Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis1,2. Abiraterone is metabolized in patients to Δ4-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone3. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-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 5α-reductase inhibitor), 3-keto-5α-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 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 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.
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Gene Expression Omnibus
Microarray results have been deposited in the NCBI Gene Expression Omnibus database under accession number GSE75387.
We thank T. Penning for use of the AKR1C2 construct and D. Russell for LY191704. This work was supported in part by funding from a Howard Hughes Medical Institute Physician-Scientist Early Career Award (to N.S.), a Prostate Cancer Foundation Challenge Award (to N.S.), an American Cancer Society Research Scholar Award (12-038-01-CCE; to N.S.), grants from the National Cancer Institute (R01CA168899, R01CA172382, and R01CA190289; to N.S.), a grant from the US Army Medical Research and Materiel Command (PC121382 to Z.L.), a Prostate Cancer Foundation Young Investigator Award (to Z.L.), grants from the National Cancer Institute (P01 CA163227 and P50 CA090381), and a Prostate Cancer Foundation Challenge Award (to S.P.B.). Janssen provided clinical trial support (to M.-E.T.).
Extended data figures
This file contains Supplementary Methods and Supplementary Table 1.
About this article
Nature Reviews Urology (2017)