FDA Approves Enzalutamide for High-Risk Nonmetastatic Castration-Sensitive Prostate Cancer


The FDA has expanded the indication for enzalutamide to include patients with high-risk nonmetastatic castration-sensitive prostate cancer.

FDA Approves Enzalutamide for High-Risk Nonmetastatic Castration-Sensitive Prostate Cancer

FDA Approves Enzalutamide for High-Risk Nonmetastatic Castration-Sensitive Prostate Cancer

The FDA has approved enzalutamide (Xtandi) with or without a gonadotropin-releasing hormone (GnRH) analog therapy, as a treatment for patients with nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence who are high risk for metastasis (high-risk BCR), according to Pfizer, the manufacturer of the drug.

The FDA made their decision based on results from the phase 3 EMBARK trial (NCT02319837), which evaluated enzalutamide plus leuprolide (n = 355), placebo plus leuprolide (n = 355), and single-agent enzalutamide (n = 358), in individuals with high-risk BCR nmCSPC.

Patients who received enzalutamide plus leuprolide achieved a statistically significant reduction in their risk of metastasis or death compared to placebo plus leuprolide, meeting the trial’s primary endpoint. Specifically, the introduction of enzalutamide was associated with a 58% reduction in risk (HR, 0.42; 95% CI, 0.30-0.61; P < .0001).2

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

Of note, 46% of patients receiving the experimental regimen reported grade 3 or worse adverse events (AEs), compared with 50% of patients receiving single-agent enzalutamide, and 43% of patients in the placebo/leuprolide arm. The rate of AE-related treatment discontinuation in the 3 arms was 21%, 18%, and 10%, respectively.1


EMBARK is a phase 3, randomized, double-blind, placebo-controlled, multinational trial that enrolled 1068 patients across the United States, Canada, Europe, South America, and the Asia-Pacific Region.

In this trial, patients were considered to be “high-risk BCR” if their prostate-specific antigen doubling time was less than or equal to 9 months, their serum testosterone was 150 ng/dL or greater,and if their screening PSA by the central laboratory was greater than 1 ng/mL following a radical prostatectomy as their primary treatment or their PSA was at least 2 ng/mL, if radiotherapy had been their primary treatment.

In this trial, patients were randomly assigned to received wither a 160-mg daily dose of enzalutamide plus leuprolide, a 160-mg dose of enzalutamide as a single agent, or placebo plus leuprolide. Leuprolide was given as 22.5-mg dose every 12 weeks.

The primary end point in this trial was MFS, or the duration of time between randomization and the earliest objective evidence of radiographic progression, or death of any cause.


The rate of biochemical recurrence is approximately 20% to 40% among men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy, or both. Approximately 9 out of 10 men with high-risk BCR prostate cancer will develop metastatic disease, and an estimated 1 of out 3 of these men will ultimately die because of their disease.

Enzalutamide is an androgen receptor signaling inhibitor that is already a standard treatment in men with metastatic castration-sensitive prostate cancer, metastatic castration-resistant prostate cancer, and non-metastatic castration-resistant prostate cancer. In a press release, investigators expressed optimism over adding this treatment to the arsenal of therapies for those with high-risk BCR disease.

“Previously, treatment options for these BCR patients, especially those who have a high likelihood of developing metastases were limited,” 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, said.

“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,” Shore added.

Patient advocate groups also voiced their support for the new indication.

“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 CEO of ZERO Prostate Cancer. “This approval of XTANDI is a promising treatment option for the community, offering a ray of hope to patients and their caregivers during these challenging times.”


  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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