Hormonal therapy for prostate cancer: toward further unraveling of androgen receptor function

Prostate cancer is a major cause of cancer-related death in men. Prostate cancer is an androgen-responsive tumor and the treatment of advanced prostate cancer involves hormonal therapy. First-line treatment for advanced prostate cancer is androgen deprivation therapy (ADT), usually with agents that suppress gonadotropins through a pituitary mechanism. Gonadotropin-releasing hormone agonists and antagonists both suppress gonadal release of testosterone, although their activity profiles vary. ADT down-regulates androgen receptor (AR) transcriptional activity in the tumor but the response in metastatic disease is transient and tumors progress as castration-resistant prostate cancer (CRPC). Although serum testosterone concentrations decline dramatically with ADT, CRPC growth remains largely dependent on AR activity. Secondary hormonal therapies are then often employed to further dampen AR-driven transcription. These secondary hormonal therapies either further deplete adrenal or intratumoral androgen synthesis, or directly and competitively antagonize AR. New hormonal agents with both of these mechanisms are in clinical trials and show promising activity in patients with CRPC. Abiraterone acetate is an inhibitor of CYP17, which is an enzyme required for the synthesis of all androgens and estrogens. MDV3100 is an AR antagonist that has a higher affinity for AR than any other AR antagonist in clinic use. In phase I and phase II clinical trials, both agents have significant activity. These agents and the promise of the development of others provide hope that more effective hormonal therapies may soon be offered to patients, which will improve clinical outcomes.