FDA Grants Priority Review to Enzalutamide for nmCSPC With High-Risk Biochemical Recurrence

The FDA has accepted and granted priority review to a supplemental new drug application (sNDA) seeking the approval of enzalutamide (Xtandi) in patients with nonmetastatic castration-sensitive prostate cancer (nmCSPC) with high-risk biochemical recurrence.¹

The sNDA is supported by data from the phase 3 EMBARK trial (NCT02319837), which met its primary end point of metastasis-free survival (MFS) when the addition of enzalutamide to leuprolide (n = 355) reduced the risk of metastasis or death by 58% vs leuprolide alone (n = 358; HR, 0.42; 95% CI, 0.30-0.61; P < .0001) in this population. At a median follow-up of 60.7 months in the enzalutamide arm and 60.6 months in the placebo arm, the median MFS in the enzalutamide arm was not yet reached (NR; 95% CI, NR-NR) and NR (95% CI, 85.1-NR) in the placebo arm.² The 3-year MFS rates were 92.9% and 83.5%, respectively, and the 5-year rates were 87.3% and 71.4%, respectively.

Moreover, those who received single-agent enzalutamide (n = 355) experienced a 37% reduction in the risk of metastasis or death vs placebo (HR, 0.63; 95% CI, 0.46-0.87; P = .0049). The median MFS with enzalutamide monotherapy was NR (95% CI, NR-NR).

Under the Prescription Drug User Fee Act, the FDA will decide on the application in the fourth quarter of this year.

“The FDA’s granting of a priority review designation reinforces the need to bring new treatment options for patients with high-risk biochemical recurrent nmCSPC,” Chris Boshoff, MD, PhD, chief oncology research and development officer and executive vice president at Pfizer, stated in a press release.¹ “We believe the EMBARK data demonstrate the potential of [enzalutamide,] if approved, to help patients earlier in the course of their disease, building on [enzalutamide’s] foundation as an existing standard of care in prostate cancer.”

The double-blind, placebo-controlled, phase 3 trial enrolled patients with nmCSPC with high-risk biochemical recurrence.² To be eligible for participation, patients were required to have a prostate-specific antigen (PSA) doubling time of 9 months or less, a screening PSA of at least 1 ng/mL by central laboratory for those who underwent radical prostatectomy as primary treatment for prostate cancer, and at least 2 ng/mL above the nadir for those who had radiotherapy only as primary treatment for their cancer, and a serum testosterone level of at least 150 ng/dL.

Exclusion criteria included having undergone treatment with hormonal therapy, cytotoxic chemotherapy, major surgery within 4 weeks prior to randomization, and those with evidence of distant metastatic disease by radiographic imaging.

Study participants were randomly assigned 1:1:1 to oral enzalutamide monotherapy at a daily dose of 160 mg, enzalutamide at a daily dose of 60 mg plus intramuscular or subcutaneous leuprolide at 22.5 mg once every 12 weeks, or placebo plus intramuscular or subcutaneous leuprolide at 22.5 mg once every 12 weeks.^2,3

MFS by blinded independent central review served as the primary end point of the trial. Important secondary end points included MFS with enzalutamide vs placebo plus leuprolide, time to PSA progression, time to antineoplastic therapy, and overall survival (OS) of enzalutamide/leuprolide or enzalutamide monotherapy vs placebo/leuprolide.

Additional data indicated that the addition of enzalutamide to leuprolide resulted in a 93% reduction in the risk of PSA progression vs placebo (HR, 0.07; 95% CI, 0.03-0.14; P < .0001). Enzalutamide monotherapy led to a 67% reduction in risk of PSA progression vs placebo (HR, 0.33; 95% CI, 0.23-0.49; P < .0001). Moreover, patients who received the enzalutamide combination reduced progression risk in terms of starting a new antineoplastic therapy by 64% vs placebo (HR, 0.36; 95% CI, 0.26-0.49; P < .0001); this percentage was 46% in those who received single-agent enzalutamide (HR, 0.54; 95% CI, 0.41-0.71; P < .0001).^2,3

At the time of the presentation delivered at the 2023 AUA Annual Meeting, OS data were still immature. A positive trend that favored the enzalutamide combination arm over the placebo arm was observed (HR, 0.59; 95% CI, 0.38-0.90; P = .0142) but this did not cross the interim efficacy boundary defined as P < .0001. A trend favoring enzalutamide monotherapy over the placebo regimen was also noted (HR, 0.77; 95% CI, 0.51-1.15; P = .1963).²

The toxicity profile of the agents examined in the trial proved to be in line with what has previously been reported.¹ The most common adverse effects (AEs) observed in those who received the enzalutamide doublet included fatigue, hot flush, and arthralgia. With single-agent enzalutamide, the most common AEs comprised fatigue, gynecomastia, and arthralgia.

Data from EMBARK are being shared with other regulatory authorities to support additional license applications for enzalutamide in this indication, according to Pfizer Inc. and Astellas Pharma Inc.

References

1. 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 August 23, 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
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 August 23, 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