Quo vadis: advanced prostate cancer-clinical care and clinical research in the era of multiple androgen receptor-directed therapies

The novel androgen receptor-directed therapies abiraterone acetate and enzalutamide, having demonstrated improved survival in randomized phase 3 studies of men with metastatic castration-resistant prostate cancer, have ushered in a new era in the treatment of this disease. Additional novel androgen receptor-directed therapies, such as ARN-509 and orteronel, are in various phases of clinical trials and development. However, the emergence of therapeutic resistance and clinical disease progression is inevitable. Although advances in genomic technologies have led to unprecedented understanding of the biology of castration-resistant prostate cancer, efforts only now are underway to elucidate the mechanisms of resistance associated with abiraterone and enzalutamide. A tremendous challenge in the near future will be to determine the optimal sequence or combination of therapies to overcome resistance mechanisms. In this review, the current landscape of androgen receptor-directed therapies and future directions necessary to enhance their clinical efficacy for the maximal benefit of patients are discussed.