HSD3B1 Variant and Response to Nonsteroidal CYP17A1 Inhibition in Castration-Resistant Prostate Cancer

Key Points

  • In men with metastatic castration-resistant prostate cancer, the median duration of ketoconazole therapy increased with the increasing number of variant alleles.
  • Median progression-free survival increased with the increasing number of variant alleles. 

As reported in JAMA Oncology by Almassi et al, extragonadal androgen ablation with the nonsteroidal CYP17A1 inhibitor ketoconazole improved outcome in men with metastatic castration-resistant prostate cancer according to the number of inherited HSD3B1 (1245C) alleles. HSD3B1 (1245C) is associated with faster progression to castration-resistant prostate cancer.

Study Details

The observational study included 90 patients treated with ketoconazole between June 1998 and December 2012 who had not received abiraterone before or during ketoconazole treatment. Data were available to determine the duration of ketoconazole treatment in 88 patients and the time to disease progression in 81 patients. Patients had a median age of 61.5 years.

Time to Disease Progression

The median duration of ketoconazole therapy increased with the number of inherited HSD3B1 (1245C) variant alleles: 5.0 months for 0 variant alleles (49% of patients), 7.5 months for 1 variant allele (38% of patients), and 12.3 months for 2 variant alleles (13% of patients; P = .01 for trend). Median progression-free survival according to the number of variant alleles was 5.4 months for 0 variant alleles, 9.7 months for 1 variant allele, and 15.2 months for 2 variant alleles (P = .03 for trend).

The investigators concluded: “Inheritance of the HSD3B1 (1245C) variant allele, which is a predictive biomarker of resistance to castration, is also a predictive biomarker of sensitivity to extragonadal androgen ablation with a nonsteroidal CYP17A1 inhibitor. These findings signal a possible pathway of treatment stratification for patients with prostate cancer.”

The study was supported by the Howard Hughes Medical Institute, the Prostate Cancer Foundation, the American Cancer Society, the U.S. Army Medical Research and Materiel Command, and the National Cancer Institute. A patent application has been filed by Cleveland Clinic for a method of steroid-dependent disease treatment based on HSD3B1. Nima Sharifi, MD, is listed as a co-inventor on this patent application.

Nima Sharifi, MD, of the Lerner Research Institute, Cleveland Clinic, is the corresponding author of the JAMA Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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