Abstract and Introduction
Abstract
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years. Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved. A number of other agents appear promising in early studies, suggesting that the armamentarium against castrate-resistant prostate cancer is likely to continue to expand. Emerging androgen pathway inhibitors include androgen synthesis inhibitors (TAK700), androgen receptor inhibitors (ARN-509, ODM-201), AR DNA binding domain inhibitors (EPI-001), selective AR downregulators or SARDs (AZD-3514), and agents that inhibit both androgen synthesis and receptor binding (TOK-001/galeterone). Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab). Biologic agents targeting the molecular drivers of disease are also being investigated as single agents, including cabozantinib (Met and VEGFR2 inhibitor) and tasquinimod (angiogenesis and immune modulatory agent). Despite the disappointing results seen from studies evaluating docetaxel in combination with other agents, including GVAX, anti-angiogentic agents (bevacizumab, aflibercept, lenalinomide), a SRC kinase inhibitor (dasatinib), endothelin receptor antagonists (atrasentan, zibotentan), and high-dose calcitriol (DN-101), the results from the trial evaluating docetaxel in combination with the clusterin antagonist, custirsen, are eagerly awaited. New therapeutic hurdles consist of discovering new targets, understanding resistance mechanisms, the optimal sequencing and combinations of available agents, as well as biomarkers predictive for benefit. Novel agents targeting bone metastases are being developed following the success of zoledronic acid and denosumab. Finally, all of these modalities do not appear curative, suggesting that clinical trial enrollment and a better understanding of biology remain of paramount importance.
Introduction
Until 2010, the only systemic regimen known to extend survival in men with metastatic castration-resistant prostate cancer (mCRPC) was docetaxel-based chemotherapy. Since April 2010, five new agents have been approved in the United States based on an extension of survival including sipuleucel-T, cabazitaxel, abiraterone acetate (AA), enzalutamide, and radium-223. Sipuleucel-T (for minimally symptomatic disease), radium-223 (for docetaxel-ineligible or post-docetaxel symptomatic bone metastases without visceral metastases), and AA are available for both chemonaive and post-docetaxel patients, while cabazitaxel and enzalutamide are currently available only for post-docetaxel patients in the United States.
Despite the dramatic expansion in the therapeutic armamentarium, all of the aforementioned agents provide incremental gains and extend median survival by 3–5 months. Hence, there is a need to better understand the biology of the disease and to develop more effective agents. This review highlights the ongoing efforts to make further gains, following the success of the first wave of new agents we have summarized earlier.