Resistance to androgen deprivation is an ominous milestone in the natural history of metastatic prostate cancer:this disease state, now referred to as castration-refractory prostate cancer (CRPC), is historically associated with a median survival of less than two years. Until recently, only docetaxel(Drug information on docetaxel) (in combination with prednisone(Drug information on prednisone) or estramustine(Drug information on estramustine)) demonstrated a benefit in overall survival vs comparator therapy with mitoxantrone(Drug information on mitoxantrone) plus prednisone.[1,2] However, in the past year, compelling data in support of several promising new treatments for CRPC have been reported. The new data offer evidence-based treatment options, but also raise many questions for patient management and future clinical research.
Kantoff et al published a phase III study of the active cellular immunotherapy, sipuleucel-T, that led to its recent FDA approval for CRPC in the U.S. In this study, men with asymptomatic or minimally symptomatic prostate cancer were randomized to receive autologous antigen presenting cells cultured ex vivo, with or without a prostatic acid phosphatase-GM-CSF fusion protein, PA2024. There was a 4.1 month improvement in the primary endpoint of overall survival favoring the active treatment group. However, no difference was seen in the secondary endpoint of time to objective disease progression. Similar results had been seen in an earlier phase III study in which progression-free survival had been the primary endpoint. Available data do not offer a definitive explanation for the discrepancy between overall and progression-free survival. Similar observations were noted in a randomized, placebo-controlled phase II study of PROSTVAC-VF, a PSA-targeted poxviral vaccine in men with metastatic, castration-refractory prostate cancer. The primary endpoint of the study (improvement in progression-free survival, either radiographic or symptomatic), was not met and there were no objective responses by RECIST. However, there was a statistically significant improvement in the secondary endpoint of overall survival. The median overall survival was 25.1 months in the PROSTVAC-VF arm and 16.5 months in the control arm (Log Rank P = .0095 for the randomized population (N = 125)). However, there was no improvement in progression-free survival, nor was there a significant rate radiographic or symptomatic response. The overall survival benefit without impact on disease progression that was observed in the sipuleucel-T and PROSVAC-VF studies raises a question as to the validity of progression-free survival, as currently defined, as a surrogate for overall survival and clinical benefit. The Prostate Cancer Clinical Trials Working Group (PCCTWG) has published consensus guidelines for the design of efficacy endpoints for phase II clinical trials of interventions for CRPC. Based on these consensus guidelines, neither sipuleucel-T nor PROSVAC-VF showed clinical activity by the PCCTWG criteria. The improvement in overall survival was detected only because of the control-randomized design of these studies. The question arises: Are there other endpoints that would correlate better with overall survival, such as levels of circulating tumor cells, serum markers of tumor or host metabolic activity, or functional radiographic studies? Adding to the complexity of the problem is the possibility that some classes of treatments, such as cytotoxic chemotherapy, have generally maintained a good correlation between progression-free and overall survival, whereas other treatment modalities, such as immunotherapies, may not. Developing valid surrogates of clinical benefit is critical for the identification of an efficacy signal for novel agents, which can then be selected for larger randomized studies.
The lack of impact on progression-free survival raises immediate questions for the incorporation of sipuleucel-T into the sequence of available and emerging therapies for patients with CRPC. In most men who receive sipuleucel-T, serum PSA will continue to rise, and radiographically detected disease will continue to progress following treatment, providing an impetus to administer additional systemic therapy. However, the impact of subsequent therapy such as cytotoxic chemotherapy or corticosteroids on the immune-mediated benefit of sipuleucel-T has not yet been studied. What is the optimal time to initiate further therapy for CRPC, for men who have received sipuleucel-T? At the time of PSA progression? Radiographic progression? Symptomatic progression? Does starting cytotoxic agents or corticosteroids too soon have a deleterious effect on the immunotherapeutic benefit of sipuleucel-T? On the other hand, there may be risk associated with delaying additional therapy: In the phase III study of sipuleucel-T by Kantoff et al, men who had received chemotherapy within three months of the study or corticosteroids within one month were excluded. It is reasonable to adhere to these criteria in men for whom sipuleucel-T is being considered Beyond that, we have little information on the optimal timing of sipuleucel-T relative to other therapies.
Several novel hormonal agents have shown promising activity in CRPC, for example, abiraterone acetate is a potent inhibitor of androgen synthesis via inhibition of both the 17-alpha-hydroxylase and 17,20-lyase activities of cytochrome P (CYP) 17. Treatment with abiraterone lowered testosterone levels in men treated with an LHRH agonist,[8,9] and published Phase II studies have shown significant clinical activity as measured by PSA, radiographic and clinical responses.[8,10] At the 2010 ESMO meeting, Johann de Bono presented the results of a phase III study of abiraterone plus predinisone vs placebo vs prednisone in men with CRPC who had progressed through docetaxel-based chemotherapy. The study met its primary endpoint of overall survival: Median survival was 14.8 months in the abiraterone arm and 10.7 months in the placebo arm. Improvements in radiographic progression-free survival, time to PSA progression, and PSA response rates were observed as well. A study of abiraterone plus prednisone vs placebo plus prednisone is ongoing in men with CRPC who are minimally symptomatic and had not received prior chemotherapy (clinicaltrials.gov NCT00887198). However, the role of abiraterone and other emerging hormonal agents in prostate cancer beyond the post-cheomotherapy setting remains to be defined. Is there a benefit in men with CRPC who have not received chemotherapy? Could there be a benefit in using abiraterone in addition to LHRH agonist in men with hormone sensitive metastatic disease? The role of conventional LHRH agonists in the adjuvant setting after radical prostatectomy, and in the setting of biochemical (PSA-only) recurrence has not been well defined. Prednisone (at a dose of 10 mg daily) was administered in the phase III studies of abiraterone to ameliorate the mineralocorticoid excess seen with abiraterone alone. The consequences of extended exposure to low dose corticosteroid is a consideration in the potential use of abiraterone in earlier stage disease. While it is provocative to consider the potential benefit of abiraterone and other novel endocrine therapies in these early disease states, the long overall and progression-free survival of these patients necessitates large numbers of subjects and many years of follow up to properly assess their potential.
MDV3100 is another potent androgen receptor antagonist that is being studied in men with CRPC. A phase I-II study of MDV3100 in men with CRPC showed clinical activity, including a PSA response rate of 56% and a radiographic response rate of soft tissue disease of 22%. MDV3100 is now being compared to placebo in phase III studies in men with docetaxel-refractory and chemotherapy-naïve patients with CRPC (clinicaltrials.gov NCT00974311 and NCT01212991, respectively). Additional endocrine agents are in clinical trials as well.
Until recently there was no standard of care with demonstrated benefit for men with docetaxel-refractory CRPC. Cabazitaxel (XRP6258; TXD258; RPR116258A; Jevtana®) is a taxane that was identified to have activity against cell lines with acquired resistance to docetaxel or paclitaxel(Drug information on paclitaxel) in vitro. A phase III study was recently reported in which 755 men with CRPC refractory to docetaxel were randomized to receive cabazitaxel (25 mg/m2 every 21 days) plus prednisone vs mitoxantrone (12 mg/m2 every 21 days) plus prednisone. The study specified that a maximum of ten cycles of treatment would be delivered to subjects in each arm. Median overall survival was 15.1 months for cabazitaxel and 12.7 months for mitoxantrone (P < .0001). Time to PSA progression, PSA response rate, time to progression, and radiographic response rate were all superior for cabazitaxel. Forty-five percent of subjects had pain at the time of study entry, and the pain response rates (9.2% for cabazitaxel and 7.7% for mitoxantrone) were not statistically different. The results of this study stand in contrast to a randomized, double-blind phase III study of the oral cytotoxic agent satraplatin, compared to placebo (plus prednisone 5 mg twice-daily), which was conducted in men with CRCP. The study was designed with two primary endpoints: overall survival and progression-free survival, defined as radiographic progression (by RECIST or two new bone lesions), a new skeletal event, symptomatic progression or death from any cause. An advantage to satraplatin was seen in the composite PFS primary endpoint (11.1 vs 9.7 weeks; P < .001, HR 0.67). Satraplatin demonstrated an improvement in the important secondary endpoint of pain response (24% vs 13%) and was associated with a 36% reduction in risk of pain progression, however there was no difference in overall survival. The cabazitaxel and satraplatin studies present an intriguing contrast: The former demonstrated a benefit in overall survival but did not demonstrate an advantage in pain response, whereas the latter demonstrated significant improvement in pain control and time to pain progression, but no benefit in overall survival. The contrast could be due in part to differences in the patient population: Only 51% of the subjects in the satraplatin study received docetaxel (others received mitoxantrone, paclitaxel, or other agents), whereas all subjects had received prior docetaxel in the cabazitaxel study. Alternatively, the two agents work by different mechanisms, and the clinical results could represent a genuine difference in their biological effects.
Several new agents have been FDA-approved or are in late-stage clinical trials for prostate cancer; including immunotherapies, and hormonal and cytotoxic agents. The emergence of several active agents with different mechanisms raises many questions regarding the optimal sequencing of these agents as well as the optimal criteria for defining disease progression on a particular agent. The data that demonstrate efficacy are in the setting of castration-refractory metastatic disease. There is potential for these interventions to have benefit in earlier disease states, but large randomized clinical trials, which may take a long time to reach their primary endpoints, would first need to be performed.
Financial Disclosure: Dr. Appleman is a clinical trial site investigator for Cougar Biotechnology and Medivation.