FDA Approves Enzalutamide for nmCSPC With High-Risk Biochemical Recurrence


The FDA has approved enzalutamide for the treatment of patients with nonmetastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis.



The FDA has approved enzalutamide (Xtandi) for the treatment of patients with nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis.1

Notably, patients with nmCSPC with high-risk biochemical recurrence may be treated with enzalutamide with or without a gonadotropin-releasing hormone analog therapy.

The regulatory decision was supported by data from the phase 3 EMBARK trial (NCT02319837), which showed that the addition of enzalutamide to leuprolide (n = 355) reduced the risk of metastasis or death by 58% vs leuprolide plus placebo (n = 358; HR, 0.42; 95% CI, 0.30-0.61; P < .0001).2

At a median follow-up of 60.7 months in the enzalutamide arm and 60.6 months in the placebo arm, the median metastasis-free survival (MFS) was not yet reached (NR; 95% CI, NR-NR) in the enzalutamide arm and NR (95% CI, 85.1-NR) in the placebo arm. The 3-year MFS rates were 92.9% and 83.5%, respectively, and the 5-year rates were 87.3% and 71.4%, respectively.

“For patients who were previously treated for prostate cancer and had achieved remission, only to later receive the distressing news of disease recurrence with a risk of metastasis, the emotional toll can be profound,” Courtney Bugler, president and chief executive officer of ZERO Prostate Cancer, stated in a news release.1 “This approval of [enzalutamide] is a promising treatment option for the community, offering a ray of hope to patients and their caregivers during these challenging times.”

The international, randomized EMBARK trial enrolled adult patients with prostate cancer with biochemical recurrence after local therapy if they had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet-cell features, or small-cell features at the time of the initial biopsy before primary definitive therapy.2

High-risk disease was defined as a prostate-specific antigen (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. Other key inclusion criteria consisted of a serum testosterone level of at least 150 ng/dL and an ECOG performance status of 0 or 1.

Patients were randomly assigned in a 1:1:1 fashion to receive enzalutamide plus leuprolide, placebo plus leuprolide, or enzalutamide monotherapy. Notably, the two combination arms were double blinded.

MFS for patients treated with enzalutamide plus leuprolide vs those given leuprolide plus placebo served as the trial's primary end point. Key secondary end points included MFS in the monotherapy group vs leuprolide alone; time to PSA progression; time to new antineoplastic therapy; and overall survival.

Additional data showed that patients treated with enzalutamide monotherapy (n = 355) experienced a 5-year MFS rate of 80.0% (95% CI, 75.0%-84.1%). The risk of metastasis or death was reduced by 36.9% with enzalutamide monotherapy vs leuprolide plus placebo (HR, 0.63; 95% CI, 0.46-0.87; P = .005).

In the enzalutamide/leuprolide, leuprolide/placebo, and enzalutamide monotherapy arms, the 5-year rates of patients free from PSA progression were 97.4% (95% CI, 94.7%-98.8%), 70.0% (95% CI, 64.1%-75.1%), and 88.9% (95% CI, 84.6%-92.1%), respectively. Both enzalutamide/leuprolide (HR, 0.07; 95% CI, 0.03-0.14; P < .001) and enzalutamide monotherapy (HR, 0.33; 95% CI, 0.23-0.49; P < .001) were associated with a reduced risk of PSA progression vs leuprolide/placebo.

The 5-year OS rates were 92.2% (95% CI, 88.7%-94.7%) in the enzalutamide/leuprolide group, 87.2% (95% CI, 83.0%-90.4%) in the leuprolide/placebo group, and 89.5% (95% CI, 85.6%-92.4%) in the enzalutamide monotherapy group. Both enzalutamide/leuprolide (HR, 0.59; 95% CI, 0.38-0.91; P = .02) and enzalutamide monotherapy (HR, 0.78; 95% CI, 0.52-1.17; P = .23) were linked with a reduced risk of death vs leuprolide/placebo.

Regarding safety, grade 3 or higher adverse effects (AEs) occurred in 46% of patients treated with enzalutamide/leuprolide, 50% of patients treated with enzalutamide alone, and 43% of patients given leuprolide/placebo.1

AEs led to permanent treatment discontinuation in 21% of patients in the enzalutamide/leuprolide arm, 18% of patients in the enzalutamide monotherapy arm, and 10% of patients in the leuprolide/placebo arm.

“Today’s FDA approval is the culmination of over a decade of research and development as we’ve worked to bring [enzalutamide] forward for as many patients with prostate cancer as possible who may benefit,” said Ahsan Arozullah, MD, MPH, senior vice president and head of Oncology Development at Astellas, stated in a news release. “With every milestone, our clinical development program has played an instrumental role in changing the course of patients’ lives. We are proud that [enzalutamide] can now be offered to a subset of men with nmCSPC with biochemical recurrence and at high risk for metastases.”


  1. Pfizer and Astellas' Xtandi approved by U.S. FDA in earlier prostate cancer treatment setting. News release. Astellas. November 17, 2023. Accessed November 17, 2023. https://www.astellas.com/en/news/28626
  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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