A combination of enzalutamide and the hormone therapy leuprolide—already used for metastatic prostate cancer—appears to extend survival when given earlier to men whose cancer returned after surgery or radiation. The phase 3 EMBARK trial found a significant overall survival benefit for the combination in men with high‑risk, biochemically recurrent disease.
EMBARK, funded by Pfizer Astellas Pharma and reported Oct. 19 in the New England Journal of Medicine and at the ESMO Congress, enrolled more than 1,000 men at 244 sites across 17 countries. Eligible patients had rapidly rising PSA after primary treatment, defined as a PSA doubling time of nine months or less—a marker of heightened risk for developing metastatic disease.
Participants were randomized to one of three arms: leuprolide alone, enzalutamide alone, or the combination. After about eight years of follow‑up, overall survival was 78.9% in the combination group versus 69.5% in the leuprolide‑only group, corresponding to a greater than 40% reduction in the risk of death. Outcomes for enzalutamide alone did not differ significantly from leuprolide alone.
Investigators and outside experts view these findings as part of a trend toward treating some men more aggressively earlier in the disease course to delay metastasis and improve survival. They caution, however, that the survival advantage must be balanced against treatment harms and the possibility of overtreatment.
The combination produced expected side effects: the most common were hot flashes and fatigue, with gynecomastia and nipple pain also reported. Rates of falls and bone fractures were higher in the combination arm, highlighting the importance of weighing benefits against potential harms when considering intensified early therapy.
A notable limitation is that PSMA PET imaging—now widely used to detect small metastases—was not standard at the time the trial began, so some men may have had undetected metastatic disease at enrollment. That factor could affect interpretation of who benefits most from earlier combination therapy.
Investigators emphasize careful patient selection: enzalutamide plus leuprolide can benefit certain high‑risk men with biochemical recurrence, but clinicians should discuss the expected survival gain, possible side effects, and the risk of overtreatment when considering this approach.
