Castration-resistant Prostate CanCer

• Objective: To review therapeutics for castrationresistant prostate cancer (CRPC). • Methods: Literature review. • Results: Targeting of androgen-dependent pathways in CRPC post-chemotherapy has been shown to improve survival with the lyase inhibitor abiraterone and lead to PSA and objective responses with an androgen receptor antagonist (MDV3100). However, the addition of bevacizumab to docetaxel/prednisone in treating metastatic CRPC failed to provide a survival benefit. Cabazitaxel in metastatic CRPC post-docetaxel did demonstrate a survival benefit. Provenge, an autologous dendritic cell-based vaccine, demonstrated a reduction in the risk of death in metastatic CRPC. Other immunotherapy agents, including Prostvac and ipilumumab, are under investigation. We also discuss the receptor tyrosine kinase inhibitor XL184 and poly (ADP-ribose) polymerase inhibitors which are in early clinical trials. • Conclusion: Recent advances in androgen targeting, chemotherapy, immunotherapy, and other targeted therapies have led to significant improvements in the care of CRPC patients. Castration-resistant prostate cancer (CRPC) is the second leading cause of cancer-related deaths in U.S. men, with approximately 30,000 deaths per year [1]. While metastatic CRPC remains an incurable disease, significant progress has been made in developing new therapeutics that prolong life. Targeting the androgen axis as well as the immune system has proven to improve outcomes. This article will discuss therapeutics that have demonstrated clinical benefits. Androgens/Androgen receptor signaling Studies have shown that intratumoral androgen levels remain high and androgen receptor activation persists in CRPC despite low levels of circulating androgens [2]. Montgomery et al [3] found that testosterone levels within metastases from anorchid men were significantly higher than levels within primary prostate cancers from eugonadal men. Other mechanisms of maintaining androgen receptor signaling in a low androgen environment (castration) include androgen receptor mutations [4], androgen receptor over-expression [5,6], androgen receptor splice variants [7], and changes in androgen receptor coregulatory proteins [8]. New therapies for prostate cancer with varied actions, including hormonal, targeted, immune, and cytotoxic, are rapidly emerging. For hormonal therapy, recent evidence suggests that continued targeting of androgen-dependent pathways is effective in CRPC even after treatment with chemotherapy. Clinical data now available for a C (17–20) lyase inhibitor (abiraterone) and an androgen receptor antagonist (MDV3100) show that both demonstrate favorable responses and, in the case of abiraterone, a survival advantage in CRPC following chemotherapy.