Enzalutamide Receives Go Ahead From European Commission in nmHSPC

A label extension for enzalutamide (Xtandi) alone and in combination with androgen deprivation therapy has received approval from the European Commission (EC) for the treatment of adult patients with high-risk biochemical recurrent (BCR) nonmetastatic hormone-sensitive prostate cancer (nmHSPC) who are not suitable for salvage radiotherapy.¹

The regulatory decision was supported by findings from the phase 3 EMBARK trial (NCT02319837), which showed that patients with high-risk BCR prostate cancer who received enzalutamide plus leuprolide (n = 355) or enzalutamide monotherapy (n = 355) achieved 5-year metastasis-free survival (MFS) rates of 87.3% (95% CI, 83.0%-90.6%) and 80.0% (95% CI, 75.0%-84.1%), respectively, compared with 71.4% (95% CI, 65.7%-76.3%) among those who received leuprolide monotherapy (n = 358). In terms of MFS, both enzalutamide plus leuprolide (HR, 0.42; 95% CI, 0.30-0.61; P < .001) and enzalutamide monotherapy (HR, 0.63; 95% CI, 0.46-0.87; P = .005) were superior to leuprolide alone.²

“When nmHSPC recurs and is allowed to evolve, it could potentially lead to metastasis,” Antonio Alcaraz, PhD, chairman of the Department of Urology at the University Hospital Clinic of Barcelona in Spain, said in a press release. “Facing a particularly high risk and poorer outcomes in this stage of prostate cancer are men with a rapidly rising prostate-specific antigen [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 nmHSPC at high risk of metastasizing, which could become a new standard of care.”¹

EMBARK was an international study that enrolled adult patients with high-risk BCR prostate cancer without neuroendocrine differentiation, signet-cell features, or small-cell features. Eligible patients also needed to have a PSA doubling time of 9 months or less and a PSA level of at least 2 ng/mL above nadir after radiation therapy or at least 1 ng/mL after radical prostatectomy with or without postoperative radiation therapy; a serum testosterone level of at least 150 ng/dL; and an ECOG performance status of 1 or 0. The study randomly assigned patients 1:1:1 to receiveenzalutamide at 160 mg daily plus leuprolide at 22.5 mg every 12 weeks, placebo plus leuprolide, or enzalutamide monotherapy.²

The primary end point was MFS by blinded independent central review in the combination arm vs the leuprolide monotherapy arm. MFS in the enzalutamide monotherapy arm vs the leuprolide monotherapy arm represented a key secondary end point; patient-reported outcomes and safety were other secondary end points.

In terms of safety, patients in the combination, leuprolide monotherapy, and enzalutamide monotherapy arms experienced any-grade adverse effects (AEs) at rates of 97.2%, 97.5%, and 98.0%, respectively. Patients in each arm also experienced any-grade treatment-related (86.4% vs 79.9% vs 88.1%), serious (34.8% vs 31.6% vs 37.0%), and treatment-related serious (7.4% vs 2.3% vs 4.8%) AEs. AEs leading to dose reduction (7.1% vs 4.5% vs 15.8%) and permanent treatment discontinuation (20.7% vs 10.2% vs 17.8%) were also reported.

The approval of enzalutamide by the EC follows a positive opinion issued by the Committee for Medicinal Products for Human Use of the European Medicines Agency in March 2024, which recommended the agent be approved for the treatment of patients with high-risk BCR nmHSPC. Enzalutamide also received approval from the FDA in November 2023 for the treatment of patients with nonmetastatic castration-sensitive prostate cancer with BCR who are at a high risk for metastasis.¹

“This expanded approval for [enzalutamide] 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,” Ahsan Arozullah, MD, MPH, senior vice president and head of Oncology Development at Astellas, said in the press release. “Efficacy and safety results from the EMBARK study demonstrate the potential for [enzalutamide] as a new option for treatment in the early, recurrent, HSPC setting. Astellas is in active discussions with regulatory authorities around the world to bring [enzalutamide] to those who may benefit.”

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 24, 2024. Accessed April 24, 2024. https://www.astellas.com/en/news/29146#:~:text=(TSE%3A%204503%2C%20President%20and,biochemical%20recurrent%20(BCR)%20non%2D
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