Inherited variants in SRD5A genes and response to hormonal therapy in prostate cancer (SWOG S1216)

BackgroundSteroid 5α-reductase isoenzymes, encoded by the SRD5A1, SRD5A2, and SRD5A3 genes, catalyze the conversion of testosterone to the more potent androgen, 5α-dihydrotestosterone (DHT). Inherited variants in SRD5A genes may influence DHT availability, especially under castrate testosterone levels produced by androgen deprivation therapy (ADT), and thus may potentially impact disease progression.MethodsParticipants were men with metastatic castration sensitive prostate cancer enrolled in SWOG S1216, a phase III randomized multicenter clinical trial of ADT with a CYP17,20 lyse inhibitor (TAK-700) or an androgen receptor inhibitor (bicalutamide). Inherited variants (17 variants in SRD5A1, 19 in SRD5A2, and 5 in SRD5A3) were assayed using the Illumina Global Diversity Array. Associations with progression free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and Cox proportional hazards models. Associations with 7 month PSA response (<= 0.2, 0.2-4.0, >4.0 ng/ml) were analyzed using ordinal Chi-Square tests and multinomial logistic regression models. All models were adjusted for treatment arm, extent of disease at study entry (extensive v. minimal), Zubrod performance status, and ADT status at baseline (already initiated or not).ResultsOf 364 men with genotype data, 38 (10.4%) carried variant alleles on one or more of the SRD5A genes and 25 (66%) of these men carried variant alleles on all three genes. Variant allele carriers had shorter PFS (HR=3.6; 95% CI 2.5-5.3; p<0.001) and were less likely to experience complete PSA response to treatment (p=0.006). For OS there was a statistically significant interaction between treatment arm and variant allele status (p=0.02). Among those in the TAK-700 arm, median OS was 25.5 months for variant carriers vs. 94.7 months for non-carriers (HR=5.4; 95% CI 2.9-10.1; p<0.001). The association was weaker in the Bicalutamide arm: median OS was 39.7 months for variant carriers vs. 86.1 months for non-carriers (HR=1.9; 95% CI 1.1-3.1; p=0.02).ConclusionsMen carrying SRD5A gene variants may experience worse outcomes in response to hormonal therapy, especially when ADT is combined with a selective CYP17,20 lyase inhibitor.Legal entity responsible for the studySWOG (Southwest Oncology Group).FundingNIH/NCI.DisclosureAll authors have declared no conflicts of interest.