By: Dr. Avi Verma

A groundbreaking clinical trial has found that a combination of the drugs Enzalutamide (brand name XTANDI) and Leuprolide significantly improves survival in men whose prostate cancer has recurred after initial treatment. In the Phase 3 EMBARK trial, the combo cut the risk of death by about 40 percent compared to leuprolide alone. New England Journal of Medicine

For example, a 70-year-old man whose prostate cancer recurs might expect to live around 15 more years, according to lead investigator Stephen Freedland, MD of Cedars-Sinai. “For many of these patients, I think we are turning [prostate cancer] into a chronic disease, which is really exciting.” Pfizer+1

Why This Is Significant

• Prostate cancer is the second leading cause of cancer death in men in the U.S. (after lung cancer).
• Among men treated by surgery or radiation, about one in three develops a “biochemical recurrence” (rising PSA without visible tumor). This population was the target of the study.
• In the trial: 8-year overall survival was 78.9 % for the enzalutamide + leuprolide group vs 69.5 % for leuprolide alone (hazard ratio ≈ 0.60) in the high-risk, non-metastatic, biochemical recurrence setting. PubMed+2New England Journal of Medicine+2
• Enzalutamide monotherapy did not show a statistically significant survival benefit versus leuprolide alone in this setting. 

What This Means for You or Your Loved One

If your prostate cancer has returned (after initial surgery or radiation) but no metastases are seen on imaging, and your PSA doubling time is short (e.g., ≤ 9 months), this combo therapy may be considered. The data supports the idea of earlier intervention in high-risk settings. New England Journal of Medicine+1 However, as with all oncology treatments, the decision is personal and must weigh benefits against side-effects and life circumstances.

Things to Ask Your Doctor

• Am I a candidate for the combination therapy? This approach was studied in men with non-metastatic prostate cancer, high-risk biochemical recurrence and imaging negative for metastase.
• What is my PSA doubling time? A fast doubling time (e.g., ≤ 9 months) suggests higher risk. Some men with much slower PSA rise may opt for less aggressive treatment. 
• What about my age and comorbidities? Older men (75 +) may experience more pronounced side-effects (fatigue, muscle loss, frailty). 
• Should I consider enzalutamide alone (monotherapy) instead of the combo? In certain cases where preserving sexual/physical function is a priority, monotherapy might be discussed – although survival benefit is less proven. 
• What side-effects should I expect? Common issues include fatigue, hot flashes, gynecomastia (enlarged breasts), lower libido, muscle loss. Some serious risks (e.g., seizures, falls, cardiovascular events) exist with enzalutamide. 

Decoding the Evidence

The EMBARK trial (NCT02319837) enrolled 1,068 men with non-metastatic hormone-sensitive prostate cancer and high-risk biochemical recurrence; they were randomized to:

• Enzalutamide + Leuprolide
• Leuprolide alone
• Enzalutamide monotherapy Pfizer+1

Primary endpoint: metastasis-free survival. Key secondary endpoint: overall survival (OS). The combination showed both improved OS and acceptable quality-of-life measures. New England Journal of Medicine+2AJMC+2

Important Considerations & Next Steps

• The combination is now poised to become the standard of care for men with high-risk biochemical recurrence. New England Journal of Medicine+1
• Patients who are older, frailer, or have slower PSA rise may opt for delayed treatment or monotherapy.
• Long-term data (beyond 8 years) remains limited; personal health, preferences, and life expectancy matter.
• Access and cost of treatment (both drugs, monitoring, management of side-effects) should be discussed with your healthcare team and insurer.
• Ongoing follow-up, PSA monitoring, bone health, and cardiovascular health are integral to care.

Bottom Line

The combination of enzalutamide plus leuprolide marks a significant advancement in prostate-cancer care, offering men with high-risk biochemical recurrence a substantially better chance of living longer. But with greater benefit comes greater complexity—especially around side-effects, lifestyle impact, and cost. If you or someone you know falls into this category, open and timely dialogue with your oncologist/urologist is key.

Disclaimer: This article is intended for general informational purposes only and does not constitute medical advice. Treatment decisions should always be made in consultation with a qualified healthcare professional, based on individual clinical circumstances, risks, benefits, insurance coverage and personal preferences.

Reference list includes notably: Shore ND et al., “Overall survival with enzalutamide in biochemically recurrent prostate cancer”, N Engl J Med 2025 (doi:10.1056/NEJMoa2510310).