It was announced that the phase 3 EMBARK study met its primary end point in patients with nonmetastatic castration-sensitive prostate cancer with high-risk biochemical recurrence.
Patients with nonmetastatic castration-sensitive prostate cancer (nmCSPC) who received enzalutamide (Xtandi) plus leuprolide had a lower risk of metastasis or death vs those who did not receive enzalutamide, according to a press release from Astellas Pharmaceuticals.1
Results of the phase 3 EMBARK study (NCT02319837) in patients with high-risk biochemical recurrence (BCR) that were presented at the 2023 American Urological Association Annual Meeting showed that the enzalutamide plus leuprolide arm had a 58% reduction in risk of metastasis or death compared with patients who only received placebo plus leuprolide (HR, 0.42; 95% CI, 0.30-0.61; P < .0001).
“Some patients with BCR are at very high risk for developing metastatic disease, which can lead to a cascade of therapeutic interventions,” Neal Shore, MD, US Chief Medical Officer of Urology and Surgical Oncology at GenesisCare, director of Carolina Urologic Research Center, and primary investigator for the study, stated in the press release. “The clinical goal of BCR therapy is to delay cancer progression and avoid metastatic disease. The MFS [metastasis-free survival] results from the EMBARK study demonstrate that this intervention with [enzalutamide] plus leuprolide was statistically significant for patients with high-risk BCR.”
The phase 3, double-blind, multinational study randomly assigned 1068 patients with nmCSPC who had high-risk BCR on a 1:1:1 basis to receive 160 mg daily enzalutamide plus 22.5 mg leuprolide every 12 weeks, the same dose of enzalutamide as monotherapy, or placebo plus leuprolide.
Patients were considered to have high-risk BCR if they had a prostate-specific antigen (PSA) doubling time of 9 months or less, serum testosterone of at least 150 ng/dL, and screening PSA by central laboratory of at least 1 ng/mL if they had a radical prostatectomy with or without radiotherapy as primary treatment for prostate cancer, or at least 2 ng/mL above the nadir if they had only radiotherapy as primary treatment for prostate cancer. Patients who received prior hormonal therapy or other systemic therapies including cytotoxic chemotherapy or immunotherapy were excluded.
The primary end point was MFS for the enzalutamide plus leuprolide arm vs the placebo plus leuprolide arm for a timeframe of approximately 90 months. Secondary end points included overall survival (OS), MFS for the enzalutamide alone arm, time to PSA progression, time to first use of a new neoplastic therapy, safety, and quality-of-life.
In addition to reporting that the primary end point of MFS for enzalutamide plus leuprolide was met, investigators observed a 37% reduction in metastasis or death in the enzalutamide monotherapy arm compared with the placebo plus leuprolide arm (HR, 0.63; 95% CI, 0.46-0.87; P = .0049). The risk of PSA progression was reduced by 93% in the enzalutamide plus leuprolide arm compared with the placebo plus leuprolide arm (HR 0.07; 95% CI, 0.03-0.14; P < .0001). Patients who received enzalutamide alone had a 67% reduction in risk of PSA progression vs placebo plus leuprolide (HR, 0.33; 95% CI, 0.23-0.49; P < .0001).
For patients who received enzalutamide plus leuprolide, the progression risk of starting a new antineoplastic therapy was reduced by 64% vs those in the placebo plus leuprolide arm (HR, 0.36; 95% CI, 0.26-0.49; P < .0001), whereas for those who received enzalutamide alone, it was reduced by 46% compared with those who received placebo plus leuprolide (HR, 0.54; 95% CI, 0.41-0.71; P < .0001).
Investigators observed a positive trend for OS favoring enzalutamide plus leuprolide vs the placebo arm, but data were not yet mature.
The overall safety profile observed in the trial was consistent with the known safety profile of enzalutamide and leuprolide. The most common adverse events reported in the enzalutamide plus leuprolide arm were fatigue, hot flush, and arthralgia, whereas those treated with enzalutamide monotherapy most commonly reported fatigue, gynecomastia, and arthralgia.
The detailed results will be reported in an upcoming publication. Additionally, the study’s sponsors will discuss a potential regulatory submission to the FDA for enzalutamide in the high-risk BCR nmCSPC setting. Enzalutamide is currently indicated for castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer.2
"If approved, we hope to bring a new option to men earlier in the course of their disease," 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 and co-principal investigator of the EMBARK clinical trial, stated in the press release.1
1. XTANDI® (enzalutamide) plus leuprolide reduced the risk of metastasis by 58% in non-metastatic hormone-sensitive prostate cancer versus placebo plus leuprolide. News release. Astellas. April 29, 2023. Accessed May 1, 2023. https://bit.ly/3NtE7sj
2. Xtandi. Prescribing information. Astellas; 2019. Accessed May 1, 2023. https://bit.ly/42cEWtH