Prostate Cancer, part 2

Abiraterone acetate, an inhibitor of cytochrome P450c17, a critical enzyme in androgen biosynthesis.

Apalutamide, an androgen receptor antagonist.

Enzalutamide, an androgen receptor antagonist.

In the randomized double-blind LATITUDE trial (NCT01715285), 1,199 men with high-risk metastatic castration-sensitive prostate cancer were given ADT plus either abiraterone acetate (1,000 mg PO qd) and prednisone (5 mg PO qd) or ADT plus abiraterone-prednisone placebos.[3] High-risk disease was defined as having at least two of the following three factors: Gleason score of 8 or higher, three or more bone lesions, or measurable visceral metastases.

Sources: LATITUDE · 3

In the randomized double-blind LATITUDE trial (NCT01715285), 1,199 men with high-risk metastatic castration-sensitive prostate cancer were given ADT plus either abiraterone acetate (1,000 mg PO qd) and prednisone (5 mg PO qd) or ADT plus abiraterone-prednisone placebos.[3] High-risk disease was defined as having at least two of the following three factors: Gleason score of 8 or higher, three or more bone lesions, or measurable visceral metastases.

After a median follow-up of 30.4 months, the trial was stopped because of a clear overall survival (OS) benefit in the abiraterone study group: median survival not reached versus 34.7 months OS (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.51–0.76; P < .001).[3][Level of evidence A1]

Sources: 3 · Level of evidence A1

Abiraterone therapy was well tolerated, but there was an increase in the mineralocorticoid effects of grade 3 or 4 hypertension and hypokalemia compared with the placebo study group.

A collection of patient-reported outcomes and Health-Related Quality of Life (HRQOL) data showed clinical benefits in pain progression, prostate cancer–related symptoms, fatigue, functional decline, and overall HRQOL in the abiraterone-acetate study group compared with the placebo group.[4][Level of evidence A3]

Sources: 4 · Level of evidence A3

In the randomized open-label STAMPEDE trial (NCT00268476), 1,917 men (about 95% newly diagnosed; about 50% had metastatic disease and about 50% had locally advanced or node-positive disease) were treated with ADT alone or ADT plus abiraterone acetate (1,000 mg PO qd) and prednisolone (5 mg PO qd).[5] Local radiation therapy was mandated after 6 to 9 months for men with node-negative nonmetastatic disease and optional for those with node-positive nonmetastatic disease. Hormone therapy was curtailed at 2 years or until progression. Radiation therapy was planned in about 40% of study participants.

Sources: STAMPEDE · 5

In the randomized open-label STAMPEDE trial (NCT00268476), 1,917 men (about 95% newly diagnosed; about 50% had metastatic disease and about 50% had locally advanced or node-positive disease) were treated with ADT alone or ADT plus abiraterone acetate (1,000 mg PO qd) and prednisolone (5 mg PO qd).[5] Local radiation therapy was mandated after 6 to 9 months for men with node-negative nonmetastatic disease and optional for those with node-positive nonmetastatic disease. Hormone therapy was curtailed at 2 years or until progression. Radiation therapy was planned in about 40% of study participants.

With a median follow-up of 40 months, the 3-year OS rate was 83% in the abiraterone study group compared with 76% in the ADT-only study group (HRdeath, 0.63; 95% CI, 0.52–0.76; P< .001).[5][Level of evidence A1] Although there was no clear evidence of heterogeneity in relative treatment differences in metastatic disease versus nonmetastatic disease, absolute differences were much smaller in men with nonmetastatic disease and not statistically significant, perhaps because of the short follow-up (HRdeath, 0.75; 95% CI, 0.49–1.18).

Sources: 5 · Level of evidence A1

The main additional differences in toxicity associated with abiraterone compared with ADT alone were hypertension (5% vs. 1%), mild increase in blood aminotransferase levels (6% vs. < 1%), and respiratory disorders (5% vs. 2%).

In the randomized, controlled, double-blind phase III TITAN trial (NCT02489318), 1,052 men with metastatic, castration-sensitive prostate cancer were randomly assigned to receive ADT alone or ADT plus either apalutamide (240 mg PO qd) or placebo.[6]

Sources: TITAN · 6

In the randomized, controlled, double-blind phase III TITAN trial (NCT02489318), 1,052 men with metastatic, castration-sensitive prostate cancer were randomly assigned to receive ADT alone or ADT plus either apalutamide (240 mg PO qd) or placebo.[6]

The 2-year OS rate was 82.4% in the apalutamide group and 73.5% in the placebo group (HR, 0.67; 95% CI, 0.51−0.89).

Radiographic progression-free survival (PFS) was 68.2% in the apalutamide group and 47.5% in the placebo group (HR, 0.48; 95% CI, 0.39−0.60).

Grade 3 or 4 adverse events were reported in 42.2% of patients in the apalutamide group and 40.8% of patients in the placebo group.

Apalutamide has been associated with an increased risk of seizure, so men with a history of or predisposition to seizures were excluded from this trial.

In the randomized, controlled, open-label phase III ENZAMET trial (NCT02446405), 1,125 men with castrate-sensitive prostate cancer were randomly assigned to receive ADT alone or ADT plus enzalutamide (160 mg PO qd).[7]

Sources: ENZAMET · 7

In the randomized, controlled, open-label phase III ENZAMET trial (NCT02446405), 1,125 men with castrate-sensitive prostate cancer were randomly assigned to receive ADT alone or ADT plus enzalutamide (160 mg PO qd).[7]

The 3-year OS rate was 80% in the combined-therapy arm and 72% in the ADT monotherapy arm (HR, 0.67; 95% CI, 0.52−0.86).

PSA PFS (HR, 0.39, P < .001) and clinical PFS (HR, 0.40; P < .001) were also longer in the combined-therapy arm.

Serious adverse events were reported in 42% of patients in the enzalutamide arm compared with 34% in the monotherapy arm.

In the randomized, controlled, open-label phase III ENZAMET trial (NCT02446405), 1,125 men with castrate-sensitive prostate cancer were randomly assigned to receive ADT alone or ADT plus enzalutamide (160 mg PO qd).[7] › Serious adverse events were reported in 42% of patients in the enzalutamide arm compared with 34% in the monotherapy arm.

Treatment was discontinued more frequently in the enzalutamide arm (33 vs. 14 events), and seizures and fatigue were more common in the enzalutamide arm: seven men (1%) had seizures in the enzalutamide arm versus none in the ADT-alone arm.

Six percent of men in the combined-therapy arm reported grade 3 to 4 fatigue compared with 1% in the ADT-alone arm.

Orchiectomy alone or with an androgen blocker as seen in the Southwest Oncology Group (SWOG-8894) trial.

Luteinizing hormone-releasing hormone (LH-RH) agonists, such as leuprolide in daily or depot preparations. These agents may be associated with tumor flare when used alone; therefore, the initial concomitant use of antiandrogens should be considered in the presence of liver pain, ureteral obstruction, or impending spinal cord compression.[9-12][Level of evidence A1]

Sources: 9 · 12 · Level of evidence A1

Leuprolide plus flutamide;[13] however, the addition of an antiandrogen to leuprolide has not been clearly shown in a meta-analysis to improve survival.[14]

Sources: 13 · 14

Estrogens (diethylstilboestrol [DES], chlorotrianisene, ethinyl estradiol, conjugated estrogens-USP and DES-diphosphate). DES is no longer commercially available in the United States.

A meta-analysis of seven randomized controlled trials comparing early (adjuvant or neoadjuvant) with deferred hormonal treatment (LH-RH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated with prostatectomy, radiation therapy, or watchful waiting or active surveillance/active monitoring, showed improved overall mortality with early treatment (relative risk, 0.86; 95% CI, 0.82–0.91).[24][Level of evidence A1]

Sources: 24 · Level of evidence A1

In a small, randomized trial of 98 men who underwent radical prostatectomy plus pelvic lymphadenectomy and were found to have nodal metastases (stage T1–2, N1, M0), immediate continuous hormonal therapy with the LH-RH agonist goserelin or with orchiectomy was compared with deferred therapy until documentation of disease progression.[25][Level of evidence A1];[26]

Sources: 25 · Level of evidence A1 · 26

In a small, randomized trial of 98 men who underwent radical prostatectomy plus pelvic lymphadenectomy and were found to have nodal metastases (stage T1–2, N1, M0), immediate continuous hormonal therapy with the LH-RH agonist goserelin or with orchiectomy was compared with deferred therapy until documentation of disease progression.[25][Level of evidence A1];[26]

After a median follow-up of 11.9 years, OS (P = .04) and prostate–cancer-specific survival (P = .004) were superior in the immediate adjuvant therapy arm.

At 10 years, the survival rate in the immediate therapy arm was about 80% versus about 60% in the deferred therapy arm.[27]

Sources: 27

Another trial (RTOG-8531) with twice as many randomly assigned patients showed no difference in OS with early versus late hormonal manipulation.[28]

Sources: 28

Immediate hormonal therapy with goserelin or orchiectomy has also been compared with deferred hormonal therapy for clinical disease progression in a randomized trial (EORTC-30846) of men with regional lymph node involvement but no clinical evidence of metastases (any T, N+, M0). None of the 234 men had a prostatectomy or prostatic radiation therapy.[29][Level of evidence A1]

Sources: EORTC-30846 · 29 · Level of evidence A1

Immediate hormonal therapy with goserelin or orchiectomy has also been compared with deferred hormonal therapy for clinical disease progression in a randomized trial (EORTC-30846) of men with regional lymph node involvement but no clinical evidence of metastases (any T, N+, M0). None of the 234 men had a prostatectomy or prostatic radiation therapy.[29][Level of evidence A1]

After a median follow-up of 8.7 years, the HR for OS in the deferred versus immediate hormonal therapy arms was 1.23 (95% CI, 0.88–1.71).

No statistically significant difference in OS between deferred and immediate hormonal therapy was found, but the trial was underpowered to detect small or modest differences.

Immediate hormonal treatment (e.g., orchiectomy or LH-RH agonist) versus deferred treatment (e.g., watchful waiting with hormonal therapy at progression) was examined in a randomized study in men with locally advanced or asymptomatic metastatic prostate cancer.[30][Level of evidence A1]

Sources: 30 · Level of evidence A1

Immediate hormonal treatment (e.g., orchiectomy or LH-RH agonist) versus deferred treatment (e.g., watchful waiting with hormonal therapy at progression) was examined in a randomized study in men with locally advanced or asymptomatic metastatic prostate cancer.[30][Level of evidence A1]

The initial results showed better OS and prostate–cancer-specific survival with immediate treatment.

The incidence of pathological fractures, spinal cord compression, and ureteric obstruction were also lower in the immediate treatment arm.

In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to have a bilateral orchiectomy at diagnosis or at the time of symptomatic progression (or at the time of new metastases that were deemed likely to cause symptoms).[31][Level of evidence A1]

Sources: 31 · Level of evidence A1

In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to have a bilateral orchiectomy at diagnosis or at the time of symptomatic progression (or at the time of new metastases that were deemed likely to cause symptoms).[31][Level of evidence A1]

After 12 years of follow-up, no statistically significant difference was observed in OS.

In a randomized trial, the LH-RH agonist leuprolide (1 mg subcutaneously [SQ] qd) was as effective as DES (3 mg PO qd) in any T, any N, M1 patients, but caused less gynecomastia, nausea and vomiting, and thromboembolisms.[10]

Sources: 10

In other randomized studies, the depot LH-RH agonist goserelin was as effective as orchiectomy [11,33,34] or DES at a dose of 3 mg qd.[32] A depot preparation of leuprolide, which is therapeutically equivalent to daily leuprolide, is available as a monthly or 3-monthly depot.

Sources: 11 · 33 · 34 · 32

A systematic evidence review compared nonsteroidal antiandrogen monotherapy with surgical or medical castration from 11 randomized trials in 3,060 men with locally advanced, metastatic, or recurrent disease after local therapy.[35] Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[35][Level of evidence A1]

Sources: 35 · 35 · Level of evidence A1

A small randomized study comparing 1 mg DES PO tid with 250 mg of flutamide tid in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with DES treatment.[36][Level of evidence A1] A variety of combinations of hormonal therapy have been tested.

Sources: 36 · Level of evidence A1

In a large, randomized, controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, no difference in OS was reported.[37][Level of evidence A1]

Sources: 37 · Level of evidence A1

In a large, randomized, controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, no difference in OS was reported.[37][Level of evidence A1]

Although it has been suggested that MAB may improve the more subjective end point of response rate, prospectively assessed QOL was worse in the flutamide arm than in the placebo arm primarily because of more diarrhea and worse emotional function in the flutamide-treated group.[38][Level of evidence A3]

Sources: 38 · Level of evidence A3

A meta-analysis of 27 randomized trials of 8,275 patients comparing conventional surgical or medical castration with MAB—castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide—did not show a statistically significant improvement in survival associated with MAB.[14][Level of evidence A1]When trials of androgen suppression versus androgen suppression plus either nilutamide or flutamide were examined in a subset analysis, the absolute survival rate at 5 years was better for the combined-therapy group (2.9% better, 95% CI, 0.3–5.5); however, when trials of androgen suppression versus androgen suppression plus cyproterone acetate were examined, the absolute survival trend at 5 years was worse for the combined-therapy group (2.8% worse, 95% CI, -7.6 to +2.0).[14]

Sources: 14 · Level of evidence A1 · 14

The Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality) performed a systematic review of the available randomized, clinical trial evidence of single hormonal therapies and total androgen blockade performed by its Technology Evaluation Center, an evidence-based Practice Center of the Blue Cross and Blue Shield Association. A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:[39][Level of evidence A1] Total androgen blockade was of no greater benefit than single hormonal therapy and with less patient tolerance. Also, the evidence was judged insufficient to determine whether men newly diagnosed with asymptomatic metastatic disease should have immediate androgen suppression therapy or should have therapy deferred until they have clinical signs or symptoms of progression.[40]

Sources: 39 · Level of evidence A1 · 40

The Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality) performed a systematic review of the available randomized, clinical trial evidence of single hormonal therapies and total androgen blockade performed by its Technology Evaluation Center, an evidence-based Practice Center of the Blue Cross and Blue Shield Association. A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:[39][Level of evidence A1] Total androgen blockade was of no greater benefit than single hormonal therapy and with less patient tolerance. Also, the evidence was judged insufficient to determine whether men newly diagnosed with asymptomatic metastatic disease should have immediate androgen suppression therapy or should have therapy deferred until they have clinical signs or symptoms of progression.[40]

OS at 2 years using any of the LH-RH agonists was similar to treatment with orchiectomy or 3 mg every day of DES (HR, 1.26; 95% CI, 0.92–1.39).

Survival rates at 2 years were similar or worse with nonsteroidal antiandrogens compared with orchiectomy (HR, 1.22; 95% CI, 0.99–1.50).

Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LH-RH agonists (0%–4%) than with nonsteroidal antiandrogens (4%–10%).

A systematic review of 15 randomized trials that compared continuous ADT versus IAD therapy for patients with advanced or recurrent prostate cancer found no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate cancer-specific survival, reported in five of the trials (HR, 1.02; 95% CI, 0.87–1.19); or PFS, reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HRdeath, 1.15).[42][Level of evidence A1] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.

Sources: 42 · Level of evidence A1

A systematic review of 15 randomized trials that compared continuous ADT versus IAD therapy for patients with advanced or recurrent prostate cancer found no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate cancer-specific survival, reported in five of the trials (HR, 1.02; 95% CI, 0.87–1.19); or PFS, reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HRdeath, 1.15).[42][Level of evidence A1] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.

There was minimal difference in patient-reported QOL, but most trials found better physical and sexual functioning in patients in the IAD arms.

In the analysis of three randomized trials (3,206 men), the HRdeath associated with the addition of docetaxel to standard of care was 0.77 (95% CI, 0.68–0.87; P < .0001), representing an absolute improvement of 9% in 4-year survival (95% CI, 5–14).[43][Level of evidence A1]

Sources: 43 · Level of evidence A1

In the CHAARTED trial (NCT00309985), 790 patients with metastatic, hormone-sensitive disease were randomly assigned to receive ADT with or without docetaxel (75 mg/m2 intravenously [IV] every 3 weeks for 6 cycles).[44,45] Previous adjuvant ADT was permissible if it lasted 12 months or less and progression had occurred within 12 months of completion. Patients were prospectively stratified as having a high- versus low-volume disease, with high volume defined as presence of visceral metastases or at least four bone lesions, with at least one lying outside the vertebral column or pelvis. About 65% of patients had high-volume disease by this definition.

Sources: CHAARTED · 44 · 45

In the CHAARTED trial (NCT00309985), 790 patients with metastatic, hormone-sensitive disease were randomly assigned to receive ADT with or without docetaxel (75 mg/m2 intravenously [IV] every 3 weeks for 6 cycles).[44,45] Previous adjuvant ADT was permissible if it lasted 12 months or less and progression had occurred within 12 months of completion. Patients were prospectively stratified as having a high- versus low-volume disease, with high volume defined as presence of visceral metastases or at least four bone lesions, with at least one lying outside the vertebral column or pelvis. About 65% of patients had high-volume disease by this definition.

With a median follow-up of 53.7 months, median OS in the ADT-plus-docetaxel arm was 57.6 months and in the ADT-alone arm, it was 47.2 months (HRdeath, 0.72; 95% CI, 0.59–0.89; P = .0018).[45][Level of evidence A1]

Sources: 45 · Level of evidence A1

The survival advantage was observed only in patients with high-volume disease. In the group with high-volume disease, there was a clear improvement in median OS (61.2 months vs. 34.4 months) (HR, 0.63; 95% CI, 0.50–0.79; P < .001). However, there was no observed difference in survival in men with low-volume disease (median OS, 63.5 months vs. not reached) (HR, 1.04; 95% CI, 0.70–1.55; P = .86). The test for heterogeneity of efficacy was statistically significant (P = .033).

Comparison of QOL between the two study groups, as measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale, was not found to exceed the prospectively defined minimally important difference at any time point over the 12 months of planned assessment.[46]

Sources: 46

In MRC-PR05, 311 men with bone metastases who were starting or responding to standard hormonal therapy were randomly assigned to oral sodium clodronate (2,080 mg qd) or a matching placebo for up to 3 years.[47][Level of evidence A1]

Sources: 47 · Level of evidence A1

In MRC-PR05, 311 men with bone metastases who were starting or responding to standard hormonal therapy were randomly assigned to oral sodium clodronate (2,080 mg qd) or a matching placebo for up to 3 years.[47][Level of evidence A1]

At a median follow-up of 11.5 years, OS was better in the clodronate arm: HRdeath, 0.77 (95% CI, 0.60–0.98; P = .032).

Five- and 10-year survival rates were 30% and 17% in the clodronate arm versus 21% and 9% in the placebo arm.

A parallel study (MRC-PR04) in men with locally advanced but nonmetastatic disease showed no benefit associated with clodronate.

CALGB-90202 [NCT00079001] was a randomized controlled trial that compared zoledronic acid (4 mg IV every 4 weeks) with placebo in 645 men with androgen deprivation-sensitive prostate cancer that was metastatic to bone. Patients who progressed on hormone-therapy resistance received open-label, zoledronic acid.[48][Level of evidence B1]

Sources: CALGB-90202 · 48 · Level of evidence B1

CALGB-90202 [NCT00079001] was a randomized controlled trial that compared zoledronic acid (4 mg IV every 4 weeks) with placebo in 645 men with androgen deprivation-sensitive prostate cancer that was metastatic to bone. Patients who progressed on hormone-therapy resistance received open-label, zoledronic acid.[48][Level of evidence B1]

There was no difference between the two study arms in risk of the primary end point of time to skeletal-related events (defined as the need for palliative bone radiation, clinical fracture, spinal cord compression, bone surgery, or death from prostate cancer) after up to 7 years of follow-up.

There were also no differences in PFS or OS.

In another negative randomized trial (STAMPEDE [NCT00268476]), 1,245 men with locally advanced (M0) or metastatic (M1) prostate cancer, who were initiating long-term hormonal therapy, were randomly assigned in a 2:1:1 ratio to one of three arms: standard of care, celecoxib (400 mg bid for 1 year), and celecoxib plus zoledronic acid (4 mg IV for six 3-week cycles, then 4-week cycles for 2 years).[49]

Sources: STAMPEDE · 49

In another negative randomized trial (STAMPEDE [NCT00268476]), 1,245 men with locally advanced (M0) or metastatic (M1) prostate cancer, who were initiating long-term hormonal therapy, were randomly assigned in a 2:1:1 ratio to one of three arms: standard of care, celecoxib (400 mg bid for 1 year), and celecoxib plus zoledronic acid (4 mg IV for six 3-week cycles, then 4-week cycles for 2 years).[49]

After a median follow-up of 69 months, there was no detectable improvement in survival associated with either celecoxib or celecoxib plus zoledronic acid.

Although survival was better in patients with M disease who received celecoxib plus zoledronic acid than in patients with M1 disease who received the standard of care (HRdeath, 0.78; 95% CI, 0.62–0.98), a formal test for interaction with metastasis status was not statistically significant; therefore, the unexpected finding can only be considered hypothesis-generating.

The Blue Cross and Blue Shield Association Technology Evaluation Center, an evidence-based practice center of the Agency for Healthcare Research and Quality (AHRQ), performed a systematic review of the available randomized clinical trial evidence comparing radiation therapy with radiation therapy and prolonged androgen suppression.[40][Level of evidence A1] Some patients with bulky T2b tumors were included in the studied groups.

Sources: 40 · Level of evidence A1

The Blue Cross and Blue Shield Association Technology Evaluation Center, an evidence-based practice center of the Agency for Healthcare Research and Quality (AHRQ), performed a systematic review of the available randomized clinical trial evidence comparing radiation therapy with radiation therapy and prolonged androgen suppression.[40][Level of evidence A1] Some patients with bulky T2b tumors were included in the studied groups.

The meta-analysis found a difference in 5-year OS in favor of radiation therapy plus continued androgen suppression using an LH-RH agonist or orchiectomy compared with radiation therapy alone (HR, 0.63; 95% CI, 0.48–0.83).

In a randomized, prospective clinical trial, 18 months of androgen suppression with an LH-RH agonist appears to have provided results that were similar to 36 months with respect to OS and disease-specific survival.[55][Level of evidence A1] In the trial, 630 men with stage II to stage IVA cancer (clinical stage T3–T4, or PSA >20 ng/ml, or Gleason score >7) received 70 Gy of radiation in 35 fractions alone plus a total of either 18 or 36 months of goserelin acetate.

Sources: 55 · Level of evidence A1

In a randomized, prospective clinical trial, 18 months of androgen suppression with an LH-RH agonist appears to have provided results that were similar to 36 months with respect to OS and disease-specific survival.[55][Level of evidence A1] In the trial, 630 men with stage II to stage IVA cancer (clinical stage T3–T4, or PSA >20 ng/ml, or Gleason score >7) received 70 Gy of radiation in 35 fractions alone plus a total of either 18 or 36 months of goserelin acetate.

With a median follow-up of 9.4 years, OS was nearly identical in each study arm (62% at 10 years; HRdeath, 1.02; 95% CI, 0.81–1.29, P = .8), as was prostate cancer–specific survival (HRprostate death, 0.95; 95% CI, 0.58–1.55, P = .8).

Global quality of life was nearly identical on both study arms, but sexual activity and interest in sex was moderately better in the 18-month arm.[55][Level of evidence A3]

Sources: 55 · Level of evidence A3

The optimal duration of neoadjuvant hormonal therapy has been studied. In a randomized trial (TROG 96.01 [ACTRN12607000237482]) of 818 men with locally advanced (T2b, T2c, T3, and T4), nonmetastatic cancer treated with radiation therapy (i.e., 66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional nodes). Patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen deprivation therapy (NADT) (goserelin 3.6 mg SQ each month plus flutamide 250 mg PO tid) for 2 months before and during radiation, or 6 months of NADT for 5 months before and during radiation.[54][Level of evidence A1]

Sources: 54 · Level of evidence A1

The optimal duration of neoadjuvant hormonal therapy has been studied. In a randomized trial (TROG 96.01 [ACTRN12607000237482]) of 818 men with locally advanced (T2b, T2c, T3, and T4), nonmetastatic cancer treated with radiation therapy (i.e., 66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional nodes). Patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen deprivation therapy (NADT) (goserelin 3.6 mg SQ each month plus flutamide 250 mg PO tid) for 2 months before and during radiation, or 6 months of NADT for 5 months before and during radiation.[54][Level of evidence A1]

After a median follow-up of 10.6 years, there were no statistically significant differences between the radiation alone group and the radiation plus 3 months of NADT group.

However, the 6-month NADT arm showed better prostate cancer-specific mortality and overall mortality than radiation alone; 10-year all-cause mortality 29.2% versus 42.5% (HR, 0.63; 95% CI, 0.48–0.83, P = .0008).

The duration of neoadjuvant hormonal therapy was tested in another trial (RTOG-9910 [NCT00005044]) of 1,489 eligible men with intermediate-risk prostate cancer (T1b–4, Gleason score 2–6, and PSA >10 but ≤100 ng/mL; T1b–4, Gleason score 7, and PSA <20; or T1b–1c, Gleason score 8–10, and PSA <20) and no evidence of metastases. The men were randomly assigned to receive short-course neoadjuvant–androgen suppression (an LH-RH agonist plus bicalutamide or flutamide for 8 weeks before and 8 weeks during radiation therapy) or long-course neoadjuvant-androgen suppression (28 weeks before and 8 weeks during radiation therapy). Both groups received 70.2 Gy radiation in 39 daily fractions to the prostate and 46.8 Gy to the iliac lymph nodes.[56][Level of evidence A1]

Sources: RTOG-9910 · 56 · Level of evidence A1

The duration of neoadjuvant hormonal therapy was tested in another trial (RTOG-9910 [NCT00005044]) of 1,489 eligible men with intermediate-risk prostate cancer (T1b–4, Gleason score 2–6, and PSA >10 but ≤100 ng/mL; T1b–4, Gleason score 7, and PSA <20; or T1b–1c, Gleason score 8–10, and PSA <20) and no evidence of metastases. The men were randomly assigned to receive short-course neoadjuvant–androgen suppression (an LH-RH agonist plus bicalutamide or flutamide for 8 weeks before and 8 weeks during radiation therapy) or long-course neoadjuvant-androgen suppression (28 weeks before and 8 weeks during radiation therapy). Both groups received 70.2 Gy radiation in 39 daily fractions to the prostate and 46.8 Gy to the iliac lymph nodes.[56][Level of evidence A1]

After a median of 9.4 years, 10-year prostate specific mortality, the primary end point, was low in both study arms: 5% versus 4% (HR, 0.81; 95% CI, 0.48–1.39).[56][Level of evidence A1]

Sources: 56 · Level of evidence A1

No statistically significant differences in overall mortality or in locoregional disease progression were found.[56][Level of evidence A1]

Sources: 56 · Level of evidence A1

There was also no apparent differential effect of androgen suppression duration among any of the risk-group subsets.

Previous treatment.

Site of recurrence.

Coexistent illnesses.

Individual patient considerations.

In the trial, 760 men who were initially treated with radical prostatectomy for tumor stage T2 or T3, and who had a detectable prostate-specific antigen (PSA) level of 0.2 to 4.0 ng/mL, but no evidence of metastases, were randomly assigned to receive radiation (64.8 Gy over 36 fractions) and either bicalutamide (150 mg PO qd) or placebo for 24 months. The median interval from surgery to PSA detectability was 1.4 years and from surgery to randomization was 2.1 years. Median follow-up was 13 years.

Actuarial OS at 12 years was 76.3% in the bicalutamide group versus 71.3% in the placebo group (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.59–0.99; P = .04).[5][Level of evidence A1]

Sources: 5 · Level of evidence A1

Prostate–cancer-specific mortality at 12 years was 5.8% (bicalutamide) versus 13.4% (placebo), (HR, 0.49; 95% CI, 0.32–0.74; P < .001).[5][Level of evidence A1]

Sources: 5 · Level of evidence A1

Most treatment-related toxicities were similar between the two groups, except for gynecomastia, which occurred in 69.7% of the men who received bicalutamide versus 10.9% of those who received placebo. This side effect may be mitigated by prophylactic breast irradiation, which was not used in this study because of the double-blinded design.

After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease;[9] however, a substantial proportion of patients with elevated or rising PSA levels after initial therapy with curative intent may remain clinically free of symptoms for extended periods.[10] In a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA of 0.2 ng/mL or higher, which is evidence of biochemical recurrence.[11]

Sources: 9 · 10 · 11

After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease;[9] however, a substantial proportion of patients with elevated or rising PSA levels after initial therapy with curative intent may remain clinically free of symptoms for extended periods.[10] In a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA of 0.2 ng/mL or higher, which is evidence of biochemical recurrence.[11]

Of these 315 men, 103 men (34%) developed clinical evidence of recurrence.

The median time to development of clinical metastasis after biochemical recurrence was 8 years.

After the men developed metastatic disease, the median time to death was an additional 5 years.

After radiation therapy with curative intent, persistently elevated or rising PSA may be a prognostic factor for clinical disease recurrence. However, reported case series have used a variety of definitions of PSA failure. Criteria have been developed by the American Society for Therapeutic Radiology and Oncology Consensus Panel.[12,13] The implication of the various definitions of PSA failure for OS is not known, and as in the surgical series, many biochemical relapses (rising PSA alone) may not be clinically manifested in patients treated with radiation therapy.[14,15]

Sources: 12 · 13 · 14 · 15

A randomized trial (PMCC-VCOG-PR-0103 [NCT00110162]) of androgen deprivation therapy (ADT) in men who received curative therapy but had a rising PSA, provided some evidence of improved OS associated with immediate versus delayed therapy.[16] The study had important shortcomings.

Sources: PMCC-VCOG-PR-0103 · 16

A randomized trial (PMCC-VCOG-PR-0103 [NCT00110162]) of androgen deprivation therapy (ADT) in men who received curative therapy but had a rising PSA, provided some evidence of improved OS associated with immediate versus delayed therapy.[16] The study had important shortcomings.

Two groups of men were randomly assigned to open-label, immediate-versus-delayed (at least 2-year delay) ADT: Planned accrual was 750 patients, but because of slow accrual, the trial closed at 293 patients.

A randomized trial (PMCC-VCOG-PR-0103 [NCT00110162]) of androgen deprivation therapy (ADT) in men who received curative therapy but had a rising PSA, provided some evidence of improved OS associated with immediate versus delayed therapy.[16] The study had important shortcomings. › Two groups of men were randomly assigned to open-label, immediate-versus-delayed (at least 2-year delay) ADT: Planned accrual was 750 patients, but because of slow accrual, the trial closed at 293 patients.

Group 1 included men who had a PSA relapse after curative therapy (89% of the study population).

Group 2 included asymptomatic men who were considered unsuitable for curative treatment because of age, comorbidity, or locally advanced disease (11% of the study population).

A randomized trial (PMCC-VCOG-PR-0103 [NCT00110162]) of androgen deprivation therapy (ADT) in men who received curative therapy but had a rising PSA, provided some evidence of improved OS associated with immediate versus delayed therapy.[16] The study had important shortcomings.

In groups 1 and 2 combined, with a median follow-up of 5 years, the 5-year OS rate was 86.4% in the delayed ADT study arm versus 91.2% in the immediate ADT study arm (log-rank P = .047).[16][Level of evidence A1] After full adjustment for baseline characteristics, the HR for OS was 0.54 (95% CI, 0.27–1.06; P = .074).

Sources: 16 · Level of evidence A1

For group 1 only (those with PSA relapse after curative therapy, N = 261), the estimated 5-year survival rate was 78.2% versus 84.3% with delayed-versus-immediate ADT (log-rank P = .10; fully adjusted HR, 0.59; 95% CI, 0.26–1.30, P = .19).

Toxicity was greater in the immediate ADT study arm compared with delayed therapy. Serious (grade 4) adverse events were reported in 42% of patients in the immediate ADT study arm versus 31% of patients in the delayed therapy arm. Quality of life (QOL) fell by 6.1% (considered a small but clinically important drop) with immediate ADT versus 3% with delayed ADT (considered a trivial drop); this was not a statistically significant difference (P = .14).[16] Sexual activity was lower and hormone-related symptoms (hot flashes and sore or enlarged nipples) were clinically and statistically significantly worse in the immediate ADT arm compared with the delayed therapy arm.[17]

Sources: 16 · 17

This important clinical question was addressed in a noninferiority-designed, randomized, controlled trial with 1,386 men who had rising PSA levels (>3 ng/mL, with serum testosterone >5 nmol/L) more than 1 year after primary or salvage radiation therapy for localized prostate cancer.[18][Levels of evidence A1 and A3]

Sources: 18 · A1 · A3

This important clinical question was addressed in a noninferiority-designed, randomized, controlled trial with 1,386 men who had rising PSA levels (>3 ng/mL, with serum testosterone >5 nmol/L) more than 1 year after primary or salvage radiation therapy for localized prostate cancer.[18][Levels of evidence A1 and A3]

The ADT arm consisted of 8-month treatment cycles with an LH-RH agonist (combined with a nonsteroidal antiandrogen for at least the first 4 weeks) that was reinstituted if the PSA level exceeded 10 ng/mL. The study was powered to detect (with 95% confidence) an 8% lower OS rate in the IAD group compared with the CAD group at 7 years.

After a median follow-up of 6.9 years (maximum follow-up, 11.2 years), OS in the two groups was nearly identical, and the study was stopped (median survival, 8.8 vs. 9.1 years; HRdeath, 1.02; 95% CI, 0.86–1.21). This fulfilled the prospective criterion of noninferiority.

In a retrospective analysis, prostate–cancer-specific mortality was also similar in the two arms (HR, 1.18; 95% CI, 0.90–1.55; P = .24). In addition, IAD was statistically significantly better than CAD in several QOL domains, such as hot flashes, desire for sexual activity, and urinary symptoms. Patients on the IAD study arm received a median of 15.4 months of treatment versus 43.9 months on the CAD arm.

The study did not address whether the initiation of any ADT for an elevated PSA after initial local therapy extends survival compared with delay until clinically symptomatic progression. Of note, 59% of all deaths were unrelated to prostate cancer, and 14% of all patients died of prostate cancer.

A systematic review evaluated 15 randomized trials that compared CAD versus IAD therapy for patients with advanced or recurrent prostate cancer. There was no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate–cancer-specific survival, reported in five of the trials (HR, 1.02; 95% CI, 0.87–1.19); or progression-free survival (PFS), reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HR of 1.15).[19][Level of evidence A1] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.

Sources: 19 · Level of evidence A1

A systematic review evaluated 15 randomized trials that compared CAD versus IAD therapy for patients with advanced or recurrent prostate cancer. There was no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate–cancer-specific survival, reported in five of the trials (HR, 1.02; 95% CI, 0.87–1.19); or progression-free survival (PFS), reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HR of 1.15).[19][Level of evidence A1] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.

There was minimal difference in patient-reported QOL, but most trials found better physical and sexual functioning in patients in the IAD arms.

The phase III EMBARK trial (NCT02319837) included 1,068 men. Patients had received prior definitive therapy with radical prostatectomy and/or radiation therapy with curative intent, had a rapidly rising PSA, and were not candidates for salvage pelvic-directed therapy. Patients were randomly assigned in a 1:1:1 ratio to receive blinded enzalutamide (160 mg PO qd) with leuprolide, blinded placebo (PO qd) plus leuprolide, or open-label single-agent enzalutamide (160 mg PO qd).[20]

Sources: EMBARK · 20

The phase III EMBARK trial (NCT02319837) included 1,068 men. Patients had received prior definitive therapy with radical prostatectomy and/or radiation therapy with curative intent, had a rapidly rising PSA, and were not candidates for salvage pelvic-directed therapy. Patients were randomly assigned in a 1:1:1 ratio to receive blinded enzalutamide (160 mg PO qd) with leuprolide, blinded placebo (PO qd) plus leuprolide, or open-label single-agent enzalutamide (160 mg PO qd).[20]

After a follow-up of 60.7 months, the enzalutamide-leuprolide combination was superior to leuprolide monotherapy for the primary end point of 5-year metastasis-free survival (87.3% vs. 71.4%; HR, 0.42; 95% CI, 0.30–0.61; P < .001). After a follow-up of 60.7 months, enzalutamide monotherapy was superior to leuprolide monotherapy for a key secondary end point of 5-year metastasis-free survival (80.0% vs. 71.4%; HR, 0.63; 95% CI, 0.46–0.87; P < .005).[20][Level of evidence B1]

Sources: 20 · Level of evidence B1

OS data were not mature, but at the time of the report, 12% of deaths were in the overall population, 3.4% were in the enzalutamide-leuprolide combination group, 6.1% were in the leuprolide monotherapy group, and 5.4% were in the enzalutamide monotherapy group.

Treatment suspension in all arms occurred at 36 weeks if PSA reached undetectable levels (<0.2 ng/mL). Treatment could be restarted per assigned treatment arms when the PSA increased to >2.0 ng/mL for patients who had a prior prostatectomy, or >5.0 ng/mL for patients who had prior primary radiation therapy. In the enzalutamide-leuprolide combination group, 90.9% of patients had treatment suspended for a median of 20.2 months. In the leuprolide monotherapy arm, 67.8% of patients had treatment suspended for a median of 16.8 months. In the enzalutamide monotherapy arm, 85.9% of patients had treatment suspended for a median of 11.1 months.

There was no substantial between-group differences in QOL measures.

No new safety signals were reported.

Grade 3 or higher toxicities for any adverse event were 46.5% in the enzalutamide-leuprolide combination group, 42.7% in the leuprolide monotherapy group, and 50.0% in the enzalutamide monotherapy group.

The most common adverse events in the combination group and leuprolide monotherapy group were hot flashes and fatigue. The most common adverse events in the enzalutamide monotherapy group were gynecomastia, hot flashes, and fatigue.

Adverse events of special interest included fractures, cognitive and memory impairment, and seizures. Fractures occurred in 18.4% of patients in the combination group, 13.6% of patients in the leuprolide monotherapy group, and 11% of the patients in the enzalutamide monotherapy group. Cognitive and memory impairment occurred in 15% of patients in the combination group, 6.5% of patients in the leuprolide monotherapy group, and 14.1% of patients in the enzalutamide monotherapy group. Seizures occurred in 1.1% of patients in the combination group, 0% of patients in the leuprolide monotherapy group, and 0.8% of patients in the enzalutamide monotherapy group.

Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17). Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, hypertension, and cardiac dysfunction. In addition, abiraterone is associated with hepatotoxicity.[28] However, compared with other therapies, abiraterone toxicities are mild. In a double-blinded placebo-controlled trial, 1,088 men with progressing hormone-refractory disease (serum testosterone <50 ng per deciliter on previous antiandrogen therapy), no previous chemotherapy, and ECOG performance status (PS) 0 to 1 were given prednisone (5 mg PO bid) plus either abiraterone acetate (1,000 mg PO qd) or placebo.[29,30][Level of evidence A1] The coprimary end points were radiological PFS and OS. Four sequential analyses were planned.

Sources: 28 · 29 · 30 · Level of evidence A1

Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17). Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, hypertension, and cardiac dysfunction. In addition, abiraterone is associated with hepatotoxicity.[28] However, compared with other therapies, abiraterone toxicities are mild. In a double-blinded placebo-controlled trial, 1,088 men with progressing hormone-refractory disease (serum testosterone <50 ng per deciliter on previous antiandrogen therapy), no previous chemotherapy, and ECOG performance status (PS) 0 to 1 were given prednisone (5 mg PO bid) plus either abiraterone acetate (1,000 mg PO qd) or placebo.[29,30][Level of evidence A1] The coprimary end points were radiological PFS and OS. Four sequential analyses were planned.

At the second interim analysis, after a median follow-up of 22.2 months, the study was stopped and unblinded because of aggregate efficacy and safety as assessed by the data monitoring committee. At that point, the radiological PFS had reached the prespecified stopping boundary in favor of abiraterone (median PFS, 16.5 months vs. 8.3 months; HR, 0.53; 95% CI, 0.45–0.62; P < .001).

At the fourth (and final) analysis with a median follow-up of 49.2 months (maximum 60 months), 65% of patients in the abiraterone-acetate study arm had died, and 71% of patients in the placebo study arm had died (HR, 0.81; 95% CI, 0.70–0.93; P = .033). Median OS was 34.7 versus 30.3 months.[30][Level of evidence A1]

Sources: 30 · Level of evidence A1

Median time to health-related QOL deterioration was long in the abiraterone study arm, as assessed by the Functional Assessment of Cancer Therapy-Prostate Version 4 (FACT-P) total score (12.7 months vs. 8.3 months; HR, 0.78; 95% CI, 0.66-0.92; P = .003) and by the prostate–cancer-specific subscale (11.1 months vs. 5.8 months; HR, 0.70; 95% CI, 0.60–0.83; P < .0001).[31][Level of evidence A3]

Sources: 31 · Level of evidence A3

In addition, patients in the abiraterone study group had statistically significant longer median times to opiate use for pain, initiation of cytotoxic chemotherapy, decline in PS, and PSA progression.[29,31][Levels of evidence A3 and B1]

Sources: 29 · 31 · A3 · B1

Enzalutamide, an androgen receptor antagonist, has been shown to increase OS and QOL in men with metastatic prostate cancer that has progressed despite ADT. In the PREVAIL study (NCT01212991), 1,717 asymptomatic or mildly symptomatic men with recurrent metastatic prostate cancer despite ADT were randomly assigned to receive either enzalutamide (160 mg PO qd) or placebo.[32-34][Levels of evidence A1 and A3]

Sources: PREVAIL · 32 · 34 · A1 · A3

Enzalutamide, an androgen receptor antagonist, has been shown to increase OS and QOL in men with metastatic prostate cancer that has progressed despite ADT. In the PREVAIL study (NCT01212991), 1,717 asymptomatic or mildly symptomatic men with recurrent metastatic prostate cancer despite ADT were randomly assigned to receive either enzalutamide (160 mg PO qd) or placebo.[32-34][Levels of evidence A1 and A3]

After a median follow-up of 22 months, the study was stopped because of an OS benefit in the enzalutamide study arm (HR, 0.72; 95% CI, 0.6–0.84; P < .001). The proportion of men who had died was 28% versus 35%, and the median OS was 32.4 versus 30.2 months.

Median time until decline in global QOL, measured by the FACT-P score, was 11.3 months in the enzalutamide group and 5.6 months in the placebo group (P < .001). A delayed occurrence of first skeletal-related event requiring clinical intervention was also shown.[32,33][Levels of evidence A3 and B1]

Sources: 32 · 33 · A3 · B1

Grade 3 or worse adverse events were more common in the enzalutamide group (43% vs. 37%), primarily because of differences in hypertension, fatigue, and falls. Because patients receiving enzalutamide were on assigned therapy for an average of 1 year longer than those on placebo, the duration of response was longer in patients receiving enzalutamide, and this difference may have contributed to the increase in adverse events.

Enzalutamide has also been tested in patients with clinically nonmetastatic, hormone-resistant prostate cancer (defined as PSA doubling time ≤10 months while undergoing hormonal therapy).[35]

Sources: 35

Enzalutamide has also been tested in patients with clinically nonmetastatic, hormone-resistant prostate cancer (defined as PSA doubling time ≤10 months while undergoing hormonal therapy).[35]

In the double-blind phase III PROSPER trial (NCT02003924), 1,401 men without clinical metastases on imaging, but with a rapidly rising PSA, were randomly assigned in a 2:1 ratio to receive either enzalutamide (160 mg PO qd) or placebo. After follow-up of up to 41 months, enzalutamide showed superiority in the primary end point, metastasis-free survival: 77% versus 51% (median 36.6 vs. 14.7 months; HR, 0.29; 95% CI, 0.24–0.35; P < .001).[35][Level of evidence B1]

Sources: PROSPER · 35 · Level of evidence B1

OS data were not mature, but at the time of the report, 11% of the men had died in the enzalutamide arm versus 13% in the placebo arm.

The rate of decline in health-related QOL was the same in both arms.

Grade 3 or higher toxicities were more common in the enzalutamide group: 31% versus 23%.

There were also excesses in several adverse events of special interest because they had been reported previously in patients treated with enzalutamide. These events included hypertension (12% vs. 5%), major cardiovascular events (5% vs. 3%), and mental impairment disorders (5% vs. 2%).

Continuing enzalutamide in patients who were switched to abiraterone because of progression, and who had metastatic castration-resistant prostate cancer (mCRPC) and a rising PSA while receiving enzalutamide, did not appear to improve the rate of PFS or of clinical progression. This strategy was tested in the randomized PLATO trial (NCT01995513).[36][Level of evidence B1]

Sources: PLATO · 36 · Level of evidence B1

Apalutamide, an androgen receptor antagonist, was tested in patients with clinically nonmetastatic, castration-resistant prostate cancer (defined as PSA doubling time ≤10 months while undergoing androgen deprivation therapy).[37] In the trial, 1,207 men were randomly assigned in a 2:1 ratio to receive either daily apalutamide (240 mg PO) or a placebo. All patients continued their previous ADT.

Sources: 37

Apalutamide, an androgen receptor antagonist, was tested in patients with clinically nonmetastatic, castration-resistant prostate cancer (defined as PSA doubling time ≤10 months while undergoing androgen deprivation therapy).[37] In the trial, 1,207 men were randomly assigned in a 2:1 ratio to receive either daily apalutamide (240 mg PO) or a placebo. All patients continued their previous ADT.

With a median follow-up of 20.3 months, metastasis-free survival was 40.5 months in the apalutamide group compared with 16.2 months in the placebo group (HR, 0.28; 95% CI, 0.23–0.35; P < .001).[37][Level of evidence B1]

Sources: 37 · Level of evidence B1

There was a trend toward improved OS in the apalutamide group, but it did not reach statistical significance at the time of the report (HR, 0.70; 95% CI, 0.47–1.04; P = .07).

There were increases in a number of toxicities associated with apalutamide treatment, which included the following: bone fractures (11.7% vs. 6.5%), hypothyroidism (8.1% vs. 2.0%), fatigue (30.4% vs. 21.1%), hypertension (24.8% vs. 19.8%), rash (23.8% vs. 5.5%), diarrhea (20.3% vs. 15.1%), weight loss (16.1% vs. 6.3%), arthralgias (15.9% vs. 7.5%), and falls (15.6% vs. 9.0%).

In a prespecified exploratory analysis, QOL over time was similar in the apalutamide and placebo arms. QOL was assessed overall and for all component subscale scores of the FACT-P and EuroQol five-dimension, three-level (EQ-5D-3L) questionnaires.[38][Level of evidence A3]

Sources: 38 · Level of evidence A3

Darolutamide, another androgen receptor antagonist, prolonged metastasis-free survival and OS in men with nonmetastatic castration-resistant prostate cancer.[39,40] A distinguishing characteristic of darolutamide is its low penetration of the blood-brain barrier. The U.S. Food and Drug Administration (FDA) approved darolutamide specifically for nonmetastatic castration-resistant prostate cancer, a more limited label compared with enzalutamide and apalutamide.A randomized controlled trial included 1,509 men with nonmetastatic castration-resistant prostate cancer, a rising PSA, and a castrate testosterone level. Patients were randomly assigned in a 2:1 ratio to receive darolutamide or placebo while continuing ADT.[39,40]

Sources: 39 · 40 · 39 · 40

Darolutamide, another androgen receptor antagonist, prolonged metastasis-free survival and OS in men with nonmetastatic castration-resistant prostate cancer.[39,40] A distinguishing characteristic of darolutamide is its low penetration of the blood-brain barrier. The U.S. Food and Drug Administration (FDA) approved darolutamide specifically for nonmetastatic castration-resistant prostate cancer, a more limited label compared with enzalutamide and apalutamide.A randomized controlled trial included 1,509 men with nonmetastatic castration-resistant prostate cancer, a rising PSA, and a castrate testosterone level. Patients were randomly assigned in a 2:1 ratio to receive darolutamide or placebo while continuing ADT.[39,40]

The 3-year OS rate was 83% for patients who received darolutamide (95% CI, 80%–86%) and 77% for patients who received placebo (95% CI, 72%–81%).[39,40][Level of evidence A1]

Sources: 39 · 40 · Level of evidence A1

The darolutamide arm was also associated with longer metastasis-free survival (HR, 0.41; 95% CI, 0.34–0.50).

Patient-reported QOL was similar in the two arms and differences favored the darolutamide arm. There were statistically significant differences favoring darolutamide for measures of pain, well-being, and urinary symptoms, but the differences did not reach clinically meaningful levels.

In contrast to studies of enzalutamide and apalutamide, darolutamide was not associated with a higher incidence of falls or fractures, hypertension, or central nervous system–related adverse effects when compared with placebo.

Men with metastatic prostate cancer who had biochemical or clinical progression after treatment with docetaxel (N = 1,195) were randomly assigned in a 2:1 ratio to receive either abiraterone acetate (1,000 mg) (n = 797) or placebo (n = 398) by mouth every day (COU-AA-301 [NCT00638690]). Both groups received prednisone (5 mg PO bid).[41][Level of evidence A1]

Sources: COU-AA-301 · 41 · Level of evidence A1

Men with metastatic prostate cancer who had biochemical or clinical progression after treatment with docetaxel (N = 1,195) were randomly assigned in a 2:1 ratio to receive either abiraterone acetate (1,000 mg) (n = 797) or placebo (n = 398) by mouth every day (COU-AA-301 [NCT00638690]). Both groups received prednisone (5 mg PO bid).[41][Level of evidence A1]

After a median follow-up of 12.8 months, the trial was stopped when an interim analysis showed an OS advantage in the abiraterone group. The final report of the trial was published after a median follow-up of 20.2 months.

Median OS was 15.8 months in the abiraterone group versus 11.2 months in the placebo group (HRdeath, 0.74; 95% CI, 0.64–0.86; P < .0001).

Compared with placebo, abiraterone was also associated with a delay in median time to deterioration in the FACT-P QOL score (59.9 weeks vs. 36.1 weeks, P < .0001) and a clinically important improvement in QOL in men with functional status impairment at baseline (48% vs. 32%, P < .0001).[42][Level of evidence A3]

Sources: 42 · Level of evidence A3

Enzalutamide increased survival in patients with progressive prostate cancer who previously received ADT and docetaxel. In a double-blind, placebo-controlled trial, 1,129 men were randomly assigned in a 2:1 ratio to receive enzalutamide (160 mg PO qd) versus placebo.[43-46][Levels of evidence A1 and A3]

Sources: 43 · 46 · A1 · A3

Enzalutamide increased survival in patients with progressive prostate cancer who previously received ADT and docetaxel. In a double-blind, placebo-controlled trial, 1,129 men were randomly assigned in a 2:1 ratio to receive enzalutamide (160 mg PO qd) versus placebo.[43-46][Levels of evidence A1 and A3]

After a median follow-up of 14.4 months, the study was stopped at the single-planned interim analysis because improved OS, the primary end point, occurred in the enzalutamide study group (median OS, 18.4 months; 95% CI, 17.3–not-yet-reached vs. 13.6 months; 95% CI, 11.3–15.8; HRdeath, 0.63; 95% CI, 0.53–0.75; P < .001). In addition, QOL, measured by the FACT-P questionnaire, was superior in the enzalutamide arm, as was time to first skeletal-related event.[44,46]

Sources: 44 · 46

A seizure was reported in 5 of the 800 men in the enzalutamide study group versus none in the placebo group; however, the relationship to enzalutamide is not clear. Of the reported seizures, two patients had brain metastases, one patient had just received intravenous (IV) lidocaine, and one seizure was not witnessed.

External-beam radiation therapy (EBRT).

Bone-seeking radionuclides (strontium chloride Sr 89 [89Sr]).

Denosumab (a monoclonal antibody that inhibits osteoclast function).

Pain medication.

Corticosteroids.

Bisphosphonates.

EBRT can be very useful for palliation of bone pain. A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and QOL as multiple fractions (3 Gy × 10), as in the RTOG-9714 trial (NCT00003162).[52,53][Level of evidence A3]

Sources: RTOG-9714 · 52 · 53 · Level of evidence A3

A multicenter randomized trial of a single IV dose of 89Sr (150 MBq: 4 mCi) versus palliative EBRT was done in men with painful bone metastases from prostate cancer despite hormone treatment.[55][Level of evidence A1]; [56]

Sources: 55 · Level of evidence A1 · 56

A multicenter randomized trial of a single IV dose of 89Sr (150 MBq: 4 mCi) versus palliative EBRT was done in men with painful bone metastases from prostate cancer despite hormone treatment.[55][Level of evidence A1]; [56]

Similar subjective pain response rates were shown in both groups: 34.7% for 89Sr versus 33.3% for EBRT alone.

OS was better in the EBRT group than in the 89Sr group (P = .046; median survival, 11.0 months vs. 7.2 months).

No statistically significant differences in time to subjective progression or in PFS were seen.

When used as an adjunct to EBRT, 89Sr was shown to slow disease progression and to reduce analgesic requirements, compared with EBRT alone.

A placebo-controlled randomized trial (NCT00321620) compared denosumab with zoledronic acid for the prevention of skeletal events (pathological fractures, spinal cord compression, or the need for palliative bone radiation or surgery) in men with hormonal therapy-resistant prostate cancer with at least one bone metastasis.[47]

Sources: NCT00321620 · 47

A placebo-controlled randomized trial (NCT00321620) compared denosumab with zoledronic acid for the prevention of skeletal events (pathological fractures, spinal cord compression, or the need for palliative bone radiation or surgery) in men with hormonal therapy-resistant prostate cancer with at least one bone metastasis.[47]

The median time to first on-study skeletal event was 20.7 months in the denosumab group and 17.1 months in the zoledronic acid group (HR, 0.82; 95% CI, 0.71–0.95).

Serious adverse events were reported in 63% of patients who received denosumab versus 60% in patients who received zoledronic acid. The cumulative incidence of osteonecrosis of the jaw was low in both study arms (2% in the denosumab arm vs. 1% in the zoledronic acid arm). There was grade 3 to 4 toxicity and no difference in survival. The incidence of hypocalcemia was higher in the denosumab arm (13% vs. 6%).[57]

Sources: 57

A randomized placebo-controlled trial included 1,432 men with castration-resistant prostate cancer with no evidence of any metastases. Patients were given denosumab (120 mg administered subcutaneously every 4 weeks) to prevent the first evidence of bone metastasis (whether symptomatic or not).[57][Level of evidence B1]

Sources: 57 · Level of evidence B1

A randomized placebo-controlled trial included 1,432 men with castration-resistant prostate cancer with no evidence of any metastases. Patients were given denosumab (120 mg administered subcutaneously every 4 weeks) to prevent the first evidence of bone metastasis (whether symptomatic or not).[57][Level of evidence B1]

After a median follow-up of 20 months, median bone metastasis-free survival was 29.5 versus 25.2 months in the denosumab versus placebo arms (HR, 0.85; 95% CI, 0.73–0.98; P = .028).

Symptomatic bone metastases were reported in 69 (10%) denosumab patients versus 96 (13%) placebo patients (HR, 0.67; 95% CI, 0.49–0.92; P = .01).

There were no differences in OS between the two groups.

Osteonecrosis occurred in 33 (5%) of men on the denosumab arm versus none on the placebo arm. Hypocalcemia occurred in 12 (2%) versus 2 (<1%) men, and urinary retention in 54 (8%) of men on denosumab versus 31 (4%) of men on placebo.

Chemotherapy for hormone-sensitive or hormone-resistant prostate cancer.

Sources: Chemotherapy for hormone-sensitive or hormone-resistant prostate cancer

Immunotherapy.

Sources: Immunotherapy

Radiopharmaceutical therapy.

Sources: Radiopharmaceutical therapy

Radiopharmaceutical therapy.

Alpha emitter radiation therapy.

Sources: Alpha emitter radiation therapy

Beta emitter radiation therapy.

Sources: Beta emitter radiation therapy

Poly (ADP-ribose) polymerase (PARP) inhibitors for men with mCRPC and BRCA1, BRCA2, or ATM variants.

Sources: Poly (ADP-ribose) polymerase (PARP) inhibitors for men with mCRPC and BRCA1, BRCA2, or ATM variants

Poly (ADP-ribose) polymerase (PARP) inhibitors for men with mCRPC and BRCA1, BRCA2, or ATM variants.

Olaparib.

Sources: Olaparib

Hormone therapy with PARP inhibitors for men with mCRPC and BRCA1, BRCA2, or ATM variants.

Sources: Hormone therapy with PARP inhibitors for men with mCRPC and BRCA1, BRCA2, or ATM variants

Hormone therapy with PARP inhibitors for men with mCRPC and BRCA1, BRCA2, or ATM variants.

PARP inhibitors as first-line therapy for men with mCRPC and BRCA1 or BRCA2 variants.

Sources: PARP inhibitors as first-line therapy for men with mCRPC and BRCA1 or BRCA2 variants

PARP inhibitors as first-line therapy for men with mCRPC and variants in homologous recombination repair genes.

Sources: PARP inhibitors as first-line therapy for men with mCRPC and variants in homologous recombination repair genes

A randomized trial showed improved pain control in patients with hormone-resistant prostate cancer treated with mitoxantrone plus prednisone compared with those treated with prednisone alone.[58] Differences in OS or measured global QOL between the two treatments were not statistically significant.

Sources: 58

Docetaxel has been shown to improve OS compared with mitoxantrone. In a randomized trial involving patients with hormone-refractory prostate cancer, docetaxel (75 mg/m2 every 3 weeks) and docetaxel (30 mg/m2 weekly for 5 out of every 6 weeks) were compared with mitoxantrone (12 mg/m2 every 3 weeks). All patients received oral prednisone (5 mg bid). Patients in the docetaxel arms also received high-dose dexamethasone pretreatment for each docetaxel administration (8 mg given at 12 hours, 3 hours, and 1 hour before the 3-week regimen; 8 mg given at 1 hour before the 5 out-of-every-6 weeks' regimen).[59]

Sources: 59

Docetaxel has been shown to improve OS compared with mitoxantrone. In a randomized trial involving patients with hormone-refractory prostate cancer, docetaxel (75 mg/m2 every 3 weeks) and docetaxel (30 mg/m2 weekly for 5 out of every 6 weeks) were compared with mitoxantrone (12 mg/m2 every 3 weeks). All patients received oral prednisone (5 mg bid). Patients in the docetaxel arms also received high-dose dexamethasone pretreatment for each docetaxel administration (8 mg given at 12 hours, 3 hours, and 1 hour before the 3-week regimen; 8 mg given at 1 hour before the 5 out-of-every-6 weeks' regimen).[59]

OS at 3 years was statistically significantly better in the 3-weekly docetaxel arm (18.6%) than in the mitoxantrone arm (13.5%, HRdeath, 0.79; 95% CI, 0.67–0.93).

However, the OS rate for the 5 out-of-every-6 weeks docetaxel regimen was 16.8%, which was not statistically significantly better than mitoxantrone.

QOL was also superior in the docetaxel arms compared with mitoxantrone (P = .009).[60][Levels of evidence A1 and A3]

Sources: 60 · A1 · A3

In another randomized trial involving patients with hormone-refractory prostate cancer, a 3-week regimen of estramustine (280 mg PO tid for days 1 to 5, plus daily warfarin and 325 mg aspirin to prevent vascular thrombosis), and docetaxel (60 mg/m2 IV on day 2, preceded by dexamethasone [20 mg × 3 starting the night before]) was compared with mitoxantrone (12 mg/m2 IV every 3 weeks) plus prednisone (5 mg qd).[61][Level of evidence A1]

Sources: 61 · Level of evidence A1

In another randomized trial involving patients with hormone-refractory prostate cancer, a 3-week regimen of estramustine (280 mg PO tid for days 1 to 5, plus daily warfarin and 325 mg aspirin to prevent vascular thrombosis), and docetaxel (60 mg/m2 IV on day 2, preceded by dexamethasone [20 mg × 3 starting the night before]) was compared with mitoxantrone (12 mg/m2 IV every 3 weeks) plus prednisone (5 mg qd).[61][Level of evidence A1]

After a median follow-up of 32 months, median OS was 17.5 months in the estramustine/docetaxel arm versus 15.6 months in the mitoxantrone arm (HRdeath, 0.80; 95% CI, 0.67–0.97; P = .02).

Global QOL and pain palliation measures were similar in the two treatment arms.[62][Level of evidence A3]

Sources: 62 · Level of evidence A3

A 2-weekly regimen of docetaxel has been compared with a 3-weekly regimen. OS appeared to be better in the 2-week regimen, and hematologic toxicity was less.[63][Level of evidence A1]

Sources: 63 · Level of evidence A1

A 2-weekly regimen of docetaxel has been compared with a 3-weekly regimen. OS appeared to be better in the 2-week regimen, and hematologic toxicity was less.[63][Level of evidence A1]

In the trial, 361 men with metastatic hormone-resistant prostate cancer were randomly assigned to receive docetaxel either in a 2-weekly regimen (50 mg/m2 IV) or a 3-weekly regimen (75 mg/m2 IV) until progression. All patients were also to receive prednisolone (10 mg PO qd) and dexamethasone (7.5–8.0 mg qd), starting the day before and continuing for 1 to 2 days after each docetaxel dose. Fifteen randomly assigned patients (4.2%) were deemed ineligible in retrospect or withdrew consent, and they were dropped from the analysis.

With a median follow-up of 18 months, there was a small difference in time to treatment failure, the primary end point of the study (5.6 months [95% CI, 5.0–6.2] vs. 4.9 months [95% CI, 4.5–5.4]; P = .014). However, there was a larger difference in median OS, a secondary end point, in favor of the 2-week regimen (19.5 months [95% CI, 15.9–23.1] vs. 17.0 months [95% CI, 15.0 –19.1]; P = .02).

There was a lower rate of grade 3 to 4 neutropenia with the 2-week regimen (36% vs. 53%; P < .0001) and a lower rate of febrile neutropenia (4% vs. 14%; P = .001).

In patients with mCRPC and no previous chemotherapy, cabazitaxel and docetaxel appeared to provide similar results with respect to OS.[64]

Sources: 64

In patients with mCRPC and no previous chemotherapy, cabazitaxel and docetaxel appeared to provide similar results with respect to OS.[64]

In the FIRSTANA trial (NCT01308567), 1,168 men with mCRPC were randomly assigned in a 1:1:1 ratio to receive cabazitaxel 20 mg/m2, cabazitaxel 25 mg/m2, or docetaxel 75 mg/m2 IV every 3 weeks (plus prednisone 10 mg PO qd) until disease progression. Median OS was similar across all three study arms and not statistically significantly different (24.5 vs. 25.2 vs. 24.3 months, respectively), with virtually overlapping survival curves.[64][Level of evidence A1]

Sources: FIRSTANA · 64 · Level of evidence A1

However, toxicities varied across the study arms, with adverse event rates of 41.2%, 60.1%, and 46.0%, respectively, which required urgent treatment.

In patients with mCRPC whose disease progressed during or after treatment with docetaxel, cabazitaxel was shown to improve survival compared with mitoxantrone in a randomized trial (NCT00417079).[65] In this trial, 755 such men were treated with prednisone (10 mg PO qd) and randomly assigned to receive either cabazitaxel (25 mg/m2 IV) or mitoxantrone (12 mg/m2 IV) every 3 weeks.[65][Level of evidence A1]

Sources: NCT00417079 · 65 · 65 · Level of evidence A1

In patients with mCRPC whose disease progressed during or after treatment with docetaxel, cabazitaxel was shown to improve survival compared with mitoxantrone in a randomized trial (NCT00417079).[65] In this trial, 755 such men were treated with prednisone (10 mg PO qd) and randomly assigned to receive either cabazitaxel (25 mg/m2 IV) or mitoxantrone (12 mg/m2 IV) every 3 weeks.[65][Level of evidence A1]

Median OS was 15.1 months in the cabazitaxel arm and 12.7 months in the mitoxantrone study arm (HRdeath, 0.70; 95% CI, 0.59–0.83; P < .0001).

A noninferiority-design randomized trial compared cabazitaxel (20 mg/m2 IV every 3 weeks) with cabazitaxel (25 mg/m2 IV every 3 weeks) in a similar population of 1,200 men with mCRPC who had received previous docetaxel. The lower dose of cabazitaxel fulfilled noninferiority criteria with respect to OS (HRdeath, 1.024; upper boundary of CI, 1.184), but with less toxicity.[66][Level of evidence A1]

Sources: 66 · Level of evidence A1

Paclitaxel.

Estramustine/etoposide.

Estramustine/vinblastine.

Estramustine/paclitaxel.

In the largest trial (Immunotherapy for Prostate Adenocarcinoma Treatment: IMPACT trial [NCT00065442]), 512 patients with hormone-refractory metastatic disease were randomly assigned in a 2:1 ratio to receive sipuleucel-T (n = 341) versus placebo (n = 171) by IV in a 60-minute infusion every 2 weeks for a total of 3 doses.[71] Patients with visceral metastases, pathological bone fractures, or ECOG performance status worse than 0–1 were excluded from the study. At documented disease progression, patients in the placebo group could receive, at the physician’s discretion, infusions manufactured with the same specifications as sipuleucel-T but using cells that had been cryopreserved at the time that the placebo was prepared (63.7% of the placebo patients received these transfusions). Time to disease progression and time to development of disease-related pain were the initial primary end points, but the primary end point was changed before unblinding based upon survival differences in two previous trials of similar design (described below).[71][Level of evidence A1]

Sources: IMPACT · 71 · 71 · Level of evidence A1

In the largest trial (Immunotherapy for Prostate Adenocarcinoma Treatment: IMPACT trial [NCT00065442]), 512 patients with hormone-refractory metastatic disease were randomly assigned in a 2:1 ratio to receive sipuleucel-T (n = 341) versus placebo (n = 171) by IV in a 60-minute infusion every 2 weeks for a total of 3 doses.[71] Patients with visceral metastases, pathological bone fractures, or ECOG performance status worse than 0–1 were excluded from the study. At documented disease progression, patients in the placebo group could receive, at the physician’s discretion, infusions manufactured with the same specifications as sipuleucel-T but using cells that had been cryopreserved at the time that the placebo was prepared (63.7% of the placebo patients received these transfusions). Time to disease progression and time to development of disease-related pain were the initial primary end points, but the primary end point was changed before unblinding based upon survival differences in two previous trials of similar design (described below).[71][Level of evidence A1]

After a median follow-up of 34.1 months, the overall mortality was 61.6% in the sipuleucel-T group versus 70.8% in the placebo group (HRdeath, 0.78; 95% CI, 0.61–0.98; P = .03). However, the improved survival was not accompanied by measurable antitumor effects.

There was no difference between the study groups in rate of disease progression. In 2011, the estimated price of sipuleucel-T was $93,000 for a 1-month course of therapy. This translates into an estimated cost of about $276,000 per year-of-life saved.[72]

Sources: 72

The same investigators previously performed two smaller trials (D9901 and D9902A [NCT00005947]) of nearly identical design to the IMPACT trial.[73,74]

Sources: D9901 and D9902A · 73 · 74

The same investigators previously performed two smaller trials (D9901 and D9902A [NCT00005947]) of nearly identical design to the IMPACT trial.[73,74]

The combined results of the two smaller trials, involving a total of 225 patients randomly assigned in a 2:1 ratio of sipuleucel-T to placebo were like those in the IMPACT trial. The HRdeath was 0.67 (95% CI, 0.49–0.91), but the time-to-progression rates were not statistically significantly different.

A randomized comparison of prednisone (5 mg qid) with flutamide (250 mg tid) was conducted in patients with disease progression after androgen ablative therapy (castration or LH-RH agonist).[76]

Sources: 76

A randomized comparison of prednisone (5 mg qid) with flutamide (250 mg tid) was conducted in patients with disease progression after androgen ablative therapy (castration or LH-RH agonist).[76]

Prednisone and flutamide produced similar OS, symptomatic response, PSA response, and time to progression. However, there were statistically significant differences in pain, nausea and vomiting, and diarrhea in patients who received prednisone. For more information, see Cancer Pain, Nausea and Vomiting Related to Cancer Treatment, and Gastrointestinal Complications.

Sources: Cancer Pain · Nausea and Vomiting Related to Cancer Treatment · Gastrointestinal Complications

In a placebo-controlled trial, 921 men with symptomatic castration-resistant prostate cancer, two or more bone metastases, and no known visceral metastases, were randomly assigned in a 2:1 ratio to receive 223Ra at a dose of 50kBq per kg body weight every 4 weeks for six injections versus placebo. All study participants had already received docetaxel, were not healthy enough to receive it, or declined it.[77,78]

Sources: 77 · 78

In a placebo-controlled trial, 921 men with symptomatic castration-resistant prostate cancer, two or more bone metastases, and no known visceral metastases, were randomly assigned in a 2:1 ratio to receive 223Ra at a dose of 50kBq per kg body weight every 4 weeks for six injections versus placebo. All study participants had already received docetaxel, were not healthy enough to receive it, or declined it.[77,78]

Median OS was 14.9 months in the 223Ra study group versus 11.3 months in the placebo groups (HRmortality, 0.70; 95% CI, 0.58–0.83; P < .001).[77][Level of evidence A1]

Sources: 77 · Level of evidence A1

The rates of symptomatic skeletal events (33% vs. 38%) and spinal cord compression (4% vs. 7%) were also statistically significantly improved.

Prospectively measured, QOL was also better in the 223Ra study group (25% vs. 16% had a ≥10 point improvement on a scale of 0 to 156; P = .02).[77][Level of evidence A3]

Sources: 77 · Level of evidence A3

With administration of 223Ra at a dose of 50kBq per kg of body weight every 4 weeks for 6 injections, the side effects were like those of a placebo.

The phase III, international, open label VISION study (NCT03511664) enrolled 831 patients with mCRPC previously treated with androgen receptor-directed therapy as well as taxane-based chemotherapy. Eligible patients were required to have at least one PSMA-positive lesion without a dominant PSMA-negative metastatic lesion, using approved PSMA imaging agents. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 every 6 weeks for four to six cycles plus protocol-permitted standard care or standard care alone. Standard care included abiraterone, enzalutamide, bisphosphonates, radiation therapy, denosumab, and/or glucocorticoids and excluded chemotherapy, immunotherapy, 223Ra, and investigational drugs when the trial was designed (e.g., olaparib). Alternate primary end points included image-based PFS and OS.[79]

Sources: VISION · 79

The phase III, international, open label VISION study (NCT03511664) enrolled 831 patients with mCRPC previously treated with androgen receptor-directed therapy as well as taxane-based chemotherapy. Eligible patients were required to have at least one PSMA-positive lesion without a dominant PSMA-negative metastatic lesion, using approved PSMA imaging agents. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 every 6 weeks for four to six cycles plus protocol-permitted standard care or standard care alone. Standard care included abiraterone, enzalutamide, bisphosphonates, radiation therapy, denosumab, and/or glucocorticoids and excluded chemotherapy, immunotherapy, 223Ra, and investigational drugs when the trial was designed (e.g., olaparib). Alternate primary end points included image-based PFS and OS.[79]

The median follow-up was 20.9 months. The median image-based PFS was 8.7 months in the 177Lu-PSMA-617-plus-standard care group and 3.4 months in the standard care-alone group (HRprogression or death, 0.40; 99.2% CI, 0.29–0.57; P < .001). The median OS was 15.3 months in the 177Lu-PSMA-617-plus-standard care group and 11.3 months in the standard care-alone group (HRdeath, 0.62; 95% CI, 0.52–0.74; P < .001).[79][Level of evidence A1]

Sources: 79 · Level of evidence A1

All key secondary end points significantly favored the 177Lu-PSMA-617-plus-standard care group, including median time to first symptomatic skeletal event or death (11.5 months vs. 6.8 months; HR, 0.50; 95% CI, 0.40–0.62; P < .001).

The most common adverse events in the 177Lu-PSMA-617-plus-standard care group were fatigue, dry mouth, and nausea, nearly all of which were grade 1 or 2 in severity. Grade 3 or higher adverse events occurred in 52.7% of patients in the 177Lu-PSMA-617-plus-standard care group and 38% of patients in the standard care-alone group. The most common grade 3 or higher adverse event in the 177Lu-PSMA-617-plus-standard care group was anemia (12.9% vs. 4.9% in the standard care-alone group).

There was delayed worsening of heath-related QOL in the 177Lu-PSMA-617-plus-standard care group versus the standard care-alone group, including FACT-P scores (HR, 0.54; 0.45–0.66), BPI-SF pain intensity scores (HR, 0.52; 0.42–0.63), and EQ-5D-5L utility scores (HR, 0.65; 0.54–0.78).[80]

Sources: 80

The PARP inhibitor olaparib was tested in an open-label, phase III, randomized controlled trial in men with mCRPC and variants in one of 15 prespecified homologous recombination repair genes, including BRCA1 or BRCA2. The men had previously received enzalutamide, abiraterone, or both, with or without previous taxane chemotherapy.[81] The trial enrolled 387 men and randomly assigned them in a 2:1 ratio to receive olaparib (300 mg twice daily) or physician's choice of enzalutamide or abiraterone plus prednisone. Cohort A included 245 patients with at least one variant in BRCA1, BRCA2, or ATM. Cohort B included 142 patients with at least one variant in one of the other 12 prespecified genes.

Sources: 81

The PARP inhibitor olaparib was tested in an open-label, phase III, randomized controlled trial in men with mCRPC and variants in one of 15 prespecified homologous recombination repair genes, including BRCA1 or BRCA2. The men had previously received enzalutamide, abiraterone, or both, with or without previous taxane chemotherapy.[81] The trial enrolled 387 men and randomly assigned them in a 2:1 ratio to receive olaparib (300 mg twice daily) or physician's choice of enzalutamide or abiraterone plus prednisone. Cohort A included 245 patients with at least one variant in BRCA1, BRCA2, or ATM. Cohort B included 142 patients with at least one variant in one of the other 12 prespecified genes.

The median OS in cohort A was 19.1 months for patients who received olaparib and 14.7 months for patients who received the control regimen (HR, 0.69; 95% CI, 0.50–0.97). A sensitivity analysis adjusting for crossover to olaparib in the control arm reported an HR of 0.42 (95% CI, 0.19–0.91).

There was no significant OS benefit in cohort B.

There was no significant OS benefit in the overall population.

The most common adverse events for patients who received olaparib were anemia (50%), nausea (43%), and fatigue or asthenia (42%).

The phase III, randomized, double-blinded, PROpel trial (NCT03732820) studied the PARP inhibitor olaparib with abiraterone and prednisone (or prednisolone) as first-line treatment in patients with mCRPC. In the trial, 796 patients were randomly assigned in a 1:1 ratio to receive either (1) olaparib (300 mg twice daily) with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily) or (2) placebo with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily). Prior systemic therapy for mCRPC was excluded, but prior docetaxel for metastatic hormone-sensitive prostate cancer was allowed. The presence of variants in tumor homologous recombination repair genes (including BRCA) was determined retrospectively using both tumor tissue and circulating tumor DNA (ctDNA). The study design did not prospectively evaluate variants in homologous recombination repair genes or BRCA, nor did it stratify randomization by biomarker status. The primary end point was investigator-assessed radiographic PFS.[82]

Sources: PROpel · 82

The phase III, randomized, double-blinded, PROpel trial (NCT03732820) studied the PARP inhibitor olaparib with abiraterone and prednisone (or prednisolone) as first-line treatment in patients with mCRPC. In the trial, 796 patients were randomly assigned in a 1:1 ratio to receive either (1) olaparib (300 mg twice daily) with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily) or (2) placebo with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily). Prior systemic therapy for mCRPC was excluded, but prior docetaxel for metastatic hormone-sensitive prostate cancer was allowed. The presence of variants in tumor homologous recombination repair genes (including BRCA) was determined retrospectively using both tumor tissue and circulating tumor DNA (ctDNA). The study design did not prospectively evaluate variants in homologous recombination repair genes or BRCA, nor did it stratify randomization by biomarker status. The primary end point was investigator-assessed radiographic PFS.[82]

In the intent-to-treat (ITT) population, the median radiographic PFS was 24.8 months in the olaparib group and 16.6 months in the placebo group (HR, 0.66; 95% CI, 0.54–0.81).

In an exploratory analysis of the subset of patients with BRCA-altered disease (n = 85, 11% of the ITT population), the observed median radiographic PFS was not reached in the olaparib group and was 8 months in the placebo group (HRradiographic PFS,0.24; 95% CI, 0.12–0.45; and HROS, 0.30; 95% CI, 0.74–1.14).[82,83][Level of evidence B1]

Sources: 82 · 83 · Level of evidence B1

Data from the exploratory analysis suggested that the radiographic PFS benefit in the ITT population was primarily attributable to BRCA-altered status. Therefore, the FDA has only approved this drug for patients with BRCA-altered disease.

OS, a key secondary end point, was not significantly different between treatment groups at the final prespecified analysis. Median OS was 42.1 months in the olaparib group and 36.5 months in the placebo group (HR, 0.81; 95% CI, 0.67–1.00; P = .054).[84]

Sources: 84

Grade 3 or higher adverse events occurred in 41% of patients in the olaparib group and 34% of patients in the placebo group. Anemia was the most common grade 3 or higher adverse event (occurring in 3% of patients in the olaparib group and 16% of patients in the placebo group). Of the patients with anemia who required at least one blood transfusion, 18% were in the olaparib group and 4% were in the placebo group.

FACT-P questionnaire scores were similar between treatment groups, indicating no significant detriment to patients' health-related QOL with the addition of olaparib with abiraterone.

The combination of a PARP inhibitor, talazoparib, with enzalutamide was tested in the phase III, double-blind, randomized, multicohort TALAPRO-2 study (NCT03395197) as first-line therapy in men with mCRPC. The trial enrolled two cohorts in which patients were prospectively assessed for variants in homologous recombination repair genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11, NBN, PALB2, and RAD51C) in tumor tissue and/or ctDNA. Patients were randomly assigned in a 1:1 ratio to receive either talazoparib (0.5 mg once daily) or placebo with enzalutamide (160 mg once daily). Prior systemic therapy for mCRPC was excluded. Prior docetaxel and abiraterone for metastatic castration-sensitive prostate cancer was permitted. Results from combined cohorts of the homologous recombination repair gene-altered population included 399 patients. The primary end point was radiographic PFS.[85,86]

Sources: TALAPRO-2 · 85 · 86

The combination of a PARP inhibitor, talazoparib, with enzalutamide was tested in the phase III, double-blind, randomized, multicohort TALAPRO-2 study (NCT03395197) as first-line therapy in men with mCRPC. The trial enrolled two cohorts in which patients were prospectively assessed for variants in homologous recombination repair genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11, NBN, PALB2, and RAD51C) in tumor tissue and/or ctDNA. Patients were randomly assigned in a 1:1 ratio to receive either talazoparib (0.5 mg once daily) or placebo with enzalutamide (160 mg once daily). Prior systemic therapy for mCRPC was excluded. Prior docetaxel and abiraterone for metastatic castration-sensitive prostate cancer was permitted. Results from combined cohorts of the homologous recombination repair gene-altered population included 399 patients. The primary end point was radiographic PFS.[85,86]

The median radiographic PFS was not reached in the talazoparib-with-enzalutamide group and was 13.8 months in the placebo-with-enzalutamide group (HR, 0.45; 95% CI, 0.33–0.61; P < .0001). In patients with BRCA-altered mCRPC (n = 155) the HRradiographic PFS was 0.20 (95% CI, 0.11–0.36). The median follow-up for radiographic PFS was 17.5 months in the talazoparib group and 16.8 months in the placebo group.[85,86][Level of evidence B1]

Sources: 85 · 86 · Level of evidence B1

Grade 3 or higher adverse events occurred in 68% of patients in the talazoparib-with-enzalutamide group and 40% of patients in the placebo-with-enzalutamide group.

The most common grade 3 or higher adverse event was anemia (41% in the talazoparib group and 5% in the placebo group). Thirty-nine percent of patients in the talazoparib group required a blood transfusion.

Talazoparib with enzalutamide significantly prolonged time to definitive, clinically meaningful deterioration versus placebo with enzalutamide (HR, 0.69; 95% CI, 0.49–0.97; P = .032).

The stage of the cancer (level of PSA, Gleason score, Grade Group, how much of the prostate is affected by the cancer, and whether the cancer has spread to other places in the body).

Sources: stage · Grade Group

The patient's age.

Whether the cancer has just been diagnosed or has recurred (come back).

Sources: recurred

Whether the patient has other health problems.

The expected side effects of treatment.

Sources: side effects

Past treatment for prostate cancer.

The wishes of the patient.

There are different types of treatment for people with prostate cancer.

The following types of treatment are used:

The following types of treatment are used:

Watchful waiting or active surveillance

Surgery

Radiation therapy and radiopharmaceutical therapy

Hormone therapy

Chemotherapy

Targeted therapy

Immunotherapy

Bisphosphonate therapy

There are treatments for bone pain caused by bone metastases or hormone therapy.

New types of treatment are being tested in clinical trials.

New types of treatment are being tested in clinical trials.

Cryosurgery

High-intensity focused ultrasound therapy

Proton beam radiation therapy

Photodynamic therapy

Treatment for prostate cancer may cause side effects.

Patients may want to think about taking part in a clinical trial.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Follow-up care may be needed.

Radical prostatectomy: A surgical procedure to remove the prostate, surrounding tissue, and seminal vesicles. Removal of nearby lymph nodes may be done at the same time. The main types of radical prostatectomy include:

Sources: Radical prostatectomy · tissue · seminal vesicles · lymph nodes

Radical prostatectomy: A surgical procedure to remove the prostate, surrounding tissue, and seminal vesicles. Removal of nearby lymph nodes may be done at the same time. The main types of radical prostatectomy include:

Open radical prostatectomy: An incision (cut) is made in the retropubic area (lower abdomen) or the perineum (the area between the anus and scrotum). Surgery is performed through the incision. It is harder for the surgeon to spare the nerves near the prostate or to remove nearby lymph nodes with the perineum approach.

Sources: Open radical prostatectomy · incision · abdomen · perineum · anus · scrotum · nerves

Radical laparoscopic prostatectomy: Several small incisions (cuts) are made in the wall of the abdomen. A laparoscope (a thin, tube-like instrument with a light and lens for viewing) is inserted through one opening to guide the surgery. Surgical instruments are inserted through the other openings to do the surgery.

Sources: Radical laparoscopic prostatectomy · laparoscope · lens

Robot-assisted laparoscopic radical prostatectomy: Several small cuts are made in the wall of the abdomen, as in regular laparoscopic prostatectomy. The surgeon inserts an instrument with a camera through one of the openings and surgical instruments through the other openings using robotic arms. The camera gives the surgeon a 3-dimensional view of the prostate and surrounding structures. The surgeon uses the robotic arms to do the surgery while sitting at a computer monitor near the operating table.

Sources: Robot-assisted laparoscopic radical prostatectomy · 3-dimensional

Pelvic lymphadenectomy: A surgical procedure to remove the lymph nodes in the pelvis. A pathologist views the tissue under a microscope to look for cancer cells. If the lymph nodes contain cancer, the doctor will not remove the prostate and may recommend other treatment.

Sources: Pelvic lymphadenectomy · pelvis · pathologist · microscope · cells

Transurethral resection of the prostate (TURP): A surgical procedure to remove tissue from the prostate using a resectoscope (a thin, lighted tube with a cutting tool) inserted through the urethra. This procedure is done to treat benign prostatic hypertrophy and it is sometimes done to relieve symptoms caused by a tumor before other cancer treatment is given. TURP may also be done in men whose tumor is in the prostate only and who cannot have a radical prostatectomy.

Sources: Transurethral resection of the prostate · resectoscope · urethra · benign prostatic hypertrophy

Impotence.

Sources: Impotence

Leakage of urine from the bladder or stool from the rectum.

Sources: urine · bladder · stool · rectum

Shortening of the penis (1 to 2 centimeters). The exact reason for this is not known.

Sources: penis · centimeters

Inguinal hernia (bulging of fat or part of the small intestine through weak muscles into the groin). Inguinal hernia may occur more often in men treated with radical prostatectomy than in men who have some other types of prostate surgery, radiation therapy, or prostate biopsy alone. It is most likely to occur within the first 2 years after radical prostatectomy.

Sources: hernia · small intestine · groin · radiation therapy · biopsy

External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Conformal radiation is a type of external radiation therapy that uses a computer to make a 3-dimensional (3-D) picture of the tumor and shapes the radiation beams to fit the tumor. This allows a high dose of radiation to reach the tumor and causes less damage to nearby healthy tissue.Hypofractionated radiation therapy may be given because it has a more convenient treatment schedule. Hypofractionated radiation therapy is radiation treatment in which a larger than usual total dose of radiation is given once a day over a shorter period of time (fewer days) compared to standard radiation therapy. Hypofractionated radiation therapy may have worse side effects than standard radiation therapy, depending on the schedules used.

Sources: External radiation therapy · Conformal radiation · 3-dimensional · Hypofractionated radiation therapy · dose · side effects

Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. In early-stage prostate cancer, the radioactive seeds are placed in the prostate using needles that are inserted through the skin between the scrotum and rectum. The placement of the radioactive seeds in the prostate is guided by images from transrectal ultrasound or computed tomography (CT). The needles are removed after the radioactive seeds are placed in the prostate.

Sources: Internal radiation therapy · radioactive · seeds · catheters · early-stage · transrectal ultrasound · computed tomography

Radiopharmaceutical therapy uses a radioactive substance to treat cancer. Radiopharmaceutical therapy includes:

Sources: Radiopharmaceutical · therapy · radioactive

Radiopharmaceutical therapy uses a radioactive substance to treat cancer. Radiopharmaceutical therapy includes:

Alpha emitter radiation therapy uses a radioactive substance to treat prostate cancer that has spread to the bone. A radioactive substance called radium-223 is injected into a vein and travels through the bloodstream. The radium-223 collects in areas of bone with cancer and kills the cancer cells.

Sources: Alpha emitter radiation therapy · radium-223 · injected · vein

Abiraterone acetate can prevent prostate cancer cells from making androgens. It is used in men with advanced prostate cancer that has not gotten better with other hormone therapy. It is also used in men with high-risk prostate cancer that has improved with treatments that lower hormone levels.

Sources: Abiraterone acetate · androgens · advanced · high-risk

Orchiectomy is a surgical procedure to remove one or both testicles, the main source of male hormones, such as testosterone, to decrease the amount of hormone being made.

Sources: Orchiectomy · testicles · testosterone

Estrogens (hormones that promote female sex characteristics) can prevent the testicles from making testosterone. However, estrogens are seldom used today in the treatment of prostate cancer because of the risk of serious side effects.

Sources: Estrogens

Luteinizing hormone-releasing hormone agonists can stop the testicles from making testosterone. Examples are leuprolide, goserelin, and buserelin.

Sources: Luteinizing hormone-releasing hormone agonists · leuprolide · goserelin · buserelin

Antiandrogens can block the action of androgens (hormones that promote male sex characteristics), such as testosterone. Examples are flutamide, bicalutamide, enzalutamide, apalutamide, nilutamide, and darolutamide.

Sources: Antiandrogens · flutamide · bicalutamide · enzalutamide · apalutamide · nilutamide · darolutamide

Drugs that can prevent the adrenal glands from making androgens include ketoconazole, aminoglutethimide, hydrocortisone, and progesterone.

Sources: adrenal glands · ketoconazole · aminoglutethimide · hydrocortisone · progesterone

PARP inhibitors block an enzyme involved in many cell functions, including the repair of DNA damage. Blocking this enzyme may help keep cancer cells from repairing their damaged DNA, causing them to die. Olaparib is a PARP inhibitor used to treat patients with prostate cancer that has spread to other parts of the body and has mutations in certain genes, such as BRCA1 or BRCA2.

Sources: PARP inhibitors · enzyme · DNA · Olaparib · mutations · genes · BRCA1 · BRCA2

Pain medicine.

Sources: medicine

External radiation therapy.

Strontium-89 (a radioisotope).

Sources: Strontium-89 · radioisotope

Targeted therapy with a monoclonal antibody, such as denosumab.

Sources: Targeted therapy · monoclonal antibody · denosumab

Bisphosphonate therapy.

Corticosteroids.

Sources: Corticosteroids

Watchful waiting.

Sources: Watchful waiting

Active surveillance. If the cancer begins to grow, hormone therapy may be given.

Sources: Active surveillance · cancer · hormone therapy

Radical prostatectomy, usually with pelvic lymphadenectomy. Radiation therapy may be given after surgery.

Sources: Radical prostatectomy · pelvic · lymphadenectomy · Radiation therapy · surgery

External radiation therapy. Hormone therapy may be given after radiation therapy.

Sources: External radiation therapy

Internal radiation therapy with radioactive seeds.

Sources: Internal radiation therapy · radioactive seeds

Watchful waiting.

Sources: Watchful waiting

Active surveillance. If the cancer begins to grow, hormone therapy may be given.

Sources: Active surveillance · cancer · hormone therapy

Radical prostatectomy, usually with pelvic lymphadenectomy. Radiation therapy may be given after surgery.

Sources: Radical prostatectomy · pelvic lymphadenectomy · Radiation therapy · surgery

External radiation therapy. Hormone therapy may be given after radiation therapy.

Sources: External radiation therapy

Internal radiation therapy with radioactive seeds.

Sources: Internal radiation therapy · radioactive seeds

External radiation therapy. Hormone therapy may be given after radiation therapy.

Sources: External radiation therapy · Hormone therapy · radiation therapy

Hormone therapy. Radiation therapy may be given after hormone therapy.

Radical prostatectomy. Radiation therapy may be given after surgery.

Sources: Radical prostatectomy · surgery

Watchful waiting.

Sources: Watchful waiting

Active surveillance. If the cancer begins to grow, hormone therapy may be given.

Sources: Active surveillance · cancer

External radiation therapy.

Internal radiation therapy with radioactive seeds.

Sources: Internal radiation therapy · radioactive seeds

Hormone therapy.

Transurethral resection of the prostate (TURP).

Sources: Transurethral resection of the prostate

Hormone therapy.

Sources: Hormone therapy

Hormone therapy combined with chemotherapy.

Sources: chemotherapy

Bisphosphonate therapy.

Sources: Bisphosphonate

External radiation therapy. Hormone therapy may be given after radiation therapy.

Sources: External radiation therapy · radiation therapy

Alpha emitter radiation therapy.

Sources: Alpha emitter radiation therapy

Watchful waiting.

Sources: Watchful waiting

Active surveillance. If the cancer begins to grow, hormone therapy may be given.

Sources: Active surveillance · cancer

Transurethral resection of the prostate (TURP).

Sources: Transurethral resection of the prostate

Radiation therapy.

Hormone therapy.

Sources: Hormone therapy

Chemotherapy for patients already treated with hormone therapy.

Sources: Chemotherapy

Immunotherapy with sipuleucel-T for patients already treated with hormone therapy.

Sources: Immunotherapy · sipuleucel-T

External radiation therapy.

Sources: External radiation therapy

Prostatectomy for patients already treated with radiation therapy.

Sources: Prostatectomy · radiation therapy

Alpha emitter radiation therapy.

Sources: Alpha emitter radiation therapy

PARP inhibitor therapy for patients already treated with hormone therapy who have mutations in certain genes, such as BRCA1 or BRCA2.

Sources: PARP inhibitor · mutations · genes