Enzalutamide granted approval in EU for nmHSPC

The European Commission has approved an expanded indication 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 radiation, according to a news release from Astellas Pharma, the developer of the therapy.¹

"With this expanded approval for enzalutamide, clinicians now have an important new option to treat men with non-metastatic hormone-sensitive prostate cancer at high risk of metastasizing, which could become a new standard of care," says Antonio Alcaraz, PhD.

This extended approval makes enzalutamide the first and only novel hormone therapy available for this patient population in the European Union (EU).
“This expanded approval for XTANDI is a vitally important advance for patients with nmHSPC with high-risk BCR and is a testament to our long and ongoing collaboration with a global network of dedicated clinical trial investigators, patient groups, clinical trial participants and their families. Efficacy and safety results from the EMBARK study demonstrate the potential for XTANDI as a new option for treatment in the early, recurrent hormone-sensitive prostate cancer setting. Astellas is in active discussions with regulatory authorities around the world to bring XTANDI to those who may benefit,” said Ahsan Arozullah, MD, MPH, Senior Vice President and Head of Oncology Development at Astellas, in the news release.¹

The EU approval follows a positive opinion issued by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) in March 2024 recommending approval of enzalutamide in the high-risk biochemically recurrent nmHSPC setting.² Additionally, in April 2024, the European Association of Urology revised their treatment guidelines to include a recommendation for enzalutamide with or without ADT after surgery or radiation in this patient population.

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 BCR at high risk for metastasis.³

The approval of enzalutamide by the European Commission and the US FDA were supported by data from the phase 3 EMBARK trial (NCT02319837), which demonstrated that enzalutamide with or without leuprolide prolonged metastasis-free survival compared with leuprolide alone in patients with high-risk biochemically recurrent nmCSPC.⁴

At 5-year follow-up, the rate of metastasis-free survival was 87.3% in the enzalutamide/leuprolide combination arm, 80.0% in the enzalutamide monotherapy arm, and 71.4% in the leuprolide 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. Patients were randomly assigned 1:1:1 to receive enzalutamide plus leuprolide (n = 355), enzalutamide alone (n = 355), or leuprolide alone (n = 358). 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.

Antonio Alcaraz, PhD, Chairman of the Department of Urology at the University Hospital Clinic of Barcelona, added in the news release on the EU approval,¹ “When non-metastatic hormone-sensitive prostate cancer recurs and is allowed to evolve, it could potentially lead to metastasis. Facing a particularly high risk and poorer outcomes in this stage of prostate cancer are men with a rapidly rising PSA, where PSA levels double within 9 months. It is critical to manage the cancer carefully then, and I urge clinicians not to delay treatment in this setting. With this expanded approval for enzalutamide, clinicians now have an important new option to treat men with non-metastatic hormone-sensitive prostate cancer at high risk of metastasizing, which could become a new standard of care.”

References

1. Astellas' XTANDI (enzalutamide) granted European Commission approval for use in additional recurrent early prostate cancer treatment setting. News release. Astellas Pharma Inc. April 23, 2024. Accessed April 24, 2024. https://www.astellas.com/en/news/29146

2. Astellas receives positive CHMP opinion for XTANDI in additional recurrent early prostate cancer treatment setting. News release. Astellas Pharma Inc. March 25, 2024. Accessed April 24, 2024. https://www.astellas.com/en/news/29021

3. Pfizer and Astellas' XTANDI approved by U.S. FDA in earlier prostate cancer treatment setting. Published online November 17, 2023. Accessed April 24, 2024. https://www.astellas.com/en/news/28626

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