Landmark Study Shows Survival Benefit for High-Risk Biochemically Recurrent Prostate Cancer

Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer | New England Journal of Medicine

Combination therapy with enzalutamide and hormone therapy demonstrates significant 8-year overall survival advantage in EMBARK trial's final analysis

A major clinical trial has delivered encouraging news for men with high-risk biochemically recurrent prostate cancer, showing that combination therapy can significantly extend overall survival compared to standard hormone therapy alone. The findings represent a paradigm shift in managing this challenging patient population.

Study Results: Survival Advantage Confirmed

The EMBARK trial's final analysis, published October 19, 2025, in the New England Journal of Medicine, found that 78.9% of patients treated with enzalutamide plus leuprolide were alive at 8 years, compared to 69.5% of those receiving leuprolide alone—a statistically significant difference that translates to a 40% reduction in the risk of death.

The trial enrolled 1,068 men with biochemically recurrent prostate cancer considered at high risk due to a PSA doubling time of 9 months or less. Patients were randomly assigned to receive either enzalutamide plus leuprolide (combination therapy), leuprolide alone (standard androgen deprivation therapy), or enzalutamide as a single agent (monotherapy). The median follow-up was approximately 94 months across all treatment groups.

Regulatory Impact and Clinical Practice

On November 16, 2023, the Food and Drug Administration approved enzalutamide (Xtandi) for non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis, making it the first and only androgen receptor signaling inhibitor approved by the FDA for this patient population. The approval was granted under Project Orbis, an initiative providing a framework for concurrent submission and review among international partners.

The European Medicines Agency approved enzalutamide for patients with high-risk biochemical recurrence who are unsuitable for salvage radiotherapy in April 2024. Major clinical practice guidelines have been updated to reflect these approvals.

The NCCN Guidelines now recommend enzalutamide with or without leuprolide as a Category 2A treatment option for certain high-risk patients with non-metastatic castration-sensitive prostate cancer after maximal pelvic therapy. Similarly, the 2024 EAU guidelines contain a "strong" recommendation for providers to offer enzalutamide with or without ADT to patients with high-risk biochemical recurrence.

What Makes This Significant

Biochemically recurrent prostate cancer with a PSA doubling time of 9 months or less indicates high risk for death from prostate cancer. This condition has a very high prevalence, occurring in upwards of 70,000 U.S. patients per year. Historically, this patient population has had limited treatment options beyond standard hormone therapy.

The survival benefit was achieved despite a unique feature of the trial protocol: treatment was suspended at week 37 if PSA levels dropped below 0.2 ng/mL and only restarted when PSA rose to specific thresholds. This intermittent approach was designed to minimize side effects while maintaining efficacy, with treatment suspension occurring more often in the enzalutamide arms—over 90% in enzalutamide plus ADT and over 85% in enzalutamide monotherapy—versus 67% with ADT alone.

Monotherapy Results

Enzalutamide monotherapy showed an 8-year survival rate of 73.1%, which did not differ significantly from leuprolide alone. However, monotherapy was superior to leuprolide alone with respect to previously reported key secondary endpoints and thus remains a treatment option, particularly for patients who are concerned about preserving sexual health.

Recent analyses published in European Urology demonstrated that enzalutamide monotherapy significantly prolonged the time to deterioration in sexual activity measures such as sexual interest, activity, satisfaction, and erectile function.

Additional Clinical Benefits

Beyond survival, the combination therapy showed that 82 events of first use of new antineoplastic therapy occurred in the combination group compared to 173 in the leuprolide-alone group, representing a 63% risk reduction.

Only 16 first symptomatic skeletal events occurred in the combination group compared to 37 in the leuprolide-alone group, a 60% risk reduction. These skeletal events include bone pain requiring treatment, fractures, or spinal cord compression.

Previous analyses from the trial showed that enzalutamide plus leuprolide and enzalutamide monotherapy prolonged metastasis-free survival without negatively affecting health-related quality of life compared with leuprolide alone.

Safety Profile

The median duration of treatment, excluding periods of treatment suspension, in all groups was 46.2 months. No new safety signals were reported in the long-term follow-up.

The most common adverse events occurring in at least 30% of patients were hot flashes and fatigue in the combination and leuprolide-alone groups and fatigue and gynecomastia in the monotherapy group. Gynecomastia was reported in 8.8% of patients in the combination group, 9.0% in the leuprolide-alone group, and 46.0% in the monotherapy group.

While fractures were more common overall in the combination group at 22.4% compared to 15.0% with leuprolide alone, the time to first symptomatic skeletal event was longer with combination therapy, suggesting lower clinically significant skeletal morbidity.

The Evolving Imaging Landscape

The trial's findings must be interpreted in the context of rapid advances in molecular imaging. Recent advances in molecular imaging suggest that, although patients had no evidence of metastasis on conventional imaging, many patients in the trial might have had metastasis detectable with PSMA PET, principally in the form of locoregional or oligometastatic disease.

PSMA-PET/CT has emerged as a highly sensitive imaging modality for prostate cancer, particularly for detecting biochemical recurrence and identifying metastatic disease that may be missed by conventional imaging methods like CT, MRI, and bone scans. In the CONDOR trial, almost two-thirds of patients experienced a change in their intended disease management based on PSMA PET results.

Recent studies have shown that patients with locally advanced, high-risk prostate cancer who have PSMA PET-positive lesions at biochemical recurrence following radical prostatectomy experience a metastasis-free survival period three times shorter compared to patients without PSMA PET-positive lesions.

Current AUA/ASTRO/SUO guidelines now state that for patients with biochemical recurrence following radical prostatectomy in whom salvage radiation is being considered, clinicians should perform next-generation molecular PET imaging.

Clinical Context and Future Directions

The findings support enzalutamide plus androgen deprivation as the standard of care for patients with prostate cancer with high-risk biochemical recurrence and complement previous trials showing survival benefits with enzalutamide in other prostate cancer settings.

Dr. Stephen Freedland of Cedars-Sinai noted that many patients with these high-risk biochemical recurrences will now be treated with the enzalutamide and leuprolide combination, acknowledging that while side effects are a concern, there are significant benefits including delaying metastasis.

Ongoing trials are investigating whether the concept of more potent androgen-receptor pathway inhibition could be applied even earlier—for example, at the time of salvage radiation therapy, particularly in patients with metastatic disease detected by PSMA PET and no metastasis on conventional imaging.

Several studies are currently assessing the role of intensified androgen receptor suppression with salvage radiation therapy, including RTOG 3506 (STEEL) comparing enzalutamide with ADT versus ADT alone, and the ECOG/ACRIN EA8191 (INDICATE) study comparing apalutamide with ADT versus ADT alone in conjunction with salvage radiation.

What This Means for Patients

This final analysis provides robust evidence that combination therapy with enzalutamide and leuprolide can extend life for men with high-risk biochemically recurrent prostate cancer. Patients should weigh the risks and benefits of treatment options with their physicians, considering factors such as survival benefit, side effects, and personal priorities like sexual health preservation.

The results are particularly relevant for men whose PSA is rising rapidly after initial treatment with surgery or radiation, as this often signals aggressive disease requiring more intensive therapy. As stated by ZERO Prostate Cancer president Courtney Bugler, this approval offers "a ray of hope to patients and their caregivers during these challenging times" when facing the distressing news of disease recurrence with risk of metastasis.

Sources

Primary Research Articles

  1. Shore ND, de Almeida Luz M, De Giorgi U, Gleave M, Gotto GT, Pieczonka CM, Haas GP, et al., Freedland SJ. Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer. New England Journal of Medicine. Published online October 19, 2025. DOI: 10.1056/NEJMoa2510310. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2510310

  2. Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. New England Journal of Medicine. 2023;389(16):1453-1465. DOI: 10.1056/NEJMoa2303974. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2303974

  3. Freedland SJ, Gleave M, De Giorgi U, et al. Enzalutamide and Quality of Life in Biochemically Recurrent Prostate Cancer. NEJM Evidence. 2023;2(12):EVIDoa2300251. DOI: 10.1056/EVIDoa2300251. Available at: https://evidence.nejm.org

  4. De Giorgi U, Freedland SJ, Rannikko A, et al. Enzalutamide in Patients with High-Risk Biochemically Recurrent Prostate Cancer According to the European Association of Urology Definition: A Post Hoc Analysis of EMBARK. Prostate Cancer and Prostatic Diseases. Published online March 26, 2025. DOI: 10.1038/s41391-025-00959-8. Available at: https://www.nature.com/articles/s41391-025-00959-8

  5. Shore N, De Giorgi U, Freedland SJ. Enzalutamide in Men With High-Risk Biochemically Recurrent Prostate Cancer: Rationale and Treatment Considerations From EMBARK. Journal of Urology. 2025;213(1):110-113. Available at: https://www.auajournals.org/doi/10.1097/JU.0000000000004228

  6. Freedland SJ, Woo HH. Effects of Enzalutamide on the Sexual Activity of Patients with Biochemically Recurrent Prostate Cancer: A Post Hoc Analysis of Patient-reported Outcomes in the EMBARK Study. European Urology. Published online February 26, 2025. DOI: 10.1016/S0302-2838(25)00094-6. Available at: https://www.europeanurology.com/article/S0302-2838(25)00094-6/fulltext

Regulatory Approvals

  1. U.S. Food and Drug Administration. FDA Approves Enzalutamide for Non-Metastatic Castration-Sensitive Prostate Cancer with Biochemical Recurrence. November 16, 2023. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-non-metastatic-castration-sensitive-prostate-cancer-biochemical-recurrence

  2. Pfizer Inc. and Astellas Pharma Inc. Pfizer and Astellas' XTANDI® Approved by U.S. FDA in Earlier Prostate Cancer Treatment Setting. Press release, November 16, 2023. Available at: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-astellas-xtandir-approved-us-fda-earlier

  3. Pfizer Inc. and Astellas Pharma Inc. XTANDI® Plus Leuprolide Significantly Improves Survival Outcomes in Men with Non-Metastatic Hormone-Sensitive Prostate Cancer with High-Risk Biochemical Recurrence. Press release, July 10, 2025. Available at: https://www.pfizer.com/news/press-release/press-release-detail/xtandir-plus-leuprolide-significantly-improves-survival

Clinical Practice Guidelines

  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 1.2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

  2. Schaeffer EM, Cheng HH, Eastham JA, et al. NCCN Guidelines® Insights: Prostate Cancer, Version 3.2024. Journal of the National Comprehensive Cancer Network. 2024;22(3):140-150. DOI: 10.6004/jnccn.2024.0019. Available at: https://jnccn.org/view/journals/jnccn/22/3/article-p140.xml

  3. Cornford P, Tilki D, van den Bergh R, et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. European Association of Urology, 2024. Available at: https://uroweb.org/guidelines/prostate-cancer

  4. Morgan TM, Boorjian SA, Buyyounouski MK, et al. Salvage Therapy for Prostate Cancer: AUA/ASTRO/SUO Guideline Part I: Introduction and Treatment Decision-Making at the Time of Suspected Biochemical Recurrence after Radical Prostatectomy. Journal of Urology. 2024;211:509-517. DOI: 10.1097/JU.0000000000003892. Available at: https://www.auanet.org/guidelines-and-quality/guidelines/salvage-therapy-for-prostate-cancer

  5. Lowrance W, Dreicer R, Jarrard DF, et al. Updates to Advanced Prostate Cancer: AUA/SUO Guideline (2023). Journal of Urology. 2023;209(6):1082-1090. DOI: 10.1097/JU.0000000000003452. Available at: https://www.auanet.org

Network Meta-Analysis and Reviews

  1. Aprikian A, Chilelli A, McLean T, et al. Comparing the Safety and Efficacy of Systemic Therapies for High-Risk Biochemically Recurrent Hormone-Sensitive Prostate Cancer: A Network Meta-Analysis. Frontiers in Oncology. 2025;15. DOI: 10.3389/fonc.2025.1638405. Available at: https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1638405/full

PSMA PET Imaging Research

  1. Fendler WP, Calais J, Hope TA, et al. PSMA-PET/CT Findings in Patients With High-Risk Biochemically Recurrent Prostate Cancer With No Metastatic Disease by Conventional Imaging. JAMA Network Open. 2025;8(1):e2450799. DOI: 10.1001/jamanetworkopen.2024.50799. Available at: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2828651

  2. Islam R, Desai S, Moran M, Golombos DM. The Role of PSMA PET Imaging in Prostate Cancer: Current Applications and Future Directions. Current Urology Reports. 2025;26(1):46. DOI: 10.1007/s11934-025-01268-2. Available at: https://pubmed.ncbi.nlm.nih.gov/40448740/

  3. van Altena EJE, Jansen BHE, Korbee ML, et al. Prostate-specific Membrane Antigen Positron Emission Tomography Before Reaching the Phoenix Criteria for Biochemical Recurrence of Prostate Cancer After Radiotherapy: Earlier Detection of Recurrence. European Urology Oncology. 2024. DOI: 10.1016/j.euo.2024.09.015. Available at: https://www.urologytimes.com/view/psma-pet-ct-can-reveal-prostate-cancer-recurrences-before-biochemical-criteria-met

Conference Presentations and Commentaries

  1. Shore ND. Overall Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer. Presented at: 2025 European Society for Medical Oncology Annual Congress; Berlin, Germany; September 2025. Available at: https://www.urotoday.com/conference-highlights/esmo-2025/esmo-2025-prostate-cancer/164089-esmo-2025-overall-survival-with-enzalutamide-in-biochemically-recurrent-prostate-cancer.html

  2. Freedland SJ, Shore ND. Is Quality of Life Impacted for Patients With High-Risk Biochemical Recurrence When Enzalutamide Is Prescribed? ASCO 2024 Highlight. AUA News. August 31, 2024. Available at: https://auanews.net/issues/articles/2024/september-2024/asco2024-highlight-is-quality-of-life-impacted-for-patients-with-high-risk-biochemical-recurrence-when-enzalutamide-is-prescribed

  3. Shore ND, Woo HH. Enzalutamide in Biochemically Recurrent Prostate Cancer: Key Findings from the EMBARK Study. Future Oncology. 2025;21(10):1151-1156. DOI: 10.1080/14796694.2025.2479331. Available at: https://pubmed.ncbi.nlm.nih.gov/40145508/

  4. Shore ND, Woo HH. Enzalutamide in Biochemically Recurrent Prostate Cancer: Design and Rationale of the EMBARK Study. Future Oncology. 2025;21(10):1145-1149. DOI: 10.1080/14796694.2025.2478786. Available at: https://www.tandfonline.com/doi/full/10.1080/14796694.2025.2478786

News and Educational Resources

  1. National Cancer Institute. Xtandi Approved for High-Risk Prostate Cancer. Cancer Currents Blog. Updated 2024. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2024/fda-xtandi-prostate-cancer-psa-recurrence

  2. Klaassen Z, Sayyid RK. NCCN 2024 Prostate Cancer Guideline Updates: Progressive M0 CSPC Management. UroToday. Available at: https://www.urotoday.com/video-lectures/nccn-2024/video/3955-nccn-2024-prostate-cancer-guideline-updates-progressive-m0-cspc-management-rashid-sayyid-zachary-klaassen.html

  3. Tilki D. High-Risk Biochemical Recurrence After Radical Prostatectomy and Negative PSMA PET: What to Do? The Guideline's View. Presented at: 2024 European Association of Urology Annual Congress; Paris, France; April 2024. Available at: https://www.urotoday.com/conference-highlights/eau-2024/eau-2024-prostate-cancer/151133-eau-2024-high-risk-biochemical-recurrence-after-radical-prostatectomy-and-negative-psma-pet-what-to-do-the-guideline-s-view.html

Clinical Trial Registry

  1. ClinicalTrials.gov. EMBARK: A Study of Enzalutamide Plus Leuprolide Acetate and Enzalutamide Monotherapy in Men With Nonmetastatic Hormone Sensitive Prostate Cancer. Identifier: NCT02319837. Available at: https://clinicaltrials.gov/study/NCT02319837

This article summarizes findings from the EMBARK phase 3 clinical trial, sponsored by Pfizer and Astellas Pharma. The study was conducted at 244 sites in 17 countries from January 2015 through August 2018, with final survival analysis completed in May 2025. For personalized medical advice, patients should consult with their healthcare providers.

 

Comments

Post a Comment

Popular posts from this blog

A 10-Second Steam Blast: The New Weapon Against Prostate Cancer?

Image
Vanquish® Water Vapor Ablation System, Francis Medical Steams Out Prostate Cancer The Vanquish® Water Vapor Ablation System, developed by Francis Medical, Inc. , represents an innovative approach to treating prostate cancer using water vapor (steam) to ablate cancerous tissue. This minimally invasive technique aims to target and destroy prostate cancer cells while minimizing damage to surrounding healthy tissue, potentially reducing common side effects associated with traditional treatments like surgery and radiation, Mechanism of Action:  The Vanquish system utilizes the thermal energy stored in sterile water vapor to ablate cancerous prostate tissue. During the procedure, a catheter is inserted through the urethra into the prostate, delivering water vapor directly to the targeted tissue. As the vapor condenses back into liquid, it releases stored thermal energy, effectively destroying the cancerous cells. This method is designed to respect the prostate's natural boundaries, ...
Read more

Dr. Christopher Kane of UCSD Health Appointed Chairman of the American Board of Urology

Image
  Dr. Christopher Kane of UCSD Health Appointed Chairman of the American Board of Urology SAN DIEGO, May 21, 2025 - Dr. Christopher Kane, a distinguished urologist and Professor of Urology at UC San Diego Health, has been appointed Chairman of the American Board of Urology (ABU), the organization announced today. Dr. Kane, who has served as CEO of UC San Diego Health Physician Group and Dean of Clinical Affairs at the UC San Diego School of Medicine, brings decades of experience in urologic oncology and leadership to this prestigious national position. Extensive Academic and Research Background Dr. Kane earned his medical degree from Uniformed Services University in Bethesda, Maryland, followed by a residency in urology at the Naval Medical Center San Diego and a fellowship in urologic oncology at the National Cancer Institute. He joined the UCSD faculty in 2007 after serving as a Navy physician for 12 years. As the C. Lowell and JoEllen Parsons Endowed Chair in Urology, Dr. ...
Read more

PSMA-Targeted Therapies for Prostate Cancer: Move Treatment Earlier in Disease Course

Image
  Interactive Graphic PSMA-Targeted Therapies for Prostate Cancer: Move Treatment Earlier in Disease Course Landmark FDA approval expands access to radioligand therapy while new research explores next-generation treatments By [Your Name] for the IPCSG Newsletter The landscape of prostate cancer treatment has undergone a seismic shift in recent months, with groundbreaking advances in prostate-specific membrane antigen (PSMA)-targeted therapies offering new hope to patients across different stages of the disease. Most significantly, the FDA's March 2025 expansion of Pluvicto (lutetium-177-PSMA-617) approval now allows treatment before chemotherapy, potentially tripling the number of eligible patients. Major FDA Approval Expands Treatment Access On March 28, 2025, the FDA approved a crucial expansion of Pluvicto's indication, allowing its use in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen recepto...
Read more