Abiraterone in prostate cancer: a new angle to an old problem

Abstract

Abiraterone acetate is an orally administered potent inhibitor of cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17), which is essential for synthesis of testosterone from cholesterol. Although decreasing serum testosterone through inhibition of testicular function is the first line of treatment for men with metastatic prostate cancer, residual androgens may still be detected in patients treated with luteinizing hormone-releasing hormone agonists or antagonists. Treatment with abiraterone results in rapid, and complete, inhibition of androgen synthesis in the adrenal glands and potentially within the tumor itself. An overall survival benefit of maximal androgen suppression was recently shown in a randomized placebo-controlled phase III clinical trial of abiraterone with prednisone versus prednisone in men with metastatic castrate-resistant prostate cancer previously treated with docetaxel chemotherapy. Abiraterone's efficacy shows the importance of androgen signaling in patients with castrate-resistant metastatic disease, with additional confirmation from recent studies of other novel agents such as MDV3100, an androgen receptor signaling inhibitor. These promising results now pose a new angle to an old problem about hormonal therapy and raise new questions about how resistance develops, how to best sequence therapy, and how to optimize combinations with other emerging novel agents.

Figure 1

Therapies targeting the androgen signaling axis. Abiraterone is a potent and selective inhibitor of CYPc17, blocking synthesis of testosterone and DHT. Other agents such as MDV3100 target the AR directly. Resistance to abiraterone is proposed to occur through upregulation of intratumoral CYPc17 and other genes involved in synthesis of intratumoral androgens to restore DHT levels and through increased levels of AR receptor and receptor splice variants. Abiraterone resistance pathways are depicted in red, agents that may be combined with abiraterone are indicated in blue.