Leuprorelin and Enzalutamide Combination Shows Promise as Potential New Standard for Prostate Cancer Relapse
A new treatment combination—leuprorelin plus enzalutamide—has demonstrated a significant reduction in the risk of death for men with prostate cancer experiencing high-risk biochemical relapse, according to results from the international Embark trial. The findings, presented at the 2025 Congress of the European Society for Medical Oncology (Esmo) on October 19, 2025, and published in The New England Journal of Medicine, suggest a potential paradigm shift in treatment for this challenging patient population.
Decades-Old Therapy Falls Short, New Hope Emerges
For 30 years, hormone therapy has been a mainstay in treating prostate cancer, but its impact on overall survival has remained limited. “Hormone therapy, which we have been offering to patients for 30 years, has not improved survival, any more than any other treatment,” a lead researcher stated in a release from Cedars-Sinai. “These results are a real game-changer.” The Embark trial, funded by Astellas Pharma/Pfizer and led by a team from Cedars-Sinai, indicates the combination of leuprorelin and enzalutamide could finally address this unmet need.
Embark Trial Details and Key Findings
The Embark trial enrolled 1,068 patients with prostate cancer who had previously undergone treatment with either surgery or radiotherapy. Biochemical relapse, defined by a rapid increase in prostate-specific antigen (PSA) levels, signaled the recurrence of the disease. Participants were randomly assigned to one of three treatment arms: standard hormone therapy with leuprorelin (also known as leuprolide) alone (n = 358), the leuprorelin/enzalutamide combination (n = 355), or enzalutamide alone (n = 355).
After a median follow-up of 7.8 years, the data revealed compelling differences in survival rates. The combination group exhibited an overall survival rate of 78.9%, compared to 69.5% in the hormone therapy alone group and 73.1% in the enzalutamide alone group. This translates to a 40% reduction in the risk of death for patients receiving the combination therapy compared to those on leuprorelin alone, and a 17% reduction compared to those receiving enzalutamide alone.
Relapse-Free Survival and Treatment Considerations
The benefits extended to relapse-free survival as well. During the follow-up period, 82 patients in the combination group required a first antineoplastic treatment, compared to 173 in the leuprorelin group (HR = 0.37). The enzalutamide alone group also showed improvement, with 126 patients needing further treatment compared to 173 in the leuprorelin group (HR = 0.57).
However, the combination therapy was associated with a higher risk of fractures (22.4%) compared to the other groups (15% and 14.1% for the leuprorelin and enzalutamide alone groups, respectively). This is consistent with known risks associated with androgen receptor inhibitors, which can increase the likelihood of falls and fractures.
Side Effects and Patient Experience
Side effects were reported in at least 98% of patients across all treatment arms. Common side effects included hot flashes and fatigue in the leuprorelin groups, and gynecomastia and fatigue in the enzalutamide group. Importantly, the proportion of severe side effects was comparable across all three groups.
The Embark trial’s findings offer a significant advancement in the treatment of prostate cancer with high-risk biochemical relapse, potentially offering a new standard of care for men facing this challenging diagnosis.
