ABSTRACT: Improving survival in metastatic castration-resistant prostate cancer (CRPC) is no longer an elusive goal. With the expansion of knowledge regarding the biology of the disease, we are witnessing a plethora of novel therapeutics that are undergoing testing in clinical trials. Since the approval of docetaxel(Drug information on docetaxel) for metastatic CRPC in 2004, three additional agents have demonstrated improvements in overall survival in randomized phase III trials: two agents (cabazitaxel and sipuleucel-T) were approved by the FDA in 2010, and a third (abiraterone) was approved in April of 2011. A threshold has clearly been crossed in the management of advanced prostate cancer; however, the impact on survival has been relatively modest, and efforts at personalized therapy have lagged behind those for other solid tumors. Further meaningful advances are needed, and the foundation for future clinical trials must be high-quality, high-impact translational science that focuses on disease biology, the defining of relevant pathways and validated predictive biomarkers, and adequate preclinical characterization of agents and combinations that will facilitate more personalized therapy.
Introduction
Prior to 2004, major treatment options for advanced prostate cancer were limited to hormonal therapy for hormone-sensitive disease, mitoxantrone(Drug information on mitoxantrone) (Novantrone) and strontium-89 (Metastron) for pain palliation, and zoledronic acid(Drug information on zoledronic acid) (Zometa) to minimize skeletal-related events (SREs) in castration-resistant prostate cancer (CRPC).[1-4] The landmark studies demonstrating a survival improvement for patients treated with docetaxel (Taxotere) not only dramatically influenced the management of CRPC but also energized more research in this setting, leading to more FDA-approved agents available for use (Table 1).[5,6]
FDA-Approved Non-Hormonal Agents for Castration-Resistant Prostate Cancer
Just in 2010, three agents were approved by the FDA: cabazitaxel (Jevtana) and sipuleucel-T (Provenge) for the treatment of metastatic CRPC based on improvements in overall survival, and denosumab (XGEVA) for the supportive management of bone disease.[7-9] In April 2011, the FDA approved abiraterone (Zytiga) for the treatment of metastatic CRPC post docetaxel. These agents work by quite distinct mechanisms; they thus reflect the complex nature of CRPC and the potential therapeutic opportunities. The expansion in the understanding of the biology of CRPC has led to a plethora of agents that are currently under clinical investigation in a variety of advanced disease settings (Tables 2 and 3). This review will discuss recently FDA-approved agents for advanced prostate cancer and those under investigation in phase III trials.
Microtubule Inhibitors
Based on cumulative scientific clinical data, particularly data on docetaxel, the microtubule is considered a validated therapeutic target in metastatic CRPC. Microtubules have numerous cellular functions, including preservation of cellular shape, intracellular transport, and formation of the mitotic spindle for movement of sister chromatids during mitosis.[10] The most widely tested microtubule inhibitors are the taxanes and the epothilones, both of which suppress microtubule activity, leading to mitotic arrest and apoptosis. The epothilones (eg, ixabepilone, patupilone) have been studied in phase II trials in patients with metastatic CRPC with variable efficacy.[11-14] The nanoparticle albumin-bound (nab) formulations of docetaxel and paclitaxel(Drug information on paclitaxel) are being evaluated in CRPC.[15,16]
Cabazitaxel
Cabazitaxel is the microtubule inhibitor most recently approved by the FDA. The preclinical activity of cabazitaxel in tumor models resistant to docetaxel and paclitaxel led to clinical studies demonstrating antitumor activity in metastatic CRPC refractory to docetaxel.[10,17] This paved the way for an international, multicenter, phase III study that randomly assigned 755 men with metastatic CRPC with disease progression after docetaxel to receive prednisone(Drug information on prednisone) plus either mitoxantrone or cabazitaxel.[18] While all patients were previously treated with docetaxel, 16% in the cabazitaxel group and 13% in the mitoxantrone group had received two or more docetaxel-containing regimens. The median time from the last docetaxel dose to disease progression was 0.8 months in the cabazitaxel group and 0.7 months in those receiving mitxantrone. Patients treated with cabazitaxel had a median overall survival of 15.1 months (95% confidence interval [CI], 14.1-16.3), compared with 12.7 months (95% CI, 11.6-13.7) in the mitoxantrone-treated patients, with a hazard ratio (HR) for death of 0.7 (95% CI, 0.59-0.83, P < .0001) for men receiving cabazitaxel. The cabazitaxel-treated patients had a median progression-free survival of 2.8 months (95% CI, 2.4-3.0) compared with 1.4 months (95% CI, 1.4-1.7) in those receiving mitoxantrone (HR, 0.74; 95% CI, 0.64-0.86; P < .0001). In patients with measurable disease, 14.4% (95% CI, 9.6-19.3) of cabazitaxel-treated patients had an objective response, compared with only 4.4% (95% CI, 1.6-7.2%) in the mitoxantrone group (P < .0005). Nearly all patients experienced some degree of myelosuppression, but more patients treated with cabazitaxel experienced grade 3 or higher neutropenia (82% vs 58%) and neutropenic fever (8% vs 1%). Grade 3 or higher anemia and diarrhea were also seen more often in patients treated with cabazitaxel (11% vs 5%, and 6% vs < 1%, respectively). In addition, more deaths occurred within 30 days of receiving the last dose of drug in cabazitaxel-treated patients (18 deaths [5%], including 7 from neutropenia and its consequences and 5 from cardiac causes) than in the mitoxantrone group (9 deaths [2%], 6 of which were due to disease progression).
Cabazitaxel was approved by the FDA in 2010 for salvage therapy after disease progression following docetaxel-based therapy.[8] However, the toxicities associated with this treatment, notably myelosuppression, warrant particular caution. Careful monitoring of blood counts is needed, and growth factor support is recommended for patients, including the elderly, who are at high risk for complications from myelosuppression. In addition, the increase in cardiac deaths seen with cabazitaxel compared with mitoxantrone warrants careful administration and monitoring in patients with underlying cardiac disease.
Immunomodulatory Agents
The immune system is heavily involved in the development and progression of cancer. Over the past several years, several strategies have been developed exploiting this concept in a multitude of malignancies, including prostate cancer.
Sipuleucel-T
Sipuleucel-T is an active cellular immunotherapy agent composed of autologous antigen-presenting cells (APCs) that have been cultured with the fusion protein PA2024, which consists of prostatic acid phosphatase and granulocyte–macrophage colony-stimulating factor, and which is designed to stimulate an immune response against prostate cancer cells.[19]
The initial phase III study using sipuleucel-T in prostate cancer, published in 2006, randomly assigned 127 patients with asymptomatic metastatic CRPC to treatment with sipuleucel-T or to a control group (in which patients received APCs cultured in the absence of PA2024). The difference in median time to disease progression (the primary endpoint) between the two groups was not statistically significant (11.7 weeks in the sipuleucel-T group vs 10.0 weeks in the control group). However, the median overall survival, a secondary endpoint, was 25.9 months in the sipuleucel-T group compared with 21.4 months in the control group (HR, 1.71 [95% CI, 1.13-2.58];P = .01). Another small phase III study of patients with asymptomatic metastatic CRPC showed a non-statistically significant trend towards increased overall survival (a secondary endpoint) with sipuleucel-T (19.7 months vs 15 months), but with no significant difference in the time to disease progression, the primary endpoint of the study.[20] A third phase III trial, with overall survival as the primary endpoint, randomly assigned patients with asymptomatic or minimally symptomatic metastatic CRPC in a 2:1 ratio to treatment with sipuleucel-T or to a control arm (in which patients received APCs cultured in the absence of PA2024).[21] Patients randomly assigned to the control arm who developed progressive disease were unblinded and offered treatment with sipuleucel-T manufactured using the patient’s cryopreserved APCs. Of the 171 patients in the control arm, a total of 109 (63.7%) received sipuleucel-T as salvage therapy, with 84 of these (49.1%) receiving it as initial therapy following disease progression. Most patients in both cohorts received additional therapy beyond sipuleucel-T. In the experimental arm, 81.8% received additional treatment and 57.2% received docetaxel after a median of 12.3 months, whereas 73.1% in the control arm received additional therapy, 50.3% of whom received docetaxel after a median 13.9 months. The results showed that sipuleucel-T–treated patients had a four-month improvement in overall survival (25.8 months vs 21.7 months; HR, 0.78 [95% CI, 0.61-0.98]; P = .03). As in the other two studies, no antitumor effect was seen, as reflected by the lack of difference in time to disease progression, symptom improvement, decrease in PSA level, or other measure of disease response.
The most common adverse reaction seen with sipuleucel-T was an infusion reaction, occurring within 24 hours in 71.2% of patients (3.5% had grade 3 reactions) and manifested by chills, fever, fatigue, nausea, tachycardia, and hypertension.[19-21] Other common side effects included headache, back pain, and joint pain. Overall, grade 3 or 4 adverse events occurred in 23.6% and 4% of patients, respectively, with the most common being back pain and chills.[7] In one trial, cerebrovascular events occurred in 7.5% of patients treated with sipuleucel-T (11 of 147) vs 2.6% of patients in the control group (2 of 76).[21]
A common concern regarding sipuleucel-T has been the lack of any demonstrable antitumor effect in any of the randomized trials as compared with results in the control groups—and therefore, the inability to assess response at the individual patient level.[22,23] It remains to be proven whether conventional response measures are appropriate with this class of agents or not. If not, then until adequate efficacy assessment measures are established, we strongly recommend that future phase III testing of such agents include an active control arm proven to be of benefit so as to allow confidence in the trial results with regard to comparable or superior outcome. This is especially important considering the per-patient cost of treatment with sipuleucel-T and the fact that it does not obviate the need for chemotherapy.[23] Proponents of this agent argue that the cost is comparable to that of other biologic agents approved by the FDA and that the price may be offset by the more favorable side-effect profile of sipuleucel-T (compared to chemotherapy).[24] However, since this agent was tested in a different patient population than that included in the docetaxel trials (which allowed accrual of patients with pain and visceral disease), and since none of the trials compared sipuleucel-T to an active control with established clinical benefit, the fact remains that thousands of patients will receive a full course of therapy without the certainty of knowing who may be benefiting.
Selected Pathways, Targets, and Agents Being Evaluated in Clinical Trials in Advanced Prostate Cancer[91]
Ipilimumab
Under normal conditions, activation of cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) leads to inhibition of T-cell activation.[25] Ipilimumab (Yervoy) is a human monoclonal antibody against CTLA-4. Early work on prostate cancer has shown that this agent potentiates a sustained T-cell immune response and leads to clinical benefit.[26] Recent reports demonstrate activity in advanced prostate cancer when ipilimumab is combined with androgen ablation; 55% of patients in one study achieved undetectable PSA levels after 3 months of combined therapy compared with 38% of patients treated with androgen ablation alone.[27,28] Side effects included diarrhea (4.5%); colitis (4.5%); and cutaneous changes, such as localized vitiligo, etc (27.7%). A phase III study evaluating the effect of ipilimumab on overall survival in patients with metastatic CRPC is ongoing.[29]
