On November 16, 2023, the US Food and Drug Administration approved enzalutamide (Xtandi, Astellas Pharma US, Inc.) for non-metastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR).

Efficacy was evaluated in EMBARK (NCT02319837), a randomized, controlled clinical trial of 1068 patients with nmCSPC with high-risk BCR. All patients had prior definitive therapy with radical prostatectomy and/or radiotherapy with curative intent, had PSA doubling time ≤ 9 months, and were not candidates for salvage radiotherapy at enrollment.

Patients were randomized 1:1:1 to receive blinded enzalutamide 160 mg once daily plus leuprolide, open-label single- agent enzalutamide 160 mg once daily, or blinded placebo once daily plus leuprolide.

The major efficacy measure was metastasis-free survival (MFS), assessed by blinded independent central review, for enzalutamide plus leuprolide compared to placebo plus leuprolide.

MFS for enzalutamide monotherapy compared to placebo plus leuprolide and overall survival (OS) were additional efficacy outcome measures.

A statistically significant improvement in MFS was demonstrated for enzalutamide plus leuprolide compared with placebo plus leuprolide with a median that was not reached for either arm (hazard ratio 0.42; 95% CI: 0.30, 0.61; p-value<0.0001).

A statistically significant improvement in MFS was also demonstrated for enzalutamide monotherapy compared to placebo plus leuprolide (hazard ratio 0.63; 95% CI: 0.46, 0.87; p-value = 0.0049). At the time of the MFS analysis, OS 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 haemorrhage.

The most common adverse reactions in patients who received enzalutamide monotherapy were fatigue, gynaecomastia, musculoskeletal pain, breast tenderness, hot flush, and haemorrhage.

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 GnRH 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 concurrent submission and review of oncology drugs among international partners. For this review, 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 (RTOR) 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. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.