Prostate Cancer Guidelines

Guidelines on prostate cancer screening have been issued by the following organizations:

• American Cancer Society (ACS) ^[1]
• National Comprehensive Cancer Network (NCCN) ^[2]
• American Urological Association (AUA) ^[3]
• U.S. Preventive Services Task Force (USPSTF) ^[4]
• European Society for Medical Oncology (ESMO) ^[5]
• European Association of Urology/European Society for Radiotherapy and Oncology/International Society of Geriatric Oncology (EAU/ESTRO/SIOG) ^[6]

The guidelines differ in their recommendations regarding whether or not to provide routine prostate-specific antigen (PSA)–based prostate cancer screening, in what age groups and life expectancies, and at what intervals. The guidelines agree that PSA-based prostate cancer screening requires an informed, shared decision-making process, and that the decision should reflect the patient’s understanding of the possible benefits and risks and should respect the patient’s preferences and values.

ACS Screening Guidelines

Current ACS guidelines for early detection of prostate cancer do not recommend routine screening in any age group. Instead, asymptomatic men with at least a 10-year life expectancy should be given an opportunity to make an informed decision with their health care provider after receiving information on the uncertainties, risks, and benefits of screening

Men should receive the information starting at the following ages:

• Age 50 for those at average risk of developing prostate cancer
• Age 45 for those at high risk, including African Americans and men with a first-degree relative (father, brother, son) diagnosed with prostate cancer before age 65
• Age 40 for those at higher risk (more than one first-degree relative diagnosed with prostate cancer at an early age)

For men who are unable to decide whether they wish to be screened, the ACS advises that the patient’s health care provider can make the screening decision, taking into account the patient’s general health preferences and values.

Men who decide to be screened should be tested with a PSA test. A digital rectal exam (DRE) may also be done as a part of screening.

If screening does not detect cancer, the time between subsequent screenings depends on the results of the blood test, as follows:

• PSA < 2.5 ng/ml – Retesting may be done every 2 years
• PSA ≥ 2.5 ng/ml – Retesting should be done annually

Even after the decision to screen has been made, the discussion about the risks and benefits of testing should be repeated as new information becomes available.

NCCN Screening guidelines

The NCCN recommends performing a baseline evaluation, with a history and physical examination that includes the following:

• Family history
• Medications
• History of prostate disease and screening, including prior PSA and/or isoforms, exams, and biopsies
• Race
• Family or personal history of BRC1/2 mutations

The clinician should then discuss of the risks and benefits of a baseline PSA test with the patient, and consider a baseline DRE to identify high-risk cancers associated with a seemingly normal PSA. In patients 45-75 years of age, subsequent evaluation is based on the results of those tests, as follows ^[2] .

• PSA < 1 ng/mL, DRE normal (if done): Repeat testing at 2–4 year intervals
• PSA 1-3 ng/mL, DRE normal (if done): Repeat testing at 1–2 year intervals
• PSA > 3 ng/mL and/or very suspicous DRE result: Evaluate for biopsy

For men above the age of 75, screening may be cautiously considered in selected cases of very healthy men with little or no comorbidity. If PSA is measured and is < 4 ng/mL, the DRE is normal (if done), and no other indications for biopsy are present, the NCCN recommends repeat testing in selected patients at 1-4 year intervals. If the PSA is ≥ 4 ng/mL or DRE results are very suspicious, the patient should be evaluated for biopsy.

The NCCN notes that men ≥60 years of age with serum PSA < 1.0 ng/mL have a very low risk of metastasis or death from prostate cancer and may not benefit from further testing. The same is true of men age 75 years with a PSA of < 3.0 ng/mL.

Evaluation for biopsy includes the following:

• Repeat PSA
• Perform DRE, if not done performed during initial risk assessment
• Workup for benign disease

AUA screening guidelines

The current recommendations of the AUA were published in 2013 and confirmed in 2018. ^[3] The guidelines do not recommend routine screening for the following groups:

• Any man with a life expectancy less than 10-15 years
• Men younger than 40 years
• Men between ages 40 to 54 years at average risk
• Men over age 70

For men 55 to 69 years of age, the decision to undergo PSA screening involves weighing the benefits and risks. The guidelines strongly recommend the following:

• Shared decision-making for men age 55-69 years who are considering PSA screening, and proceeding based on patients’ values and preferences

• A routine screening interval of two years or more in those men who have participated in shared decision-making and decided on screening

USPSTF screening guidelines

The USPSTF guidelines, which were updated in 2018, recommend that in men age 55 to 69 years, the decision whether to undergo periodic PSA-based screening for prostate cancer should be an individual one (grade C recommendation). The guidelines advise that in making this decision, "patients and clinicians should consider the balance of benefits and harms on the basis of family history, race/ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs. " In men age 70 years and older, the USPSTF recommends against PSA-based screening for prostate cancer (grade D). ^[4]

ESMO screening guidelines

ESMO guidelines, which were updated in 2020, recommend against population-based PSA screening for prostate cancer, as it reduces prostate cancer mortality at the expense of overdiagnosis and overtreatment. ^[5] ESMO suggests that early PSA testing (baseline PSA measurement followed by risk-adapted follow-up) can be offered to the following:

• Men older than 50 years
• Men older than 45 years with a family history of prostate cancer
• African-American men older than 45 years
• BRCA1/2 carriers older than 40 years

ESMO recommends against testing for prostate cancer in asymptomatic men with a life expectancy < 10 years. ^[5]

EAU/ESTR/SIOG screening guidelines

Joint guidelines issued by EAU/ESTRO/SIOG, updated in 2021, recommend against subjecting men to PSA testing without counselling them on the potential risks and benefits, but recommend offering an individualized risk-adapted strategy for early detection to a well-informed men with a life expectancy of at least 10-15 years. ^[7] The guidelines advise that early PSA testing may be offered to well-informed men at elevated risk of having prostate cancer, as follows:

• Men ≥ age 50 
• Men ≥ age 45 and a family history of prostate cancer
• Men of African descent ≥ age 45 
• Men carrying BRCA2 mutations from 40 years of age.

Offer follow-up testing at intervals of 2 years for the following at risk groups:

• Men with a PSA level of > 1 ng/mL at age 40 
• Men with a PSA level of > 2 ng/mL at age 60 

Postpone follow-up to 8 years in those not at risk.

Discontinue testing based on life expectancy and performance status; men who have a life expectancy of < 15-years are unlikely to benefit.

Prostate biopsy

In patients with elevated PSA levels on repeated testing, European Society for Medical Oncology (ESMO) guidelines recommendations are as follows ^[5] :

• Multiparametric magnetic resonance imaging (mpMRI) should be carried out before prostate biopsy.
• A prostate cancer risk calculator and/or mpMRI should be used to confirm the indication for biopsy in men with elevated PSA.
• Transperineal biopsies are recommended, rather than transrectal ultrasound-guided biopsies.
• Each biopsy should be reported individually and evaluated using the International Society of Urological Pathology Consensus recommendations .

Joint European guidelines (EAU/ESTRO/SIOG) offer similar recommendations, as follows ^[6] :

• In asymptomatic men with a PSA level of 3–10 ng/mL and a normal DRE, repeat the PSA test prior to further investigations.
• In asymptomatic men with a PSA level of 2–10 ng/mL and a normal DRE, use a risk calculator or prostate MRI scan to determine whether biopsy is indicated; additionally, a serum, urine, or tissue biomarker test may be considered.
• Perform MRI before prostate biopsy. When MRI is positive (ie, Prostate Imaging–Reporting and Data System [PI-RADS] score > 3), combine targeted and systematic biopsy. When MRI is negative (ie, PI-RADS < 2) and clinical suspicion of prostate cancer is low (eg. PSA density < 0.15 ng/mL), omit biopsy based on shared decision-making with the patient.
• Perform prostate biopsy using the transperineal approach due to the lower risk of infectiouscomplications.

​EAU/ESTRO/SIOG recommendations for repeat biopsy are as follows ^[7] :

• Perform MRI before prostate biopsy. When MRI is positive (ie, PI-RADS > 3), perform targeted biopsy only. When MRI is negative (ie, PI-RADS < 2) but clinical suspicion of prostate cancer is high, perform systematic biopsy based on shared decision-making with the patient.

The EAU/ESTRO/SIOG guidelines also offer detailed recommendations regarding the prostate biopsy procedure. ^[6]

Risk stratification and staging

For patients with clinically localized prostate cancer, National Comprehensive Cancer Network (NCCN) guidelines define five risk categories: very low, low, intermediate, high, and very high. ^[8] In contrast, the 2022 update of the American Urological Association/American Society for Radiation Oncology (AUA/ASTRO) defines three risk categories: low, intermediate, and high; the update combines the prior categories of very low risk and low-risk disease, as the recommended management for these patients is consistent. ^[6]  Both the NCCN and the AUA/ASTRO guidelines subdivide intermediate risk into favorable and unfavorable categories. ^{[8, 9]} ESMO guidlines also recommend classifying localized prostate cancer as low, intermediate, or high risk, as a guide to prognosis and therapy. ^[5]  See the Table below.

Table: Risk Stratification of Prostate Cancer (Open Table in a new window)

NCCN guidelines list the following options for additional evaluation ^[8] :

• In patients at very low, low, or favorable intermediate risk - Assessment of the appropriateness of active surveillance with confirmatory testing (ie, prostate biopsy, mpMRI with calculation of PSA density and repeat biopsy as indicated, and/ormolecular tumor analysis), performed within the first 6 to 12 months after diagnosis
• In patients at unfavorable intermediate, high, or very high risk - Bone and soft tissue imaging (bone imaging should be performed for any patient with symptoms consistent with bone metastasis)

ESMO guidelines include the following recommendations on risk stratification and staging ^[5] :

• Stage patients with intermediate-risk disease for metastases using MRI or computed tomography (CT) of the abdomen and pelvis and bone scan.
• Stage patients with high-risk disease for metastases using CT (chest, abdomen, and pelvis) and bone scan.

 AUA/ASTRO guidelines include the following recommendations for risk stratification and staging in patients with clinically localized prostate cancer ^[9] : 

• Use clinical T stage, PSA, Grade Group (Gleason score), and tumor volume on biopsy to risk-stratify patients with newly diagnosed prostate cancer.
• In asymptomatic patients with low- or intermediate-risk prostate cancer, do not routinely perform abdomino-pelvic CT scan or bone scan.
• In patients with high-risk prostate cancer, obtain a bone scan and either pelvic mpMRI or CT scan.
• In patients with prostate cancer at high risk for metastatic disease with negative conventional imaging, clinicians may obtain molecular imaging to evaluate for metastases. 

American Urological Association/American Society for Radiation Oncology (AUA/ASTRO) guidelines include the following recommendations for genetic testing in patients with clinically localized prostate cancer ^[9] :

• Consider selectively using tissue-based genomic biomarkers when added risk stratification may alter clinical decision-making.
• Do not routinely use tissue-based genomic biomarkers for risk stratification or clinical decision-making. 
• Perform an assessment of patient and tumor risk factors to guide the decision to offer germline testing that includes mutations known to be associated with aggressive prostate cancer and/or known to have implications for treatment.

National Comprehensive Cancer Network (NCCN) guidelines recommend that at the time of initial diagnosis of prostate cancer, clinicians should inquire about family and personal history of cancer. ^[8] The NCCN recommends germline genetic testing, with or without pretest genetic counseling, for patients with prostate cancer and any of the following:

• A positive family history of cancer (eg, prostate, breast)
• High-risk, very-high-risk, regional or metastatic prostate cancer, regardless of family history
• Ashkenazi Jewish ancestry
• Intraductal histology

Germline testing, when performed, should include the following:

• MLH1, MSH2, MSH6, and  PMS2 (for Lynch syndrome)
• The homologous recombination genes  BRCA2, BRCA1, ATM, PALB2,and  CHEK2

Clinicians may also consider a next-generation sequencing (NGS) panel to test for cancer predisposition. At minimum, the panel should include the following:

• BRCA2
• BRCA1
• ATM
• CHEK2
• PALB2
• MLH1
• MSH2
• MSH6
• PMS2

​ Testing of additional genes may be appropriate, depending on the clinical context. For example, HOXB13 is a prostate cancer risk gene; although its presence does not currently have clear therapeutic implications in the advanced disease setting, testing for it may be valuable for family counseling.

Somatic tumor testing based on risk groups

NCCN recommendations for testing of prostate cancer tumors are as follows:

• Tumor testing for homologous recombination gene mutations (HRRm) and for microsatellite instability (MSI) or mismatch repair deficiency (dMMR) can be considered in patients with regional prostate cancer.

• Tumor testing for somatic HRRm (eg, BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2) is recommended in patients with metastatic prostate cancer.

• Multigene molecular testing can be considered for patients with low- and favorable-intermediate risk prostate cancer and life expectancy ≥10 years.

• The Decipher molecular assay can be considered as part of counseling for risk stratification in patients with PSA resistance/recurrence after radical prostatectomy.

• If mutations in BRCA2, BRCA1, ATM, CHEK2,  or PALB2  are found, the patient should be referred for genetic counseling to assess for the possibility of hereditary breast and ovarian cancer (HBOC) syndrome.

• If MSI testing is performed, testing using an NGS assay validated for prostate cancer is preferred. If high MSI (MSI-H) or dMMR is found, the patient should be referred for genetic counseling to assess for the possibility of Lynch syndrome. MSI-H or dMMR indicate eligibility for pembrolizumab in second and subsequent lines of treatment of castration-resistant prostate cancer.

NCCN recommendations for the workup in patients diagnosed with clinically localized prostate cancer include the following ^[8] :

• Perform physical exam
• Perform DRE to confirm clinical stage
• Perform and/or collect PSA and calculate PSA density
• Obtain and review diagnostic prostate biopsies
• Estimate life expectancy
• Inquire about known high-risk germline mutations
• Obtain family history
• Assess quality-of-life measures

Similarly, for patients with regional or metastatic prostate cancer, NCCN recommendations for the workup include the following:

• Perform physical exam 
• Perform DRE to confirm clinical stag
• Perform and/or collect PSA and calculate PSA doubling time 
• Estimate life expectancy
• Inquire about known high-riskgermline mutations
• Obtain family historyc
• Assess quality-of-life measures

 

 

American Urological Association/American Society for Radiation Oncology

AUA/ASTRO guidelines for management of clinically localized prostate cancer include the following recommendations for low-risk disease ^[9] :

• Clinicians should facilitate a shared decision-making approach to management that involves informing patients of the risks of prostate cancer treatments and the risk posed by the cancer and takes into account the patient's life expectancy, comorbidities, pre-existing medical conditions, and personal preferences.
• Clinicians should provide an individualized risk estimate of post-treatment prostate cancer recurrence.
• For patients with low-risk prostate cancer, clinicians should recommend active surveillance as the preferred management option.
• In asymptomatic patients with prostate cancer and limited life expectancy (determined on a patient-specific basis), clinicians should recommend watchful waiting.
• For patients with favorable intermediate-risk prostate cancer, clinicians should discuss active surveillance, radiation therapy, and radical prostatectomy.
• Clinicians should inform patients with intermediate-risk prostate cancer who are considering whole-gland or focal ablation that there are a lack of high-quality data comparing outcomes of ablation with outcomes of radiation therapy, surgery, and active surveillance.
• For patients with unfavorable intermediate- or high-risk prostate cancer and estimated life expectancy of more than than 10 years, clinicians should offer a choice between radical prostatectomy or radiation therapy plus androgen deprivation therapy (ADT).
• Clinicians should not recommend whole-gland or focal ablation for patients with high-risk prostate cancer outside of a clinical trial.
• Clinicians may recommend palliative ADT alone for patients with high-risk prostate cancer, local symptoms, and limited life expectancy.

European Society for Medical Oncology

The ESMO guidelines include the following treatment recommendations ^[5] :

• Watchful waiting with delayed ADT for symptomatic progression is an option for men who are not suitable for, or are unwilling to have, radical treatment. 
• Active surveillance is recommended for men with low-risk disease. 
• Radical prostatectomy (RP) or radiation therapy (RT; external beam or brachytherapy) is an option for men with low-risk disease not suitable for active surveillance, and is recommended for men with intermediate-risk disease. 
• Primary ADT alone is not recommended as standard initial treatment for non-metastatic disease. 
• External beam RT plus ADT is recommended for men with high-risk or locally advanced prostate cancer. 
• RP plus pelvic lymphadenectomy is an option for selected men with high-risk disease. 
• Men receiving radical RT for intermediate-risk disease should have short-course ADT for 4-6 months. 
• Men receiving radical RT for high-risk disease should have long-course ADT (18-36 months). 
• Neoadjuvant docetaxel chemotherapy may be offered before RT for young, fit men with very high-risk localized prostate cancer. 
• Following RP, patients should have their serum PSA level monitored, with salvage RT recommended in the event of PSA failure. 
• Adjuvant postoperative RT after RP is not routinely recommended.

Cancer Care Ontario/American Society of Clinical Oncology

In 2016, the American Society of Clinical Oncology (ASCO) endorsed Cancer Care Ontario’s guideline on active surveillance for the management of localized prostate cancer. ^[10] The recommendations include the following:

• Active surveillance is the recommended disease management strategy for most patients with low‐risk (Gleason score ≤6) localized prostate cancer.
• Because of heterogeneity within this population, factors such as younger age, high-volume Gleason 6 cancer, patient preference, and/or African American ethnicity should be taken into account in the decision to use active surveillance.
• Young patients (under age 55) with high-volume Gleason 6 cancer should be closely scrutinized for the presence of higher‐grade cancer; definitive therapy may be warranted for select patients.
• For patients with limited life expectancy (< 5 years) and low‐risk cancer, watchful waiting may be more appropriate than active surveillance.
• Active treatment (radical prostatectomy or radiotherapy) is recommended for most patients with intermediate‐risk (Gleason score 7) localized prostate cancer, but active surveillance may be offered to select patients with low‐volume, intermediate‐risk (Gleason 3+4=7) localized prostate cancer.

The guidelines recommend that the active surveillance protocol include the following tests:

• PSA testing every 3 to 6 months
• DRE at least every year
• At least a 12-core confirmatory transrectal ultrasound (TRUS)–guided biopsy (including anterior directed cores) within 6 to 12 months, then serial biopsy every 2 to 5 years thereafter, or more frequently if clinically warranted; men with limited life expectancy may transition to watchful waiting and avoid further biopsies.
• Ancillary tests that are still under investigation but may be included in the protocol could include  mpMRI and/or genomic testing. Such tests may be indicated when a patient’s clinical findings are discordant with the pathologic findings

National Comprehensive Cancer Network

NCCN guidelines recommendations for treatment of clinically localize prostate cancer are based on risk stratification and include the following ^[8] :

• Patients with very-low-risk prostate cancer and life expectancy ≥10 years - Active surveillance is preferred (observation is preferred for patients with very-low-risk disease whose life expectancy is < 10 years).
• Patients with low-risk prostate cancer and life expectancy ≥10 years - Active surveillance is preferred in most cases; however, upfront treatment with RP or prostate RT may be preferred for patients with risk factors for near-term grade reclassification (eg, high PSA density, a high number of positive cores [eg, ≥3], and high genomic risk on tissue-based molecular tumor analysis); treatment choice in these cases should be based on shared decision-making with the patient.
• Patients with favorable intermediate-risk prostate cancer and life expectancy >10 years - Active surveillance may be considered, especially in patients with a low percentage of Gleason pattern 4 cancer, low tumor volume, low PSA density, and/or low genomic risk (from tissue-based molecular tumor analysis.
• Patients with unfavorable intermediate-risk prostate cancer and life expectancy >10 years - RP plus pelvic lymph node dissection (PLND), with consideration of adjuvant therapy or  external beam radiation therapy (EBRT) plus ADT (4–6 mo)  or EBRT plus brachytherapy with or without ADT (4–6 mo)
• Patients with unfavorable intermediate-risk prostate cancer and life expectancy 5-10 years - EBRT plus ADT (4–6 mo)  or  EBRT plus brachytherapy with or without ADT (4–6 mo) or observation
• Patients with high- or very-high-risk prostate cancer who are symptomatic or whose life expectancy is > 5 y - EBRT plus ADT, with or without brachytherapy  or , for very-high-risk patients, EBRT plus ADT plus aberaterone  or RP plus PLND, with consideration of adjuvant therapy
• Patients with high- or very-high-risk prostate cancer who are asymptomati or whose life expectany is ≤ 5 y - Observation or  ADT or EBRT

NCCN principles of active surveillance are as follows ^[8] :

• PSA no more often than every 6 months unless clinically indicated.
• DRE no more often than every 12 months unless clinically indicated.
• Repeat prostate biopsy no more often than every 12 months unless clinically indicated.
• Consider repeat mpMRI no more often than every 12 months unless clinically indicated; in patients with a suspicious lesion on mpMRI, MRI-ultrasound fusion biopsy improves the detection of higher grade (Grade Group ≥2) cancers.
• Patients should be transitioned to observation when life expectancy is < 10 years. 
• Repeat molecular tumor analysis is discouraged. 
• The intensity of surveillance may be tailored based on patient life expectancy and risk of reclassification.

The following organizations have published guidelines for the treatment of castration-sensitive prostate cancer (CRPC):

• American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology (AUA/ASTRO/SUO)
• American Society of Clinical Oncology (ASCO)
• National Comprehensive Cancer Network (NCCN)
• European Society for Medical Oncology (ESMO)

American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology

AUA/ASTRO/SUO guidelines include the following recommendations for determining prognosis in patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) ^[11] :

• Assess the extent of metastatic disease (bone, lymph node and visceral metastasis) using conventional imaging.
• Determine whether the metastatic disease is low volume or high volume. High-volume disease is defined as four or more bone metastases with at least one metastasis outside of the spine/pelvis and/or the presence of visceral metastases. 
• Determine whether the patient is experiencing symptoms from metastatic disease.
• Obtain a baseline PSA and serial PSAs at three- to six-month intervals after initiation of androgen deprivation therapy (ADT) and consider periodic conventional imaging.
• Regardless of the patient's age and family history, offer genetic counseling and germline testing. 

AUA/ASTRO/SUO guidelines include the following recommendations regarding treatment of mHSPC ^[11] :

• Offer ADT with either luteinizing hormone–releasing hormone (LHRH) agonists or antagonists or surgical castration.
• Offer continued ADT in combination with either androgen pathway–directed therapy (abiraterone acetate plus prednisone, apalutamide, enzalutamide) or chemotherapy (docetaxel).
• In selected mHSPC patients with low-volume metastatic disease, consider offering primary radiotherapy to the prostate in combination with ADT. 
• Do not offer first-generation antiandrogens (bicalutamide, flutamide, nilutamide) in combination with LHRH agonists, except to block testosterone flare.
• Do not offer oral androgen pathway–directed therapy (eg, abiraterone acetate plus prednisone, apalutamide, bicalutamide, darolutomide, enzalutamide, flutamide, nilutamide) without ADT.

American Society of Clinical Oncology

Updated American Society of Clinical Oncology (ASCO) guidelines on initial hormonal management of noncastrate advanced, recurrent, or metastatic prostate cancer state that the combinations of ADT with docetaxel, abiraterone, enzalutamide, or apalutamide represent four separate standards of care for these patients. The use of any of these agents in any particular combination or series cannot yet be recommended. ^[12]

ASCO recommendations for use of these regimens are as follows: ^[12]

• Docetaxel plus ADT should be offered to men with metastatic noncastrate prostate cancer with high-volume disease (ie, four or more bone metastases, one or more of which is outside of the spine or pelvis, and/or any visceral disease) who are candidates for treatment with chemotherapy, but should not be offered to those with low-volume metastatic disease. The recommended regimen of docetaxel in this setting is six doses of 75 mg/m², either alone or with prednisolone, administered at 3-week intervals.

• Abiraterone plus ADT should be offered to men with high-risk de novo metastatic noncastrate prostate cancer, and may be offered to men with low-risk de novo metastatic noncastrate prostate cancer. The recommended regimen in this setting is abiraterone 1,000 mg with either prednisolone or prednisone 5 mg once daily until progressive disease is documented.

• Enzalutamide plus ADT should be offered to men with metastatic noncastrate prostate cancer, including both those with de novo metastatic disease and those who have received prior therapies, such as radical prostatectomy (RP) or radiotherapy (RT) for localized disease. The recommended enzalutamide dosage in this setting is 160 mg/day.

• Apalutamide plus ADT should be offered to men with metastatic noncastrate prostate cancer, including those with de novo metastatic disease or those who have received prior therapy, such as RP or RT for localized disease. The recommended apalutamide dosage in this setting is 240 mg/day.

National Comprehensive Cancer Network Recommendations:

NCCN guidelines recommend that patients with castration-sensitive prostate cancer without distant metastasis (M0) can be treated with observation (preferred) or ADT. ^[8] For patients with castration-sensitive prostate cancer with distant metastasis (M1), NCCN guidelines state that ADT with treatment intensification is preferred for most patients with metastatic prostate cancer, while ADT alone is appropriate for some patients. ADT may comprise any of the following:

• Orchiectomy
• LHRH agonist (goserelin, leuprolide, triptorelin)
• LHRH agonist plus first-generation antiandrogen (nilutamide, flutamide,  bicalutamide)
• LHRH antagonist (degarelix, relugolix)
• Orchiectomy plus abiraterone 
• LHRH agonist plus abiraterone
• Degarelix plus abiraterone

ADT with treatment intensification may comprise any of the following:

• Orchiectomy plus abiraterone, enzalutamide, or apalutamide
• Orchiectomy plus docetaxel and abiraterone or darolutamide
• LHRH agonist plus abiraterone, enzalutamide, or apalutamide
• LHRH agonist plus docetaxel and abiraterone or darolutamide
• Degarelix plus abiraterone, enzalutamide, or apalutamide
• Degarelix plus docetaxel and abiraterone or darolutamide
• Any ADT plus EBRT to primary tumor (for low metastatic burden M1)

European Society for Medical Oncology

ESMO recommendations for treatment of metastatic hormone-naive prostate cancer are as follows ^[5] :

• ADT is recommended as first-line treatment, in combination with abiraterone/prednisone, apalutamide, docetaxel, or enzalutamide. 
• RT to the primary tumor combined with the systemic treatment is recommended for patients with low-volume disease. 
• ADT alone is recommended as first-line systemic treatment in men who are unfit for abiraterone, apalutamide, enzalutamide, and docetaxel. 
• For men starting on ADT, management to prevent cancer treatment–induced bone loss is recommended.

The following organizations have published guidelines for the treatment of castration-resistant prostate cancer (CRPC):

• American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology (AUA/ASTRO/SUO)
• American Society of Clinical Oncology (ASCO)/Cancer Care Ontario (CCO)
• National Comprehensive Cancer Network (NCCN)
• European Association of Urology/European Society for Radiotherapy and Oncology/International Society of Geriatric Oncology (EAU/ESTRO/SIOG)
• European Society for Medical Oncology (ESMO)

American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology

AUA/ASTRO/SUO guidelines include the following recommendations for determing prognosis in patiens with metastatic castration-resistant prostate cancer (mCRPC) ^[11] :

• Obtain baseline laboratory studies (eg, PSA, testosterone, lactate dehydrogenase [LDH], hemoglobin, alkaline phosphatase) and review location of metastatic disease (bone, lymph node, visceral), disease-related symptoms, and performance status to inform discussions of prognosis and treatment decision making.

• Assess the extent of metastatic disease using conventional imaging at least annually or at intervals determined by lack of response to therapy.

• Offer germline and somatic tumor genetic testing to identify DNA repair deficiency mutations and microsatellite instability (MSI) status that may inform prognosis and counseling regarding family risk as well as potential targeted therapies.

AUA/ASTRO/SUO guidelines include the following recommendations for treatment of mCRPC ^[11] :

•  In patients with newly diagnosed mCRPC, offer continued ADT with abiraterone acetate plus prednisone, docetaxel, or enzalutamide.

• In patients who are asymptomatic or minimally symptomatic, consider offering sipuleucel-T.

• Offer radium-223 to patients with symptoms from bony metastases from mCRPC and without known visceral disease or lymphadenopathy > 3 cm.

• When sequencing agents, consider prior treatment and consider recommending therapy with an alternative mechanism of action.

• In patients who received prior docetaxel chemotherapy with or without prior abiraterone acetate plus prednisone or enzalutamide for the treatment of CRPC, consider offering cabazitaxel.

• In patients who received prior docetaxel chemotherapy and abiraterone acetate plus prednisone or enzalutamide, recommend cabazitaxel rather than an alternative androgen pathway–directed therapy.

• Offer a poly (ADP-ribose) polymerase (PARP) inhibitor to patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene–mutated mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy. Platinum-based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor.

• In patients with mismatch repair deficient (dMMR) or MSI high mCRPC, offer pembrolizumab. 

• Prescribe a bone-protective agent (denosumab or zoledronic acid) for patients with bony metastases to prevent skeletal-related events. 

American Society of Clinical Oncology

ASCO and Cancer Care Ontario released a joint clinical practice guideline for treatment of men with metastatic CRPC (mCRPC) in 2014. ^[13] The guideline recommendations include the following:

• Pharmacologic ADT should be continued indefinitely.
• Offer patients one of three treatment options in addition to hormone deprivation: abiraterone/prednisone, enzalutamide, or (if cancer has spread to bone) radium-223.
• When considering chemotherapy, docetaxel/prednisone should be an option but adverse effects must be discussed.
• Offer cabazitaxel to men whose disease worsens even if docetaxel has been tried, but again, discuss adverse effects.
• Offer sipuleucel-T to men with no symptoms or minimal symptoms of cancer.
• Offer mitoxantrone, but include a discussion of the drug's limited clinical benefit and adverse effect risk.
• Offer ketoconazole or the anti-androgen therapies bicalutamide, flutamide, or nilutamide but discuss the limited clinical benefit of those three medications.
• Do not offer bevacizumab, estramustine, or sunitinib
• Begin discussion of palliative care early on while discussing treatment options

A focused update in 2022 by ASCO added recommendations regarding ¹⁷⁷Lutetium-PSMA-617 (¹⁷⁷Lu-PSMA-617), a radioligand therapy that delivers targeted beta-particle radiation to cancer cells that express prostate-specific membrane antigen (PSMA) ^[14] :

• Use of ¹⁷⁷Lu-PSMA-617, once every 6 weeks for 4-6 cycles, is recommended as a treatment option in patients with PSMA PET/CT–positive mCRPC who have progressed on one prior line of androgen receptor pathway inhibitor and at least one line of prior chemotherapy.
• To determine eligibility for  ¹⁷⁷Lu-PSMA-617 therapy, use PSMA PET with either Ga-68 PSMA-11 or F-18 piflufolastat as a radiotracer.

National Comprehensive Cancer Network recommendations

The NCCN guidelines for prostate cancer offer treatment recommendations for CRPC based on the presence or absence of distant metastases. For the most part, these recommendations are based on high-level evidence and are supported by uniform NCCN consensus (category 1 recommendations). ^[8]

CRPC without distant metastasis:

• Continue ADT to maintain castrate serum levels of testosterone(< 50 ng/dL)
• For patients with PSA doubling time (PSADT < 10 months, monitoring is preferred, but other secondary hormone therapy may be used.
• For patients with PSADT ≥ 10 months, preferred regimens are apalutamide, darolutamide, or enzalutamide.

CRPC with distant metastasis:

•  Biopsy of metastatic lesion, with tumor testing for MSI-high or dMMR and homologous recombination repair gene mutations (HRRm), if not previously performed; consider tumor mutational burden (TMB) testing
•  Continue ADT to maintain castrate levels of serum testosterone
• Additional treatment options are bone antiresorptive therapy with denosumab or zoledronic acid if bone metastases are present, palliative RT for painful bone metastases, and best supportive care.
• Further treatment varies, depending on whether the tumor is an adenocarcinoma or small cell/neuroendocrine prostate cancer(NEPC)

Systemic therapy for mCRPC adenocarcinoma

In patients with no prior docetaxel or novel hormone therapy, category 1 treatment recommendations are as follows:

• Preferred regimens - Abiraterone, docetaxel, or enzalutamide
• Useful in certain circumstances - Radium-223 for symptomatic bone metastases; sipuleucel-T for asymptomatic or minimally symptomatic patients with no liver metastases, life expectancy > 6 mo, and ECOG performance status 0–1.

In patients who have had prior docetaxel or novel hormone therapy, treatment recommendations are as follows:

• Preferred regimens - Abiraterone (category 1), cabazitaxel, enzalutamide (category 1)
• Useful in certain circumstances - Cabazitaxel/carboplatin; mitoxantrone for palliation in symptomatic patients who cannot tolerate other therapies; radium-223

Systemic therapy for metastatic castration-resistant NEPC

Treatment options for first-line and subsequent treatment are chemotherapy and best supportive care. Recommended chemotherapy regimens are as follows:

• Cisplatin/etoposide
• Carboplatin/etoposide
• Docetaxel/carboplatin
• Cabazitaxel/carboplatin

European Association of Urology/European Society for Radiotherapy and Oncology/International Society of Geriatric Oncology recommendations

For patients with non-metastatic CRPC, the EAU/ESTRO/SIOG recommends offering apalutamide, darolutamide, or enzalutamide to patients at high risk of developing metastasis (PSADT < 10 months), to prolong time to metastases and overall survival. The guideline recommendations for patients with mCRPC include the following ^[7] :

• Confirm that testosterone levels are < 50 ng/dL before diagnosing mCRPC.

• Counsel, manage, and treat patients with mCRPC in a multidisciplinary team.

• Offer mCRPC patients somatic and/or germline molecular testing as well as testing for MMR deficiencies or MSI.

• Base the choice of treatment on performance status (PS), symptoms, co-morbidities, location and extent of disease, genomic profile, patient preference, and on previous treatment for hormone-sensitive metastatic prostate cancer. Systemic treatment options are (in alphabetical order) abiraterone, cabazitaxel, docetaxel, enzalutamide, olaparib, radium-223, and sipuleucel-T.

• In patients who are candidates for cytotoxic therapy and are chemotherapy naïve, offer docetaxel with 75 mg/m² every 3 weeks.

• In patients with mCRPC progression following docetaxel chemotherapy, further life-prolonging treatment options include abiraterone, cabazitaxel, enzalutamide, radium-223, and olaparib in case of DNA homologous recombination repair (HRR) alterations.

• Base further treatment decisions on PS, previous treatments, symptoms, co-morbidities, genomic profile, extent of disease, and patient preference.

• In patients previously treated with one or two lines of chemotherapy, offer abiraterone or enzalutamide.

• Avoid sequencing of androgen receptor–targeted agents.

• Offer chemotherapy to patients previously treated with abiraterone or enzalutamide.

• Offer cabazitaxel to patients previously treated with docetaxel and those with disease progression within 12 months of treatment with abiraterone or enzalutamide.

• Offer PARP inhibitors to pre-treated mCRPC patients with relevant DNA repair gene mutations.

• Offer ¹⁷⁷Lu-PSMA-617 to pre-treated mCRPC patients who have one or more metastatic lesions with high PSMA expression (exceeding the uptake in the liver) on the diagnostic radiolabelled PSMA PET/CT scan.

• Offer bone-protective agents to patients with skeletal metastases, to prevent osseous complications. Monitor serum calcium and offer calcium and vitamin D supplementation when prescribing either denosumab or bisphosphonates.

• Treat painful bone metastases early on with palliative measures such as intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) plus image-guided radiation therapy (IGRT) and adequate analgesia.

• In patients with spinal cord compression, start immediate high-dose corticosteroids and assess for spinal surgery followed by irradiation. Offer radiation therapy alone if surgery is not appropriate.

European Society for Medical Oncology

For treatment of non-metastatic CRPC, ESMO guidelines recommend considering apalutamide, darolutamide, or enzalutamide as options for men with M0 (on bone scan and CT) CRPC and a high risk of disease progression. For mCRPC, ESMO recommendations include the following ^[5] :

• Abiraterone or enzalutamide is recommended for asymptomatic/mildly symptomatic men with chemotherapy-naive mCRPC. 
• Docetaxel is recommended for men with mCRPC. 
• In patients with mCRPC who have received docetaxel, recommended options are abiraterone, enzalutamide, or cabazitaxel.
• In patients with bone metastases from CRPC at risk for clinically significant skeletal-related events, a bisphosphonate or denosumab is recommended.
• Radium-223 ( ²²³Ra) is recommended for men with bone-predominant, symptomatic mCRPC without visceral metastases. Radium-223 is not recommended in combination with abiraterone and prednisolone. 
• The use of a second androgen receptor inhibitor (ie, abiraterone after enzalutamide or vice versa) is not recommended.