Background The common HSD3B1 (1245C) germline variant encodes for a 3βHSD1 missense that increases enzyme activity that allows tumors to utilize extragonadal androgens and is a predictive biomarker of resistance to ADT and sensitivity to CYP17A1 inhibition by the nonsteroidal drug ketoconazole. However, 3βHSD is also the first enzyme necessary in the conversion from abiraterone, a steroidal CYP17A1 inhibitor, to 5α-abiraterone, which stimulates the androgen receptor (AR) and prostate cancer progression. The HSD3B1 (1245C) variant might therefore increase 5α-abiraterone synthesis in patients on abiraterone therapy, possibly limiting clinical benefit.

Significance This work aims to characterize the pharmacokinetics of steroidal metabolites of abiraterone and to determine the association between HSD3B1 genotype and the generation of 5α-abiraterone metabolites.

Patients and Methods Part 1: 15 healthy male volunteers received a single oral dose of 1000 mg abiraterone acetate plus 240 mg of the AR antagonist apalutamide, steroidal metabolites of abiraterone were quantitated at 12 time points from 0.5-96 hours post-dose. Part 2: 5α-abiraterone metabolites and HSD3B1 genotype was determine in 30 patients with castration-resistant prostate cancer (CRPC) on abiraterone therapy. Metabolite concentrations were normalized to the 8 hour time point of the pharmacokinetic study and the association between HSD3B1 genotype and 5α-abiraterone metabolites was determined.

Results There were 8, 19, and 3 pts with homozygous wild-type, heterozygous, and homozygous variant HSD3B1 genotypes. Patients who inherit 0, 1 and 2 copies of the HSD3B1 (1245C) variant have a stepwise increase in serum concentrations of 5α-abiraterone metabolites (p=0.002).

Conclusion The generation of 5α-abiraterone preferentially in patients with the HSD3B1 (1245C) variant might negate the benefits of abiraterone specifically in a patient subset that is otherwise more likely to benefit from CYP17A1 inhibition by the nonsteroidal drug ketoconazole.

Citation Format: Mohammad Alyamani, Hamid Emamekhoo, Sunho Park, Jennifer Taylor, Nima Almassi, Sunil Upadhyay, Allison Tyler, Michael P. Berk, Tae Hyun Hwang, Petros Grivas, Brian Rini, Jorge Garcia, Richard J. Auchus, Nima Sharifi. HSD3B1 genotype and abiraterone metabolism in patients with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2572.