Approach

Treatment may consist of observation, active surveillance (also known as expectant management), androgen deprivation therapy (ADT), external beam radiation therapy (EBRT), brachytherapy, radical prostatectomy, or a combination of two or more of these modalities.

EBRT, brachytherapy, and radical prostatectomy are definitive treatments. If they are used in patients with nonmetastatic disease, the treatment goal is cure. ADT alone is not curative, but it may slow progression and help control symptoms.

Additional treatment options are available for metastatic disease, including antiandrogen therapy, chemotherapy, immunotherapies, and targeted therapies.

The treatment decision depends on:

  • The patient's risk group assigned at diagnosis.[3][5]​​​​[144]​​ Risk stratification groups defined by the National Comprehensive Cancer Network (NCCN) are employed in the treatment sections of this topic. Other risk groups may be used depending on region; therefore, local guidance should be consulted when assigning risk groups to patients with prostate cancer. See Classification.

  • The patient's life expectancy (i.e., >10 years or <10 years) based on age, comorbidities, and health status. The International Society of Geriatric Oncology (SIOG) recommends that treatment should be based on health status rather than age.[146] Older patients (ages >70 years) are assigned a health status group (healthy, vulnerable, frail) premised upon assessment of dependence, comorbidities, and nutritional status. SIOG recommends screening for frailty with the G8 tool and for cognitive impairment with the Mini-COG instrument.[146]

  • Patient preferences (e.g., adverse effects of treatment versus living with cancer) and shared decision-making with the patient.[148]

Nomograms (e.g., the Partin nomogram and the Memorial-Sloan-Kettering Cancer Center nomogram) provide individualized disease-related risk estimations that facilitate management-related decisions.[3][115] Brady Urological Institute: the Partin tables Opens in new window Memorial-Sloan-Kettering Cancer Center: prostate cancer nomograms Opens in new window

Compared with other prediction tools, nomograms have the highest accuracy and the best discriminating characteristics for predicting outcomes in patients with prostate cancer.[116]

Observation

Observation involves monitoring the course of the disease with a view to delivering treatment or palliative therapy when symptoms arise or when there is a change in clinical findings that suggest symptoms are imminent.[3]

Observation should include a history and physical exam no more often than every 12 months (without prostate biopsies).[144]​ If patients become symptomatic, assessment should be performed (including prostate specific antigen [PSA] and PSA doubling time [PSADT], life expectancy estimate, and quality-of-life measures) to determine need for, and consideration of, treatment or palliation.[3]

Active surveillance

Involves monitoring the course of the disease (with additional use of prostate biopsies) until symptoms or signs of disease become clinically evident, with the expectation to treat with definitive treatment (e.g., radiation therapy or radical prostatectomy, with or without ADT) if there is disease progression.

For active surveillance, PSA levels and digital rectal exam (DRE) are checked no more than every 6 and 12 months, respectively, unless clinically indicated.[3][144]​ Repeat prostate biopsy and repeat multiparametric magnetic resonance imaging (MRI) are carried out no more often than every 12 months, unless clinically indicated.[3]​ Intensity of active surveillance may be individualized based on patient and tumor factors, risk of progression, and life expectancy. However, most patients should have repeat biopsies every 2-5 years.

Confirmatory testing before active surveillance

Recommended before starting active surveillance (within 6-12 months of diagnosis) if multiparametric MRI was not performed prior to diagnostic biopsy.[149] The role of confirmatory testing is to identify those at high risk for future disease upgrading or progression, and to ensure appropriate patients are selected for active surveillance.[149] 

Confirmatory testing for active surveillance involves performing a multiparametric MRI (with PSA density calculation), if available, and/or repeat biopsy (systematic and targeted), and/or molecular tumor analysis.[3][103][150]​​ All patients should have a confirmatory prostate biopsy within 1-2 years of initial diagnostic biopsy.[3]

Androgen deprivation therapy (ADT)

Androgen deprivation may be achieved medically, with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist, or by surgical castration (bilateral orchiectomy).[151] Surgical castration is rarely used.

External beam radiation therapy (EBRT)

EBRT precisely delivers radiation to cancerous tissue. Intensity-modulated radiation therapy and image-guided radiation therapy are the standard EBRT techniques because they allow for a highly conformal delivery of radiation that minimizes dose to normal tissues (bladder, rectum, and small bowel), thereby potentially decreasing toxicity to these structures. Stereotactic body radiation therapy (SBRT) is the technique used to deliver ultra-hypofractionated radiation therapy.

Biocompatible and biodegradable perirectal spacer materials can be implanted between the prostate and rectum in patients with organ-confined disease to reduce toxicity to the rectum.[3][152][153]

Patients with significant baseline urinary symptoms may not be good candidates for EBRT due to increased risk of urinary obstruction.

Hypofractionation

Conventional fractionated EBRT typically employs daily doses of 1.8 to 2 Gy for 7-9 weeks (excluding weekends) to a total dose of 75.6 to 80 Gy. However, data suggest that hypofractionation (i.e., shorter treatment courses over 4-6 weeks using larger daily doses [>2-4 Gy], but smaller total doses [56-72 Gy]) may yield equivalent results to conventional fractionation.[154][155] [ Cochrane Clinical Answers logo ] ​ Hypofractionation is now the preferred approach.[156] Although it shortens treatment duration, it may slightly increase the risk of acute gastrointestinal adverse effects compared with conventional fractionation.[154]

Ultra-hypofractionation

Ultra-hypofractionation may be considered for patients with localized disease, low metastatic burden disease, or oligometastatic disease.[156][157][158][159][160][161][162][163]​ A commonly used dosing schedule for ultra-hypofractionation is 7.25 Gy given every other day for 2 weeks (excluding weekends) to a total dose of 36.25 Gy.[156] Other ultra-hypofractionation schedules ranging from 4-9 fractions of 5-10 Gy to a total dose of 36.25 to 50 Gy have been reported.[157] Studies suggest comparable biochemical control and toxicity with ultra-hypofractionation versus more protracted fractionation schedules, but higher total doses are associated with a greater risk of severe late genitourinary complications.[157]

Brachytherapy

Brachytherapy (low-dose rate or high-dose rate) can be given as monotherapy, or with EBRT and ADT (i.e., brachytherapy boost), depending on risk.[3][164]

Low-dose rate brachytherapy involves the permanent transperineal implantation of radioactive sources into the prostate without any incision. The highest radiation dose is confined to the prostate and a small volume of surrounding tissue. The strength of radiation decreases over time, but low levels of radioactivity in the prostate will persist for 4-6 months depending on the half-life of the isotope used. Precautions should be taken in the short term to minimize close contact with pregnant women and small children.

High-dose rate brachytherapy involves the transperineal placement of treatment catheters through which an individual radioactive source is robotically placed temporarily at various dwell positions to achieve a conformal dose of radiation to the prostate. At the end of treatment, the catheters are removed. Treatment is repeated up to five times to achieve a curative dose to the prostate.

Radical prostatectomy

Radical prostatectomy is an option (depending on patient preference and suitability for surgery) when the tumor is confined to the prostate and life expectancy is ≥10 years; pelvic lymph nodes may be dissected depending on the nomogram predictions of risk of lymph node metastases. Classically, the prostate and prostatic capsule are removed by excision of the urethra at the prostatomembranous junction. The seminal vesicles, ampulla, and vas deferens are also removed. Of the two classic open surgical approaches (retropubic/suprapubic and perineal), the retropubic/suprapubic approach is preferred by many urologists, as this approach facilitates access for pelvic lymph node dissection.

Laparoscopic and robotic-assisted radical prostatectomy are alternative approaches that typically involve five or six small incisions in the abdomen from which the entire prostate is removed, theoretically sparing nerves more easily damaged by a retropubic/suprapubic approach.[165][166]​ A Cochrane review found that laparoscopic or robotic-assisted radical prostatectomy may result in shorter hospital stays and fewer blood transfusions compared with open surgical radical prostatectomy, but improvements in oncologic outcomes (e.g., recurrence or survival) were inconclusive.[167] Complications (e.g., sexual and urinary dysfunction) appear to be similar between these alternative approaches and the open surgical approach.[167][168]

Radical prostatectomy in men with clinically localized prostate cancer that was not detected through PSA screening improves prostate cancer-specific mortality, overall survival, and risk of local disease progression and metastasis, compared with active surveillance.[169][170]​ These benefits have been shown to continue over the long-term, particularly in those ages ≤65 years.[171][172]

Radical prostatectomy in men with PSA-detected localized prostate cancer does not significantly reduce all-cause mortality or prostate cancer-specific mortality compared with active surveillance or observation.[173][174][175][176]​ Furthermore, radical prostatectomy is associated with a higher frequency of adverse events than active surveillance and observation.[173][174][175][176][177] [ Cochrane Clinical Answers logo ]

Very low-risk disease

For very low-risk disease, the following criteria must be met:[3]

  • cT1c tumor

  • Grade Group 1

  • PSA <10 nanograms/mL

  • <3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/core

  • PSA density <0.15 nanograms/mL/g.

The treatment option for patients with very low-risk disease and a life expectancy <10 years is observation. Patients with life expectancy ≤5 years who become symptomatic during observation can receive ADT alone for palliation.[3]

If life expectancy is ≥10 years, active surveillance is recommended.[3]

Low-risk disease

For low-risk disease, patients have all of the following and do not qualify for very low-risk disease:[3]

  • cT1-cT2a tumor

  • Grade Group 1

  • PSA <10 nanograms/mL.

The treatment option for patients with low-risk disease and life expectancy <10 years is observation. Patients with life expectancy ≤5 years who become symptomatic during observation can receive ADT alone for palliation.[3]

If life expectancy is ≥10 years, treatment options include:[3][178][179][180]

  • Active surveillance

  • Brachytherapy

  • EBRT

  • Radical prostatectomy (depending on patient preference and suitability for surgery).

Active surveillance is the preferred approach for most patients with low-risk disease if life expectancy is ≥10 years, but is often underutilized due to patient preference and lack of adherence.[181][182]​​ Use of standardized patient information, clinician education, and guidelines may improve uptake of and adherence to active surveillance.[181]​ Decisions about starting treatment should take into account factors that may increase the likelihood of regrading, including high PSA density, ≥3 positive cores, high genomic risk, and/or a known BRCA2 germline mutation.[3]

Favorable or unfavorable intermediate-risk disease

For favorable intermediate-risk disease, patients have no high-risk or very high-risk features and all of the following:[3]

  • One intermediate risk factor (cT2b-c tumor; Grade Group 2; or PSA 10-20 nanograms/mL)

  • Grade Group 1 (if not Grade Group 2)

  • Percentage of positive biopsy cores <50%

The treatment options for patients with favorable intermediate-risk disease are generally the same as for patients with low-risk disease, except that EBRT or brachytherapy may be offered if life expectancy is 5-10 years (although observation is preferred).[178][179][180]​​ Patients with life expectancy ≥10 years who are treated with radical prostatectomy may undergo pelvic lymph node dissection (depending on nomogram assessment).

For unfavorable intermediate-risk disease, patients have no high-risk or very high-risk features and one or more of the following:[3]

  • Two or three intermediate risk factors (cT2b-c tumor; Grade Group 2 or 3; and/or PSA 10-20 nanograms/mL)

  • Grade Group 3 alone

  • Percentage of positive biopsy cores ≥50%.

The treatment option for patients with unfavorable intermediate-risk disease and life expectancy ≤5 years is observation. ADT alone can be used for palliation if patients become symptomatic during observation.[3]

If life expectancy is 5-10 years, treatment options for unfavorable intermediate-risk disease are:

  • Observation

  • EBRT (with or without brachytherapy boost) plus ADT for 4-6 months

If life expectancy is >10 years, treatment options for unfavorable intermediate-risk disease are:

  • EBRT (with or without brachytherapy boost) plus ADT for 4-6 months 

  • Radical prostatectomy with pelvic lymph node dissection, depending on patient preference and suitability for surgery

There is no standard approach to managing patients with intermediate-risk disease. Few randomized trials have compared effectiveness between primary treatments. Assessment of the comparative effectiveness and harms of localized prostate cancer treatments is difficult because of limitations in the evidence.[183][184]​

Adverse effects of treatments may influence treatment choice.[185][186][187][188]​​​​​​ Worse urinary incontinence and sexual/erectile dysfunction have been reported in patients who had radical prostatectomy compared with other treatments.[189][190][191][192]​ Brachytherapy may be associated with worse short-term urinary obstruction and irritation, and EBRT with worse bowel function and short-term bowel symptoms.[190][192][193]

ADT (e.g., an LHRH agonist or antagonist) may be given before, during, and/or after EBRT, for a total of 4-6 months.[3] ADT greater than 6 months duration is not recommended in patients with intermediate-risk disease.[194][195]​ ADT may have multiple synergistic effects when combined with radiation therapy, and is associated with significant clinical benefit.[196][197][198][199][200][201][202][203]​ 

High-dose radiation to the prostate and periprostatic tissue is recommended for patients who are candidates for radiation therapy plus ADT.[204][205][206][207][208]​​ Prophylactic pelvic nodal irradiation may also be considered in highly selected patients with intermediate-risk disease who are undergoing radiation therapy, but only if further risk assessment (e.g., nomograms, biomarker testing) indicates aggressive disease.[3][209]

High-risk or very high-risk disease

For high-risk disease, patients have no very high-risk features and one of the following high-risk features:

  • cT3a tumor

  • Grade Group 4 or 5

  • PSA >20 nanograms/mL

For very high-risk (locally advanced) disease, patients have at least one of the following:

  • cT3b-cT4 tumor

  • Primary Gleason pattern 5

  • Two or three high-risk features

  • >4 cores with Grade Group 4 or 5

The treatment options for patients with high-risk or very high-risk disease who are asymptomatic and have a life expectancy ≤5 years include:[3] 

  • Observation

  • ADT

  • EBRT

Observation is the usual approach. However, ADT or EBRT may be considered if symptoms or complications (e.g., hydronephrosis) of untreated disease or metastases are expected within 5 years.

The treatment options for patients with high-risk or very high-risk disease who are symptomatic or have a life expectancy >5 years include:[3] 

  • EBRT (with or without brachytherapy boost) plus ADT

  • EBRT (with or without brachytherapy boost) plus ADT (2 years) plus abiraterone (for selected very high-risk disease)

  • Radical prostatectomy with pelvic lymph node dissection, which may be considered in highly selected patients (e.g., fit patients without tumor fixation to the pelvic musculature or skeleton), depending on patient preference and suitability for surgery

  • ADT alone (for patients unsuitable for surgery or radiation therapy)

ADT may be given before, during, and/or after EBRT, for a total of 1.5 to 3 years.[210][211][212][213][214][215][216][217]​ However, the optimal duration of ADT for these patients remains controversial.[218] A significant improvement in disease-free survival is demonstrated for a longer duration of ADT in patients with high-risk disease.[212][218][219][220]​ Use of combined radiation therapy with ADT significantly increases some treatment-related symptoms (e.g., pain with urination and overall urinary and bowel bother), although none are serious. However, given the substantial survival benefit of combined treatment, the increased risk of symptoms seems acceptable and has little extra effect on quality of life after 4 years compared with ADT alone.[221][222][223][224][225][226]

The addition of brachytherapy boost to EBRT (with or without ADT) may provide superior disease control compared with EBRT plus ADT for patients with high-risk or very high-risk disease.[227][228][229]​​ In a randomized study, EBRT plus brachytherapy plus ADT improved biochemical disease-free survival compared with EBRT plus ADT.[227] No benefit in overall survival was demonstrated.[227] In an observational study, improved prostate cancer-specific mortality and time to distant metastases was reported in patients with Gleason score 9-10 who received EBRT plus brachytherapy plus ADT versus EBRT plus ADT, or versus radical prostatectomy.[228] In another observational study, no difference in survival was reported between EBRT plus brachytherapy (with or without ADT) versus radical prostatectomy, but improved survival was reported versus EBRT plus ADT.[229]

High-dose radiation to the prostate and periprostatic tissue is recommended for patients who are candidates for radiation therapy plus ADT.[204][205][206][207][208]​ Prophylactic pelvic nodal irradiation should also be considered in patients with high-risk or very high-risk disease who are undergoing radiation therapy.[3][209]​ 

ADT alone can be used for patients who are unsuitable for surgery or definitive radiation therapy due to medical comorbidities. Exclusionary medical comorbidities may include inflammatory bowel disease or prior pelvic irradiation.[225] ADT on an intermittent rather than a continuous basis may be considered, although whether this approach has a positive impact on quality of life is controversial.[230][231][232]

Abiraterone (a second-generation antiandrogen) is approved for use in metastatic disease. However, off-label use in combination with EBRT and 2 years of ADT (e.g., an LHRH agonist or antagonist) is recommended for selected patients with very high-risk (nonmetastatic) disease (e.g., those with two or more of the following features: cT3 or cT4 tumor, PSA ≥40, and Grade Group 4 or 5).[3][233][234]​​​​​ Abiraterone should not be used concurrently with another antiandrogen (e.g., nilutamide, bicalutamide, flutamide), and it should always be given with prednisone or methylprednisolone (depending on the formulation of abiraterone). The addition of abiraterone to primary ADT has been shown to improve overall and failure-free survival in a randomized study of men with locally advanced prostate cancer (radiation therapy was required if node negative, and encouraged if node positive) or metastatic disease.[233] Overall survival data for the subgroup of patients with nonmetastatic disease at randomization are immature.[233] However, there are data showing improved metastasis-free survival in this subgroup.[235]

Adjuvant and salvage therapy

Adjuvant or salvage therapy may be required following definitive treatment in patients with localized or locally advanced disease. The goal of adjuvant and salvage therapy is cure.

Adjuvant/early salvage therapy after radical prostatectomy

For patients with adverse pathologic or laboratory features (e.g., positive margins, extracapsular extension [pT3 disease], seminal vesicle invasion, or a detectable PSA) and no lymph node metastases after radical prostatectomy, options include:[3][236]​​​​​​

  • Monitoring with consideration of early salvage EBRT for a detectable, rising PSA level, or a PSA >0.1 nanograms/mL (before PSA reaches 0.5 nanograms/mL)

  • Adjuvant EBRT (with or without ADT)

For patients with lymph node metastases, options include:[3]

  • Monitoring with consideration of early salvage EBRT for a detectable, rising PSA level, or a PSA >0.1 nanograms/mL (before PSA reaches 0.5 nanograms/mL)

  • Adjuvant ADT (with or without EBRT)

Risk assessment (including use of nomograms) should be carried out to inform decision-making in these patients. The Decipher molecular assay may also be considered to guide decision-making, along with clinical and pathologic information, PSA level, and PSADT.[3][237][238][239][240]​​​​​ Shared decisions about treatment should be based on assessment of potential benefits and harms.[3][149]​​​​​ For patients with life expectancy ≤5 years, observation is recommended instead of adjuvant or salvage therapy.[3][241]

Monitoring, with early salvage EBRT performed only when PSA failure is detected, reduces overtreatment with radiation therapy (and associated adverse events) compared with immediate adjuvant EBRT. Monitoring is the preferred option, unless the patient has positive nodes or multiple high-risk features.[3]

Randomized controlled trials have shown that early salvage EBRT results in similar biochemical control and event-free survival rates, and lower genitourinary toxicity, compared with immediate adjuvant EBRT.[242][243][244][245]​​​​​ Systematic reviews of preliminary data support a role for early salvage therapy postprostatectomy; one review recommends reserving this approach for carefully selected patients with favorable characteristics.[245][246]​​​​​​

PSA failure after radical prostatectomy has no single accepted definition. The American Urological Association defines biochemical recurrence in the postprostatectomy setting as a rise in PSA ≥0.2 nanograms/mL and a confirmatory value of >0.2 nanograms/mL.[236][247]​​​​​ The National Comprehensive Cancer Network defines postprostatectomy PSA recurrence as undetectable postprostatectomy PSA with a subsequent detectable PSA that increases on two or more measurements or increases to PSA >0.1 nanograms/mL.[3] Patients receiving early salvage EBRT at lower PSA levels (≥0.1 to 0.2 nanograms/mL) have demonstrated better outcomes compared with those receiving salvage EBRT at higher PSA levels.[236][248]

​​​Adjuvant EBRT has been shown to improve progression-free survival, metastasis-free survival, and overall survival in patients with adverse pathologic features discovered during radical prostatectomy, compared with no adjuvant therapy.[249][250][251][252]​​​​​ The addition of adjuvant ADT to EBRT may be of benefit in selected patients with negative lymph nodes, such as those with a high Decipher score (e.g., >0.6).[3][253]

Adjuvant ADT (with or without EBRT) initiated immediately in patients with positive nodes (discovered during prostatectomy) has been shown to improve survival compared with deferring adjuvant ADT until disease progression.[254][255][256]​​​​​ Retrospective studies and analysis of data from a US cancer database suggest that adjuvant ADT with EBRT may improve survival compared with ADT alone.[3][257][258]

Salvage therapy after radical prostatectomy

Salvage therapy is indicated for patients with life expectancy >5 years if there is PSA persistence (PSA does not fall to undetectable levels) or recurrence (increase of previously undetectable PSA on two or more measurements or to PSA >0.1 nanograms/mL) after radical prostatectomy.[3][236]

Evaluation for distant metastases should be carried out (e.g., if the patient develops symptoms or PSA is increasing rapidly), which may include bone and soft tissue imaging. Prostate bed biopsy may be helpful, especially if imaging suggests local recurrence.[3] Risk assessment (including use of nomograms) should be carried out to inform decision-making about salvage therapy. The Decipher molecular assay may also be considered to aid decision-making discussions, along with clinical and pathologic information, PSA level, and PSADT.[3][237][238][239][240]

If negative for pelvic nodal recurrence and distant metastases, options for patients with PSA persistence or recurrence include:[3][236]​​​

  • EBRT with or without ADT followed by monitoring for progression (physical exam and PSA every 3-6 months, and imaging for symptoms or increasing PSA)

  • Monitoring for progression with consideration of salvage therapy (EBRT with or without ADT) before PSA reaches 0.5 nanograms/mL (if the patient continues to be negative for distant metastases)

If positive for pelvic nodal recurrence, EBRT plus ADT with or without abiraterone (plus prednisone or methylprednisolone) is recommended, followed by monitoring for progression.

EBRT (with or without ADT) is the main treatment option for postoperative salvage therapy.[3][259][260]​​​[261] Combining ADT with salvage EBRT reduces the likelihood of progression and may improve survival outcomes compared with salvage EBRT alone, but decisions (including duration of ADT) should be individualized, based on an assessment of potential benefits and harms, and shared decision-making.[259][260][261][262]

Monitoring may be an alternative to salvage therapy in some patients with PSA persistence or recurrence after radical prostatectomy, following a careful review of the balance of risks and benefits.[240] However, salvage radiation therapy is more effective when given at lower levels of PSA, and should be considered for local or regional control before PSA levels reach 0.5 nanograms/mL.[236]

Salvage therapy after primary EBRT

Salvage therapy is indicated for patients with life expectancy >5 years if there is PSA recurrence or positive DRE after primary EBRT.[3] PSA recurrence after EBRT is defined as PSA increase of ≥2 nanograms/mL above the nadir PSA.[263]​ Evaluation for salvage therapy can also be considered if the PSA is increasing but has not reached 2 nanograms/mL above nadir. 

Treatment decisions should be individualized, guided by risk stratification; PSA density, and bone and soft tissue imaging should be performed, with consideration of prostate/seminal vesicle biopsy if imaging is negative for metastases.[3][264]

If negative for regional lymph nodes and distant metastases, options include:[3][264][265][266][267]

  • Monitoring for progression (with consideration of prostate/seminal vesicle biopsy)

  • ADT (based on PSA density)

  • Local secondary therapy alone, which may include:

    • Salvage prostatectomy plus pelvic lymph node dissection

    • Salvage cryotherapy

    • Reirradiation (low- or high-dose rate brachytherapy, or SBRT)

    • High-intensity focused ultrasound

If positive for regional lymph nodes and negative for distant metastases, options include:

  • Monitoring (with consideration of prostate/seminal vesicle biopsy)

  • ADT with or without abiraterone (plus prednisone or methylprednisolone)

  • Consideration of local secondary therapy (e.g., pelvic lymph node dissection, pelvic lymph node radiation or reirradiation [low- or high-dose rate brachytherapy, or SBRT]) with or without ADT

Observation is recommended instead of salvage therapy in patients with life expectancy ≤5 years.[3]

Salvage brachytherapy provides precise treatment for pathologically confirmed (e.g., using MRI-guided biopsy) locally recurrent disease, therefore minimizing toxicity to adjacent organs. Use of salvage prostatectomy and salvage cryotherapy is limited by treatment-related adverse effects (e.g., erectile dysfunction).[267][268][269][270][271][272][273]

Nonmetastatic castration-resistant disease

Patients with nonmetastatic castration-resistant prostate cancer are those with clinical, radiographic, or biochemical (PSA) progression despite treatment with ADT, but who do not have metastases. These patients are at high risk for developing metastases, particularly if PSADT is short (e.g., ≤10 months). ADT with an LHRH agonist or antagonist should continue in these patients to maintain castrate serum levels of testosterone, but further hormonal treatment may be added depending on the PSADT.[3]

If PSADT is >10 months, monitoring with continued ADT is the preferred option. A secondary hormone therapy can be added to ADT (if not previously used), although evidence of survival benefit is lacking. Secondary hormone therapy may include:[3]

  • Ketoconazole plus hydrocortisone

  • First-generation antiandrogen (e.g., nilutamide, bicalutamide, flutamide)

  • Corticosteroid (e.g., hydrocortisone, prednisone, dexamethasone)

Antiandrogen withdrawal (i.e., to exclude an antiandrogen withdrawal effect) may be an option for nonmetastatic castration-resistant disease.[274][275][276]

Ketoconazole may cause severe liver injury and adrenal insufficiency. It is contraindicated in patients with liver disease and expert guidance should be sought if used. Liver and adrenal function should be monitored before and during treatment.[277]

If PSADT is ≤10 months, the following second-generation antiandrogens can be added to ADT.[3]

  • Apalutamide

  • Darolutamide

  • Enzalutamide

Randomized studies of second-generation antiandrogens in patients with nonmetastatic castration-resistant prostate cancer and PSADT ≤10 months have demonstrated improved overall survival, metastasis-free survival, and time to progression compared with placebo, without compromising quality of life.[278][279][280][281][282][283][284][285][286]​ It is not known if similar benefit would be achieved in men with a PSADT >10 months.

Alternative options for patients with nonmetastatic castration-resistant disease and PSADT ≤10 months include other secondary hormone options or antiandrogen withdrawal (as described for PSADT >10 months).[3][274][275]​​[276]​​

Metastatic disease: castration-sensitive

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumor deposits.

Patients with castration-sensitive metastatic disease include those with metastatic disease at presentation, and those who are not receiving ADT when metastatic disease develops (i.e., castration-naive).

Genetic testing (germline and somatic) should be carried out in all patients with metastatic disease (if not done previously) to inform prognosis and guide treatment decisions, including eligibility for clinical trials and suitability for novel targeted therapies.[287][288]​​​​​ See Diagnosis approach.

Therapeutic approaches to castration-sensitive metastatic disease

Combination therapy with ADT (e.g., an LHRH agonist or antagonist) plus a second-generation antiandrogen with or without docetaxel is recommended.[233][288]​​​​​​[289][290][291][292][293][294][295][296][297][298][299][300]​​​​​​​​ EBRT to the primary tumor may be an option for some patients depending on disease volume and timing of metastases.[3][301]​​​[302]

Specific treatment options include:[3][234][300][303]

  • ADT plus docetaxel and abiraterone or darolutamide

  • ADT plus abiraterone, apalutamide, or enzalutamide

  • ADT plus EBRT to the primary tumor alone or with abiraterone or docetaxel

Abiraterone should always be given with prednisone or methylprednisolone (depending on the formulation of abiraterone).

For patients with high-volume disease (i.e., visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral bodies and pelvis) with synchronous metastases, ADT plus a second-generation antiandrogen with or without docetaxel is preferred. For low-volume disease (i.e., nonregional lymph-node-only disease, or presence of <4 bone metastases without visceral/other metastasis) with metachronous metastases, ADT plus a second-generation antiandrogen is preferred.[3][304]

ADT plus docetaxel and abiraterone or darolutamide may improve survival compared with ADT plus docetaxel alone, particularly in those with high-volume castration-sensitive disease.[305][306]

Improved survival has been demonstrated with EBRT plus ADT versus ADT alone in patients with low-volume castration-sensitive disease.[161][307][308][301]​​​​​ Hypofractionation and ultra-hypofractionation are the preferred approaches for EBRT.[3][161]

ADT is usually given continuously, but intermittent ADT may be considered if adverse effects occur with continuous ADT.[72][309][310][311][312][313]

ADT alone is not recommended for patients with castration-sensitive metastatic disease unless combination treatment is clearly contraindicated or the patient is asymptomatic and has a life expectancy of ≤5 years.[3]​ Surgical castration (bilateral orchiectomy) is an option for patients with castration-sensitive metastatic disease, but is rarely used.

A PSA level ≤0.2 nanograms/mL after 7 months of ADT is a strong predictor for longer overall survival in patients with castration-sensitive metastatic disease.[314] 

Oligometastatic disease

Patients with 1-5 metastatic lesions are generally considered to have oligometastatic disease, although there is no agreed definition for this disease state.[315] The standard treatment for oligometastatic disease is similar to that for low metastatic burden disease.

Focal therapy with SBRT may be an option for patients with oligometastatic disease (when the goal is metastasis-directed ablation) or for patients with oligometastatic progression (when the goal is progression-free survival).[3][162][316]

One randomized study of SBRT in oligometastatic cancers reported improved overall survival and progression-free survival in patients receiving SBRT compared with standard palliative care.[163][317]​ The optimal treatment approach for managing oligometastatic disease is unclear.

Metastatic disease: castration-resistant

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumor deposits.

Patients with castration-resistant metastatic disease are those who develop metastatic disease despite achieving castrate levels of testosterone with primary ADT.

Genetic testing (germline and somatic) should be carried out in patients with metastatic disease (if not done previously) to inform prognosis and guide treatment decisions, including eligibility for clinical trials and suitability for novel targeted therapies.[287][288]​​​​​​ See Diagnosis approach.

Treatment options for patients with castration-resistant metastatic disease have expanded rapidly. Optimal sequencing of drugs following docetaxel-based regimens and/or second-generation antiandrogen therapy is unclear, although studies are ongoing and may help guide decisions.[318][319][320]​​​​​

Initial treatment options for castration-resistant metastatic disease

Treatment decisions should take into account patient goals and preferences, prior treatment exposures, the presence or absence of symptoms, performance status, the location and number of metastases, potential adverse effects, and the presence of certain biomarkers.[3] ADT should be continued to maintain castrate levels of testosterone in patients with castration-resistant metastatic disease. Patients should be closely monitored for progression, and treatments added sequentially.[3]

For patients with no prior treatment with second-generation antiandrogen therapy (abiraterone, enzalutamide, darolutamide, or apalutamide), ADT can be combined with one of the following options:[321][322][323][324]​​​​​​[325][326][327][328][329]​​​​​​[330]​​[331][332]

  • Abiraterone (with prednisone or methylprednisolone)

  • Enzalutamide

  • Docetaxel-based regimen (e.g., docetaxel plus prednisone, if no prior use)

  • Cabazitaxel plus prednisone (if prior docetaxel)

For patients with progression following treatment with second-generation antiandrogen therapy and no prior docetaxel treatment, ADT plus a docetaxel-based regimen is recommended.[3] The poly (ADP-ribose) polymerase (PARP) inhibitors olaparib or rucaparib may be considered as alternative options in this setting if the patient has a BRCA1 or BRCA2 mutation.[333][334][335][336]​​ 

Cabazitaxel is an option for patients who have had prior docetaxel and prior second-generation antiandrogen treatment.[329][330]​​​​[331][337]​​​​​ Docetaxel rechallenge is a further option for patients treated previously with docetaxel for castration-sensitive disease.[3]

For patients who are starting to show signs of progression while taking abiraterone plus prednisone, switching from prednisone to dexamethasone may be beneficial.[338][339]​​​ 

Further treatment options for castration-resistant metastatic disease

The following treatments may be considered for selected patients with castration-resistant metastatic disease. Optimal sequencing is unknown; patients can try any of these options, if indicated.

  • Sipuleucel-T:

    • An autologous active cellular immunotherapy, sipuleucel-T may be an option for asymptomatic or minimally symptomatic patients with good functional status (e.g., an Eastern Cooperative Oncology Group performance status of 0 to 1).[3][340]​​​[341]

    • Sipuleucel-T is not recommended for patients with visceral disease and a life expectancy of less than 6 months, or patients with hepatic metastases.[3][340]

  • PARP inhibitors:

    • Olaparib can be considered for patients with a homologous recombination repair (HRR) gene mutation who have had prior second-generation antiandrogen therapy.[3][234][333][334][335]​​​​ Efficacy may vary depending on the genes involved; in one study of patients with an alteration in one of 15 prespecified HRR genes, those with a BRCA1 or BRCA2 mutation appeared to derive the greatest survival benefit.[335] 

    • Rucaparib can be considered for patients with a BRCA1 or BRCA2 mutation who have had prior second-generation antiandrogen therapy.[3][336][342][343]​​​​ Rucaparib is not recommended for patients without a BRCA1 or BRCA2 mutation.[3][344]

    • Olaparib or niraparib may be used in combination with abiraterone (plus prednisone or methylprednisolone) for patients with a BRCA1 or BRCA2 mutation who have not received prior second-generation antiandrogen therapy.[3][345]​​​[346][347]​​ 

    • Talazoparib plus enzalutamide may be an option for patients with an HHR mutation who have had no prior docetaxel therapy.[3][348][349]​​

    • Anemia, fatigue, and nausea are commonly reported with PARP inhibitors. Careful monitoring for anemia and renal and hepatic function is required.[3]

  • Pembrolizumab:

    • A programmed death receptor-1 (PD-1)-blocking monoclonal antibody, pembrolizumab may be considered for patients with mismatch repair deficient (dMMR), microsatellite instability-high (MSI-H), or high tumor mutational burden (TMB-H) metastatic castration-resistant prostate cancer.[3][288]​ 

    • Much of the evidence for this treatment is based on different tumor types; however, early phase trials report antitumor activity among specific subsets of patients with metastatic castration-resistant prostate cancer.[350][351][352][353]

    • Pembrolizumab may cause severe, life-threatening immune-mediated adverse reactions.[354] 

  • Lutetium (Lu-177) vipivotide tetraxetan:

    • A radioligand therapeutic agent that delivers beta-radiation to prostate-specific membrane antigen (PSMA)-expressing cells and the surrounding microenvironment. Can be considered for patients with progression after taxane-based chemotherapy and second-generation antiandrogen therapy who have PSMA-positive castration-resistant metastatic disease.[3][234]​​[288][355][356]

    • PSMA-PET imaging is required for patient selection. Gallium (Ga-68) PSMA-11, piflufolastat F-18, or flotufolastat F-18 may be used as radiotracers to detect PSMA expression and determine eligibility.[3][355][357]

  • Mitoxantrone:

    • May be considered in combination with prednisone for palliative treatment of symptomatic patients who have progressed on prior docetaxel and cannot tolerate other therapies. It has not been shown to improve survival.[3][358]​​​[359]

  • Radium-223:

    • A calcium mimetic that localises to the bone and delivers radiation directly to bone metastases, radium-223 can be considered for patients with castration-resistant metastatic disease who have symptomatic bone metastases without visceral metastases.[3][360]

    • Radium-223 is associated with adverse effects including anemia, neutropenia, thrombocytopenia, bone pain, and gastrointestinal disorders. There have also been reports of increased risk of fracture and deaths when used in combination with abiraterone plus prednisone.[361][362]​​ 

    • The European Medicines Agency has restricted the use of radium-223 to symptomatic patients who have received two prior treatments for metastatic prostate cancer, or who cannot receive other treatments. It should not be used with abiraterone and prednisone or with other systemic cancer therapies (except hormone therapy).[362]

    • A careful assessment of risk of fractures should be carried out before, during, and after treatment with radium-223. Bisphosphonates or denosumab are recommended before starting or resuming treatment with radium-223 to increase bone strength.[3][362]

Supportive care

Supportive care should be considered to prevent skeletal-related adverse events and testosterone flare, and to manage complications and symptoms related to metastatic disease.

Prevention of skeletal-related events

Denosumab (a fully human monoclonal antibody that inhibits RANK ligand) and the bisphosphonates zoledronic acid and alendronate are recommended to reduce the risk of bone fractures in patients with nonmetastatic disease if they are receiving ADT and have osteoporosis (e.g., T score -2.5 on dual-energy x-ray absorptiometry [DXA] scan) or an increased risk of fractures (e.g., ≥20% for 10-year risk of major osteoporotic fractures, or ≥3% for 10-year risk of hip fractures, based on FRAX® [Fracture Risk Assessment Tool]).[3][363][364] University of Sheffield: FRAX tool Opens in new window

Denosumab and zoledronic acid are recommended to prevent skeletal-related events (e.g., bone fracture, spinal cord compression) in patients with bone metastases.[3][365] [ Cochrane Clinical Answers logo ] ​​​ Denosumab is preferred to zoledronic acid due to its superior efficacy.[3][366]​ Other bisphosphonates can be considered if denosumab and zoledronic acid are unsuitable or unavailable.[367]

Safety communications

In June 2018, the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued a safety alert following a pooled analysis of four phase 3 studies of denosumab in patients with advanced malignancies involving bone.[368] New primary malignancies were reported more frequently among patients receiving denosumab than those receiving zoledronic acid (cumulative incidence of new primary malignancy at 1 year was 1.1% for denosumab and 0.6% for zoledronic acid). No treatment-related patterns for individual cancers or cancer groupings were identified.

In January 2024, the Food and Drug Administration (FDA) warned of an increased risk of severe hypocalcemia in patients with advanced chronic kidney disease who are receiving denosumab (Prolia® 60 mg/mL approved for treatment to increase bone mass in men at high risk for fracture receiving ADT for nonmetastatic prostate cancer).[369] Two safety studies showed a significant increase in the risk of severe hypocalcemia in patients treated with denosumab compared with those treated with bisphosphonates, with the highest risk reported in patients with advanced kidney disease, particularly those on dialysis. Severe hypocalcemia was more common in those with mineral and bone disorder. Patients with advanced chronic kidney disease taking denosumab are at risk of serious outcomes from severe hypocalcemia, including hospitalization and death.

Before prescribing denosumab, healthcare professionals should assess kidney function and calcium levels, and consider other treatment options for patients at risk. During treatment, frequent monitoring and prompt management of hypocalcemia are essential. The FDA has not issued a warning with respect to the brand of denosumab approved specifically for the prevention of skeletal-related adverse events in malignancy (Xgeva® 120 mg/1.7 mL).

Prevention of testosterone flare in metastatic disease

LHRH agonists may cause an increase in testosterone levels during the first week of treatment (testosterone flare), which may exacerbate symptoms in patients with metastatic disease.[370][371][372]​​​ An LHRH antagonist (e.g., degarelix, relugolix) should be used for 1 month prior to transitioning to an LHRH agonist if used in the metastatic setting. 

Palliative care for metastatic disease

Systemic radiation therapy with the beta-particle emitters strontium-89 or samarium-153 can be considered for palliation in patients with symptomatic bone metastases without visceral metastases. Their use is purely palliative and has largely been superseded by radium-223, which confers a survival advantage.

Radiation therapy in palliative doses can be given to sites of painful bony metastasis. Radiation may include a single treatment or a 1- or 2-week course depending on normal tissue toxicity and patient convenience.[373]​ Studies do not show a consistent difference between regimens for pain control, but some have reported higher rates of reirradiation in patients receiving single-fraction regimens (although the reason for this is unclear).[373][374][375][376]​​​​ SBRT may be considered instead of conventional palliative radiation therapy for some patients with painful bony metastases (e.g., with an Eastern Cooperative Oncology Group performance status 0 to 2, without neurologic symptoms, and not receiving surgery).[373][377]​​​ Evidence is lacking to guide the use of SBRT combined with targeted therapy and immunotherapy.[378] Radiation may also be given to the pelvis, if previously untreated, in palliative doses to relieve obstructive symptoms or bleeding.

Male urethral catheterization: animated demonstration
Male urethral catheterization: animated demonstration

How to insert a urethral catheter in a male patient using sterile technique.

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