Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy.

ABSTRACT: Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to ?(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5?-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5?-reduced and three 5?-reduced metabolites in human serum. The initial 5?-reduced metabolite, 3-keto-5?-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?-reductase inhibitor), 3-keto-5?-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?-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5?-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.

SUBMITTER: Li Z 

PROVIDER: S-EPMC5111629 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature