Could the leuprorelin + enzalutamide combination become a new reference treatment in prostate cancers with high-risk biochemical relapse? This is what the results of the international multicenter Embark trial, led by a team from Cedars-Sinai (United States) and financed by Astellas Pharma/Pfizer, promise, showing that the combination reduced the risk of death by 40% at 8 years compared to standard hormone therapy alone. “Hormone therapy, which we have been offering to patients for 30 years, has not improved survival, any more than any other treatment. These results are a real game-changer.”the authors rejoiced in a press release from Cedars-Sinai.
The study, published in The New England Journal of Medicinewas presented at the 2025 Congress of the European Society for Medical Oncology (Esmo) on October 19, 2025. Previous work had also shown that enzalutamide, an androgen receptor inhibitor already authorized in the United States, considerably improved survival in other cases of prostate cancer such as castration-resistant cancers or metastatic prostate cancers. susceptible to castration.
The combination does better than each compound alone
The trial included 1,068 patients with prostate cancer who had failed treatment with surgery or radiotherapy. Recurrence was characterized biochemically by the rapid increase in prostate-specific antigen (PSA) levels after the first processing line. “We know that these patients are at high risk of developing metastatic disease and dying from their cancer if we do not provide them with an effective treatment option,” said Professor Stephen Freedland, urologist and director of the Center for Integrated Cancer and Lifestyle Research at Cedars-Sinai Cancer.
Patients were randomized to receive either standard hormonal therapy alone with leuprorelin, also called leuprolide, (n = 358), the leuprorelin/enzalutamide combination (n = 355), or enzalutamide alone (n = 355). After a median follow-up of 7.8 years, the authors found an overall survival of 78.9% in the combination group, 69.5% in the hormone therapy alone group and 73.1% in the enzalutamide alone group. This represents a risk of death reduced by 40% in the combination group compared to the leuprorelin alone group and by 17% in the enzalutamide group compared to the leuprorelin group.
Regarding relapse-free survival, 82 patients in the combination group compared to 173 in the leuprorelin group used a first antineoplastic treatment (HR = 0.37) during follow-up. The HR was 0.57 for the enzalutamide alone group compared to leuprorelin. Finally, regarding the fracture risk, it was higher in the combination group (22.4%) than in the others (15 and 14.1%, for the leuprorelin and enzalutamide alone groups). Treatment with androgen receptor inhibitors is in fact associated with an increased risk of falls and fractures.
Side effects were found in at least 98% of patients in each arm, mainly hot flashes and fatigue in the groups taking leuprorelin, and gynecomastia and fatigue in the enzalutamide group. The proportion of severe side effects was similar in all groups.
