The phase 3 EMBARK trial of enzalutamide plus leuprolide is the first to elicit a statistically significant improvement in metastasis-free survival in non-metastatic hormone-sensitive prostate cancer with high-risk biochemical recurrence.
Enzalutamide (Xtandi) administered in combination with leuprolide demonstrated a statistically significant and clinically meaningful improvement in metastasis-free survival (MFS) compared with placebo plus leuprolide in patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC) who have high-risk biochemical recurrence (BCR).1
"A robust phase 3 trial to better inform patient physician shared decision making for BCR patients has been an unmet need, specifically for the important endpoint of metastasis free survival," Neal Shore, MD, FACS, US chief medical officer of Surgery and Oncology, GenesisCare USA, and director, CPI, Carolina Urologic Research Center, told Targeted OncologyTM.
With the MFS improvement, the phase 3 EMBARK study (NCT02319837) met its primary end point, according to topline results announced by Pfizer and Astellas Pharma, Inc. Findings also showed that the study met its key secondary end points of prostate-specific antigen (PSA) progression, and time to first use of new antineoplastic therapy.2
"The EMBARK trial is the first study to demonstrate a statistically significant improvement in MFS using the combination Xtandi plus leuprolide in men with this stage of disease," Ahsan Arozullah, MD, MPH, senior vice president and head of Development Therapeutic Areas, Astellas, in a press release.
Among patients treated with enzalutamide plus leuprolide, there was a trend toward overall survival (OS) improvement compared with those who received the control combination. The study continues to follow patients to determine the final OS. No new safety signals were revealed in the study at the time of the preliminary safety analysis. The safety profile of enzalutamide in the study was consistent with prior knowledge of the agent.
Full results from the EMBARK will be presented a medical meeting in the future. Pfizer also plans to discuss the results with the FDA and other regulatory authorities.
"As EMBARK is a positive trial, the results will assuredly better inform healthcare provider’s and patient’s regarding treatment choices," said Shore.
EMBARK is a randomized, double-blind, placebo-controlled, multinational trial that included 1,068 patients with nmHSPC and high-risk BCR who were treated at site in the United States, Canada, Europe, South America, and the Asia-Pacific region. All patients had histologically or cytologically confirmed disease, were initially treated with prostatectomy or radiotherapy, had PSA doubling time ≤ 9 months, screening PSA of ≥ 1 ng/mL in the prior prostatectomy group or 2 ng/mL in the prior radiotherapy group, and serum testosterone of ≥ 150 ng/dL.
The study excluded patients who had prior or present distant metastatic disease. Patients were also ineligible if they were previously treated with hormonal therapy close to the time of the study, cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone acetate, enzalutamide, 5-α reductase inhibitors, or systemic biologic therapy. Patients who underwent major surgery within 4 weeks of the study were excluded, as were patients with known or suspected brain metastases, and those with a history of another invasive cancer within 3 years of screening for EMBARK.
Patients in the study are randomized 1:1:1 to an arm of enzalutamide 160/mg per day plus leuprolide, enzalutamide monotherapy at matching dose, or matching placebo plus leuprolide. At week 37, treatment is halted if PSA concentrations are < 0.2 ng/mL and reinstated if levels rise to ≥ 2.0 ng/mL with RP or ≥ 5.0 ng/mL without radical prostatectomy. However, patients who have a PSA ≥ 0.2 ng/mL at week 37 will continue treatment until discontinuation criteria are met.
EMBARK is ongoing with a prospective completion date of September 2026.
“While current treatment options for localized prostate cancer are intended to be curative, some men remain at higher risk for biochemical recurrence following primary treatment, which may result in metastases,” said Ahsan Arozullah, M.D., MPH, senior vice president and Head of Development Therapeutic Areas, Astellas, in the press release.
1. Phase 3 study shows Xtandi® (enzalutamide) plus leuprolide significantly improves metastasis-free survival in men with non-metastatic prostate cancer. News release. Pfizer and Astellas Pharma, Inc. March 16, 2023. Accessed March 17, 2023. https://bit.ly/3yNylcm
2. Freedland SJ, Giogi UD, Gleave M, et al. A phase 3 randomised study of enzalutamide plus leuprolide and enzalutamide monotherapy in high-risk non-metastatic hormone-sensitive prostate cancer with rising PSA after local therapy: EMBARK study design. BMJ Open. 2021 Aug 12;11(8):e046588. doi:10.1136/bmjopen-2020-046588.