<i>HSD3B1</i> and overall survival (OS) in high-risk non-metastatic (M0) and metastatic (M1) prostate cancer starting androgen deprivation therapy (ADT) in the enzalutamide (ENZ) and abiraterone acetate plus prednisolone (AAP) STAMPEDE phase 3 trial.

234 Background: The HSD3B1 gene encodes for the 3βHSD1 enzyme which regulates the rate-limiting step in potent androgen synthesis from non-gonadal precursors. The missense-encoding adrenal-permissive form of HSD3B1 generates a hyperactive 3βHSD1 enzyme compared to the adrenal-restrictive form. We aimed to test associations with OS for HSD3B1 genotyped patients randomized 1:1 to ADT vs. ADT+ENZ+AAP in the STAMPEDE platform protocol. Methods: HSD3B1 genotype was performed in germline DNA using a validated melting assay. We included patients who donated saliva or white blood cells for translational studies and were not planned for “triplet therapy with” docetaxel. Association between HSD3B1 gene and overall survival was estimated using Cox survival models adjusted for randomised group, age at randomization, WHO performance status, regular aspirin or NSAID use, planned radiotherapy and metastatic disease status. Predictive effect was estimated with the addition of an interaction term. We pre-specified M1 low volume as of primary interest given prior associations in the CHAARTED trial. Results: Germline HSD3B1 genotype was obtained for 259 men in the ADT arm and 335 men in the ADT+ENZ+AAP arm (594 total). 319 (54%) men were adrenal-permissive and 275 were adrenal-restrictive. Adrenal-permissive HSD3B1 was associated with shorter OS (HR, 1.32 [1.04-1.67, p=0.025]), which by pre-specified sub-group analysis was most strongly prognostic in low volume (N=185, HR 1.70 [1.12-2.59], p=0.012) versus M0 (N=248, HR 1.21 [0.74-1.96], p=0.442) or M1 high volume (N=161, HR 1.14 [0.78-1.67] p=0.490) Although, there was no evidence of an interaction between treatment arm and genotype (p=0.800, 0.231 and 0.480 for M0, M1 LV and M1 HV, respectively), the treatment effect in the M1 LV restrictive group was 0.37 [0.19, 0.71] versus 0.7 [0.41, 1.21] in the permissive group. Conclusions: Adrenal-permissive HSD3B1 inheritance is associated with increased risk of death in men starting long-term ADT ± ENZ+AAP in STAMPEDE. This result is consistent with prior analyses of the CHAARTED trial and prostatectomy cohorts. This effect is most notable in M1 LV and not overcome by addition of ENZ+AAP to ADT.