HSD3B1 (1245A>C) germline variant and clinical outcomes in metastatic castration-resistant prostate cancer patients treated with abiraterone and enzalutamide: results from two prospective studies

Abstract

Background: A common polymorphism (1245A>C) in the HSD3B1 gene is associated with increased de novo synthesis of androgens and worse outcomes in men treated with androgen-deprivation therapy for metastatic castrationsensitive prostate cancer. The objective of the study was to determine whether this polymorphism is associated with outcomes for metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide. Patients and methods: A total of 547 patients treated with abiraterone or enzalutamide from two prospective cohorts were evaluated. The HSD3B1 genotype was determined by targeted sequencing and/or TaqMan single-nucleotide polymorphism genotyping. In cohort 1, patients were randomized to receive abiraterone þ prednisone or enzalutamide. In cohort 2, patients received either agent according to investigator's choice. Prostate-specific antigen (PSA) response rate, time to PSA progression (TTPP), time to progression (TTP) and overall survival were determined. Associations between HSD3B1 genotypes and outcomes were evaluated via univariate Cox regression. Multivariable Cox model was used to determine the independent association of each covariate. Results: The HSD3B1 variant genotype (CC) was present in 15% of patients and was associated with worse TTP [hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.02e1.67, P ¼ 0.032] and PSA response rates (48% for CC versus 62% and 65% for AA and AC, respectively [P ¼ 0.019]), with no significant difference in TTPP (HR 1.28, 95% CI 0.99e1.66, P ¼ 0.064). The effect of genotype was similar for treatment with abiraterone or enzalutamide with a negative test for interaction for TTPP (P ¼ 0.997) and TTP (P ¼ 0.749). Multivariable analysis did not show a significant association between genotype and TTP or TTPP. Conclusions: The HSD3B1 (CC) genotype was associated with shorter TTP and lower PSA response rate in patients with mCRPC treated with abiraterone or enzalutamide. However, the CC genotype did not provide prognostic information beyond that conferred by standard clinical variables, suggesting that it may not be a suitable stand-alone biomarker in mCRPC.

Clinical impact of HSD3B1 polymorphism by metastatic volume and somatic HSD3B1 alterations in advanced prostate cancer

“…In addition, HSD3B1 genetic amplification was observed in some cases with metastatic tumour and CRPC, which lead to increased 3β-hydroxysteroid dehydrogenase resulting in castration resistance by both wild type and variant type (Chang et al, 2013). Thus, for the first time, this study suggested that dehydrogenase might be implicated in anticancer efficacy by abiraterone treatment (Almassi et al, 2018;Alyamani et al, 2018;Khalaf et al, 2020;Li et al, 2015;Lu et al, 2020;Shiota, Narita, et al, 2019). Therefore, testing for somatic alteration in addition to germline genotyping in HSD3B1 would be important for precision medicine.…”

“…Meanwhile, as distinct mechanism of 3β‐hydroxysteroid dehydrogenase overexpression, loss of heterozygosity by deletion of wild‐type HSD3B1 has been found in cases with heterozygous inheritance, which was shown to result in abundant expression of variant‐type 3β‐hydroxysteroid dehydrogenase (Chang et al, 2013). In addition, enzymatic activity of 3β‐hydroxysteroid dehydrogenase might be implicated in anticancer efficacy by abiraterone treatment (Almassi et al, 2018; Alyamani et al, 2018; Khalaf et al, 2020; Li et al, 2015; Lu et al, 2020; Shiota, Narita, et al, 2019). Therefore, testing for somatic alteration in addition to germline genotyping in HSD3B1 would be important for precision medicine.…”

Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer

“…The adrenal permissive variant of HSD3B1 (promotes conversion of AED and T to downstream androgens, and of abiraterone to D4 abiraterone and 3-keto-5α-abiraterone) has been consistently associated with more rapid progression on ADT (39), and potentially with worse outcomes in response to AA and enzalutamide in some but not all studies (40)(41)(42)(43).…”

Inhibiting 3βHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer

“…Patients with higher plasma levels of progesterone after abiraterone treatment might have more potent activity of 3βHSD1, which has been reported as a risk factor of treatment failure. 69 , 70 However, the patients enrolled in this real-world analysis were not as rigorously examined as patients enrolled in clinical trials, and the patient number should be increased to confirm the role of progesterone as a predictive biomarker for the response to abiraterone.…”