EMA Validates Type II Variation Application for Enzalutamide in Nonmetastatic Hormone-Sensitive Prostate Cancer

Ahsan Arozullah, MD, MPH

The European Medicines Agency (EMA) has validated its Type II variation for enzalutamide (Xtandi) as an option in patients with nonmetastatic hormone-sensitive prostate cancer (nmHSPC) at high risk of biochemical recurrence who are not suitable for salvage radiotherapy.¹

The application is based on findings from the phase 3 EMBARK trial (NCT02319837), in which enzalutamide plus leuprolide (n = 355) resulted in a 58% reduction in the risk of metastasis or death compared with placebo plus leuprolide (n = 358) in this population, meeting the trial’s primary end point of metastasis-free survival (MFS; HR, 0.42; 95% CI, 0.30-0.61; P < .0001).²

At a median follow-up of 60.7 months in the investigative arm and 60.6 months in the control arm, the median MFS was not yet reached in both arms. The 3-year MFS rate in the enzalutamide arm was 92.9% vs 83.5% in the placebo arm; the 5-year rates were 87.3% and 71.4%, respectively.

Treatment with enzalutamide monotherapy (n = 355) reduced the risk of metastasis or death by 37% compared with placebo plus leuprolide (HR, 0.63; 95% CI, 0.46-0.87; P = .0049). The median MFS with single-agent enzalutamide was NR (95% CI, NR-NR).

“As the most commonly diagnosed cancer in men in Europe, prostate cancer impacts hundreds of thousands of patients across the continent, and for those who have received initial curative treatment, a risk remains that their cancer may return in the form of BCR. These patients, particularly those with rapidly rising prostate-specific antigen [PSA] levels, need new therapeutic needs,” Ahsan Arozullah, MD, MPH, senior vice president and head of the Oncology Department at Astellas Pharma, Inc., stated in a press release.1 “The validation of the Type II variation by the EMA marks an important step toward potentially making [enzalutamide], an existing standard of care for advanced prostate cancer in the European Union, available to patients with earlier stages of the disease who are at risk of their cancer spreading.”

Patients with nmHSPC at high risk of BCR were enrolled to the double-blind, placebo-controlled, multinational, randomized phase 3 EMBARK trial. High-risk BCR was defined as having a PSA doubling time of up to 9 months, serum testosterone of 150 ng/dL or higher, and screening PSA by central laboratory of 1 ng/mL of 1 or higher if they had radical prostatectomy as primary treatment for their cancer, or at least 2 ng/mL above the nadir if they received radiotherapy only as their primary cancer treatment.

If patients received hormone therapy, cytotoxic chemotherapy, major surgery within 4 weeks before randomization, and those with evidence of distant metastatic disease by radiographic imaging, they were excluded.

Patients were randomly assigned 1:1:1 to enzalutamide at a daily dose of 160 mg plus leuprolide at 22.5 mg every 12 weeks, single-agent enzalutamide at 160 mg, or placebo plus leuprolide at 22.5 mg every 12 weeks.^2,3

In addition to MFS with enzalutamide plus leuprolide vs leuprolide serving as the trial’s primary end point, secondary end points comprised MFS with enzalutamide monotherapy vs leuprolide, time to PSA progression, time to antineoplastic therapy, and overall survival (OS) for the enzalutamide doublet or single-agent enzalutamide vs leuprolide alone.²

Enzalutamide plus leuprolide reduced the risk of PSA progression by 93% compared with leuprolide alone (HR, 0.07; 95% CI, 0.03-0.14; P < .0001), and single-agent enzalutamide reduced the risk of PSA progression by 67% vs leuprolide alone (HR, 0.33; 95% CI, 0.23-0.49; P < .0001). Those given the enzalutamide doublet experienced a 64% reduction in progression risk with regard to starting a new antineoplastic therapy compared with leuprolide (HR, 0.36; 95% CI, 0.26-0.49; P < .0001); with enzalutamide monotherapy, this rate was 46% vs leuprolide alone (HR, 0.54; 95% CI, 0.41-0.71; P < .0001).^2,3

OS findings were still immature at the time of the 2023 AUA Meeting presentation, although a positive trend favoring the enzalutamide doublet vs leuprolide alone was observed (HR, 0.59; 95% CI, 0.38-0.90; P = .0142); this did not cross the interim efficacy boundary of P < .0001. An OS trend favoring single-agent enzalutamide vs leuprolide alone was also noted (HR, 0.77; 95% CI, 0.51-1.15; P = .1963).²

The toxicity profiles observed on the trial were in line with what has previously been reported with each agent.¹ The adverse effects that were most frequently experienced with the addition of enzalutamide to leuprolide were fatigue, hot flush, and arthralgia. In the single-agent enzalutamide arm, the most common toxicities included fatigue, gynecomastia, and arthralgia.

Findings from the trial are being shared with regulatory authorities on a global scale, according to Astellas. In August 2023, the FDA accepted and granted priority review to a supplemental new drug application seeking approval of enzalutamide in patients with nonmetastatic castration-sensitive prostate cancer with high-risk BCR.⁴ The application was based on EMBARK data.

References

1. European Medicines Agency validates Type II variation for Astellas’ Xtandi (enzalutamide) for treatment of non-metastatic hormone-sensitive prostate cancer with high-risk biochemical recurrence. News release. Astellas Pharma, Inc. September 12, 2023. Accessed September 13, 2023. https://www.astellas.com/en/news/28496
2. Shore N, de Almeida Luz M, De Giorgi U, et al. EMBARK: a phase 3 randomized study of enzalutamide or placebo plus leuprolide acetate and enzalutamide monotherapy in high-risk biochemically recurrent prostate cancer. Presented at: 2023 AUA Annual Meeting; April 28-May 1, 2023; Chicago, IL. Abstract LBA02-09.
3. XTANDI (enzalutamide) plus leuprolide reduced the risk of metastasis by 58% in non-metastatic hormone-sensitive prostate cancer versus placebo plus leuprolide. News release. Astellas Pharma Inc. April 29, 2023. Accessed September 13, 2023. https://newsroom.astellas.us/2023-04-29-XTANDI-R-enzalutamide-plus-Leuprolide-Reduced-the-Risk-of-Metastasis-by-58-in-Non-Metastatic-Hormone-Sensitive-Prostate-Cancer-versus-Placebo-plus-Leuprolide
4. FDA grants priority review for XTANDI in non-metastatic castration-sensitive prostate cancer with high-risk biochemical recurrence. News release. Pfizer Inc. and Astellas Pharma Inc. August 23, 2023. Accessed September 13, 2023. https://newsroom.astellas.us/2023-08-23-FDA-Grants-Priority-Review-for-XTANDI-R-in-Non-Metastatic-Castration-Sensitive-Prostate-Cancer-with-High-Risk-Biochemical-Recurrence