A new study reveals that intensified treatment can reverse the poor prognosis typically associated with the HSD3B1 gene mutation in prostate cancer patients. The research, a genetic analysis of the phase III ENZAMET trial, indicates that androgen deprivation therapy (ADT) combined with enzalutamide or a nonsteroidal antiandrogen leads to more favorable survival outcomes for patients with the adrenal-permissive HSD3B1 allele.
The study, published in The Journal of Clinical Investigation, addresses a critical challenge in prostate cancer treatment, where approximately 50% of men with the inherited, androgen-driving HSD3B1 gene face a poorer prognosis. According to Dr. Nima Sharifi, Scientific Director of the Desai Sethi Urology Institute (DSUI) at the University of Miami Miller School of Medicine and a discoverer of the HSD3B1 genotype, these findings demonstrate that intensified treatment can successfully reverse these poor outcomes.
The Role of HSD3B1 in Prostate Cancer
Dr. Sharifi's earlier research, published in Cell in 2013, highlighted that HSD3B1 stimulates local production of active androgens in prostate cancer. Subsequent studies revealed that about half of men with prostate cancer possess the adrenal-permissive HSD3B1 genotype, making them more prone to rapidly developing castrate-resistant disease and experiencing worse outcomes. This understanding prompted a genetic analysis within the ENZAMET trial to identify therapeutic solutions for the HSD3B1 challenge.
Intensified Treatment Strategy
The ENZAMET study revealed that participants with the HSD3B1 allele, who typically experience worse outcomes, showed improved results with upfront treatment intensification that blocks adrenal androgens. This approach contrasts with ADT alone, which proved less effective for prostate cancer patients with the hyperactive HSD3B1 allele.
"This is a very positive step forward in understanding the genetics of advanced prostate cancer at a clinical level," Dr. Sharifi stated. He emphasized the need to further pursue these findings to better focus clinical trials, develop more targeted therapies, reduce mortality, and improve survival for patients with advanced prostate cancer.
Impact and Future Directions
According to the American Cancer Society, prostate cancer is the second-leading cause of cancer death in American men. In 2024, an estimated 300,000 men in the U.S. will be diagnosed with prostate cancer, and over 35,000 will die from the disease. The ENZAMET trial's findings offer a potential avenue for improving treatment strategies and outcomes for a significant subset of these patients.
Study co-author Dr. Ian Davis, a medical oncologist and professor of medicine at Monash University, noted, "Our research findings enable us to better assess specific genetic factors for men living with advanced prostate cancer that ultimately gives us more power to predict a patient’s response to treatment to help improve their survival outcomes."
The ENZAMET trial was led by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group and sponsored by the University of Sydney, in collaboration with other cancer trial groups. Astellas Pharma provided drug and financial support but was not involved in the study design, conduct, or data analysis.
