BERLIN — For men with high-risk biochemically recurrent prostate cancer, adding enzalutamide (Xtandi) to standard androgen deprivation therapy cuts the risk of death by 40% over 8 years, according to final overall survival results from the phase 3 EMBARK trial. 

“To our knowledge, this is the greatest survival benefit based upon hazard ratio ever seen in a prostate cancer global phase 3 trial based upon all patients in the study — not small, little subsets,” co-principal investigator Stephen Freedland, MD, of Cedars-Sinai Medical Center in Los Angeles, reported at the 2025 annual meeting of the European Society for Medical Oncology (ESMO).

“It's a great day for our patients,” Freedland said to enthusiastic applause.

Based on earlier results from EMBARK showing improved metastasis-free survival with enzalutamide, the androgen receptor pathway inhibitor (ARPI) was approved for patients with non-metastatic biochemically recurrent prostate cancer by both the FDA and European Medicines Agency. 

The new overall survival findings, published simultaneously in The New England Journal of Medicine, should solidify enzalutamide plus leuprolide as the standard of care for those patients, Freedland said.

EMBARK enrolled 1068 patients with high-risk, biochemically recurrent disease that was negative on conventional imaging. High risk was defined as a prostate specific antigen (PSA) doubling time of less than 9 months and a PSA level of at least 1 ng/mL if they had previously undergone radical prostatectomy (with or without radiotherapy) or at least 2 ng/mL above nadir if they had received primary radiotherapy only.

Patients were randomized to receive either enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary endpoint was metastasis-free survival, and overall survival was a secondary endpoint.

Over 8 years, patients who received enzalutamide plus leuprolide had an overall survival of 78.9% vs 69.5% among those who received leuprolide alone, with a hazard ratio for death of 0.60 ( 95% CI, 0.44 to 0.80; P < .001).

Unlike combination therapy, enzalutamide monotherapy did not improve overall survival compared with leuprolide alone: The risk of death was reduced by 17%, but the difference did not reach statistical significance (HR, 0.83; P = .19).

However, some other secondary endpoints were better with either combination therapy or enzalutamide monotherapy versus leuprolide alone, including first use of a new antineoplastic therapy (HR, 0.37 and 0.57, respectively) and first symptomatic skeletal event (HR, 0.40 and 0.49).

Enzalutamide monotherapy, therefore, remains a treatment option, the researchers explained, particularly for patients who are concerned about preserving sexual health, given previous analyses of patient-reported outcomes.

Discussant Derya Tilki, MD, of University Hospital Hamburg-Eppendorf, Hamburg, Germany, agreed that enzalutamide monotherapy should remain an option for patients but noted that the main conclusion is that the overall survival data lend further support to the combination of enzalutamide plus ADT as standard of care.

“After seeing these results, we really know how to use androgen deprivation in high-risk biochemical recurrence,” Tilki said. “If we decide to use ADT, it should be ADT plus ARPI.”

As for adverse events, no new safety signals emerged with the additional 2.5 years of follow-up. The most common clustered adverse events (occurring in at least 10% of patients in each group) were fatigue, falls, fractures, hypertension, and musculoskeletal events. Serious adverse events related to the study drug occurred in 8.5% of patients in the combination group, 7.6% of those in the enzalutamide monotherapy group, and 2.5% of those in the leuprolide-only group. 

More research is needed, the investigators said, to explore strategies that maintain the improved outcomes with enzalutamide while minimizing adverse events. In EMBARK, treatment was suspended if PSA levels fell below 0.2 ng/mL, then reinitiated if they reached protocol-specified levels. Future studies, the researchers noted, should dig into the question of which patients can safely suspend treatment again.

The study was sponsored by Pfizer Inc. and Astellas Pharma Inc., the codevelopers of enzalutamide. Freedland disclosed being a consultant to Astellas Pharma and Pfizer, among others. Tilki disclosed being a consultant to or receiving research funding or travel expenses from Astellas Pharma and Pfizer.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for more than 30 years about all areas of medicine.