HSD3B1 encodes 3β-hydroxysteroid dehydrogenase-1, which converts adrenal dehydroepiandrosterone to 5α-dihydrotestosterone and is inherited in adrenal-permissive (AP) or adrenal-restrictive forms. The AP allele is linked to castration resistance, mainly in low-volume tumors. Here, we investigate the association of HSD3B1 alleles with outcomes in ARCHES, a multinational, double-blind, randomized, placebo-controlled phase 3 trial that demonstrated clinical benefit with enzalutamide plus androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC) compared to those treated with placebo plus ADT. There are no significant differences between genotypes for clinical efficacy endpoints. Enzalutamide significantly improves radiographic progression-free survival and overall survival vs. placebo irrespective of HSD3B1 status. Men with the AP genotype have higher post-progression mortality and treatment-emergent adverse events, including hypertension, cardiovascular events, and gynecomastia, but a lower fracture rate. Overall, enzalutamide is beneficial in men with mHSPC independent of the HSD3B1 genotype. Inherited polymorphisms of HSD3B1 may account for differential toxicities.
Cell reports. Medicine. 2024 Aug 20 [Epub]
Nima Sharifi, Arun A Azad, Mona Patel, Jason W D Hearn, Michele Wozniak, Fabian Zohren, Jennifer Sugg, Gabriel P Haas, Arnulf Stenzl, Andrew J Armstrong
Desai Sethi Urology Institute and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: ., Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Desai Sethi Urology Institute and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA., Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA., Astellas Pharma Inc., Northbrook, IL, USA., Pfizer Inc., San Diego, CA, USA., Department of Urology, University Hospital, Eberhard Karls University of Tübingen, Tübingen, Germany., Divisions of Medical Oncology and Urology, Duke Cancer Institute Center for Prostate & Urologic Cancers, Durham, NC, USA.