EMA recommends approval of enzalutamide for nmHSPC

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Astellas expects a decision on EU marketing authorization of enzalutamide in nmHSPC by June 2024.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending approval of enzalutamide (Xtandi) as a monotherapy or in combination with androgen deprivation therapy (ADT) for the treatment of patients with high-risk biochemical recurrent (BCR) non-metastatic hormone sensitive prostate cancer (nmHSPC) who are unsuitable for salvage radiotherapy, announced Astellas, the developer of the therapy, in a news release.1

Both the EMA submission and the US FDA approval were supported by data from the phase 3 EMBARK trial.

Both the EMA submission and the US FDA approval were supported by data from the phase 3 EMBARK trial.

"Men with nmHSPC with high-risk biochemical recurrence are very likely to experience disease progression. With approximately 9 out of 10 of these men developing metastatic disease, the need for new and effective treatment options is critical. Today's positive opinion from the Committee is an important step forward for providing an additional treatment option for these patients and complements the existing efficacy and safety data supporting the use of XTANDI across the prostate cancer disease continuum. We look forward to XTANDI being potentially the first and only androgen receptor signaling inhibitor approved for this patient population in the European Union,” said Ahsan Arozullah, MD, MPH, in the news release.1 Arozullah is the senior vice president and the head of oncology development at Astellas.

Following the EMA’s positive recommendation, the European Commission will now review the application for enzalutamide for potential approval in the nmHSPC setting in all 27 EU member states, as well as Iceland, Liechtenstein, and Norway. Astellas expects a decision on EU marketing authorization by June 2024.

Enzalutamide also received FDA approval in November 2023 for use with or without a GnRH analog therapy for the treatment of patients with nonmetastatic castration-sensitive prostate cancer (nmCSPC, also known as nmHSPC) with biochemical recurrence (BCR) at high risk for metastasis.2

Both the EMA submission and the US FDA approval of enzalutamide were supported by data from the phase 3 EMBARK trial (NCT02319837), which demonstrated superior metastasis-free survival with enzalutamide plus leuprolide compared with leuprolide alone in patients with high-risk biochemically recurrent prostate cancer.3

At 5-year follow-up, the rate of metastasis-free survival was 87.3% in the enzalutamide/leuprolide combination arm, 71.4% in the leuprolide monotherapy arm, and 80.0% in the enzalutamide monotherapy arm. Regarding metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P < .001), and enzalutamide monotherapy was superior to leuprolide monotherapy (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P = .005).

In terms of safety, the profile for the combination was similar to that of enzalutamide and leuprolide as individual agents, with no new safety signals observed. Grade 3 or higher adverse events (AEs) were reported among 46% of patients who received enzalutamide plus leuprolide, 50% of patients who received enzalutamide monotherapy, and 43% of patients who received leuprolide alone. Discontinuation of treatment due to AEs occurred in 21% of patients who received enzalutamide plus leuprolide, 18% of patients who received enzalutamide alone, and 10% of patients who received leuprolide alone.

There was no substantial difference observed between the groups in regard to quality-of-life measures.

In total, the double-blind, placebo controlled, phase 3 EMBARK trial enrolled 1068 adult patients across centers in the US, Canada, Europe, South America, and the Asia-Pacific region.4 Patients were randomly assigned 1:1:1 to receive enzalutamide plus leuprolide (n = 355), leuprolide alone (n = 358), or enzalutamide alone (n = 355). Enzalutamide 160 mg was administered daily, and leuprolide 22.5 mg was administered every 12 weeks. The median follow-up was 60.7 months.

The primary end point for the trial was metastasis-free survival in the combination arm compared with the leuprolide monotherapy arm, as assessed by blinded independent central review. Secondary end points included metastasis-free survival in the enzalutamide monotherapy arm compared with the leuprolide monotherapy arm, as well as patient-reported outcomes and safety.

References

1. Astellas receives positive CHMP opinion for XTANDI in additional recurrent early prostate cancer treatment setting. News release. Astellas Pharma Inc. Published online and accessed March 22, 2024. https://www.prnewswire.com/news-releases/astellas-receives-positive-chmp-opinion-for-xtandi-in-additional-recurrent-early-prostate-cancer-treatment-setting-302097043.html

2. Pfizer and Astellas' XTANDI approved by U.S. FDA in earlier prostate cancer treatment setting. Published online November 16, 2023. Accessed March 22, 2024. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-astellas-xtandir-approved-us-fda-earlier

3. Freedland SJ, Luz MDA, De Giorgi U, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-1465. doi:10.1056/NEJMoa2303974

4. European Medicines Agency validates Type II Variation for Astellas' XTANDI (enzalutamide) for treatment of nonmetastatic hormone-sensitive prostate cancer with high-risk biochemical recurrence. News release. Astellas Pharma Inc. September 12, 2023. Accessed March 22, 2024. https://newsroom.astellas.us/2023-09-12-European-Medicines-Agency-Validates-Type-II-Variation-for-Astellas-XTANDI-R-enzalutamide-for-Treatment-of-Non-Metastatic-Hormone-Sensitive-Prostate-Cancer-with-High-Risk-Biochemical-Recurrence

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