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

Cell Rep Med. 2024 Aug 20;5(8):101644. doi: 10.1016/j.xcrm.2024.101644.

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.

Keywords: HSD3B1; androgens; enzalutamide; metabolism; metastatic hormone-sensitive prostate cancer.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase III
  • Multicenter Study

MeSH terms

  • Aged
  • Alleles
  • Androgen Antagonists* / therapeutic use
  • Benzamides* / therapeutic use
  • Double-Blind Method
  • Genotype*
  • Humans
  • Male
  • Middle Aged
  • Multienzyme Complexes* / genetics
  • Neoplasm Metastasis
  • Nitriles* / therapeutic use
  • Phenylthiohydantoin* / therapeutic use
  • Progesterone Reductase* / genetics
  • Progesterone Reductase* / metabolism
  • Prostatic Neoplasms* / drug therapy
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / pathology
  • Steroid Isomerases* / genetics
  • Treatment Outcome

Substances

  • 3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase
  • Androgen Antagonists
  • Benzamides
  • enzalutamide
  • Multienzyme Complexes
  • Nitriles
  • Phenylthiohydantoin
  • Progesterone Reductase
  • Steroid Isomerases