Advancements in Prostate Cancer Treatment: EMBARK Trial Highlights the Promise of Enzalutamide


Prostate cancer is one of the most prevalent malignancies affecting men worldwide. In the United States alone, it is estimated that there will be approximately 288,300 new cases of prostate cancer and 34,700 deaths from the disease in 2023. These statistics underscore the critical need for continued research and innovation in the field of prostate cancer management. A recent study published in the New England Journal of Medicine, led by Professor Stephen J. Freedland from Cedars-Sinai Urology and Professor Neal D. Shore from the Carolina Urologic Research Center, offers new insights into the treatment of high-risk biochemical recurrence after definitive therapy for prostate cancer.

Biochemical recurrence, characterized by an increase in prostate-specific antigen (PSA) levels, occurs in a significant percentage of patients within 10 years after receiving definitive therapy for prostate cancer. This rise in PSA levels can signify various disease states, including micrometastatic, localized, regional, or distant disease, all of which contribute to an increased risk of illness and death related to prostate cancer. Managing biochemical recurrence is challenging, primarily due to the limited availability of Level 1 clinical evidence to guide treatment decisions. Consequently, risk stratification is a common approach for managing these patients. Those with a PSA doubling time of less than 9 months are considered at high risk for rapid disease progression and increased prostate cancer-related mortality. In recent years, next-generation hormonal therapies, such as enzalutamide, have emerged as promising options for managing prostate cancer. Clinical trials have demonstrated that enzalutamide can significantly prolong imaging-based progression-free survival, overall survival, and delay the development of castration-resistant prostate cancer when compared to androgen-deprivation therapy alone in patients with metastatic hormone-sensitive prostate cancer. One noteworthy finding is the correlation between nadir PSA levels and improved clinical outcomes across various stages of prostate cancer. This observation suggests that PSA may serve as a valuable biomarker for identifying patients who are likely to respond favorably to therapy. It also raises the possibility of deintensifying therapy in patients who achieve a low PSA nadir, thereby reducing the burden of treatment-related side effects.

The EMBARK trial aimed to evaluate the efficacy and safety of enzalutamide in combination with leuprolide and enzalutamide monotherapy, as compared to leuprolide alone, in patients with high-risk biochemical recurrence of prostate cancer. The authors enrolled 1068 patients from 244 sites across 17 countries and reported its findings as of January 31, 2023. The baseline characteristics of the study population were well-balanced among the three treatment groups. Most patients were of White ethnicity, with a median age of 69 years. The median PSA doubling time was 4.9 months, and the median PSA level at baseline was 5.2 ng per milliliter. These baseline characteristics provide a representative snapshot of the patient population included in the trial.

The researchers’ primary efficacy endpoint was metastasis-free survival, a critical measure of the time elapsed until the occurrence of metastasis or death. The trial results demonstrated significant improvements in metastasis-free survival for both the combination therapy group and the enzalutamide monotherapy group when compared to the leuprolide-alone group. Notably, the risk of metastasis or death was substantially lower in these treatment arms, with hazard ratios of 0.42 and 0.63, respectively. Furthermore, the authors reported impressive outcomes regarding PSA progression. The percentage of patients free from PSA progression at 5 years was substantially higher in the combination and monotherapy groups compared to the leuprolide-alone group. Additionally, the time to the first use of new antineoplastic therapy was longer in the combination and monotherapy groups, indicating a delay in disease progression and the need for further treatment. Other secondary endpoints, including time to distant metastasis, symptomatic progression, and first symptomatic skeletal events, also favored the combination therapy. Enzalutamide plus leuprolide demonstrated a lower risk of castration resistance and resumption of any hormonal therapy when compared to leuprolide alone. Importantly, patient-reported outcomes indicated that adverse events did not negatively impact the overall quality of life in the combination and monotherapy groups. Regarding overall survival, while the data were still immature, a trend toward improved survival was observed in the combination therapy group compared to the leuprolide-alone group. It is essential to note that long-term consequences and the tolerability of subsequent treatments following prolonged exposure to enzalutamide require further investigation.

Safety remains a paramount concern in cancer therapy. According to the authors, the safety profile of enzalutamide in the trial was consistent with previous studies, with no new safety signals identified. Adverse events were reported in more than 97% of patients across all groups, with the most common events being hot flashes and fatigue. However, the nature of adverse events differed among treatment groups. Notably, gynecomastia, nipple pain, and breast tenderness were more common in the enzalutamide monotherapy group but were generally mild to moderate in severity.

The study’s protocol included a treatment suspension at week 37 for patients whose PSA levels reached undetectable levels (<0.2 ng per milliliter). This decision was based on previous studies that demonstrated improved PSA nadir with hormonal treatment. A significant proportion of patients in the combination and monotherapy groups had their treatment suspended, with a longer duration of suspension observed in the combination group. The shorter duration of suspension in the monotherapy group was attributed to the absence of testosterone suppression. Resumption of eugonadal testosterone levels and its clinical impact on enzalutamide monotherapy are subjects of ongoing analysis.

In conclusion, the EMBARK trial represents a significant advancement in the management of high-risk biochemical recurrence after definitive therapy for prostate cancer. Enzalutamide, whether used in combination with leuprolide or as monotherapy, has demonstrated remarkable efficacy in prolonging metastasis-free survival and delaying PSA progression, with no significant impact on patients’ overall quality of life. These findings provide compelling evidence for the incorporation of enzalutamide into the treatment arsenal for patients with high-risk biochemical recurrence of prostate cancer.

As we await further data on long-term outcomes and the impact of enzalutamide exposure on subsequent treatments, it is imperative that we continue to explore innovative approaches to optimize prostate cancer management. The EMBARK trial exemplifies the collaborative efforts of researchers, clinicians, and patients in advancing our understanding of prostate cancer and improving the lives of those affected by this disease. This study heralds a promising era in prostate cancer therapy and underscores the significance of precision medicine in tailoring treatment strategies to individual patients, ultimately aiming for better outcomes and enhanced quality of life.

Advancements in Prostate Cancer Treatment: EMBARK Trial Highlights the Promise of Enzalutamide - Medicine Innovates

About the author

Neal D. Shore, MD, FACS

Director, CPI (Certified Principal Investigator by the Association of Clinical Research Professionals)

Neal D. Shore, MD, FACS is the Medical Director for the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina.

Dr. Shore has conducted more than 250 clinical trials, focusing mainly on GU Oncology, and serves on the Executive Boards of: Society of Urologic Oncology Board, Society of Urologic Oncology Clinical Trials Consortium, Secretary-Treasurer, and the Large Urology Group Practice Association, President-elect. He is a Founder for both: CUSP Clinical Trials Consortium, as well as for DASHKO, large urology practices data registries. He serves as the National Urology Research Director for 21st Century Oncology. He has served on the AUA Male Health Committee; he is currently a member of the AUA Data Committee, the SITC Task Force for Prostate Cancer, the Bladder Cancer Advocacy Think Tank and the editorial boards of Urology Times, Current Urology Reports, Chemotherapy Advisor, OncLive, PLOS ONE(Academic Editor) and Urology Practice. He has more than 100 peer reviewed publications and numerous book chapters; he performs peer review for multiple high impact scientific journals.

About the author

Professor Stephen J. Freedland, MD

Cedars-Sinai, Urology
Los Angeles, California

Stephen Freedland, MD, is director of the Center for Integrated Research in Cancer and Lifestyle and associate director for Training and Education at the Samuel Oschin Comprehensive Cancer Institute. He is the Warschaw, Robertson, Law Families Chair in Prostate cancer and professor in the Department of Urology at Cedars-Sinai. Freedland’s clinical expertise focuses on urological diseases, particularly benign prostatic hyperplasia and prostate cancer. His approach toward cancer prevention and awareness focuses on treating the whole patient, not just the disease, by combining traditional Western medicine with complementary holistic interventions. His research interests include urological diseases and the role of diet, lifestyle and obesity in prostate cancer development and progression, as well as prostate cancer among racial groups and risk stratification for men with prostate cancer. Freedland has published over 700 studies, and his research has appeared in the Journal of the American Medical Association, Journal of the National Cancer Institute, Journal of Clinical Oncology, Journal of Urology, Cancer Prevention Research, Cancer and BJUI, among others. Freedland is an active reviewer for more than 50 journals. He sits on the editorial board for Cancer Prevention Research, International Journal of Urology, Nature Reviews Urology, Asian Journal of Andrology, and serves as editor-emeritus for Prostate Cancer and Prostatic Diseases. Freedland earned his MD from the University of California, Davis. He completed a residency in urology at UCLA and a fellowship in urological oncology at Johns Hopkins. Before joining Cedars-Sinai, he was at Duke University, where he specialized in surgical oncology and urologic oncology, and served as an associate professor in the Division of Urology.


Freedland SJ, de Almeida Luz M, De Giorgi U, Gleave M, Gotto GT, Pieczonka CM, Haas GP, Kim CS, Ramirez-Backhaus M, Rannikko A, Tarazi J, Sridharan S, Sugg J, Tang Y, Tutrone RF Jr, Venugopal B, Villers A, Woo HH, Zohren F, Shore ND. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med. 2023 ;389(16):1453-1465. doi: 10.1056/NEJMoa2303974.

Go To N Engl J Med.