Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born

Abstract

The number of life-prolonging therapies proven effective in the treatment of metastatic castrate-resistant prostate cancer (CRPC) has been limited until recently. In the past 2 years several such therapies have come to market. In 2010, the autologous immunotherapy sipuleucel-T and the next-generation taxane cabazitaxel were approved in this setting. However, abundant evidence has shown that CRPC growth continues to be driven through androgen-dependent signaling. Both of these drugs fail to take advantage of this targetable oncogenic pathway. Potent specific inhibitors of cytochrome P450-17 have been engineered with the aim of suppressing androgen synthesis beyond that seen with the luteinizing hormone-releasing hormone agonists/antagonists. Abiraterone acetate was developed by rational design based on a pregnenolone parent structure. Its approval by the US Food and Drug Administration (FDA) was granted in 2011 based on phase III data demonstrating an overall survival advantage compared with placebo. More recently, other drugs that act along the androgen signaling pathway, such as orteronel (TAK-700), galeterone (TOK-001), enzalutamide (MDV3100) and ARN-509, have shown promise in clinical trials. Some of these are expected to gain FDA approval in the near future. Here, we review abiraterone and other novel androgen-directed therapeutic strategies for the management of advanced prostate cancer.

Keywords: abiraterone; androgen; androgen receptor; enzalutamide; galeterone; orteronel; prostate cancer.

Figure 1.

Drug targets involving the androgen–androgen receptor pathway. ACTH, adrenocorticotropic hormone; AR, androgen receptor; ARE, androgen response element; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone.

Figure 2.

Steroid/androgen synthesis pathway and the sites of inhibition of ketoconazole (keto), abiraterone (abi), TAK-700, TOK-001 and the 5-α-reductase inhibitors (5α-RIs). A, androgen pathway; ACTH, adrenocorticotropic hormone; CYP17, cytochrome P450-17; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; G, glucocorticoid pathway; M, mineralocorticoid pathway.