Enzalutamide Plus Hormone Therapy Extended Survival in Recurrent Prostate Cancer

CATEGORY: MEN’S HEALTH

For men whose prostate cancer comes back aggressively after surgery or radiation, adding the drug enzalutamide to standard hormone therapy was linked to a 40% lower risk of death over eight years in a large randomized trial.¹ In the final survival analysis of the phase 3 EMBARK study, 78.9% of men on the combination were alive at eight years, compared with 69.5% of men on hormone therapy alone.

PSA Doubling Within Nine Months in 1,068 Men

Within about ten years of surgery or radiation for prostate cancer, roughly 20% to 50% of men experience biochemical recurrence—a rise in PSA, the prostate-made protein measured by a common blood test, signaling the cancer is active again even though no tumor is visible on scans. EMBARK enrolled the highest-risk version of this situation: 1,068 men whose PSA was doubling within nine months, a pace linked to a higher chance of the cancer spreading and shortening life.

Three Arms and Treatment Pauses at Week 37

The men were randomly assigned to one of three treatments: leuprolide (standard hormone therapy, which shuts down production of testosterone—the hormone that fuels prostate cancer cells) plus enzalutamide (a daily pill that blocks testosterone’s signal from reaching those cells), leuprolide alone, or enzalutamide alone. The trial used an unusual intermittent design: if a man’s PSA fell to a very low level by week 37, his treatment was paused and only restarted if PSA climbed again—giving many men breaks from therapy and its side effects. Researchers then tracked survival for roughly eight years. An earlier analysis had already found the combination delayed the cancer’s spread; this final, preplanned analysis answered the harder question of whether men actually lived longer.¹ 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, 73.1% Alive at Eight Years

Enzalutamide taken alone, without hormone therapy, did not clearly extend survival: 73.1% of those men were alive at eight years, a result that was not statistically different from hormone therapy alone. The survival advantage came from the combination. Fatigue and hot flashes were the most common side effects, and the survival analysis found no new safety concerns beyond those already reported. The trial was funded by Pfizer and Astellas, the companies that make enzalutamide.

PRESTO, 503 Men, 48% Lower Risk of PSA Rising

PRESTO, another randomized trial in 503 men with the same rapidly rising PSA, added an androgen-blocking drug, apalutamide, to hormone therapy: it was linked to a 48% lower risk of PSA rising again, but did not report 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 So far, longer survival itself has been shown only in EMBARK.

Key Takeaways

• In 1,068 men with rapidly rising PSA 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 versus 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 was seen with the combination.
• The trial’s 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.