HSD3B1 genotype and outcomes in metastatic hormone-sensitive prostate cancer with androgen deprivation therapy and enzalutamide: ARCHES

Sharifi, N; Azad, AA; Patel, M; Hearn, JWD; Wozniak, M; Zohren, F; Sugg, J; Haas, GP; Stenzl, A; Armstrong, AJ

Author(s): Sharifi, N; Azad, AA; Patel, M; Hearn, JWD; Wozniak, M; Zohren, F; Sugg, J; Haas, GP; Stenzl, A; Armstrong, AJ;
Details: Publication Year 2024-08-20,Volume 5,Issue #8,Page 101644
Journal Title: Cell Reports Medicine
Publication Type: Research article
Abstract: 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.
Publisher: Elsevier
Keywords: Humans; Male; *Phenylthiohydantoin/therapeutic use; *Nitriles/therapeutic use; *Benzamides/therapeutic use; *Progesterone Reductase/genetics/metabolism; *Androgen Antagonists/therapeutic use; *Genotype; *Steroid Isomerases/genetics; *Multienzyme Complexes/genetics; Treatment Outcome; Aged; Prostatic Neoplasms/genetics/drug therapy/pathology; Neoplasm Metastasis; Double-Blind Method; Middle Aged; Alleles; Hsd3b1; androgens; enzalutamide; metabolism; metastatic hormone-sensitive prostate cancer
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1016/j.xcrm.2024.101644
Open Access at Publisher's Site: https://doi.org/10.1016/j.xcrm.2024.101644
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-09-19 04:50:56

Last Modified: 2024-09-19 04:57:04