martes, 24 de septiembre de 2019

Prostate Cancer Treatment (PDQ®) 8/8 –Health Professional Version - National Cancer Institute

Prostate Cancer Treatment (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Prostate Cancer Treatment (PDQ®)–Health Professional Version

Recurrent or Hormone-Resistant Prostate Cancer Treatment

Overview

In recurrent or hormone-resistant prostate cancer, the selection of further treatment depends on many factors, including the following:
  • Previous treatment.
  • Site of recurrence.
  • Coexistent illnesses.
  • Individual patient considerations.
Definitive radiation therapy can be given to patients with disease that fails only locally after prostatectomy.[1-4] A randomized trial (RTOG-9601 [NCT00002874]) has shown improved overall survival (OS) and prostate–cancer-specific survival with the addition of high-dose bicalutamide to radiation therapy compared with radiation therapy alone in men with locally recurrent prostate cancer after radical prostatectomy.[5]
  • 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 (P = .04; hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.59–0.99).[5][Level of evidence: 1iA]
  • 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: 1iB]
  • Most treatment-related toxicities were similar between the two groups, except for gynecomastia, which occurred in 69.7% of the men on bicalutamide versus 10.9% of those on placebo. This side effect may be mitigated by prophylactic breast irradiation, which was not used in this study because of the double-blinded design.
Some patients with a local recurrence after definitive radiation therapy can be salvaged with prostatectomy;[6] however, only about 10% of patients treated initially with radiation therapy will have local relapse only. In these patients, prolonged disease control is often possible with hormonal therapy, with median cancer-specific survival of 6 years after local failure.[7]
Cryosurgical ablation of recurrence after radiation therapy is associated frequently with a high complication rate. This technique is still undergoing clinical evaluation.[8]
Hormonal therapy is used to manage most relapsing patients with disseminated disease who initially received locoregional therapy with surgery or radiation therapy. (Refer to the Standard Treatment Options for Stage IV Prostate Cancer section of this summary for more information.)

Immediate Versus Deferred Hormonal Therapy

Refer to the Treatment Option Overview for Prostate Cancer section for information on the use of immediate hormonal therapy (bicalutamide or luteinizing hormone-releasing hormone [LH-RH] agonists) plus radiation in the setting of locally recurrent prostate cancer after radical prostatectomy.
PSA is often used to monitor patients after initial therapy with curative intent, and elevated or rising PSA is a common trigger for additional therapy even in asymptomatic men. Despite how common the situation is, it is not clear whether additional treatments given because of rising PSA in asymptomatic men with prostate cancer increase OS. The quality of evidence is limited.
  1. 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.
  2. 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]
  3. A randomized trial (PMCC-VCOG-PR-0103 [NCT00110162]) of androgen deprivation therapy (ADT) in men who received curative therapy but have a rising PSA, provides some evidence of improved OS associated with immediate versus delayed therapy.[16] The study had important shortcomings.
    1. Two groups of men were randomly assigned to open-label, immediate-versus-delayed (at least 2-year delay) ADT:
      • 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).
      Planned accrual was 750 patients, but because of slow accrual, the trial closed at 293 patients.
    2. 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: 1iiA] After full adjustment for baseline characteristics, the HR for OS was 0.54 (95% CI, 0.27–1.06; P = .074).
    3. 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).
    4. 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); but 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]

Hormonal Therapy for Recurring Disease

Continuous versus intermittent hormonal therapy

Most men who are treated for recurrence after initial local therapy are asymptomatic, and the recurrence is detected by a rising PSA. It is possible that intermittent androgen deprivation (IAD) therapy can be used as an alternative to continuous androgen deprivation therapy (continuous ADT, or CAD) to improve QOL and decrease the amount of time during which the patient experiences the side effects of hormonal therapy, without decreasing the survival rate.
  1. 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: 1iiA, 1iiB, 1iiC]
    • 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 = 0.24). 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 does not address the unanswered question about 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 only 14% of all patients died of prostate cancer.
  2. A systematic review of 15 randomized trials that compared CAD 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 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: 1iiA] 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.

Nonsteroidal antiandrogen monotherapy versus surgical or medical castration

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.[20] The use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[20][Level of evidence: 1iiA]

Hormonal approaches

As noted above, studies have shown that chemotherapy with docetaxel or cabazitaxel and immunotherapy with sipuleucel-T can prolong OS in patients with hormone-resistant metastatic prostate cancer. Nevertheless, hormonal therapy has also been shown to improve survival even in men who have progressed after other forms of hormonal therapy as well as chemotherapy. Some forms of hormonal therapy are effective in the management of metastatic hormone–refractory prostate cancer.
Because there are no head-to-head comparisons, there are no trials to help decide which of these agents should be used first or in what sequence they should be used.
Even among patients with metastatic hormone-refractory prostate cancer, some heterogeneity is found in prognosis and in retained hormone sensitivity. In such patients who have symptomatic bone disease, several factors are associated with worsened prognosis: poor performance status, elevated alkaline phosphatase, abnormal serum creatinine, and short (<1 year) previous response to hormonal therapy.[21] The absolute level of PSA at the initiation of therapy in relapsed or hormone-refractory patients has not been shown to be of prognostic significance.[22]
Some patients whose disease has progressed on combined androgen blockade can respond to a variety of second-line hormonal therapies. Aminoglutethimide, hydrocortisone, flutamide withdrawal, progesterone, ketoconazole, and combinations of these therapies have produced PSA responses in 14% to 60% of patients treated and have also produced clinical responses of 0% to 25% when assessed. The duration of these PSA responses has ranged from 2 to 4 months.[23] Survival rates are similar whether ketoconazole plus hydrocortisone is initiated at the same time as antiandrogen (e.g., flutamide, bicalutamide, or nilutamide) withdrawal or when PSA has risen after an initial trial of antiandrogen withdrawal, as seen in the CLB-9583 trial (NCT00002760), for example.[24][Level of evidence: 1iiA] There are conflicting data on whether PSA changes in men undergoing chemotherapy are predictive of survival.[22,25]
Patients treated with either luteinizing-hormone agonists or estrogens as primary therapy are generally maintained with castrate levels of testosterone. One study from the Eastern Cooperative Oncology Group (ECOG) showed that a superior survival resulted when patients were maintained on primary androgen deprivation;[9] however, another study from SWOG (formerly the Southwest Oncology Group) did not show an advantage to continued androgen blockade.[26]
Evidence (hormonal approaches for progressive disease with no previous chemotherapy):
  1. 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.[27] 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.[28,29][Level of evidence: 1iA] The coprimary endpoints were radiologic 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 radiologic 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% had died in the abiraterone-acetate study arm and 71% had died in the placebo study arm (HR, 0.81; 95% CI, 0.70–0.93: P = .033). Median OS was 34.7 versus 30.3 months.[29][Level of evidence: 1iA]
    • 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).[30][Level of evidence: 1iC]
    • 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.[28,30][Levels of evidence: 1iC and 1iDiii]
  2. Enzalutamide, an androgen-receptor signaling inhibitor, has been shown to increase OS and QOL in men with metastatic prostate cancer that has progressed despite ADT. In the PREVAIL (NCT01212991) study, 1,717 asymptomatic or mildly symptomatic men with recurrent metastatic prostate cancer despite ADT were randomly assigned to receive enzalutamide (160 mg PO qd) versus placebo.[31-33][Levels of evidence: 1iA, 1iC]
    • 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 versus 5.6 months in the enzalutamide and placebo groups (P < .001), and delayed occurrence of first skeletal-related event requiring clinical intervention was also shown.[31,32][Levels of evidence: 1iC, 1iDi]
    • 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.
  3. Enzalutamide has also been tested in the setting of clinically nonmetastatic, hormone-resistant prostate cancer (defined as PSA doubling time ≤10 months while undergoing hormonal therapy).[34]
    • 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 endpoint, metastasis-free survival: 77% versus 51% (median 36.6 vs. 14.7 months; HR, 0.29; 95% CI, 0.24–0.35; P < .001).[34][Level of evidence: 1iDiii]
    • 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 quality of life was the same in both arms.
    • Grade 3+ toxicities were more common in the enzalutamide group: 31% versus 23%.
    • There were also excesses in several adverse events of special interest because they have been reported previously in patients treated with enzalutamide, including hypertension (12% vs. 5%), major cardiovascular events (5% vs. 3%), and mental impairment disorders (5% vs. 2%).
  4. Continuing enzalutamide in patients who were switched to abiraterone because of progression, and who had castration-resistant metastatic prostate cancer and a rising PSA while receiving enzalutamide, did not appear to improve the rate of PFS or of clinical progression, a strategy that was tested in the randomized PLATO trial (NCT01995513).[35][Level of evidence: 1iDiii]
  5. Apalutamide, a competitive inhibitor of the androgen receptor, has been tested in the setting of clinically nonmetastatic, hormone-resistant prostate cancer (defined as PSA doubling time ≤10 months while undergoing hormonal therapy).[36]
    • In the trial, 1,207 men were randomly assigned in a 2:1 ratio to either daily apalutamide (240 mg PO) or a placebo. All 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 on placebo (HR, 0.28; 95% CI, 0.23–0.35; P < .001).[36][Level of evidence: 1iDii]
    • 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, quality of life over time was similar in the apalutamide and placebo arms, as assessed overall and for all component subscale scores of the FACT-P and EuroQol five-dimension, three-level (EQ-5D-3L) questionnaires.[37][Level of evidence: 1iC]
Evidence (hormonal approaches for progressive disease with previous chemotherapy):
  1. 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).[38][Level of evidence; 1iA]
    • 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 delay in median time to deterioration in the FACT-P QOL score (59.9 weeks vs. 36.1 weeks, P < .0001) and clinically important improvement in QOL in men with functional status impairment at baseline (48% vs. 32%, P < .0001).[39][Level of evidence: 1iC]
  2. Enzalutamide has also been shown to increase survival in patients with progressive prostate cancer who previously received ADT as well as 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.[40-43][Levels of evidence: 1iA, 1iC]
    • After a median follow-up of 14.4 months, the study was stopped at the single-planned interim analysis because improved OS, the primary endpoint, was found 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.[41,43]
    • 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.

Prevention of bone metastases

Painful bone metastases can be a major problem for patients with prostate cancer. Many strategies have been studied for palliation, including the following:[44-48]
  • 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.
(Refer to the PDQ summary on Cancer Pain for more information.)
Evidence (palliation for bone metastases using radiation therapy):
  1. EBRT for palliation of bone pain can be very useful. 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) was seen in the RTOG-9714 trial (NCT00003162), for example.[49,50][Level of evidence: 1iiC]
Evidence (palliation for bone metastases using strontium chloride):
The use of radioisotopes such as 89Sr has been shown to be effective as palliative treatment of some patients with osteoblastic metastases. As a single agent, 89Sr has been reported to decrease bone pain in 80% of patients treated.[51]
  1. 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.[52][Level of evidence: 1iiA]; [53]
    • 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.
Evidence (palliation or prevention of bone metastases using denosumab):
  1. A placebo-controlled randomized trial (NCT00321620) compared denosumab with zoledronic acid for the prevention of skeletal events (pathologic 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.[44]
    • The trial reported that denosumab was more effective than zoledronic acid; median time to first on-study skeletal event was 20.7 versus 17.1 months (HR, 0.82; 95% CI, 0.71–0.95).
    • Serious adverse events were reported in 63% of denosumab patients versus 60% in patients on 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. There was no difference in survival. The incidence of hypocalcemia was higher in the denosumab arm (13% vs. 6%).[54]
  2. A randomized, placebo-controlled trial included 1,432 men with castration-resistant prostate cancer with no evidence of any metastases who were given denosumab (120 mg administered subcutaneously every 4 weeks) to prevent the first evidence of bone metastasis (whether symptomatic or not).[54][Level of Evidence: 1iDiii]
    • 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.

Treatment Options for Recurrent Prostate Cancer

Treatment options for patients with recurrent prostate cancer include the following:

Chemotherapy for hormone-resistant prostate cancer

Evidence (chemotherapy for hormone-resistant prostate cancer):
  1. 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.[55] Differences in OS or measured global QOL between the two treatments were not statistically significant.
  2. 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).[56]
    • 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).[57][Levels of evidence: 1iiA, 1iiC]
  3. 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).[58][Level of evidence: 1iiA]
    • 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.[59][Level of evidence: 1iiC]
  4. 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.[60][Level of evidence: 1iiA]
    • 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 thought to be 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 endpoint 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 endpoint, 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).
  5. In patients with metastatic hormone/castrate-refractory prostate cancer (mCRPC) and no previous chemotherapy, cabazitaxel and docetaxel appeared to provide similar results with respect to OS.[61]
    • In the FIRSTANA trial (NCT01308567), 1,168 men with mCRPC were randomly assigned (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.[61][Level of evidence; 1iiA]
    • However, toxicities varied across the study arms, with adverse event rates of 41.2%, 60.1%, and 46.0%, respectively, which required urgent treatment.
  6. 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).[62] 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.[62][Level of evidence; 1iiA]
    • 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).
  7. In a noninferiority-design randomized trial comparing 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; CI, upper bound at 1.184), but with less toxicity.[63][Level of evidence; 1iiA]
Other chemotherapy regimens reported to produce subjective improvement in symptoms and reduction in PSA level include the following:[64][Level of evidence: 3iiiDiii]; [65]
  • Paclitaxel.
  • Estramustine/etoposide.
  • Estramustine/vinblastine.
  • Estramustine/paclitaxel.
A study suggests that patients whose tumors exhibit neuroendocrine differentiation are more responsive to chemotherapy.[66]

Immunotherapy

Sipuleucel-T, an active cellular immunotherapy, has been shown to increase OS in patients with hormone-refractory metastatic prostate cancer. Sipuleucel-T consists of autologous peripheral blood mononuclear cells that have been exposed ex vivo to a recombinant fusion protein (PA2024) composed of prostatic acid phosphatase fused to granulocyte-macrophage colony-stimulating factor.
Side effects are generally consistent with cytokine release and include chills, fever, headache, myalgia, sweating, and influenza-like symptoms, usually within the first 24 hours of infusion. No increase in autoimmune disorders or secondary malignancies has been noted.[67]
Evidence (immunotherapy):
  1. 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.[68] Patients with visceral metastases, pathologic 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 endpoints, but the primary endpoint was changed before unblinding based upon survival differences in two previous trials of similar design (described below).[68][Level of evidence: 1iA]
    • 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.[69]
  2. The same investigators previously performed two smaller trials (D9901 and D9902A [NCT00005947]) of nearly identical design to the IMPACT trial.[70,71]
    • 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.
Low-dose prednisone may palliate symptoms in some patients.[72]
Evidence (low-dose prednisone for palliation):
  1. 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).[73]
    • 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. (Refer to the PDQ summaries on Cancer Pain and Treatment-Related Nausea and Vomiting; refer to the PDQ summary on Gastrointestinal Complications for information on diarrhea.)
Ongoing clinical trials continue to explore the value of chemotherapy for these patients.[10-13,55,64-66]

Radiopharmaceutical Therapy

Alpha emitter radiation

Radium Ra 223 (223Ra) emits alpha particles (i.e., two protons and two neutrons bound together, identical to a helium nucleus) with a half-life of 11.4 days. It is administered by IV and selectively taken up by newly formed bone stroma. The high-energy alpha particles have a short range of <100 mcM. 223Ra improved OS in patients with prostate cancer metastatic to the bone.
Evidence (alpha emitter radiation):
  1. 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.[74,75]
    • 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).[74][Level of evidence: 1iA]
    • 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).[74][Level of evidence: 1iC]
    • 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.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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  33. Beer TM, Armstrong AJ, Rathkopf D, et al.: Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol 71 (2): 151-154, 2017. [PUBMED Abstract]
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  35. Attard G, Borre M, Gurney H, et al.: Abiraterone Alone or in Combination With Enzalutamide in Metastatic Castration-Resistant Prostate Cancer With Rising Prostate-Specific Antigen During Enzalutamide Treatment. J Clin Oncol 36 (25): 2639-2646, 2018. [PUBMED Abstract]
  36. Smith MR, Saad F, Chowdhury S, et al.: Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med 378 (15): 1408-1418, 2018. [PUBMED Abstract]
  37. Saad F, Cella D, Basch E, et al.: Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial. Lancet Oncol 19 (10): 1404-1416, 2018. [PUBMED Abstract]
  38. de Bono JS, Logothetis CJ, Molina A, et al.: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364 (21): 1995-2005, 2011. [PUBMED Abstract]
  39. Harland S, Staffurth J, Molina A, et al.: Effect of abiraterone acetate treatment on the quality of life of patients with metastatic castration-resistant prostate cancer after failure of docetaxel chemotherapy. Eur J Cancer 49 (17): 3648-57, 2013. [PUBMED Abstract]
  40. Scher HI, Fizazi K, Saad F, et al.: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367 (13): 1187-97, 2012. [PUBMED Abstract]
  41. Fizazi K, Scher HI, Miller K, et al.: Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol 15 (10): 1147-56, 2014. [PUBMED Abstract]
  42. Sternberg CN, de Bono JS, Chi KN, et al.: Improved outcomes in elderly patients with metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: results from the phase III AFFIRM trial. Ann Oncol 25 (2): 429-34, 2014. [PUBMED Abstract]
  43. Cella D, Ivanescu C, Holmstrom S, et al.: Impact of enzalutamide on quality of life in men with metastatic castration-resistant prostate cancer after chemotherapy: additional analyses from the AFFIRM randomized clinical trial. Ann Oncol 26 (1): 179-85, 2015. [PUBMED Abstract]
  44. Fizazi K, Carducci M, Smith M, et al.: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377 (9768): 813-22, 2011. [PUBMED Abstract]
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  46. Dearnaley DP, Sydes MR, Mason MD, et al.: A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 95 (17): 1300-11, 2003. [PUBMED Abstract]
  47. Ernst DS, Tannock IF, Winquist EW, et al.: Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 21 (17): 3335-42, 2003. [PUBMED Abstract]
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  52. Oosterhof GO, Roberts JT, de Reijke TM, et al.: Strontium(89) chloride versus palliative local field radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of the European Organisation for Research and Treatment of Cancer, Genitourinary Group. Eur Urol 44 (5): 519-26, 2003. [PUBMED Abstract]
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  56. Tannock IF, de Wit R, Berry WR, et al.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351 (15): 1502-12, 2004. [PUBMED Abstract]
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Key References for Prostate Cancer

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of prostate cancer treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for prostate cancer. Listed after each reference are the sections within this summary where the reference is cited.

Changes to This Summary (09/20/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Treatment Option Overview for Prostate Cancer
Added text to state that robot-assisted prostatectomy is an alternative to open prostatectomy and has become the most common technique in developed countries. Added that in a randomized trial of 308 men suitable for prostatectomy, urinary, sexual, and bowel functional outcomes were similar between open retropubic and robotic surgeries at a median follow-up of 24 months (added Coughlin et al as reference 24).
Stage II Prostate Cancer Treatment
Add text to state that in a randomized, prospective clinical trial, 18 months of androgen suppression with a luteinizing hormone-releasing hormone (LH-RH) agonist appears to have provided results that were similar to 36 months with respect to overall survival (OS) and disease-specific survival (added Nabid et al. as reference 36 and levels of evidence 1iiA, 1iiB). Also added that 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 (added level of evidence 1iiC).
Stage III Prostate Cancer Treatment
Add text to state that 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 (added Nabid et al. as reference 30 and levels of evidence 1iiA, 1iiB). Also added that 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 (added level of evidence 1iiC).
Stage IV Prostate Cancer Treatment
Added text to state that the cornerstone of hormonal therapy for prostate cancer is medical or surgical castration to stop the production of testosterone by the testes, commonly referred to as androgen deprivation therapy (ADT) and achieved with bilateral orchiectomy or administration of gonadotropin-releasing hormone agonists or antagonists.
Added text to state that randomized controlled trials have reported that combination therapy with an ADT drug plus ADT results in longer OS than does ADT alone.
Added text to state that 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 or placebo. Two-year OS was 82.4% in the apalutamide group compared to 73.5% in the placebo group; radiographic progression-free survival (PFS) was 68.2% in the apalutamide group compared to 47.5% in the placebo group; and 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 (added Chi et al. as reference 6).
Added text to state that in the randomized, controlled, open-label, phase III ENZAMET trial, 1,125 men with castrate-sensitive prostate cancer were randomly assigned to receive ADT alone or ADT plus enzalutamide. Added that 3-year OS was 80% in the combined therapy arm compared to 72% in the ADT monotherapy arm; prostate-specific antigen (PSA) PFS and clinical PFS were also longer in the combined-therapy arm; and serious adverse events were reported in 42% of patients in the enzalutamide arm compared to 34% in the monotherapy arm (cited Davis et al. as reference 7).
Added text to state that randomized controlled trials in humans have failed to support the hypothesis that intermittent androgen deprivation (IAD) would delay the development of castration-resistant disease; if there are benefits from IAD, they appear to be in the realm of physical and sexual functioning.
Add text to state that 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 (added Nabid et al. as reference 55 and levels of evidence 1iiA, 1iiB). Also added that 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 (added level of evidence 1iiC).
Recurrent or Hormone-Resistant Prostate Cancer Treatment
Added Beer et al. as reference 33.
Added text to state that enzalutamide has also been tested in the setting of clinically nonmetastatic, hormone-resistant prostate cancer. 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 or placebo. After follow-up of up to 41 months, enzalutamide showed superiority in the primary endpoint, metastasis-free survival: 77% versus 51% (added Hussain et al. as reference 34 and level of evidence 1iDiii).
Added text to state that continuing enzalutamide in patients who were switched to abiraterone because of progression, and who had castration-resistant metastatic prostate cancer and a rising PSA while receiving enzalutamide, did not appear to improve the rate of PFS or of clinical progression, a strategy that was tested in the randomized PLATO trial (NCT01995513) (added Attard et al. as reference 35 and level of evidence 1iDiii).
Added text to state that a prespecified exploratory analysis, quality of life over time was similar in the apalutamide and placebo arms, as assessed overall and for all component subscale scores of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EuroQol five-dimension, three-level (EQ-5D-3L) questionnaires (added Saad et al. as reference 37 and level of evidence 1iC).
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Prostate Cancer Treatment is:
  • Timothy Gilligan, MD (Cleveland Clinic Taussig Cancer Institute)
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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Prostate Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/prostate/hp/prostate-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389471]
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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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