Patients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown.
In this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leuprolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety.
A total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P=0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures.
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. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837. opens in new tab.)
Biochemical recurrence after local treatment occurs in 20-50% of patients within a decade. Limited level 1 evidence complicates treatment decisions, leading to risk stratification as a common strategy. Phase 3 trials have demonstrated the efficacy of next-generation hormonal therapies, such as enzalutamide, in metastatic hormone-sensitive prostate cancer, non-metastatic castration resistant prostate cancer and metastatic castration resistant prostate cancer.
The EMBARK trial aimed to assess enzalutamide (enza) plus leuprolide (leupro) and enzalutamide monotherapy compared to leuprolide alone in patients with biochemical recurrence after primary +/- salvage local treatment. This international, randomised, phase 3 trial involved 1,068 patients with high-risk biochemical recurrence, defined as a PSA doubling time of ≤9 months and a PSA level of ≥2 ng per millilitre above nadir after radiation therapy (RT) or ≥1 ng per millilitre after radical prostatectomy with or without postoperative radiation therapy. Metastatic disease was excluded on conventional imaging and patients were randomly assigned in a 1:1:1 ratio to receive enza (160 mg per day) plus leupro (22.5 mg every 12 weeks), placebo plus leupro, or enza monotherapy for 37 weeks. At week 37, the treatment was suspended if the PSA level was less than 0.2 ng per millilitre and was restarted when the PSA level was ≥ 5.0 ng per millilitre (if the patient had previous RT) or ≥ 2.0 ng per millilitre (if the patient had previously had radical prostatectomy). The primary endpoint was metastasis-free survival (MFS), secondary endpoints were time to PSA progression, overall survival, and safety.
After a median follow-up of 60.7 months, both enza plus leupro and enza monotherapy significantly improved MFSl compared to leupro alone: MFS at 5 years was 87.3% in enza + leupro group (95% CI, 83.0 to 90.6) vs 71.4% in placebo + leupro group (95% CI, 65.7 to 76.3), vs 80.0% in enza group (95% CI, 75.0 to 84.1). The risk of metastasis or death was 58% lower in the enza + leupro group (95% CI, 0.30 to 0.61; P<0.001) and 37% lower in the enza group (95% CI, 0.46 to 0.87; P=0.005) as compared to leupro alone. Study arms with enza treatment also showed longer times to PSA progression and use of new antineoplastic therapy. The authors didn’t observe any new safety signals.
The EMBARK trial provides strong evidence supporting the efficacy of enza in high-risk biochemical recurrence, offering valuable insights into treatment strategies for recurrent prostate cancer. Based on those results, the FDA approved the use of enzalutamide as a therapeutic option for patients with high-risk biochemical relapse after local therapy. EMBARK results may be seen as standard of care. However, we should not forget that patients enrolled in this study didn’t undergo metabolic imaging. PSMA PET is commonly used nowadays and allows a more precise characterisation of patients relapse. As up to 50% of recurrences after primary radiotherapy have a local recurrence only, these results should not preclude the chance to receive a local treatment salvage. The challenging question to be answered is whether combining enza with metastasis-directed treatment would further improve outcomes.