HSD3B1(1245A>C) Variant Regulates Dueling Abiraterone Metabolite Effects in Prostate Cancer

A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3βHSD1 to multiple steroidal metabolites, including 3-keto-5α-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5α-abiraterone synthesis in patients.

First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5α-abiraterone levels and HSD3B1genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics.

Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5α-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002).

Increased generation of 3-keto-5α-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition.

Prostate Cancer Foundation Challenge Award, National Cancer Institute.

Authors: Mohammad Alyamani,1 Hamid Emamekhoo,2,3 Sunho Park,4 Jennifer Taylor,1 Nima Almassi,5 Sunil Upadhyay,6 Allison Tyler,3 Michael P. Berk,1 Bo Hu,4 Tae Hyun Hwang,4 William Douglas Figg,7 Cody J. Peer,7 Caly Chien,8 Vadim S. Koshkin,3 Prateek Mendiratta,3 Petros Grivas,3 Brian Rini,3 Jorge Garcia,3 Richard J. Auchus,6 and Nima Sharifi1,3,5

Author Information:
1. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
2. Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
3. Department of Hematology and Oncology, Taussig Cancer Institute,
4. Department of Quantitative Health Sciences, Lerner Research Institute, and
5. Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA.
6. Division of Endocrinology and Metabolism, Department of Internal Medicine and Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
7. Clinical Pharmacology Program, NCI, Bethesda, Maryland, USA.
8. Janssen Research & Development, Spring House, Pennsylvania, USA.

J Clin Invest. https://doi.org/10.1172/JCI98319
Copyright © 2018, American Society for Clinical Investigation