Targeting the Adrenal Gland in Castration-Resistant Prostate Cancer: A Case for Orteronel, a Selective CYP-17 17,20-Lyase Inhibitor

Androgen and the androgen receptor (AR) pathway remain the key targets for emerging new therapies against castration-resistant prostate cancer (CRPC). Adrenal androgens and intratumoral testosterone production appear to be sufficient to activate AR in the castration-resistant setting. This process re-engages AR and allows it to continue to be the primary target responsible for prostate cancer progression. Adrenal androgen production can be blocked by inhibiting cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), a key enzyme for androgen synthesis in adrenal glands and peripheral tissues. Therapeutic CYP17 inhibition by ketoconazole or by the recently approved adrenal inhibitor abiraterone acetate is the only available choice to target this pathway in CRPC. A new CYP17 inhibitor, with more selective inhibition of 17,20-lyase over 17α-hydroxylase, orteronel (TAK-700), is currently undergoing phase III clinical trials in pre- and postchemotherapy CRPC. In a completed phase II trial in CRPC patients, orteronel demonstrated its efficacy by lowering the levels of circulating androgens, reducing prostate-specific antigen (PSA) levels, and decreasing the levels of circulating tumor cells. Ongoing studies evaluating orteronel in CRPC will further define its safety and role in the management of this disease.