HSD3B1 genotype and abiraterone (Abi) metabolites in patients (pts) with prostate cancer (PCa).

Abstract

325 Background: Abi, a potent inhibitor of 17α-hydroxylase/17,20-lyase (CYP17A1), is an oral treatment option for metastatic PCa in castration-resistant and -sensitive settings. Abi is converted to ∆4, 3-keto-abi (D4A) by 3β-hydroxysteroid dehydrogenase (3βHSD). D4A is further metabolized to multiple downstream steroidal metabolites including 3-keto-5α-Abi (5αA), which is an androgen receptor (AR) agonist and might affect response and/or resistance to Abi. The common HSD3B1(1245C) germline variant encodes for a 3βHSD 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. However, the more active 3βHSD protein might increase 5αA synthesis, possibly limiting the clinical benefit of Abi. Methods: Blood was collected from CRPC pts on Abi and drug metabolites (MA) were extracted from serum, and analyzed by mass spectrometry. To correct for pharmacokinetics (PK) of time from last dose to blood draw in this cohort, data were normalized to the 8-hour time point of a separate PK study of Abi MAs and grouped by HSD3B1 genotype. HSD3B1 genotype was determined using germline DNA. Results: Abi MAs were evaluated in the sera of 30 CRPC pts on Abi. Abi, D4A, 5αA, were detectable in the sera of all pts. There were 8, 19, and 3 pts with homozygous wild-type, heterozygous, and homozygous variant HSD3B1 genotypes. HSD3B1 variant allele inheritance was associated with a statistically significant increase in 5αA concentrations, with highest concentration of 5αA MAs observed in homozygous variant HSD3B1 pts (Table). Conclusions: Germline HSD3B1 variant genotype is associated with higher 5αA metabolites with possible implications for AR stimulation and adverse clinical outcomes on Abi. [Table: see text]