Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis(1,2). Abiraterone is metabolized in patients to Delta(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5 alpha-reductase substrates, such as testosterone(3). Here, we show that D4A is converted to at least three 5 alpha-reduced and three 5 beta-reduced metabolites in human serum. The initial 5 alpha-reduced metabolite, 3-keto-5 alpha-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5 alpha-reductase inhibitor), 3-keto-5 alpha-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5 beta-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5 alpha-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.