Results from a new analysis of the STAMPEDE phase 3 trial have revealed crucial insights into the relationship between the HSD3B1 gene variant and survival outcomes in prostate cancer patients, with significant implications for treatment strategies.
Dr. Nima Sharifi, professor and scientific director at the Desai Sethi Urology Institute of the University of Miami, presented these findings at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco.
Genetic Impact on Treatment Response
The research focuses on a hyperfunctioning variant of the HSD3B1 gene, present in approximately half of all men. This variant produces an enzyme that accelerates androgen biosynthesis from non-testicular precursor steroids, leading to faster development of castration resistance in tumors.
STAMPEDE Trial Design and Findings
The STAMPEDE trial compared standard medical castration against an intensive combination therapy regimen. Patients were randomized to receive either standard androgen deprivation therapy (ADT) alone or ADT plus abiraterone and enzalutamide. The study included both non-metastatic and metastatic prostate cancer patients, with the latter group subdivided into low-volume and high-volume disease categories.
Key Clinical Implications
The analysis confirmed previous findings from the CHAARTED trial, demonstrating that patients with the hyperactive HSD3B1 variant experience shorter overall survival, particularly in those with low-volume metastatic disease.
Perhaps most notably, the research revealed an unexpected finding: even patients receiving intensive triple therapy (medical castration plus enzalutamide and abiraterone) showed worse overall survival if they carried the hyperfunctioning HSD3B1 variant. This suggests that current treatment intensification strategies may not be sufficient to overcome the genetic predisposition to more aggressive disease.
Future Research Directions
Dr. Sharifi emphasized the need for deeper understanding of these findings, noting that the persistence of poorer outcomes despite intensive therapy represents a significant challenge. This suggests a critical need for novel therapeutic approaches specifically tailored for patients carrying the hyperfunctioning HSD3B1 variant.
