Enzalutamide plus leuprolide lowered the risk of metastases or death by 58% compared with placebo plus leuprolide.
Enzalutamide (Xtandi), with or without leuprolide, was associated with a reduced risk of metastases or death compared with placebo plus leuprolide among patients with nonmetastatic hormone-sensitive prostate cancer (nmHSPC) with high-risk biochemical recurrence (BCR). Findings from the phase 3 EMBARK trial (NCT02319837) were presented during the 2023 AUA Annual Meeting.1
At a median follow-up of 60.7 months in the combination arm and 60.6 months in the placebo arm, patients who received enzalutamide plus leuprolide (n = 355) experienced a 58% reduction in the risk of metastasis or death by blinded independent central review (BICR) compared with those who were treated with placebo plus leuprolide (n = 358; HR, 0.42; 95% CI, 0.31-0.61; P < .0001). The median metastasis-free survival (MFS) was not yet reached (NR; 95% CI, NR-NR) in the enzalutamide/leuprolide arm vs NR (95% CI, 85.1 months–NR) in the placebo alone arm. The 3- and 5-year MFS rates for those treated with enzalutamide plus leuprolide were 92.9% and 87.3%, respectively, compared with 83.5% and 71.4%, respectively, for those given leuprolide alone.
Additionally, patients who received enzalutamide monotherapy (n = 355) also experienced a reduction in the risk of metastasis or death of 37% compared with those in the placebo arm (HR, 0.63; 95% CI, 0.46-0.87; P = .0049), meeting its MFS end point. The median MFS was NR (95% CI, NR-NR) in the enzalutamide monotherapy arm.
“There are patients with localized prostate cancer who undergo prostatectomy or radiation therapy in an attempt to cure their disease, but, unfortunately, some patients will develop BCR,” Neal Shore, MD, FACS, the US chief medical officer of Surgery and Oncology at GenesisCare USA, and the medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina, said in a news release.2 “Importantly, some patients with BCR are at very high risk for developing metastatic disease, which can lead to a cascade of therapeutic interventions. The clinical goal of BCR therapy is to delay cancer progression and avoid metastatic disease. The MFS results from the EMBARK study demonstrate that this intervention with [enzalutamide] plus leuprolide was statistically significant for patients with high-risk BCR.”
EMBARK was a double-blind, placebo-controlled trial that randomly assigned adult patients with nmHSPC with high-risk BCR (n = 1068) in a 1:1:1 fashion to receive either oral enzalutamide monotherapy at a dose of 160 mg once daily, enzalutamide 60 mg once daily in combination with intramuscular or subcutaneous leuprolide at a dose of 22.5 mg once every 12 weeks, or placebo plus intramuscular or subcutaneous leuprolide at a dose of 22.5 mg once every 12 weeks.1,3
If a patient’s prostate-specific antigen (PSA) level at week 36 was below 0.2 ng/mL, therapy was stopped at week 37 and resumed when the level rose to at least 2 ng/mL for patients who underwent primary radical prostatectomy and at least 5 ng/mL for those who did not undergo radical prostatectomy.1
Patients needed to have a PSA doubling time of 9 months or less, a screening PSA by central laboratory of at least 1 ng/mL for patients who underwent radical prostatectomy as primary treatment for prostate cancer and at least 2 ng/mL above the nadir for patients who had radiotherapy only as primary treatment for prostate cancer, and a serum testosterone level of at least 150 ng/dL. Those who underwent prior treatment with hormonal therapy, cytotoxic chemotherapy, major surgery within 4 weeks before randomization, and patients with evidence of distant metastatic disease by radiographic imaging were excluded from the study.3
The primary end point of the study was MFS by BICR. Key secondary end points included MFS of enzalutamide monotherapy vs placebo plus leuprolide, time to PSA progression, time to antineoplastic therapy, and overall survival (OS) of enzalutamide plus leuprolide or enzalutamide monotherapy vs placebo plus leuprolide.1,3
Additional findings from the study showed that patients in the enzalutamide combination arm experienced a 93% reduction in the risk of PSA progression compared with those in the placebo arm (HR, 0.07; 95% CI, 0.03-0.14; P < .0001). Patients in the enzalutamide monotherapy arm also experienced a benefit in terms of PSA progression over those who received placebo (HR, 0.33; 95% CI, 0.23-0.49; P < .0001). Progression risk in terms of starting a new antineoplastic therapy was reduced by 64% and 46% over placebo in the enzalutamide combination (HR, 0.36; 95% CI, 0.26-0.49; P < .0001) and the enzalutamide monotherapy (HR, 0.54; 95% CI, 0.41–0.71; P < .0001) arms, respectively.1,2
Although OS data were not yet mature, a positive trend favoring the enzalutamide combination arm over the placebo arm was observed (HR, 0.59; 95% CI, 0.38-0.90; P = .0142), although these data did not cross the interim efficacy boundary of P < .0001. OS findings also trended in favor of enzalutamide monotherapy over the placebo regimen (HR, 0.77; 95% CI, 0.51-1.15; P = .1963).1
In terms of safety, the profile of the combination was similar to that of enzalutamide and leuprolide as individual agents. The most common adverse effects (AEs) in the enzalutamide combination arm included fatigue, hot flush, and arthralgia. Commonly occurring any-grade AEs in the monotherapy arm consisted of fatigue, gynecomastia, and arthralgia.2
"The EMBARK study is a phase 3 trial exploring the potential of enzalutamide in patients with nmHSPC with high-risk BCR," said Stephen J. Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle and the Warschaw Robertson Law Families Chair in Prostate Cancer at Cedars-Sinai Cancer in Los Angeles, California, said in the release.2 "If approved, we hope to bring a new option to men earlier in the course of their disease."