On November 16, the U.S. Food and Drug Administration (FDA) approved the androgen receptor inhibitor enzalutamide (Xtandi) for patients with nonmetastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis.
EMBARK Trial
Efficacy was evaluated in EMBARK (ClinicalTrials.gov identifier NCT02319837), a randomized, controlled clinical trial of 1,068 patients with nonmetastatic castration-sensitive prostate cancer and high-risk biochemical recurrence. All patients had received prior definitive therapy with radical prostatectomy and/or radiotherapy with curative intent, had a prostate-specific antigen (PSA) doubling time of ≤ 9 months, and were not candidates for salvage radiotherapy at enrollment. Patients were randomly assigned 1:1:1 to receive blinded enzalutamide at 160 mg once daily plus leuprolide, open-label single- agent enzalutamide at 160 mg once daily, or blinded placebo once daily plus leuprolide.
The major efficacy measure was metastasis-free survival as assessed by blinded independent central review for enzalutamide plus leuprolide compared to placebo plus leuprolide. Metastasis-free survival for enzalutamide monotherapy compared to placebo plus leuprolide and overall survival were additional efficacy outcome measures.
A statistically significant improvement in metastasis-free survival was demonstrated for enzalutamide plus leuprolide compared with placebo plus leuprolide, with a median that was not reached for either arm (hazard ratio [HR] = 0.42, 95% confidence interval [CI] = 0.30–0.61, P < .0001). A statistically significant improvement in metastasis-free survival was also demonstrated for enzalutamide monotherapy compared to placebo plus leuprolide (HR = 0.63, 95% CI = 0.46–0.87, P = .0049). At the time of the metastasis-free survival analysis, overall survival data were immature, with 12% deaths in the overall population.
The most common adverse reactions (≥ 20% incidence) in patients who received enzalutamide plus leuprolide were hot flush, musculoskeletal pain, fatigue, fall, and hemorrhage. The most common adverse reactions in patients who received enzalutamide monotherapy were fatigue, gynecomastia, musculoskeletal pain, breast tenderness, hot flush, and hemorrhage.
The recommended enzalutamide dose is 160 mg administered orally once daily with or without food until disease progression or unacceptable toxicity. Enzalutamide may be administered with or without a gonadotropin hormone-releasing hormone analog. Enzalutamide treatment can be suspended if PSA is undetectable (< 0.2 ng/mL) after 36 weeks of therapy. Treatment may be reinitiated when PSA has increased to ≥ 2.0 ng/mL for patients who had prior radical prostatectomy or ≥ 5.0 ng/mL for patients who had prior primary radiation therapy.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for the concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with Health Canada and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.
This review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 5 weeks ahead of the FDA goal date.
This application was granted Priority Review and Fast Track designation.
