSA

recurrence).

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 persistence/

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 men.

See monitoring for N1 on ADT (PROS-10).

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-11.

Active surveillance of unfavorable intermediate and high-risk clinically localized

cancers is not recommended in patients with a life expectancy >10 years

(category 1).

RP + PLND can be considered in younger, healthier patients without tumor

fixation to the pelvic sidewall.

ADT or EBRT may be considered in selected patients with high- or very-high-

risk disease, where complications, such as hydronephrosis or metastasis, can be

expected within 5 y.

PROS-7A

FOOTNOTES

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Discussion

GENETIC AND MOLECULAR BIOMARKER ANALYSIS FOR ADVANCED PROSTATE CANCER

PROS-8

See Principles of Genetics (PROS-B).

Risk Group Clinical/Pathologic Features Germline Testing

Molecular and Biomarker Analysis of Tumor

Initial Therapy

Regional Any T, N1, M0 Recommended

Consider tumor testing for homologous recombination

gene mutations (HRRm) and for microsatellite instability

(MSI) or mismatch repair deciency (dMMR)

See PROS-9

Metastatic Any T, Any N, M1 Recommended

Recommend tumor testing for HRRm and consider tumor

testing for MSI or dMMR

See PROS-13

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Discussion

PROS-9

REGIONAL RISK GROUP (ANY T, N1, M0)

See Principles of Life Expectancy Estimation (PROS-A).

See Principles of Radiation Therapy (PROS-E).

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-D).

See Principles of Androgen Deprivation Therapy (PROS-G).

The fine-particle formulation of abiraterone can be used instead of the standard

form (category 2B; other recommended option).

Abiraterone with ADT should be considered for a total of 2 years for those men

with N1 disease who are treated with radiation to the prostate and pelvic nodes.

(See PROS-G).

See Monitoring (PROS-10)

INITIAL THERAPY

EBRT

+ ADT

(preferred)

± abiraterone

ee,

>5 y

or symptomatic

Observation

ADT

≤5 y

and asymptomatic

EXPECTED

PATIENT

SURVIVAL

ADT

± abiraterone

t,ee

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Discussion

See Principles of Imaging (PROS-C).

PSA persistence/recurrence after RP is defined as failure of PSA to fall to undetectable

levels (PSA persistence) or undetectable PSA after RP with a subsequent detectable PSA

that increases on 2 or more determinations (PSA recurrence).

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 persistence/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 men.

PSA as frequently as every 3 mo may be necessary to clarify disease status, especially in

high-risk men.

Document castrate levels of testosterone if on ADT. Workup for progression should

include bone imaging, chest CT, and abdominal/pelvic CT with contrast

or abdominal/

pelvic MRI with and without contrast. If there is no evidence of metastases, consider

C-11 choline PET/CT or PET/MRI or F-18 fluciclovine PET/CT or PET/MRI for further

soft tissue and bone evaluation or F-18 sodium fluoride PET/CT or PET/MRI for further

bone evaluation. The Panel remains unsure of what to do when M1 is suggested by these

PET tracers but not on conventional imaging.

See Principles of Imaging (PROS-C) and

Discussion.

Treatment for patients who progressed on observation of localized disease is ADT. See

Principles of Androgen Deprivation Therapy (PROS-G).

MONITORING

See NCCN Guidelines For Survivorship

RECURRENCE

Initial denitive therapy

N1 on ADT

Localized on observation

• PSA every 6–12 mo

for 5 y,

then every

year

• DRE every year, but

may be omitted if

PSA undetectable

• Physical exam + PSA

every 3–6 mo

• Imaging for symptoms

or increasing PSA

Post-RP

Post-RT

See Radical

Prostatectomy PSA

Persistence/Recurrence

(PROS-11)

PSA persistence/recurrence

Positive DRE

See Radiation

Therapy Recurrence

(PROS-12)

See Systemic Therapy for

M1 CRPC (PROS-15)

PROS-10

Progression

hh,ii

See Systemic Therapy

for Castration-Naïve

Disease (PROS-13)

N1,M0

Systemic Therapy for

M0 CRPC (PROS-14)

PSA persistence/recurrence

Radiographic evidence of

metastatic disease without

PSA persistence/recurrence

Biopsy

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Discussion

See Principles of Imaging (PROS-C).

See Principles of Radiation Therapy (PROS-E).

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-D).

See Principles of Androgen Deprivation Therapy (PROS-G).

PSA persistence/recurrence after RP is defined as failure of PSA to fall to

undetectable levels (PSA persistence) or undetectable PSA after RP with a

subsequent detectable PSA that increases on 2 or more determinations (PSA

recurrence).

Document castrate levels of testosterone if on ADT. Workup for progression

should include bone imaging, chest CT, and abdominal/pelvic CT with contrast

or abdominal/pelvic MRI with and without contrast. If there is no evidence of

metastases, consider C-11 choline PET/CT or PET/MRI or F-18 fluciclovine

PET/CT or PET/MRI for further soft tissue and bone evaluation or F-18 sodium

fluoride PET/CT or PET/MRI for further bone evaluation. The Panel remains

unsure of what to do when M1 is suggested by these PET tracers but not on

conventional imaging. See Principles of Imaging (PROS-C) and Discussion.

PSADT can be calculated to inform nomogram use and counseling and/or

Decipher molecular assay (category 2B) can be considered to inform counseling.

F-18 sodium fluoride or C-11 choline or F-18 fluciclovine PET/CT or PET/MRI

can be considered after bone scan for further evaluation when clinical suspicion

of bone metastases is high.

Histologic confirmation is recommended whenever feasible due to significant

rates of false positivity.

RADICAL PROSTATECTOMY PSA PERSISTENCE/RECURRENCE

PSA persistence/

recurrence

• Risk stratication

PSADT

Consider:

• Bone imaging

f,kk

• Chest CT

• Abdominal/pelvic CT or

abdominal/pelvic MRI

• C-11 choline or F-18

uciclovine PET/CT or

PET/MRI

f,w,ll

• Prostate bed biopsy

(especially if imaging

suggests local recurrence)

Studies negative for

distant metastases

or imaging not

performed

Studies positive for

distant metastases

EBRT

± ADT

Observation

PROS-11

Progression

See Systemic Therapy

for Castration-Naïve

Disease (PROS-13)

See Systemic Therapy

for Castration-Naïve

Disease (PROS-13)

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Discussion

RADIATION THERAPY RECURRENCE

PSA

persistence/

recurrence

Positive DRE

TRUS biopsy

negative,

studies negative

for distant

metastases

TRUS biopsy

positive, studies

negative

for distant

metastases

Studies positive

for distant

metastases

Observation

RP + PLND

Brachytherapy

Cryotherapy

High-intensity

focused

ultrasound (HIFU)

(category 2B)

Observation

ADT

Progression

PROS-12

• Risk

stratication

PSADT

• Bone imaging

f,kk

• Prostate MRI

• Transrectal

ultrasound (TRUS)

biopsy

• Consider:

Chest CT

Abdominal/pelvic

CT or abdominal/

pelvic MRI

C-11 choline or

F-18 uciclovine

PET/CT or PET/

MRI

f,ll

See Systemic

Therapy for

Castration-Naïve

Disease (PROS-13)

See Systemic

Therapy for M0

CRPC (PROS-14)

See Systemic

Therapy for M1

CRPC (PROS-15)

See footnotes (PROS-12A).

Life

expectancy

>10 y

Life

expectancy

≤10 y

Progression

NCCN Guidelines Version 2.2021

Prostate Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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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See Principles of Imaging (PROS-C).

See Principles of Radiation Therapy (PROS-E).

See Principles of Surgery (PROS-F).

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-D).

See Principles of Androgen Deprivation Therapy (PROS-G).

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 persistence/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 men.

Document castrate levels of testosterone if on ADT. Workup for progression should include bone imaging, chest CT, and abdominal/pelvic CT with contrast or

abdominal/pelvic MRI with and without contrast. If there is no evidence of metastases, consider C-11 choline PET/CT or PET/MRI or F-18 fluciclovine PET/CT or PET/

MRI for further soft tissue and bone evaluation or F-18 sodium fluoride PET/CT or PET/MRI for further bone evaluation. The Panel remains unsure of what to do when

M1 is suggested by these PET tracers but not on conventional imaging. See Principles of Imaging (PROS-C) and Discussion.

F-18 sodium fluoride or C-11 choline or F-18 fluciclovine PET/CT or PET/MRI can be considered after bone scan for further evaluation when clinical suspicion of bone

metastases is high.

Histologic confirmation is recommended whenever feasible due to significant rates of false positivity.

PSADT can be calculated to inform nomogram use and counseling.

PROS-12A

FOOTNOTES

NCCN Guidelines Version 2.2021

Prostate Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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.

NCCN Guidelines Index

Table of Contents

Discussion

SYSTEMIC THERAPY FOR CASTRATION-NAÏVE PROSTATE CANCER

Observation (preferred)

ADT

t,oo

Progression

hh,ww

Studies

negative

for distant

metastases

Studies

positive

for distant

metastases

pp,qq,rr,ss,tt

See Principles of Imaging (PROS-C).

See Principles of Radiation Therapy (PROS-E).

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-D).

See Principles of Androgen Deprivation Therapy (PROS-G).

The fine-particle formulation of abiraterone can be used instead of the standard

form (category 2B; other recommended option).

Document castrate level of testosterone if on ADT. Workup for progression

should include bone imaging, chest CT, and abdominal/pelvic CT with contrast

or abdominal/pelvic MRI with and without contrast. If there is no evidence of

metastases, consider C-11 choline PET/CT or PET/MRI or F-18 fluciclovine

PET/CT or PET/MRI for further soft tissue and bone evaluation or F-18 sodium

fluoride PET/CT or PET/MRI for further bone evaluation. The Panel remains

unsure of what to do when M1 is suggested by these PET tracers but not on

conventional imaging. See Principles of Imaging (PROS-C) and Discussion.

T he term "castration-naïve" is used to define patients who are not on ADT at

the time of progression. The NCCN Prostate Cancer Panel uses the term

"castration-naïve" even when patients have had neoadjuvant, concurrent,

or adjuvant ADT as part of radiation therapy provided they have recovered

testicular function.

Intermittent ADT can be considered for men with M0 or M1 disease to reduce

toxicity. See Principles of Androgen Deprivation Therapy (PROS-G).

EBRT to sites of bone metastases can be considered if metastases are in

weight-bearing bones or if the patient is symptomatic.

ADT alone (see PROS-G) or observation are recommended for asymptomatic

patients with metastatic disease and life expectancy ≤5 years.

Tumor and germline testing for homologous recombination gene mutations is

recommended and tumor testing for MSI or dMMR can be considered. See

Principles of Genetics (PROS-B).

SBRT to metastases can be considered in patients with oligometastatic

progression where progression-free survival is the goal.

Routine use of bone antiresorptive therapy is not recommended in the castration-

naïve setting unless for elevated fracture risk.(see PROS-G).

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.

See Principles of Immunotherapy and Chemotherapy (PROS-H).

Patients who were under observation for M0 disease should receive an

appropriate therapy for castration-naïve disease.

ADT

with one of the following:

• Preferred regimens:

Apalutamide (category 1)

Abiraterone (category 1)

t,ee

Docetaxel 75 mg/m

for 6 cycles

(category 1)

Enzalutamide (category 1)

• EBRT

to the primary tumor for low-volume M1

ADT

t,oo

PROS-13

• Physical exam +

PSA every 3–6 mo

• Imaging for

symptoms

• Consider periodic

imaging for

patients with

M1 to monitor

treatment

response

See

Systemic

Therapy for

M1 CRPC

(PROS-15)

See

Systemic

Therapy for

M0 CRPC

(PROS-14)

NCCN Guidelines Version 2.2021

Prostate Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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.

NCCN Guidelines Index

Table of Contents

Discussion

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