Stephen J. Freedland, MD

In the phase III EMBARK trial reported in The New England Journal of Medicine, Stephen J. Freedland, MD, and colleagues found that enzalutamide/leuprolide and enzalutamide alone improved metastasis-free survival vs leuprolide alone in patients with high-risk biochemical recurrence of prostate cancer.

Study Details

In the trial, 1,068 patients with a prostate-specific antigen (PSA) doubling time of ≤ 9 months from sites in 17 countries were randomly assigned 1:1:1 between January 2015 and August 2018 to receive one of the following regimens:

• Double-blind enzalutamide at 160 mg daily plus leuprolide at 22.5 mg given as an intramuscular or subcutaneous injection every 12 weeks (n = 355)
• Double-blind placebo-leuprolide (leuprolide alone group, n = 358)
• Open-label enzalutamide (enzalutamide alone group, n = 355).

The primary endpoint was metastasis-free survival on blinded independent central review in the combination group vs the leuprolide-alone group.

Metastasis-Free Survival

Median follow-up was 60.7 months. Metastasis-free survival at 5 years was 87.3% (95% confidence interval [CI] = 83.0%–90.6%) in the combination group, 71.4% (95% CI = 65.7%–76.3%) in the leuprolide alone group, and 80.0% (95% CI = 75.0%–84.1%) in the enzalutamide alone group. Hazard ratios were 0.42 (95% CI = 0.30–0.61, P < .001) for the combination group vs the leuprolide alone group and 0.63 (95% CI = 0.46–0.87, P = .005) for the enzalutamide alone group vs the leuprolide alone group.

Estimated proportions of patients who were free from PSA disease progression at 5 years were 97.4% in the combination group (hazard ratio [HR] vs leuprolide alone group = 0.07, P < .001), 70.0% in the leuprolide alone group, and 88.9% in the enzalutamide group (HR vs leuprolide alone group = 0.33, P < .001). Estimated proportions of patients who were free from antineoplastic therapy at 5 years were 83.0% in the combination group (HR vs leuprolide alone group = 0.36, P < .001), 61.7% in the leuprolide alone group, and 75.7% in the enzalutamide alone group (HR vs leuprolide alone group = 0.54, P < .001).

Adverse Events

Grade ≥ 3 adverse events occurred in 46.5% of patients in the combination group (most commonly, fatigue in 3.4% and hematuria in 2.0%), in 42.7% of those in the leuprolide alone group (most commonly, fatigue in 1.4% and COVID-19 infection in 1.1%), and in 50.0% of those in the enzalutamide alone group (most commonly, fatigue in 4.0% and hematuria in 1.7%). Serious adverse events occurred in 34.8%, 31.6%, and 37.0% of patients, respectively. Adverse events led to discontinuation of treatment in 20.7%, 10.2%, and 17.8% of patients. Adverse events led to death in six patients (1.7%) in the combination group, three patients (0.8%) in the leuprolide alone group, and eight patients (2.3%) in the enzalutamide alone group; none of the deaths were considered related to treatment.

The investigators concluded: “In patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life.”

Neal D. Shore, MD, of the Carolina Urologic Research Center and GenesisCare US, is the corresponding author of The New England Journal of Medicine article.

Disclosure: The study was funded by Pfizer and Astellas Pharma. For full disclosures of the study authors, visit nejm.org.