Beyond castration and chemotherapy: novel approaches to targeting androgen-driven pathways

In castrate-resistant prostate cancer, beyond chemotherapy, existing guidelines suggest only supportive care. However, recent evidence suggests that continued targeting of androgen-dependent pathways may be an efficacious approach. Clinical data is now available for two mechanistically distinct agents (abiraterone and MDV3100) that both ultimately target these pathways. Abiraterone is a potent and irreversible inhibitor of CYP17, a critical enzyme in androgen biosynthesis. Phase II studies indicate substantial declines in PSA amongst castrate-resistant patients treated with abiraterone, both prior to and following cytotoxic chemotherapy. In contrast to abiraterone, MDV3100 is a direct inhibitor of the androgen receptor, binding the receptor irreversibly with substantially higher affinity as compared to bicalutamide. A recent phase I/II trial of MDV3100 in castrate-resistant prostate cancer demonstrated tolerability of the agent with activity at the lowest dose level. On the basis of these compelling data, both abiraterone and MDV3100 will be examined in the phase III setting.