An overall survival (OS) analysis from the Phase 3 EMBARK study (NCT02319837) evaluating enzalutamide (Xtandi®, Pfizer and Astellas Pharma) in combination with leuprolide (Lupron Depot®; Abbvie) and as a monotherapy, in men with non-metastatic hormone-sensitive prostate cancer (nmHSPC)* with biochemical recurrence (BCR) at high risk for metastasis showed positive topline results.
Non-metastatic hormone- (or castration-) sensitive prostate cancer (nmHSPC or nmCSPC) means that there is no detectable evidence of the cancer metastases with conventional radiological methods (CT/MRI) and the cancer still responds to medical or surgical treatment to lower testosterone levels. [1][2]
High-risk biochemical recurrence
The EMBARK study focused on men with high-risk BCR. Per the EMBARK protocol, patients with nmHSPC with high-risk BCR are those initially treated by radical prostatectomy or radiotherapy, or both, with a PSA doubling time ≤ 9 months.
Patients with nmCSPC who experience BCR after local therapy may be at a higher risk of metastases and death if their PSA doubling time is ≤ 9 months. [4]
Standard of care
Enzalutamide is an androgen receptor signaling inhibitor, the drug is considered a standard of care and has received regulatory approvals in one or more countries around the world for use in men with metastatic hormone-sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer (nmCRPC) and non-metastatic hormone-sensitive prostate cancer (nmHSPC) with high-risk biochemical recurrence (BCR).
For patients treated with enzalutamide plus leuprolide versus placebo plus leuprolide, the EMBARK study met the key secondary endpoint with a statistically significant and clinically meaningful improvement in OS. The results also showed a favorable trend towards improved OS for patients treated with enzalutamide monotherapy versus placebo plus leuprolide, however the difference did not reach statistical significance. No new safety signals were observed in the analysis, and the safety results were consistent with the demonstrated safety profile of enzalutamide. [5]
Improving Survival Outcomes
“These data demonstrate that treatment with enzalutamide can extend life for men with nmHSPC and high-risk BCR 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, M.D., F.A.C.S, START Carolinas/Carolina Urologic Research Center.
“While men with nmHSPC with high-risk BCR now have expanded treatment choices, these results demonstrate a clear clinical benefit, including both MFS and OS, supporting the clinical practice of initiating enzalutamide I for these patients,” Shore added.
Among men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy, or both, an estimated 20-40% will experience BCR within 10 years. [6] About nine out of 10 men with high-risk BCR will develop metastatic disease, and one in three will die as a result of their metastatic prostate cancer.[7][8]
“Enzalutamide is the only androgen receptor inhibitor-based regimen to demonstrate a survival benefit in metastatic HSPC and nmHSPC with high-risk BCR, as well as castration-resistant prostate cancer, highlighting its significant patient impact in advanced prostate cancer,” said Johanna Bendell, M.D., Oncology Chief Development Officer, Pfizer.
“These positive results add to the robust clinical support for the use of enzalutamide and broaden clinical confidence, offering men with high-risk BCR evidence that they might live longer when they start enzalutamide early,” Bendell added.
Initial analysis
In the EMBARK study, patients were randomized to one of three study arms: enzalutamide plus leuprolide, placebo plus leuprolide, or enzalutamide monotherapy. An initial analysis was previously reported in The New England Journal of Medicine in 2023, demonstrating that the study met its primary endpoint with a statistically significant and clinically meaningful improvement in MFS for patients treated with enzalutamide plus leuprolide versus placebo plus leuprolide.[7]
The most common adverse events (occurring in ≥10% of patients) in the combination group and the leuprolide-alone group were hot flashes and fatigue. The most common adverse events in the monotherapy group were gynecomastia, hot flashes, and fatigue.[8]
Enzalutamide is currently approved in more than 80 countries, including in the United States, European Union, and Japan.
“Over 1.5 million men with advanced prostate cancer around the world have benefited from treatment with enzalutamide since its initial approval in 2012,” explained Shontelle Dodson, Executive Vice President, Head of Medical Affairs, Astellas.[9]
“The scope and rigor of the EMBARK trial exemplify Astellas’ and Pfizer’s longstanding commitment to the prostate cancer community, and we look forward to sharing detailed findings in a future scientific forum,” further noted,
Detailed OS results from EMBARK will be presented at a future medical meeting.
Note: * Non-metastatic hormone-sensitive prostate cancer (nmHSPC; also known as nonmetastatic castration-sensitive prostate cancer or nmCSPC)
Clinical trials
Safety and Efficacy Study of Enzalutamide Plus Leuprolide in Patients With Nonmetastatic Prostate Cancer (EMBARK) – ClinicalTrials.gov ID NCT02319837
Highlights of prescribing information
Enzalutamide (Xtandi®, Pfizer and Astellas Pharma)[Prescribing Information]
Leuprolide (Lupron Depot®; Abbvie)[Product Monograph]
References
[1] Cancer.net. Prostate Cancer: Types of Treatment (12-2022). https://www.cancer.net/cancer-types/prostate-cancer/types-treatment Accessed June 16, 2025.
[2] American Society of Clinical Oncology. ASCO Answers: Prostate Cancer (2023).
[3] Paller, Channing J et al. “Management of patients with biochemical recurrence after local therapy for prostate cancer.” Hematology/oncology clinics of North America vol. 27,6 (2013): 1205-19, viii. doi:10.1016/j.hoc.2013.08.005
[4] Astellas and Pfizer. Data on File, EMBARK results, July 2025.
[5] Ward JF, Moul JW. Rising prostate-specific antigen after primary prostate cancer therapy. Nat Clin Pract Urol. 2005 Apr;2(4):174-82. doi: 10.1038/ncpuro0145. PMID: 16474760.
[6] Antonarakis, Emmanuel S et al. The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up. BJU international vol. 109,1 (2012): 32-9. doi:10.1111/j.1464-410X.2011.10422
[7] Freedland, Stephen J. et al. “Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer.” N Engl J Med 2023;389:1453-1465. DOI: 10.1056/NEJMoa2303974
[8] Ward JF, Moul JW. Rising prostate-specific antigen after primary prostate cancer therapy. Nat Clin Pract Urol. 2005 Apr;2(4):174-82. doi: 10.1038/ncpuro0145. PMID: 16474760.
[9] Astellas. Data on File. XTANDI patient. June 2025.
Featured image: Physician consulting with a patients in hospital exam room. Photo courtesy: © 2018 – 2025 Fotolia/Adobe. Used with permission
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