Research JAMA Oncology | Brief Report HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer Nima Almassi, MD; Chad Reichard, MD; Jianbo Li, PhD; Carly Russell, MS; Jaselle Perry, MS; Charles J. Ryan, MD; Terence Friedlander, MD; Nima Sharifi, MD Invited Commentary page 562 IMPORTANCE The HSD3B1 (1245C) germline variant encodes for a gain-of-function missense Related article page 558 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, Author Affiliations: Glickman P = .01). Median progression-free survival also increased with number of HSD3B1 (1245C) Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio variant alleles inherited: 5.4 months (95% CI, 3.7-7.5) for 0 variant alleles; 9.7 months (95% CI, (Almassi, Reichard, Sharifi); 5.6-32.9) for 1; and 15.2 months (95% CI, 7.8-not reached) for 2 (overall comparison for trend, Department of Quantitative Health P = .03). Sciences, Cleveland Clinic, Cleveland, Ohio (Li); Division of Hematology/ Oncology, Department of Medicine, CONCLUSIONS AND RELEVANCE Inheritance of the HSD3B1 (1245C) variant allele, which is a University of California, San predictive biomarker of resistance to castration, is also a predictive biomarker of sensitivity to Francisco, Helen Diller Family extragonadal androgen ablation with a nonsteroidal CYP17A1 inhibitor. These findings signal Comprehensive Cancer Center, San Francisco (Russell, Perry, Ryan, a possible pathway of treatment stratification for patients with prostate cancer. Friedlander); Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio (Sharifi); Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (Sharifi). Corresponding Author: Nima Sharifi, MD, Department of Cancer Biology, Lerner Research Institute, Cleveland JAMA Oncol. 2018;4(4):554-557. doi:10.1001/jamaoncol.2017.3159 Clinic, Cleveland, OH 44195 Published online October 12, 2017. ([email protected]). 554 (Reprinted) jamaoncology.com © 2017 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in CRPC Brief Report Research wo major sources of androgens supply prostate can- cer: (1) gonadal testosterone and (2) extragonadal an- Key Points drogens that mainly originate from the human adrenal T Question Is inheritance of the HSD3B1 (1245C) genotype that reticularis but may also arise in part from de novo steroido- encodes for a gain-of-function in 3β-hydroxysteroid genesis from cholesterol within tumors.1 The requirement for dehydrogenase isoenzyme 1 (3βHSD1) and an increase in potent gonadal androgens and efficacy of androgen deprivation androgen synthesis from extragonadal precursor steroids therapy (ADT) by medical or surgical castration in men with associated with more favorable treatment outcomes with metastatic prostate cancer has been well established since the nonsteroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition among men with metastatic castration-resistant prostate cancer initial description by Huggins and Hodges.2 Androgen depri- (CRPC)? vation therapy remains a cornerstone treatment for men with metastatic disease and has demonstrated benefit in earlier- Findings In this study of 90 men with metastatic CRPC, the stage disease, such as when used concurrently with radio- presence of the HSD3B1 (1245C) variant allele was associated with increased duration of therapy and increased progression-free therapy for select men with localized prostate cancer.3 survival with ketoconazole treatment. Despite the initial efficacy of ADT, men with advanced dis- ease invariably develop castration-resistant prostate cancer Meaning HSD3B1 (1245C) inheritance, which is a known predictive (CRPC), which is driven by synthesis of the potent andro- biomarker of resistance to castration, is also predictive of response to nonsteroidal CYP17A1 inhibition, identifying a subset of tumors gens, testosterone and/or dihydrotestosterone, and stimula- that are clinically more dependent on extragonadal precursor tion of the androgen receptor (AR) by extragonadal precursor steroids. steroids.4,5 The enzyme 3β-hydroxysteroid dehydrogenase isoenzyme 1 (3βHSD1, encoded by the gene HSD3B1)isre- quired for intratumoral synthesis of potent androgens from peripheral blood mononuclear cells using a polymerase chain 8 extragonadal precursors.6 The common germline variant reaction–based melting curve assay, described previously. The HSD3B1 (1245C) encodes for a gain-of-function in 3βHSD1, in- primary end points of analysis were duration of ketoconazole creasing what is otherwise the rate-limiting step for intratu- therapy and time to disease progression stratified by HSD3B1 moral androgen synthesis from extragonadal precursor genotype. Clinical progression was defined as the time of first steroids.7 In 3 cohorts of patients with advanced prostate can- occurrence of either biochemical progression, using the 12 cer, HSD3B1 (1245C) inheritance is associated with more rapid Prostate Cancer Working Group 3 definition, or radio- progression from initiation of ADT to development of CRPC.8 graphic progression, using Response Evaluation Criteria in Solid 13 These findings have been independently validated in a fourth Tumors (RECIST) version 1.1 criteria. Kaplan-Meier analysis cohort9 and further support variant HSD3B1 (1245C) inheri- was used to estimate time on ketoconazole therapy and time tance as a predictive biomarker of ADT resistance. to disease progression. A log-rank test for trend was used to We hypothesized that patients with variant HSD3B1 (1245C) compare outcomes among HSD3B1 homozygous wild type, inheritance develop CRPC because they have tumors that are heterozygous, and homozygous variant genotypes. The Cox more dependent on extragonadal precursor steroids and thus proportional hazards model was used to estimate hazard would have more durable responses to pharmacologic inhibi- ratio of the primary outcomes between genotypes. tion of 17α-hydroxylase/17,20-lyase (CYP17A1), which is re- quired for extragonadal androgen synthesis. Testing this hy- pothesis with abiraterone is problematic, because this steroidal Results CYP17A1 inhibitor is also converted by 3βHSD1 to multiple downstream steroidal metabolites, including an AR agonist that Ninety men met inclusion criteria and were included in the may oppose its effects downstream of blocking endogenous study. Forty-four patients (49%) were HSD3B1 homozygous androgen synthesis.10,11 Therefore, we chose to study the as- wild type; 34 (38%), heterozygous; and 12 (13%), homozy- sociation between HSD3B1 inheritance and duration of CRPC gous variant (Table), for a total variant allelic frequency of 32%, response to ketoconazole, a nonsteroidal CYP17A1 inhibitor that which is consistent with prior cohorts.8,9 Sufficient data were is not clouded by the same issues. available to determine duration of therapy and time to pro- gression for 88 and 81 patients, respectively. Median duration of therapy increased with the number of Methods variant HSD3B1 (1245C) alleles inherited: 5.0 months (95% CI, 3.4-10.4) for 0 variant alleles; 7.5 months (95% CI, 4.9-19.2) for Men with metastatic CRPC who were treated with ketocon- 1; and 12.3 months (95% CI, 1.8-not reached) for 2 (overall com- azole and did not receive abiraterone before or during keto- parison for trend, P = .01; pairwise comparison of 0 and 1 vari- conazole treatment were identified from a prospectively main- ant alleles, P = .01; pairwise comparison of 0 and 2 variant tained database at the University of California, San Francisco, alleles, P = .03) (Figure 1). Compared