HSD3B1 polymorphism in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate and prednisone (AAP): Pharmacodynamics and therapeutic implications.

Abstract

140 Background: AAP prolongs survival in pts with mCRPC. Although it is widely used for mCRPC, no predictive biomarker for response has been identified so far. Methods: This study evaluated HSD3B1 genetic polymorphism and pharmacodynamic parameters from serum samples of mCRPC pts with disease progression after diethylstilbestrol (DES) treated with AAP in the AAP-DES study (NCT02217566). Peripheral blood samples were collected before initiating AAP therapy, after 12 weeks, and at disease progression. Sample analysis included HSD3B1 genotyping, abiraterone acetate (AbA) and D4-abiraterone serum levels, testosterone and dehydroepiandrosterone sulfate (DHEA-S) ultrasensitive analysis. Clinical characteristics, overall survival (OS), progression-free survival (PFS) and the rate of PSA decline ≥ 50% were assessed considering homozygous wild-type (AA) versus heterozygous variant (AC) + homozygous variant (CC) HSD3B1 genotypes. Results: Serum samples of 42 pts were analyzed. AA and AC + CC HSD3B1 genotypes were 50.0% each (95% CI:34.2-65.8). Mean ages at baseline was significantly higher in the AA group (71.1 years) compared to the AC+CC group (66.3 years) (p=0.047). Gleason score ≥8 was observed for 38.1% and 47.6% of AA and AC+CC genotypes, respectively (p<0.001). No statistically significant difference was observed between AA and AC+CC groups related to testosterone and DHEA-S level at baseline, week 12, and PSA progression. Serum levels of AbA and D4-abiraterone were similar, throughout treatment despite HSD3D1 genotype. Median OS was 21.3 months (95% CI: 14.8 - ; 14 events) for the AA genotype, and it was not reached at the AC+CC genotype group (9 events) (p=0.154). Regarding PFS, median estimates were 7.3 months (95% CI: 4.6 – 9.4; 16 events) for AA genotype and 7.9 months (95% CI: 5.6 – 14.4; 16 events) for AC+CC genotype (p=0.519). PSA decline ≥ 50% was 71.4% for AA genotype and 42.9% for AC+CC genotypes and the chance of PSA response in patients with AA genotype is 3.33 (95% CI: 0.93; 12.11) times greater than that in patients with AC or CC genotypes, despite not statistically significant differences (p=0.0614). Conclusions: In our study, the presence of HSD3B1 (1245C) was not significantly associated with clinical response during AAP treatment, as well as testosterone, DHEA-S, AbA and D4-abiraterone levels. The role of HSD3B1 polymorphism to predict clinical outcome of AR blockade for mCRPC patients still needs to be further analyzed in larger translational studies. [Table: see text]