Advanced prostate cancer 2010: what a year!

The year 2010 has been a remarkable one for patients with advanced prostate cancer. In 2004, the US Food and Drug Administration (FDA) approved docetaxel after phase III trials demonstrated a prolongation of survival in patients with metastatic castrate-resistant prostate cancer (mCRPC). That important observation was followed by a long lull. That has now changed. In 2010, there have been 2 new FDA approvals for patients with mCRPC and, in addition, a new positive phase III trial has been announced. Sipuleucel-T is an autologous immunotherapy comprised of antigen-presenting cells primed in vitro with a granulocyte-macrophage colony-stimulating factor (GM-CSF)-prostatic acid phosphatase fusion protein. Patients undergo pheresis and after stimulation of the cells in vitro, the patients are re-infused with the antigen loaded cells for a total of 3 infusions spaced 2 weeks apart. Sipuleucel-T is very specifically indicated for those individuals with mCRPC provided that they are either asymptomatic or mildly symptomatic at the time of treatment. As is shown in the manuscript by Kantoff et al, median survival was prolonged by 4.1 months in the sipuleucel-T group as compared to a control group receiving unprimed cells.1 Side effects consisted primarily of acute infusion reactions similar to that of a transfusion but these were rarely serious. The FDA, after careful review, decided that these data were worthy of approval after initially and appropriately turning down a request based on previous underpowered trials. In the second FDA approval of the year, cabazitaxel was shown to prolong survival by a median of 2.4 months and patients with mCRPC previously treated with a docetaxel regimen.2 This was the first study to demonstrate an improvement in survival in this setting. Cabazitaxel is a novel taxane designed to overcome docetaxel resistance in a variety of model systems. In the TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated With a Taxotere-Containing Regimen) trial, cabazitaxel plus prednisone was compared to mitoxantrone plus prednisone with a median survival of 15.1 months versus 12.7 months. Though side effects were potentially significant, particularly with regard to neutropenia and neutropenia-related infections, the FDA moved swiftly and approved cabazitaxel in near record time. This agent was unusual in that it essentially moved from phase I directly to phase III studies in mCRPC. There were no phase II studies in prostate cancer, leading many to be surprised when the TROPIC trial reported positive. The third phase III trial to meet a survival endpoint in a positive fashion was abiraterone plus prednisone versus placebo plus prednisone.3 This trial was also conducted in the patients with mCRPC post-docetaxel progression and was associated with a 3.9 month median overall survival improvement (10.9 months vs. 14.8 months). Unlike cabazitaxel, the phase I and phase II trials with abiraterone were highly publicized. The importance of this agent from a conceptual perspective is unquestioned. It conclusively demonstrated that patients with “castrate-resistant” disease were in fact sensitive to additional androgen deprivation and validated the androgen receptor (AR) as a target in the post-castration setting. The drug was well tolerated as a whole, and an FDA approval is anticipated in spring 2011. The validation of AR as a target has a number of ramifications and additional studies with AR-axis targeted therapies such as MDV3100, TAK700, TOK001, and ARN-509 are now under way. MDV3100 has completed accrual in its phase III trial postdocetaxel in mCRPC and is starting accrual in the pre-docetaxel mCRPC space. Similar trials are being done with TAK700 and prednisone versus prednisone alone. What are the next steps? Currently we do not know about optimal sequences of the new agents nor do we know whether they can or should be combined. It is likely that we will soon have 2 new ARaxis inhibiting agents (with more possibly on the way). Will they be cross-resistant or will they be non–cross-resistant? Comparative and sequential trials between abiraterone and MDV 3100 or others will likely be needed with assessment of both efficacy and toxicity endpoints. The combination of abiraterone and cabazitaxel may be intriguing since docetaxel may exert its effects in part through interruption of AR signaling.4 Does cabazitaxel have a similar action and could synergism be achieved post docetaxel? These new AR-axis targeting agents are destined to move to the pre-chemotherapy space based on their safety profile alone. When the abiraterone and MDV3100 trials in the pre-docetaxel space are reported, there will be level 1 support for such clinical movement. It is likely that the AR-axis agents will move even earlier in the disease spectrum. Groups such as Southwest Oncology Group (SWOG) and Radiation Therapy Oncology Group (RTOG) are considering trial designs to replace older anti-androgens with newer agents. What else is on the immediate horizon for mCRPC? Several trials are currently in the advanced stages. For instance, aflibercept (vascular endothelial growth factor trap), lenalidomide, and dasatinib each combined with docetaxel/prednisone are being compared to docetaxel/prednisone alone. A positive result with any one trial will change the landscape yet again. Newer immunotherapies are being tested and these include both the PSA-TRICOM vaccine Editorial