Enzalutamide/Leuprolide Combo Improves OS in High-Risk nmCSPC

Enzalutamide (Xtandi) combined with leuprolide demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) in patients with nonmetastatic hormone-sensitive prostate cancer (nmHSPC), also referred to as nonmetastatic castration-sensitive prostate cancer (nmCSPC), who have high-risk biochemical recurrence, meeting the secondary end point on the phase 3 EMBARK trial (NCT02319837).¹

These results, presented in the final OS analysis of the EMBARK trial, reinforce the clinical value of early intervention in this patient population, particularly following curative-intent therapies such as prostatectomy or radiation. The data build upon previously reported outcomes showing a substantial improvement in metastasis-free survival (MFS), which led to the FDA approval of enzalutamide in this setting in November 2023.^2,3

Importantly, no new safety concerns emerged in the final analysis. The most common adverse events with enzalutamide plus leuprolide were fatigue and hot flashes, consistent with its known safety profile. In the enzalutamide monotherapy arm, gynecomastia was also frequently observed.

“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,” said Neal Shore, MD, FACS, of START Carolinas/Carolina Urologic Research Center in Myrtle Beach, South Carolina, in a 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.”

Detailed results on OS data from EMBARK will be presented at an upcoming medical meeting.

“This is a real step forward and an advancement in our therapeutic armamentarium to have that important patient-physician shared decision making where we now have better options for patients,” Shore told Targeted Oncology^TM in an interview.

About the Phase 3 EMBARK Trial

In the double-blind, randomized EMBARK trial, 1068 patients were assigned to receive either enzalutamide plus leuprolide (n = 355), enzalutamide monotherapy (n = 355), or placebo plus leuprolide (n = 358).² The study’s primary end point was MFS, and the secondary end points included OS, time to castration resistance, composite of safety, time to prostate specific antigen (PSA) progression, time to first use of new antineoplastic therapy, and time to distant metastasis.

Eligible patients had histologically or cytologically confirmed prostate adenocarcinoma without neuroendocrine differentiation, signet cell, or small cell features. Patients must have been given initial treatment by radical prostatectomy and/or radiotherapy, have a PSA doubling time ≤ 9 months, and a serum testosterone ≥ 150 ng/dL (5.2 nmol/L). Patients with prior or present evidence of distant metastatic disease, those who received prior hormonal therapy, or those given prior cytotoxic chemotherapy were not eligible to participate in the study.

The combination of enzalutamide and leuprolide achieved a 5-year MFS rate of 87.3%, compared with 71.4% in the placebo/leuprolide group. Enzalutamide monotherapy also showed benefit, with an 80.0% MFS rate. The hazard ratios favored both enzalutamide-containing arms, with a 58% reduction in the risk of metastasis or death in the combination arm and a 37% reduction in the monotherapy arm, compared with placebo plus leuprolide.

The OS benefit seen with the enzalutamide and leuprolide combination marks a significant advancement, offering new evidence that patients treated earlier in the disease course may not only delay metastasis but also live longer.

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 Inc. July 10, 2025. Accessed July 10, 2025. https://tinyurl.com/y37ueydk

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

3. Pfizer and Astellas' Xtandi approved by U.S. FDA in earlier prostate cancer treatment setting. News release. Astellas. Updated November 17, 2023. Accessed July 10, 2025. https://tinyurl.com/5yeb5y2w