In addition to endeavors to develop new therapeutics, we should anticipate and prioritize studies that will address questions regarding the efficacy of combination therapy, timing and sequencing strategies, and the development of predictive markers to individualize and optimize therapy.
Until recently, available systemic therapy with proven efficacy for metastatic castration-resistant prostate cancer (CRPC) consisted of mitoxantrone (Novantrone), docetaxel, and zoledronic acid (Zometa). In the last 1 to 2 years, an unprecedented number of new agents have been demonstrated to improve outcomes for patients with CRPC in phase III trials. These include sipuleucel-T (Provenge), cabazitaxel (Jevtana), denosumab (Xgeva), abiraterone acetate (Zytiga), radium-223 (Alpharadin), and most recently, MDV3100. Without minimizing the importance of any of these advances, it still must be recognized that none of these treatments are curative, and that given the age and comorbidities of the patient population with CRPC, issues of symptom control and quality of life may be of paramount importance-over and above survival for many patients. Thus, the perspective taken in this comprehensive review of CRPC treatments by Rove and Crawford, with its focus on bone metastases, is fitting, since complications of metastases in the bone are a major manifestation of the disease. However, bone is not the only location where CRPC manifests; nodal disease is present in 40% to 50% of patients, and visceral metastases are found in approximately 25% of patients enrolled in clinical trials. Thus, a wider viewpoint is also needed when considering therapeutic options for CRPC.
Many agents are evaluated in terms of their effect on skeletal-related events (SREs). It is worthwhile to examine this endpoint critically. SREs in prostate cancer are defined as pathologic bone fractures, spinal cord compression, surgery to bone, radiation therapy to bone, or a change of antineoplastic therapy to treat bone pain. A reduction in an SRE, however, should not be equated with symptom benefits, such as reduced pain or improved functioning, which are best assessed via direct patient reporting. In the phase III studies of zoledronic acid and denosumab, the major SRE that occurred was radiotherapy to bone (approximately 66% and 52% of all SREs, respectively); however, the decision to initiate radiotherapy was not protocol-specified and it can be highly variable across practices depending on physician and patient preferences. Furthermore, palliative radiotherapy to bone can be well managed with a single fraction of radiotherapy (notwithstanding physician preferences to deliver more), with the result that the major choice for the patient becomes that between repeated drug administrations with the associated adverse effects, and single-fraction radiotherapy. The study that evaluated zoledronic acid demonstrated a difference in the occurrence of SREs of 33% in the zoledronic acid arm vs 44% in the placebo group (P = .021) during the study period. In other words, the number of patients needed to treat in order to prevent 1 from developing an SRE over a 15-month period was 9, with the cost per additional patient free of SREs estimated to be $51,400 in one study. No clinically significant differences in patient-reported pain were observed between the treatment and placebo arms (although the study design may not have permitted an accurate assessment of changes in pain); also, no significant differences in analgesic use, quality of life scores, or differences in overall survival were seen. The phase III study with denosumab showed an increase in median time to development of an SRE of 3.6 months (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71–0.95) compared with zoledronic acid, but progression-free survival and overall survival were not affected, and impact on patient-reported outcomes was not described.
On the other hand, there are agents that have had a demonstrated impact on overall survival that did not translate to other benefits. The autologous active cellular immunotherapy sipuleucel-T falls into this category. It improves survival by a median of 4.1 months (HR, 0.78; 95% CI, 0.61–0.98; P = .03) but makes no difference in terms of time to objective or clinical disease progression compared with placebo in patients with minimally symptomatic CRPC. To some extent, cabazitaxel also belongs in this category. In patients previously treated with docetaxel, cabazitaxel improved median overall survival by 2.4 months (HR, 0.70; 95% CI, 0.59–0.83; P < .0001) compared with mitoxantrone. Progression-free survival was significantly different but by only 1.4 months (HR, 0.74; 95% CI, 0.64–0.86; P < .0001), and the pain response rate was < 10% for both study arms (9.2% compared with 7.7% in patients treated with mitoxantrone), at the expense of sometimes severe and life-threatening chemotherapy-related toxicity. Potentially, cabazitaxel can have greater benefit and a different toxicity profile when patients are more robust, as they are in the first-line chemotherapy setting where this agent is now being tested against docetaxel (clinicaltrials.gov identifier NCT01308567).
Lastly, other treatments have provided both survival and symptom improvement benefits, and it is these treatments that will likely be highly prioritized for use by physicians and patients. Docetaxel as first-line chemotherapy improved overall survival, pain responses, and quality of life compared with mitoxantrone. Abiraterone acetate, an inhibitor of CYP17 and extragonadal androgen synthesis, has demonstrated improvement in overall survival (median, 14.8 months vs 10.9 months; HR, 0.65; 95% CI, 0.54–0.77; P < .001), pain palliation and time to SREs, and patient-reported quality-of-life scores compared with placebo in patients previously exposed to docetaxel chemotherapy. The adverse event profile of abiraterone acetate is also very favorable, with the predominant adverse events being the mechanism-based effects of mineralocorticoid excess (hypokalemia, hypertension, fluid retention, and edema), which are manageable and infrequently severe. The data on the phase III study of radium-223 vs placebo have also been recently presented; these have demonstrated overall survival benefits (median, 14.0 vs 11.2 months; HR, 0.695; 95% CI, 0.552–0.875; P = .00185) and delayed time to SRE (median, 13.6 vs 8.4 months; HR, 0.610; 95% CI, 0.461–0.807; P = .00046), with minimal hematologic or other toxicity in patients previously treated with docetaxel or considered docetaxel-ineligible. With the recent news about MDV3100, following an interim analysis of a placebo-controlled phase III study in men previously treated with docetaxel, that this next-generation androgen receptor antagonist improves overall survival (median, 18.4 months vs 13.6 months; HR, 0.631; P < .0001) (clinicaltrials.gov identifier NCT00974311), it is hoped that we can expect benefits in other outcomes-similar to what was seen with abiraterone acetate, given the similar mechanisms of these two agents (the targeting of persistent androgen receptor signaling).
The management of CRPC could be described as not just being in evolution, but as being in revolution. A period of anarchy often ensues after a revolution, and this will likely be the case with CRPC management now. A challenge for the practicing clinician is how to incorporate all these therapy choices into the management of an individual patient given the diverse mechanisms of action, differing toxicities, and different constellations of demonstrated benefits. Also complicating matters is the fact that many of these agents have been evaluated in relative isolation from the others, and it is not a foregone conclusion that the benefits will be additive when different therapies are combined or layered. Furthermore, the optimal time to start a particular treatment within a patient’s disease course is in question, due to the heterogeneity of the disease and the fact that some of the clinical trials were performed in the context of needing to obtain regulatory approval in an expedient manner.
The revolution continues, and a large number of agents are in clinical evaluation. Despite a number of successes, there have also been several agents that have not met their primary endpoints in phase III trials. Endothelin antagonists have already fallen out of favor, with recent news reports of negative analyses for both atrasentan (Xinlay) and zibotentan. Similarly, negative overall survival results in phase III trials of sunitinib (Sutent) and bevacizumab (Avastin) in combination with docetaxel have been reported. However, as mentioned by Rove and Crawford, there is an active pipeline of agents in development, including OGX-011 (Custersin), dasatinib (Sprycel), and many others. Given that the focus of this review is on bone metastases, we should also add cabozantinib (XL-184) to this list. Cabozantinib inhibits multiple receptor tyrosine kinases, including c-MET and vascular endothelilal growth factor receptor (VEGFR), and results from a randomized phase II study that were recently presented demonstrated declines in serum markers of bone turnover, bone scan improvements, and pain symptom improvements in patients with CRPC. Phase III studies are planned with this agent.
In addition to these endeavors to develop new therapeutics, we should anticipate and prioritize studies that will address questions regarding the efficacy of combination therapy, timing and sequencing strategies, and the development of predictive markers to individualize and optimize therapy. Addressing these issues is not only important for advancing patient care, but will also speak to the increasing societal concern regarding affordable health care delivery.
Financial Disclosure:Dr. Chi has served as a consultant to Amgen, AstraZeneca, Janssen Inc, sanofi aventis, Medivation, and Novartis, and he has received research funding from Amgen, AstraZeneca, Janssen, Novartis, OncogeneX Technologies Inc., and Pfizer.
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