FDA approves enzalutamide for nonmetastatic CSPC

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The FDA has approved enzalutamide (Xtandi) for use with or without a GnRH analog therapy for the treatment of patients with nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence (BCR) at high risk for metastasis.1

“Previously, treatment options for these BCR patients, especially those who have a high likelihood of developing metastases were limited. The FDA approval of Xtandi for patients with nmCSPC with BCR at high risk of metastasis represents an important advancement whereby an androgen deprivation signaling inhibitor, enzalutamide, has achieved standard of care discussion for patient-physician decision-making," said  Neal Shore, MD, FACS, primary investigator for the EMBARK trial.

“Previously, treatment options for these BCR patients, especially those who have a high likelihood of developing metastases were limited. The FDA approval of Xtandi for patients with nmCSPC with BCR at high risk of metastasis represents an important advancement whereby an androgen deprivation signaling inhibitor, enzalutamide, has achieved standard of care discussion for patient-physician decision-making," said Neal Shore, MD, FACS, primary investigator for the EMBARK trial.

The approval is based on findings from the phase 3 EMBARK trial, which showed that enzalutamide 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).2 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.2

“Having had the privilege of taking care of patients with prostate cancer for nearly 40 years, I have been fortunate to have participated in many of the prostate cancer landscape changing trials; notably, we have not progressed our evidenced-based care for patients with BCR, also known as nmCSPC, until the completion of the EMBARK trial,” Neal Shore, MD, FACS, chief medical officer of Strategic Innovation and Pharmacy, GenesisCare USA, director, CPI, Carolina Urologic Research Center, and primary investigator for the EMBARK trial, stated in a press release.1

“Previously, treatment options for these BCR patients, especially those who have a high likelihood of developing metastases were limited. The FDA approval of Xtandi for patients with nmCSPC with BCR at high risk of metastasis represents an important advancement whereby an androgen deprivation signaling inhibitor, enzalutamide, has achieved standard of care discussion for patient-physician decision-making," added Shore.1

EMBARK was a double-blind, placebo-controlled trial that randomly assigned adult patients with nmCSPC (also knowns as nonmetastatic hormone-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).2

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.2

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.2

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.2

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).2

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.2

References

1. Pfizer and Astellas' XTANDI® Approved by U.S. FDA in Earlier Prostate Cancer Treatment Setting. Published online November 16, 2023. Accessed November 17, 2023. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-astellas-xtandir-approved-us-fda-earlier

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

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