Enzalutamide Receives Positive EU CHMP Opinion for High-Risk Biochemically Recurrent nmHSPC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of enzalutamide (Xtandi) as a monotherapy or in combination with androgen deprivation therapy (ADT) for the treatment of adult patients with metastatic and high-risk biochemically recurrent non-metastatic hormone-sensitive prostate cancer (nmHSPC) who are not candidates for salvage radiotherapy.¹

This positive opinion was based on results from the phase 3 EMBARK trial (NCT02319837) in which treatment with enzalutamide with or without ADT decreased the likelihood of metastasis or death compared with placebo plus leuprolide in this high-risk population. At a median follow-up of 60.7 months, enzalutamide plus ADT (n = 355) led to a 5-year metastasis-free survival (MFS) rate of 87.3% (95% CI, 83.0%-90.6%) vs 71.4% (95% CI, 65.7%-76.3%) with ADT alone (n =358; HR, 0.42; 95% CI, 0.30-0.61; P < .001).^1,2

Patients treated with enzalutamide monotherapy (n = 355) achieved a 5-year MFS rate of 80.0% (95% CI, 75.0%-84.1%), which was also superior to the 5-year MFS with ADT monotherapy (HR, 0.63; 95% CI, 0.46-0.87; P = .005).²

Review of this positive opinion by the European Commission is anticipated.¹

“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 [enzalutamide] across the prostate cancer disease continuum,” Ahsan Arozullah, MD, MPH, senior vice president and head of Oncology Development at Astellas, stated in a press release.1 “We look forward to [enzalutamide] being potentially the first and only androgen receptor signaling inhibitor [ARSI] approved for this patient population in the European Union."

Notably, enzalutamide was approved in the United States by the FDA for the treatment of patients with biochemically recurrent nmHSPC at high risk for metastasis in November of 2023; this decision was also supported by data from EMBARK.^1,3

In nmHSPC, conventional imaging methods are unable to detect disease metastases. Approximately 20% to 40% of men treated for their disease experience biochemical recurrence within 10 years, and high-risk patients face a greater likelihood of metastasis and death. Therefore, the EMBARK trial focused on patients with high-risk recurrence after initial treatment.

"Men with nmHSPC with high-risk biochemical recurrence are very likely to experience disease progression,” Arozullah added. “With approximately 9 out of 10 of these men developing metastatic disease, the need for new and effective treatment options is critical.”

EMBARK was a randomized, double-blind, placebo-controlled, multi-national investigation that enrolled patients with nmHSPC or non-metastatic castration-sensitive prostate cancer with high-risk biochemical recurrence at sites in the United States, Canada, Europe, South America, and the Asia-Pacific region. High-risk disease was defined as a PSA doubling time of 9 months or less. This was coupled with a PSA level at least 2 ng/mL higher than the lowest point following radiation therapy in patients who received it as primary treatment, or at least 1 ng/mL higher for patients who underwent radical prostatectomy with or without postoperative radiation therapy. Additional inclusion criteria included a serum testosterone level of at least 150 ng/dL and an ECOG performance status of 0 or 1.2

Eligible patients were randomly assigned 1:1:1 to receive either 160 mg of enzalutamide daily plus leuprolide; 160 mg of enzalutamide as a single agent; or placebo plus 22.5 mg of leuprolide every 12 weeks.

Regarding safety, grade 3 or higher adverse effects (AEs) were reported in 46% of patients treated with the combination, 50% of patients treated with enzalutamide alone, and 43% of patients who received placebo plus leuprolide. In 21% of the patients treated with enzalutamide plus leuprolide, 18% of those treated with single-agent enzalutamide and 10% of patients treated with placebo plus leuprolide, permanent discontinuation of treatment due to AEs was reported.¹

References

1. Astellas receives positive CHMP opinion for Xtandi™ in additional recurrent early prostate cancer treatment setting. News release. Astellas. March 22, 2024. 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. Freedland SJ, de Almeida Luz M, 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
3. Pfizer and Astellas' Xtandi approved by U.S. FDA in earlier prostate cancer treatment setting. News release. Astellas. November 17, 2023. Accessed March 22, 2024. https://www.astellas.com/en/news/28626