Enzalutamide Prolongs Survival in nmHSPC With Biochemical Recurrence

More detailed overall survival results from the phase 3 EMBARK trial for patients with nmHSPC will be shared at an upcoming medical conference.

Recent News

Enzalutamide (Xtandi), as a monotherapy and combined with leuprolide, demonstrated positive topline overall survival (OS) results in patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC) with biochemical recurrence at high risk for metastasis in the phase 3 EMBARK trial (NCT02319837), according to a press release from the developers, Pfizer and Astellas Pharma.1

Treatment with enzalutamide plus leuprolide met the key secondary end point with a statistically significant and clinically meaningful improvement in OS vs placebo plus leuprolide. Enzalutamide monotherapy also demonstrated a favorable OS trend vs placebo plus leuprolide, though it was not statistically significant.

The safety results were consistent with the demonstrated profile of enzalutamide, with no new safety signals reported in the analysis.

More detailed OS results from the trial will be shared at an upcoming medical meeting.

In November 2023, the FDA approved enzalutamide plus leuprolide in non-metastatic castration-sensitive prostate cancer at high risk of biochemical recurrence based on results from the EMBARK trial.2 In April 2024, the European Commission approved the combination for patients with nmHSPC at high risk of recurrence and who are ineligible for salvage radiotherapy.3

"These data demonstrate that treatment with [enzalutamide] can extend life for men with nmHSPC and high-risk [biochemical recurrence] who have relapsed after initial curative-intent therapy with prostatectomy, radiation therapy or both, further validating EMBARK’s metastasis-free survival [MFS] data," stated Neal D. Shore, MD, FACS, at START Carolinas/Carolina Urologic Research Center, in the press release.1 "While men with nmHSPC with high-risk [biochemical recurrence] now have expanded treatment choices, these results demonstrate a clear clinical benefit, including both MFS and OS, supporting the clinical practice of initiating [enzalutamide] for these patients."

Previous Analysis

In 2023, primary results from the EMBARK trial were shared in the New England Journal of Medicine.4

The primary analysis showed that, with a median follow-up of 60.7 months, according to blinded independent central review, the 5-year MFS was 87.3% (95% CI, 83.0%-90.6%) in the enzalutamide plus leuprolide arm and 71.4% (95% CI, 65.7%-76.3%) in the placebo plus leuprolide group; the risk of metastasis or death was 57.6% lower with the enzalutamide combination (HR, 0.42; 95% CI, 0.30-0.61; P <.001). Among all 12 subgroups eligible for analysis, an MFS benefit was seen with enzalutamide plus leuprolide.

In the enzalutamide monotherapy group, the 5-year MFS was 80.0% (95% CI, 75.0%-84.1%); the risk of metastasis or death was 36.9% lower with monotherapy vs placebo plus leuprolide (HR, 0.63; 95% CI, 0.46-0.87; P = .005).

At the time of the interim analysis, the 5-year OS was 92.2% (95% CI, 88.7%-94.7%) with the enzalutamide combination, 87.2% (95% CI, 83.0%-90.4%) with the placebo combination, and 89.5% (95% CI, 85.6%-92.4%) in the monotherapy group. The HR for death between enzalutamide plus leuprolide and placebo plus leuprolide was 0.59 (95% CI, 0.38-0.91; P = .02); the HR for death between enzalutamide monotherapy and placebo plus leuprolide was 0.78 (95% CI, 0.52-1.17; P = .23).

Regarding safety, the median duration of treatment in all groups was 38.7 months (range, 0.1-88.9). Treatment-related adverse events (TRAEs) of any grade and grade 3 or higher occurred in 86.4% and 17.6% of the enzalutamide combination therapy arm, 79.9% and 8.8% of the placebo combination therapy arm, and 88.1% and 16.1% of the monotherapy arm. AEs leading to death occurred in 1.7% of the enzalutamide combination arm, 0.8% of the placebo combination arm, and 2.3% of the monotherapy arm.

The most common any-grade AEs in the enzalutamide plus leuprolide group were hot flash (68.8%) and fatigue (42.8%), and in the enzalutamide monotherapy group, they were fatigue (46.6%) and gynecomastia (44.9%).

Trial Breakdown

EMBARK randomly assigned, in a 1:1:1 ratio, a total of 1068 patients to receive enzalutamide plus leuprolide (n = 355), placebo plus leuprolide (n = 358), or enzalutamide monotherapy (n = 355). Enzalutamide was administered orally once daily at 160 mg, and leuprolide was administered at 22.5 mg as a single intramuscular or subcutaneous injection every 12 weeks.

Eligible patients had prostate cancer and biochemical recurrence after local therapy, and histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet-cell features, or small-cell features at the time of initial biopsy before primary definitive therapy. Additional eligibility criteria include high-risk disease, a serum testosterone level of 150 ng per deciliter or higher, and an ECOG performance status of 0 or 1.

Exclusion criteria include previous cytotoxic chemotherapy, history of seizure, evidence of distant metastatic disease on conventional imaging, or if they were considered eligible for salvage radiation therapy after radical prostatectomy, among other reasons.

The trial’s primary end point was MFS in the enzalutamide plus leuprolide group vs placebo plus leuprolide. Secondary end points were MFS in the monotherapy group vs placebo plus leuprolide, time to prostate-specific antigen progression, time to use of new antieoplastic therapy, and OS.

References

1. XTANDI® plus leuprolide significantly improves survival outcomes in men with non-metastatic hormone-sensitive prostate cancer with high-risk biochemical recurrence. News release. Pfizer and Astellas Pharma. July 10, 2025. Accessed July 10, 2025. https://tinyurl.com/472zy6r2
2. Pfizer and Astellas’ Xtandi approved by U.S. FDA in earlier prostate cancer setting. News release. Astellas. November 17, 2023. Accessed July 10, 2025. https://tinyurl.com/2vvx7fjd
3. Astellas' XTANDI™ (Enzalutamide) granted European Commission approval for use in additional recurrent early prostate cancer treatment setting. News release. Astellas. April 23, 2024. Accessed July 10, 2025. https://tinyurl.com/4uwp87a8
4. 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