The adrenal-permissive HSD3B1 genotype is associated with worse clinical outcomes in men with metastatic castration-sensitive prostate cancer, according to an analysis of data from a clinical trial. Carrying one or more copies of the allele is associated with a shorter interval from androgen-deprivation therapy "to castration-resistant prostate cancer, as well as shorter overall survival, in men with low-volume metastatic prostate cancer," Dr. Nima Sharifi of Cleveland Clinic, in OH, told Reuters Health by email. The HSD3B1(1245C) adrenal-permissive allele encodes a stable enzyme that allows for more robust conversion from dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT), whereas the adrenal-restrictive HSD3B1(1245A) allele encodes a more rapidly degraded enzyme that limits conversion from DHEA to DHT. Retrospective studies have linked inheritance of the adrenal-permissive allele to worse clinical endpoints. Dr. Sharifi and colleagues analyzed outcomes in white men enrolled in the E3805 CHAARTED trial according to HSD3B1 genotype, hypothesizing that accentuated extragonadal DHT synthesis associated with the adrenal-permissive allele would be associated with more rapid development of castration-resistant prostate cancer (CRPC) and lower overall survival. Among the 475 white men included in the study, 56.8% had the adrenal-permissive genotype, vs only 13.5% of nonwhite men. Most men (n=301) had high-volume disease, and 174 had low-volume disease. Freedom from CRPC at two years was significantly lower in men with low-volume disease with the adrenal-permissive genotype (51.0%) vs the adrenal-restrictive genotype (70.5%), the researchers report in JAMA Oncology. In multivariable analysis, the adrenal-permissive genotype was associated with 89% higher risk of CRPC. In contrast, there was no significant difference based on HSD3B1 genotype in freedom from CRPC at 2 years in men with high-volume disease. Overall survival at 5 years was significantly worse in men with low-volume disease who had the adrenal-permissive genotype (57.5%) than in those with the adrenal-restrictive genotype (70.8%). But there was no significant difference in overall survival by genotype in men with high-volume disease. Men with low-volume disease did not benefit significantly from docetaxel, but men with high-volume disease did benefit, regardless of HSD3B1 genotype. "We need additional information before routine testing is suggested," Dr. Sharifi said. "Broadly, HSD3B1 genotyping tells us how much an individual man's tumor is dependent on extragonadal (or adrenal) androgens. Additional analyses that are planned in other clinical trials will help us determine how best to use this information for clinical management." —Will Boggs MD
