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Original Investigation
February 13, 2020

HSD3B1 Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer

Author Affiliations
  • 1Department of Radiation Oncology, University of Michigan, Ann Arbor
  • 2Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 3GU Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
  • 4Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio
  • 5Memorial Sloan Kettering Cancer Center, New York, New York
  • 6University of Texas MD Anderson Cancer Center, Houston
  • 7Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio
  • 8Cancer Biostatistics Section, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
  • 9Department of Medical Oncology, University of Wisconsin Hospital and Clinics, Madison
  • 10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 11University of Virginia Cancer Center, Charlottesville
  • 12Taussig Cancer Institute, Department of Hematology and Oncology, Cleveland Clinic, Cleveland, Ohio
  • 13Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland
  • 14Department of Medical Oncology, University of Kentucky, Lexington
JAMA Oncol. Published online February 13, 2020. doi:10.1001/jamaoncol.2019.6496
Key Points

Question  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?

Findings  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.

Meaning  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.

Abstract

Importance  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).

Objective  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.

Interventions  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.

Results  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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