Enzalutamide data published in NEJM as FDA weighs nonmetastatic HSPC approval

Data from the phase 3 EMBARK trial supporting a potential FDA approval of enzalutamide (Xtandi) for nonmetastatic hormone-sensitive prostate cancer (nmHSPC) have been published in the New England Journal of Medicine.^1,2

The 5-year MFS rate 87.3% for those treated with enzalutamide plus leuprolide compared with 71.4% for those given leuprolide alone.

The application for enzalutamide the FDA is considering is specifically for the treatment of patients with nmHSPC with high-risk biochemical recurrence (BCR). The regulatory agency is scheduled to decide on the application by the end of this year.²

The phase 3 EMBARK trial showed that enzalutamide (Xtandi) plus leuprolide reduced the risk of metastasis or death by 58% compared with placebo plus leuprolide in this patient population (HR, 0.42; 95% CI, 0.30-0.61; P < .001).1 The median metastasis-free survival (MFS) was not yet reached (NR; 95% CI, NR-NR) in the enzalutamide/leuprolide arm vs NR (95% CI, 85.1 months–NR) in the leuprolide alone arm. The 5-year MFS rate 87.3% for those treated with enzalutamide plus leuprolide compared with 71.4% for those given leuprolide alone.¹

EMBARK was a double-blind, placebo-controlled trial that randomly assigned adult patients with nmHSPC (also knowns as nonmetastatic castration-sensitive prostate cancer) with high-risk BCR (n = 1068) in a 1:1:1 fashion to receive either oral enzalutamide monotherapy at a dose of 160 mg once daily (n = 355), enzalutamide 60 mg once daily in combination with intramuscular or subcutaneous leuprolide at a dose of 22.5 mg once every 12 weeks (n = 355), or placebo plus intramuscular or subcutaneous leuprolide at a dose of 22.5 mg once every 12 weeks (n = 358).¹

The median follow-up in the enzalutamide combination and the leuprolide/placebo arms was approximately 60 months. The primary end point of the study was MFS by BICR. Key secondary end points included MFS of enzalutamide monotherapy vs placebo plus leuprolide, time to PSA progression, time to antineoplastic therapy, and overall survival (OS) of enzalutamide plus leuprolide or enzalutamide monotherapy vs placebo plus leuprolide.¹

Results for the monotherapy arm showed that patients receiving single-agent enzalutamide also experienced a reduction in the risk of metastasis or death of 37% compared with those in the placebo arm (HR, 0.63; 95% CI, 0.46-0.87; P = .005), meeting its MFS end point. The median MFS was NR (95% CI, NR-NR) in the enzalutamide monotherapy arm.¹

Additional findings from the study showed that patients in the enzalutamide combination arm experienced a 93% reduction in the risk of PSA progression compared with those in the placebo arm (HR, 0.07; 95% CI, 0.03-0.14; P < .001). Patients in the enzalutamide monotherapy arm also experienced a benefit in terms of PSA progression over those who received placebo (HR, 0.33; 95% CI, 0.23-0.49; P < .001). Progression risk in terms of starting a new antineoplastic therapy was reduced by 64% and 46% over placebo in the enzalutamide combination (HR, 0.36; 95% CI, 0.26-0.49; P < .001) and the enzalutamide monotherapy (HR, 0.54; 95% CI, 0.41–0.71; P < .001) arms, respectively.¹

Although OS data were not yet mature, a positive trend favoring the enzalutamide combination arm over the placebo arm was observed (HR, 0.59; 95% CI, 0.38-0.91; P = .02), although these data did not cross the interim efficacy boundary of P ≤ .0001. OS findings also trended in favor of enzalutamide monotherapy over the placebo regimen (HR, 0.78; 95% CI, 0.52-1.17; P = .023).¹

In terms of safety, the profile of the combination was similar to that of enzalutamide and leuprolide as individual agents, with no new safety signals.¹

References

1. 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

2. FDA Grants Priority Review for XTANDI® in Non-Metastatic Castration-Sensitive Prostate Cancer with High-Risk Biochemical Recurrence. Published online and accessed August 23, 2023. https://www.prnewswire.com/news-releases/fda-grants-priority-review-for-xtandi-in-non-metastatic-castration-sensitive-prostate-cancer-with-high-risk-biochemical-recurrence-301907279.html