HSD3B1 and response to a nonsteroidal CYP17A1 inhibitor in castration-resistant prostate cancer

Nima Almassi, Chad Reichard, Jianbo Li, Carly Russell, Jaselle Perry, Charles J. Ryan, Terence Friedlander, Nima Sharifi

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

IMPORTANCE The HSD3B1 (1245C) germline variant encodes for a gain-of-function missense in 3β-hydroxysteroid dehydrogenase isoenzyme 1 (3βHSD1) that results in increased dihydrotestosterone synthesis from extragonadal precursors and is predictive of more rapid progression to castration-resistant prostate cancer (CRPC). OBJECTIVE To determine whether the HSD3B1 (1245C) genotype is predictive of clinical response to extragonadal androgen ablation with nonsteroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition in men with metastatic CRPC. DESIGN, SETTING, AND PARTICIPANTS An observational study of men with metastatic CRPC treated with ketoconazole between June 1998 and December 2012 was conducted at the University of California, San Francisco. EXPOSURES Extragonadal androgen ablation with the nonsteroidal CYP17A1 inhibitor ketoconazole among men with metastatic CRPC. MAIN OUTCOMES AND MEASURES The primary end points of analysis were duration of ketoconazole therapy and time to disease progression stratified by HSD3B1 genotype. Disease progression was defined as either biochemical or radiographic progression, using the Prostate Cancer Working Group 3 and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 definitions, respectively. Kaplan-Meier analysis was used to estimate time on therapy and time to disease progression. A log-rank test for trend was used to compare outcomes by HSD3B1 genotype. RESULTS A total of 90 men (median [interquartile range] age, 61.5 [55.3-67.0] years) with metastatic CRPC were included in the analysis, with sufficient data to determine duration of ketoconazole therapy and time to disease progression in 88 and 81 patients, respectively. The median duration of therapy increased with the number of inherited HSD3B1 (1245C) variant alleles: 5.0 months (95% CI, 3.4-10.4) for 0 variant alleles; 7.5 months (95% CI, 4.9-19.2) for 1; and 12.3 months (95% CI, 1.8-not reached) for 2 (overall comparison for trend, P = .01). Median progression-free survival also increased with number of HSD3B1 (1245C) variant alleles inherited: 5.4 months (95% CI, 3.7-7.5) for 0 variant alleles; 9.7 months (95% CI, 5.6-32.9) for 1; and 15.2 months (95% CI, 7.8-not reached) for 2 (overall comparison for trend, P = .03). CONCLUSIONS AND RELEVANCE 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.

Original languageEnglish (US)
Pages (from-to)554-557
Number of pages4
JournalJAMA Oncology
Volume4
Issue number4
DOIs
StatePublished - Apr 2018

Bibliographical note

Funding Information:
Funding/Support: This work was supported by a grant from a Howard Hughes Medical Institute Physician-Scientist Early Career Award (to Dr Sharifi), a grant from the Prostate Cancer Foundation (to Dr Sharifi), an American Cancer Society Research Scholar Award (to Dr Sharifi), a grant from the US Army Medical Research and Materiel Command (grant No. W81XWH-09-1-0301 to Dr Sharifi), and additional grants from the National Cancer Institute (grant No. R01CA172382, R01CA190289, and R01CA168899 to Dr Sharifi).

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