Li, ZhenfeiAlyamani, MohammadLi, JiannengRogacki, KevinAbazeed, MohamedUpadhyay, Sunil K.Balk, StevenTaplin, Mary-EllenAuchus, Richard J.Sharifi, Nima2016-12-022016Li, Zhenfei, Mohammad Alyamani, Jianneng Li, Kevin Rogacki, Mohamed Abazeed, Sunil K. Upadhyay, Steven P. Balk, Mary-Ellen Taplin, Richard J. Auchus, and Nima Sharifi. 2016. “Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy.” Nature 533 (7604): 547-551. doi:10.1038/nature17954. http://dx.doi.org/10.1038/nature17954.0028-0836http://nrs.harvard.edu/urn-3:HUL.InstRepos:29626087Abiraterone blocks androgen synthesis and prolongs survival in castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis1,2. Abiraterone is metabolized in patients to D4A, which has even greater anti-tumor activity and structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone3. Here, we show that D4A is converted to at least 3 5α-reduced and 3 5β-reduced metabolites. The initial 5α-reduced metabolite, 3-keto-5α-abi, is more abundant than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abi and downstream metabolites are depleted, while D4A concentrations rise, effectively blocking production of a tumor-promoting metabolite and permitting D4A accumulation. Furthermore, dutasteride does not deplete three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacologic 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.en-USJournal Article2016-12-0210.1038/nature17954