Clinical and Biochemical Consequences of CYP17A1 Inhibition with Abiraterone Given with and without Exogenous Glucocorticoids in Castrate Men with Advanced Prostate Cancer

Context: Abiraterone acetate is a small-molecule cytochrome P450 17A1 (CYP17A1) inhibitor that is active in castration-resistant prostate cancer. Objective: Our objective was to determine the impact of abiraterone with and without dexamethasone treatment on in vivo steroidogenesis. Design and Methods: We treated 42 castrate, castration-resistant prostate cancer patients with continuous, daily abiraterone acetate and prospectively collected blood and urine before and during abiraterone treatment and after addition of dexamethasone 0.5 mg daily. Results: Treatment with single-agent abiraterone acetate was associated with accumulation of steroids with mineralocorticoid properties upstream of CYP17A1. This resulted in side effects, including hypertension, hypokalemia, and fluid overload, in 38 of 42 patients that were generally treated effectively with eplerenone. Importantly, serum and urinary androgens were suppressed by more than 90% from baseline. Urinary metabolites of 17-hydroxypregnenolone and 17-hydro...