On November 16, 2023, the FDA approved a supplemental new drug application for enzalutamide (Xtandi; Astellas Pharma and Pfizer), an androgen receptor signaling inhibitor, for the treatment of nonmetastatic, castration-sensitive prostate cancer (CSPC) with biochemical recurrence (BCR) at high risk for metastasis (high-risk BCR). The FDA granted enzalutamide priority review and fast track designations for this indication.
Enzalutamide is the first drug in its class to be approved for this patient population. Enzalutamide was previously approved for the treatment of metastatic CSPC and castration-resistant prostate cancer.
This approval was based on the results of the phase 3 EMBARK clinical trial (NCT02319837), a randomized, double-blind, placebo-controlled, international study that assessed the efficacy of enzalutamide in 1068 patients with nonmetastatic CSPC with high-risk BCR. All patients had received 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 study enrollment. The patients were randomized in a 1:1 ratio to enzalutamide 160 mg orally once daily plus leuprolide, placebo plus leuprolide, or enzalutamide 160 mg once daily. Leuprolide 22.5 mg was administered as a single intramuscular or subcutaneous injection every 12 weeks.
The primary end point was metastasis-free survival (MFS) for enzalutamide plus leuprolide compared with placebo plus leuprolide. The key secondary end points included MFS for enzalutamide monotherapy compared with placebo plus leuprolide and overall survival (OS). A significant improvement in MFS was seen in the enzalutamide plus leuprolide arm versus the placebo plus leuprolide arm (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.30-0.61; P<.001). Enzalutamide monotherapy also demonstrated a significant improvement in MFS compared with placebo plus leuprolide (HR, 0.63; 95% CI, 0.46-0.87; P=.0049). At the time of the MFS analysis, the OS data were immature, with 12.2% deaths across the overall population.
The most common (≥20%) adverse events in the patients who received enzalutamide plus leuprolide were hot flush, musculoskeletal pain, fatigue, fall, and hemorrhage. The most common adverse events in patients who received enzalutamide monotherapy were fatigue, gynecomastia, musculoskeletal pain, breast tenderness, hot flush, and hemorrhage.
“We have not progressed our evidenced-based care for patients with biochemical recurrence [BCR], also known as nm [nonmetastatic] CSPC, until the completion of the EMBARK trial,” said Neal Shore, MD, FACS, Chief Medical Officer of Strategic Innovation and Pharmacy, GenesisCare USA, Director, CPI, Carolina Urologic Research Center, and primary investigator of the EMBARK trial, in a press release. “Previously, treatment options for these BCR patients, especially those who have a high likelihood of developing metastases, were limited. The FDA approval of XTANDI for patients with nmCSPC with BCR at high risk of metastasis represents an important advancement whereby an androgen deprivation signaling inhibitor, enzalutamide, has achieved standard of care discussion for patient-physician decision-making,” he noted.
The recommended dose of enzalutamide is 160 mg orally once daily with or without food until disease progression or unacceptable adverse events. Enzalutamide may be administered with or without a gonadotropin-releasing hormone analog. Treatment can be suspended if the patient’s PSA is undetectable (<0.2 ng/mL) after 36 weeks of therapy. Treatment can be reinitiated when the PSA has increased to ≥2 ng/mL for patients who had radical prostatectomy or to ≥5 ng/mL for patients who received primary radiation therapy.