FDA approves enzalutamide for non-metastatic castration-sensitive prostate cancer with biochemical recurrence

Regulatory approval: On Nov 16, 2023 (FDA posting date Nov 17), the FDA approved enzalutamide (Xtandi) for non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis. Approval was supported by the phase 3 EMBARK trial (NCT02319837), which showed statistically significant improvements in metastasis-free survival for enzalutamide plus leuprolide and for enzalutamide monotherapy versus placebo plus leuprolide. Overall survival data were immature at the time of analysis.

FDA approval (regulatory)

On Nov 16, 2023 (announced/posted Nov 17, 2023), the US Food and Drug Administration (FDA) approved enzalutamide (Xtandi; Astellas Pharma US, Inc.) for non-metastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence (BCR) at high risk for metastasis.

Supporting evidence

Efficacy was evaluated in EMBARK (NCT02319837), a randomized, controlled trial enrolling 1,068 patients with nmCSPC and high-risk BCR. Eligible patients had prior definitive therapy (radical prostatectomy and/or curative-intent radiotherapy), PSA doubling time ≤9 months, and were not candidates for salvage radiotherapy at enrollment. Patients were randomized 1:1:1 to:

  • Enzalutamide 160 mg once daily plus leuprolide (blinded)
  • Enzalutamide monotherapy 160 mg once daily (open-label)
  • Placebo plus leuprolide (control; blinded)

The primary comparison was metastasis-free survival (MFS) for enzalutamide plus leuprolide vs placebo plus leuprolide (blinded independent central review). MFS was significantly improved (median not reached in either arm; HR 0.42, 95% CI 0.30–0.61; p<0.0001). Enzalutamide monotherapy also improved MFS vs placebo plus leuprolide (HR 0.63, 95% CI 0.46–0.87; p=0.0049). Overall survival data were immature (12% deaths).

Safety and dosing (from FDA communication)

Common adverse reactions (≥20%) included hot flush, musculoskeletal pain, fatigue, fall, and hemorrhage (enzalutamide+leuprolide); and fatigue, gynecomastia, musculoskeletal pain, breast tenderness, hot flush, and hemorrhage (monotherapy). Recommended dose: 160 mg orally once daily, with or without food, with or without a GnRH analog, until progression or unacceptable toxicity.

The review was conducted under Project Orbis and used RTOR; FDA noted collaboration with Health Canada and Swissmedic, with reviews ongoing at other agencies.

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