Enzalutamide in combination with leuprolide demonstrated a significantly longer overall survival than either leuprolide or enzalutamide monotherapy in patients with biochemically recurrent prostate cancer, according to the final overall survival analysis of the phase III EMBARK trial presented at the European Society for Medical Oncology (ESMO) Congress 2025 (Abstract LBA87).
The findings, showing a reduced risk of death with the combination regimen by over 40% compared with leuprolide monotherapy, were also published in The New England Journal of Medicine.
“After initial treatment, some patients see their prostate cancer come back in an aggressive way and are at risk for their disease to spread quickly,” said co-principal study investigator Stephen Freedland, MD, Director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Cancer. “Hormone therapy, which is what we’ve been offering patients for 30 years, has not improved survival and neither has anything else. That makes these findings a real game changer.”
Study Design
In the phase III EMBARK trial, patients with prostate cancer who were at high risk for biochemical recurrence were randomly assigned in a 1:1:1 ratio to receive enzalutamide plus leuprolide, leuprolide monotherapy, or enzalutamide monotherapy. For the study, high risk for biochemical recurrence was defined as a prostate-specific antigen doubling time of up to 9 months.
“We know these patients are at high risk of developing metastatic disease and dying of their cancer unless we offer a meaningful treatment option,” said Dr. Freedland, who is also the Professor of Urology and the Warschaw, Robertson, Law Families Chair in Prostate Cancer at Cedars-Sinai.
The primary endpoint was metastasis-free survival for the enzalutamide combination vs leuprolide, and overall survival was an alpha-protected key secondary endpoint. The study also examined survival endpoints for enzalutamide monotherapy vs leuprolide monotherapy.
Findings From Final Analysis
At 8 years, the overall survival rate for the combination of enzalutamide plus leuprolide was 78.9% (95% confidence interval [CI] = 73.9%–83.1%), compared with 69.5% (95% CI = 64.0%–74.3%) with leuprolide monotherapy (HR = 0.597; 95% CI = 0.444–0.804; P = .0006). For enzalutamide monotherapy, the 8-year overall survival rate was 73.1% (95% CI = 67.6%–77.9%), similar to that of leuprolide monotherapy (HR = 0.830; 95% CI = 0.630–1.095; P = .1867).
Both the enzalutamide combination (HR = 0.374; 95% CI = 0.287–0.489; P < .0001) and monotherapy (HR = 0.570; 95% CI = 0.450–0.721; P < .0001) significantly prolonged the time to first use of new antineoplastic therapy compared with leuprolide monotherapy. Time to first symptomatic skeletal event was similarly prolonged with enzalutamide plus leuprolide (HR = 0.398; 95% CI = 0.221–0.716; P = .0015) as well as with enzalutamide monotherapy (HR = 0.493; 95% CI = 0.283–0.857; P = .0105) vs leuprolide monotherapy. Second progression-free survival was also improved with both the enzalutamide regimen (HR = 0.563; 95% CI = 0.420–0.755; P < .0001) and monotherapy (HR = 0.761; 95% CI = 0.581–0.998; P = .0465) over leuprolide alone.
“These important findings identify a treatment that prolongs survival in men with aggressive prostate cancer,” said Hyung Kim, MD, a urologic oncologist and Chair of the Department of Urologyat Cedars-Sinai, who did not participate in the study. “The latest analysis complements previous studies that found enzalutamide significantly improved survival in other prostate cancer settings, and will change how we take care of our patients.”
Safety findings were consistent with prior findings for each agent.
Disclosures: The study was sponsored by Pfizer Inc. and Astellas Pharma Inc. Dr. Freedland reports being a consultant to Astellas Pharma Inc., AstraZeneca, Bayer, Eli Lilly, Johnson & Johnson Innovative Medicine (formerly Janssen), Merck, Novartis, Pfizer Inc., Sanofi, Sumitomo Pharma America, Inc. (formerly Myovant Sciences, Inc.), and Tolmar. For full disclosures of the other study authors, visit nejm.org.
