New agents and strategies for the hormonal treatment of castration-resistant prostate cancer

Importance of the field: Hormonal therapy with medical or surgical castration is the mainstay of systemic therapy for advanced prostate cancer. Depletion of gonadal testosterone in circulation is typically initially effective, although responses are transient and metastatic disease progresses as castration-resistant prostate cancer (CRPC). Areas covered in this review: CRPC is accompanied by a gain of function in the androgen receptor (AR), which may occur at the level of AR itself or through intratumoral repletion of androgens that in turn stimulate AR. Investigational drugs in clinical trials have promising activity in CRPC. Abiraterone acetate is a CYP17A1 inhibitor that blocks the synthesis of adrenal androgens. MDV3100 is a nonsteroidal AR antagonist with a greater binding affinity than other AR antagonists currently in clinical use. Insights into the mechanisms of intratumoral steroidogenesis in CRPC have defined other potential targets. Metabolism from DHEA to testosterone and dihydrotestosterone requires 3-hydroxyl oxidation and Δ⁵ isomerization to Δ⁴ by 3β-hydroxysteroid dehydrogenase (3βHSD) and 17-keto reduction by 17β-hydroxysteroid dehydrogenase (17βHSD)-3 or-5. AR activation in CRPC by intratumoral steroids requires these enzymatic steps. Investigation into specific inhibitors of 3βHSD and 17βHSD are required to determine their efficacy and potential roles in the treatment of CPRC. What the reader will gain: Readers will gain an understanding of the biology of CRPC, new investigational hormonal agents and novel approaches to the treatment of CRPC. Take home message: Intratumoral androgens drive CRPC progression. New investigational hormonal agents that inhibit intratumoral androgens are highly active in the treatment of CRPC. Alternative strategies hold the promise for the development of other agents with novel mechanisms of action.