Targeting the Androgen Receptor in the Management of Castration-Resistant Prostate Cancer: Rationale, Progress, and Future Directions

Since the year 2000, tremendous progress has been made in the understanding of castration-resistant prostate cancer (CRPC), a disease state now recognized to retain androgen receptor (AR)—dependency in most cases. That understanding led to the rational design of novel therapeutic agents targeting hormonal pathways in metastatic crpc. Two new drugs—the CYP17 inhibitor abiraterone acetate and the potent AR antagonist enzalutamide—were recently shown to prolong overall survival after chemotherapy treatment in patients with metastatic disease, with the former agent also demonstrating impressive activity in the pre-chemotherapy setting. Other new drugs targeting the AR—as well as drugs targeting heat shock proteins that protect cytoplasmic AR from degradation—are currently undergoing clinical development. This review brief ly describes the molecular mechanisms underlying castration resistance and hormonal dependence in prostate tumours and summarizes the current ongoing and completed clinical trials that are targeting hormonal pathways in metastatic crpc. Potential mechanisms of resistance to these novel hormonal agents are reviewed. Finally, future research directions, including questions about drug sequencing and combination, are discussed.