Does inheritance of the adrenal-permissive HSD3B1(1245C) allele indicate probable worse clinical outcomes in men treated with androgen deprivation therapy with or without docetaxel for metastatic castration-sensitive prostate cancer?
In this study including 475 genotyped white men with metastatic prostate cancer treated in the E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer trial, the adrenal-permissive genotype (ie, inheritance of ≥1 HSD3B1[1245C] allele) was associated with significantly shorter time to castration-resistant disease and significantly lower overall survival in men with low-volume disease. There was no association between genotype and outcomes in men with high-volume disease.
The adrenal-permissive genotype is associated with inferior outcomes in low-volume metastatic prostate cancer and may help identify patients who could benefit from escalated therapy.
The adrenal-restrictive HSD3B1(1245A) allele limits extragonadal dihydrotestosterone synthesis, whereas the adrenal-permissive HSD3B1(1245C) allele augments extragonadal dihydrotestosterone synthesis. Retrospective studies have suggested an association between the adrenal-permissive allele, the frequency of which is highest in white men, and early development of castration-resistant prostate cancer (CRPC).
To examine the association between the adrenal-permissive HSD3B1(1245C) allele and early development of CRPC using prospective data.
Design, Setting, and Participants
The E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a large, multicenter, phase 3 trial of castration with or without docetaxel treatment in men with newly diagnosed metastatic prostate cancer. From July 28, 2006, through December 31, 2012, 790 patients underwent randomization, of whom 527 had available DNA samples. In this study, the HSD3B1 germline genotype was retrospectively determined in 475 white men treated in E3805 CHAARTED, and clinical outcomes were analyzed by genotype. Data analysis was performed from July 28, 2006, to October 17, 2018.
Men were randomized to castration plus docetaxel, 75 mg/m2, every 3 weeks for 6 cycles or castration alone.
Main Outcomes and Measures
Two-year freedom from CRPC and 5-year overall survival, with results stratified by disease volume. Patients were combined across study arms according to genotype to assess the overall outcome associated with genotype. Secondary analyses by treatment arm evaluated whether the docetaxel outcome varied with genotype.
Of 475 white men with DNA samples, 270 patients (56.8%) inherited the adrenal-permissive genotype (≥1 HSD3B1[1245C] allele). Mean (SD) age was 63 (8.7) years. Freedom from CRPC at 2 years was diminished in men with low-volume disease with the adrenal-permissive vs adrenal-restrictive genotype: 51.0% (95% CI, 40.9%-61.2%) vs 70.5% (95% CI, 60.0%-80.9%) (P = .01). Overall survival at 5 years was also worse in men with low-volume disease with the adrenal-permissive genotype: 57.5% (95% CI, 47.4%-67.7%) vs 70.8% (95% CI, 60.3%-81.3%) (P = .03). Hazard ratios were 1.89 (95% CI, 1.13-3.14; P = .02) for CRPC and 1.74 (95% CI, 1.01-3.00; P = .045) for death. There was no association between genotype and outcomes in men with high-volume disease. There was no interaction between genotype and benefit from docetaxel.
Conclusions and Relevance
Inheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.
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Hearn JWD, Sweeney CJ, Almassi N, et al. HSD3B1 Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer. JAMA Oncol. Published online February 13, 2020. doi:10.1001/jamaoncol.2019.6496
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