Introduction

Historical perspective

Prostate cancer is currently the most common malignancy in men and accounted for approximately 233,000 (27%) new cases and 30,000 deaths in the United States in 2014.[1] Since the seminal discovery of the hormone dependence of prostate cancer by Huggins and colleagues more than 7 decades ago, androgen deprivation therapy (ADT) has been the main treatment strategy for metastatic prostate cancer.[2] However, after initial response to ADT, the disease progresses in about 2 to 3 years to a state of castration-resistant prostate cancer (CRPC).[3-5]

Docetaxel was the first agent that showed an improvement in overall survival (OS) in men with metastatic CRPC (mCRPC)and was approved in 2004 for this indication.[6] In 2008, a committee of investigators convened the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) and outlined consensus guidelines for clinical trial design and conduct in mCRPC.[7] The PCWG2 applied a clinical states framework that based trial objectives, design, and outcomes on a dual-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations as an early measure of response; and (2) preventing or delaying disease manifestations in progression as a later time-to-event measure. The clinical framework was based on stepwise milestones along the continuum of progressive disease, defined in terms of primary tumor, presence/absence of metastasis, and testosterone level (whether castrate [< 50 ng/dL] or not). These guidelines have aided in the performance of several well-designed clinical trials.[8,9]

Consequently, significant advances have been made in our current-day understanding of the biology of the evolution of CRPC. Since 2010, translational research has led to the regulatory approval of six new agents for the treatment of mCRPC, including chemotherapeutic agents (cabazitaxel), newer hormonal agents (abiraterone acetate, enzalutamide), immune therapy (sipuleucel-T), radiopharmaceuticals (radium-223 [Ra-223]), and bone-targeted agents (denosumab).[10-12] However, the impact of these therapies on survival has been less than optimal. There is still an acute need to better define predictive and prognostic markers, to optimally sequence the approved agents in treatment protocols, and to develop better targeted therapies.[10-13]

The PCWG3, a group of international experts in prostate cancer, worked from June 2012 to January 2015 to update the PCWG2 recommendations based on the latest advances in our understanding of the biology of mCRPC, newer approved therapeutic agents, detection of high frequency of actionable molecular alterations, and increased recognition of disease heterogeneity.[14]

Current Approved Agents for mCRPC

Chemotherapy

In 2004, the survival benefit of docetaxel was demonstrated in two large trials, making it the standard of care for mCRPC. The phase III TAX-327 trial, which recruited 1,006 chemotherapy-naive patients, showed a 3-month improvement in OS when docetaxel was compared with mitoxantrone treatment (hazard ratio [HR], 0.76 [95% CI, 0.62–0.94]).[15] The Southwestern Oncology Group (SWOG) 99-16 trial revealed a survival advantage of 1.9 months for the combination of docetaxel and estramustine compared with mitoxantrone (HR, 0.8 [95% CI, 0.67–0.97]).[6]

Cabazitaxel is a next-generation taxane approved in 2010 to overcome resistance to docetaxel. In the TROPIC trial, 755 patients who had progressed on docetaxel therapy were randomized to cabazitaxel vs mitoxantrone. Cabazitaxel treatment resulted in a 2.4-month longer median OS (15.1 vs 12.7 months) and a 1.4-month longer progression-free survival (PFS; 2.8 vs 1.4 months; for each, P < .0001). Adverse events noted with this drug were mainly hematologic: grade 3 to 4 neutropenia (82%), febrile neutropenia (8%), and diarrhea (47%).[16]

Role of chemotherapy in metastatic hormone-sensitive (ADT-naive) prostate cancer. In the randomized, open-label, phase III GETUG-AFU 15 trial, 385 men with metastatic hormone-sensitive prostate cancer were randomized between October 2004 and December 2008 to receive ADT plus docetaxel 75 mg/m² every 3 weeks for 9 cycles (n = 192) or ADT alone (n = 193).[17] On an updated analysis, after a median follow-up of 83.9 months, the primary endpoint of median OS was 62.1 months (95% CI, 49.5–73.7 months) vs 48.6 months (95% CI, 40.9–60.6 months) for the ADT-plus-docetaxel and ADT-alone arms, respectively (HR, 0.88 [95% CI, 0.68–1.14]; P = .3). High-volume disease (HVD) was defined as visceral metastases and/or four or more bone metastases with at least one outside of the vertebral column or pelvis. For HVD patients, median OS was 39.8 months (95% CI, 28–53.4 months) vs 35.1 months (95% CI, 29.9–43.6 months) for the ADT-plus-docetaxel and ADT-alone arms, respectively (HR, 0.78 [95% CI, 0.56–1.09]; P = .14]. There was no significant difference in OS for the low-volume disease (LVD) patients. However, this post-hoc analysis was not powered to analyze this survival difference between subgroups. There was a significant improvement in the predefined secondary endpoints of biochemical PFS (bPFS; HR, 0.73 [95% CI, 0.56–0.94]; P = .014) and radiologic PFS (rPFS; HR, 0.75 [95% CI, 0.58–0.97]; P = .030) in the ADT-plus-docetaxel arm as compared with the ADT-alone arm.

The more recent Eastern Cooperative Oncology Group (ECOG) E3805 CHAARTED trial also evaluated the strategy of combining chemotherapy (docetaxel) with ADT in metastatic ADT-naive disease.[18] A total of 790 men with metastatic hormone-sensitive disease were randomized 1:1 between July 2006 and November 2012 to ADT plus docetaxel (at 75 mg/m² every 3 weeks for 6 cycles) or ADT alone. After a median follow-up of 28.9 months, the primary endpoint of median OS was 13.6 months longer (57.6 vs 44 months) in the ADT-plus-docetaxel arm compared with the ADT-alone arm (HR, 0.61 [95% CI, 0.47–0.80]; P < .001). In a subset analysis, the biggest difference in OS between the two arms was 17 months; this occurred in the 65% of patients who had HVD: 49.2 months in the ADT-plus-docetaxel arm vs 32.2 months for the ADT-alone arm (HR, 0.60 [95% CI, 0.45–0.81]; P < .001). All secondary endpoints were significantly improved in the ADT-plus-docetaxel arm compared with the ADT-alone arm: median time to biochemical, symptomatic, or radiographic progression was 20.2 vs 11.7 months, respectively (HR, 0.61 [95% CI, 0.51–0.72]; P < .001); and the rate of prostate-specific antigen (PSA) level < 0.1 ng/mL was 27.7% vs 16.8%, respectively (P < .001).

These two studies differed in several respects, which accounted for the statistical differences in outcomes. The CHAARTED study was a larger study (N = 790), and almost twice as many patients had higher-volume and higher-grade disease (66% vs 22%) compared with patients in the GETUG-AFU 15 trial (N = 385). These differences are reflected in the OS in the ADT-alone arms of the two trials (44 vs 48.6 months). Although the GETUG-AFU 15 study did not show a greater OS benefit for docetaxel therapy compared with the CHAARTED trial, both studies showed significant improvement in both bPFS and rPFS.[17,18]

In STAMPEDE, a multi-stage, multi-arm, randomized controlled trial investigating the combination of ADT plus docetaxel in hormone-sensitive metastatic prostate cancer, survival data showed a statistically significant 27% reduction in risk of death in the ADT-plus-docetaxel arm compared with the ADT-alone arm (HR, 0.73 [95% CI, 0.59–0.89]; P = .002). Median OS was 65 months (95% CI, 27 months–not reported) vs 43 months (95% CI, 24–88 months) in the ADT-plus-docetaxel arm compared with the ADT-alone arm.[19]

A systematic review and meta-analysis incorporating data from these three phase III trials (GETUG-AFU 15, CHAARTED, and STAMPEDE) that evaluated chemohormonal therapy in hormone-sensitive metastatic prostate cancer were performed.[20] A total of 2,262 patients had metastatic disease (951 received ADT plus docetaxel; 1,311 received ADT alone). In metastatic prostate cancer, the addition of docetaxel was associated with improved OS (HR, 0.73 [95% CI, 0.60–0.90]; P = .002) and PFS (HR, 0.63 [95% CI, 0.57–0.70]; P < .001). No significant relatonship was demonstrated on subgroup analysis between the addition of docetaxel and presence of HVD or LVD (P = .5).

The efficacy of docetaxel in hormone-sensitive metastatic prostate cancer has not been clearly elucidated; however, the coexistence of androgen receptor (AR)-positive and AR-negative cells in metastatic disease underlies some of the biologic rationale for using the combined hormonal therapies and chemotherapies. In addition, docetaxel has been shown to affect AR trafficking in prostate cancer, and recent discoveries have also shown that androgen ablation controls DNA repair mechanisms in the disease.[21,22] From a clinical perspective, patients with hormone-sensitive disease are in generally better overall health and have better performance status compared with those patients with mCRPC, and thus are able to tolerate dose-intense chemotherapy successfully.[13,20]

Novel hormonal agents

The revelation that CRPC still depends on the key AR-mediated signaling and downstream gene activation for growth and progression led to the discovery of novel hormonal agents.

Abiraterone acetate is a potent cytochrome p450 17A1 (CYP17A1) inhibitor that suppresses androgen synthesis in the adrenals and testes when used to treat mCRPC. It is administered with steroids (prednisone or prednisolone, 5 mg twice per day) to suppress adrenocorticotropic hormone–induced mineralocorticoid excess. Abiraterone was approved in 2011 after two large trials, COU-AA-301 and COU-AA-302, confirmed its efficacy in docetaxel-treated and chemotherapy-naive patients, respectively. In the COU-AA-301 trial, 1,195 patients who had received up to two lines of chemotherapy with at least one docetaxel-based regimen were randomized to prednisone plus abiraterone vs prednisone plus placebo. The median OS for the abiraterone arm was significantly longer: 15.8 vs 11.2 months in the placebo group (HR, 0.74 [95% CI, 0.64–0.86]; P < .001). Abiraterone/prednisone improved pain control, quality of life, and fatigue, and delayed skeletal-related events (SREs).[23] In the COU-AA-302 trial, 1,088 chemotherapy-naive patients with mCRPC with rising PSA levels and minimal symptoms were randomized to prednisone plus abiraterone vs prednisone plus placebo. On final analysis (after a median of 49.4 months of follow-up), there was a significant improvement in median OS in the abiraterone arm of 34.7 vs 30.3 months (HR, 0.8 [95% CI, 0.69–0.83]; P < .001).Common toxicities included mineralocorticoid side effects of hypertension, edema, hypokalemia, and elevated levels on liver function tests.[24,25]

Enzalutamide is a potent second-generation selective AR antagonist that binds to the AR, decreases ligand-dependent nuclear translocation and binding of the AR to DNA, and blocks cellular proliferation. In the AFFIRM trial, 1,199 mCRPC patients who had received prior docetaxel chemotherapy were randomized 2:1 to enzalutamide or placebo. There was a 4.8-month improvement in median OS (18.4 vs 13.6 months) favoring the enzalutamide arm (HR, 0.631; P < .0001).[26] In the phase III PREVAIL study, 1,717 chemotherapy-naive patients with mCRPC (asymptomatic or mildly symptomatic metastatic disease that had progressed despite ADT) were randomized to enzalutamide or placebo. There was a significant improvement in rPFS (HR, 0.19 [95% CI, 0.15–0.23]; P < .001), as well as in median OS, estimated to be 32.4 months vs 30.2 months (HR, 0.7; P < .0001), favoring the enzalutamide arm.[27] The most common side effects observed were fatigue, diarrhea, and hot flashes. These results led to the approval of enzalutamide in both the pre- and post-docetaxel mCRPC settings.

Immunotherapy

Sipuleucel-T is a first-in-class active cellular immunotherapy based on a dendritic cell–based vaccine. Peripheral blood mononuclear cells are activated ex vivo with PA2024 recombinant fusion protein (prostatic acid phosphatase fused to granulocyte-macrophage colony-stimulating factor). In the phase III IMPACT trial, 512 patients were randomized to 3 infusions of sipuleucel-T over 6 weeks vs placebo. There was a 4.1-month improvement in OS (median, 25.8 vs 21.7 months; P = .03). There were no effects on PSA level or time to disease progression. Sipuleucel-T was found to be well-tolerated overall, with side effects related to infusion, such as flu-like symptoms and myalgia.[28]

Radiopharmaceuticals

Ra-223 dichloride is a targeted α-emitter that is selectively taken up at areas of increased bone turnover, emitting high-energy α-particles to induce targeted double-stranded DNA breaks. In the phase III ALSYMPCA trial, 921 mCRPC patients with two or more symptomatic bone metastases and no visceral metastases who were pretreated with or unfit for docetaxel were randomized to Ra-223 or placebo. Patients received 6 injections once every 4 weeks over 6 months. Ra-223 was well-tolerated and resulted in a 3.6-month improvement in OS (14.9 vs 11.3 months; HR, 0.70 [95% CI, 0.58–0.83]; P < .001). All grade 3 adverse events were lower in the Ra-223 arm. Reported side effects were myelosuppression, diarrhea, vomiting, and peripheral edema.[29]

Bone-targeted agents

Denosumab is a human monoclonal antibody against receptor activator of nuclear factor kappa-β ligand and inhibits osteoclast function. In a randomized trial of 1,904 patients with mCRPC, denosumab was superior to zoledronic acid in time to first SRE (median, 20.7 vs 17.1 months; HR, 0.82 [95% CI, 0.71–0.95]; P = .008); however, there was no difference in OS.[30] Both denosumab and zoledronic acid are approved for the prevention of SREs.[11,31]