Enzalutamide Plus Hormone Therapy Extended Survival in Recurrent Prostate Cancer

CATEGORY: MEN’S HEALTH

An earlier look at the EMBARK trial had already shown that adding enzalutamide to standard hormone therapy delayed the spread of recurrent prostate cancer. The harder question was whether men lived longer. In the final survival analysis of this phase 3 trial, the combination was linked to a 40% lower risk of death over eight years: 78.9% of the men on it were alive at eight years, against 69.5% of those on hormone therapy alone.¹

A PSA That Doubles Within Nine Months

Within about ten years of surgery or radiation for prostate cancer, roughly 20% to 50% of men see biochemical recurrence. That means a rise in PSA, the prostate-made protein measured by a common blood test, signaling that the cancer is active again even though no tumor shows on scans. EMBARK went after the highest-risk version of that situation. All 1,068 men enrolled had a PSA doubling within nine months, a pace tied to a greater chance that the cancer spreads and shortens life.

Three Arms, With Pauses at Week 37

Assignment was random, to one of three treatments. Leuprolide is standard hormone therapy, shutting down production of testosterone, the hormone that fuels prostate cancer cells. Enzalutamide is a daily pill that blocks testosterone’s signal from reaching those cells. Men received leuprolide plus enzalutamide, leuprolide alone, or enzalutamide alone. The design had an unusual wrinkle. If a man’s PSA fell to a very low level by week 37, his treatment paused, restarting only if PSA climbed again, which gave many men breaks from therapy and its side effects. Survival was then tracked for roughly eight years. Metastasis-free survival was the trial’s primary endpoint, with overall survival a prespecified key secondary endpoint set aside for formal testing.¹

Enzalutamide Alone Did Not Clearly Extend Survival

Taken without hormone therapy, enzalutamide left 73.1% of those men alive at eight years, a figure not statistically different from hormone therapy alone. The survival advantage belonged to the combination. Fatigue and hot flashes were the most common side effects, and the survival analysis turned up no new safety concerns beyond those already reported. Pfizer and Astellas, the companies that make enzalutamide, funded the trial.

No other drug has yet shown longer survival in this setting. PRESTO, a randomized trial in 503 men with the same rapidly rising PSA, added a different androgen-blocking drug, apalutamide, to hormone therapy and reported a 48% lower risk of PSA rising again, without reporting survival.² An older trial that added an earlier anti-androgen drug to radiation after surgery found a 23% lower risk of death at 12 years.³

Key Takeaways

• In men whose PSA was rising rapidly after prostate cancer treatment, enzalutamide plus hormone therapy was linked to a 40% lower risk of death: about 79 of every 100 men alive at eight years, against 70 on hormone therapy alone.¹
• The finding applies to high-risk biochemical recurrence specifically, not to newly diagnosed or low-risk prostate cancer.
• Enzalutamide by itself was not clearly better than standard hormone therapy for survival. The benefit showed up with the combination.
• The design allowed treatment pauses for men whose PSA fell to very low levels, so many did not take the drugs continuously.

References

1. Shore ND, Luz MA, De Giorgi U, et al. Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med. 2026;394(6):563–575. link
2. Aggarwal R, Heller G, Hillman DW, et al. PRESTO: a phase III, open-label study of intensification of androgen blockade in patients with high-risk biochemically relapsed castration-sensitive prostate cancer (AFT-19). Journal of Clinical Oncology. 2024;42(10):1114–1123. link.
3. Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without antiandrogen therapy in recurrent prostate cancer. New England Journal of Medicine. 2017;376(5):417–428. link.