Insights from EMBARK: guiding clinical care and trial design

The EMBARK trial of enzalutamide in biochemically recurrent prostate cancer provides important insights into treatment of aggressive, relapsed disease and clinical trial design. The criterion of including patients with a prostate-specific antigen (PSA) doubling time of nine months or less after definitive therapy with radiation or prostatectomy is critical to consider when interpreting the results. In these high-risk patients, the risk of progression to metastatic disease and death is substantial without aggressive treatment (1,2). The overall survival (OS) analysis of EMBARK informs treatment of similar patients and gives guidance about future studies to advance prostate cancer care (3).

EMBARK enrolled 1,068 patients with localized castration-sensitive biochemically recurrent prostate cancer, now termed Androgen Pathway Modulation Naïve (APMN), from January 2015 through August 2018. Patients were randomized to a combination therapy group with leuprolide and enzalutamide, a leuprolide-monotherapy group, and an enzalutamide monotherapy group. Since enrollment ended in 2018, prostate-specific membrane antigen positron-emission tomography (PSMA PET) was not available. Notably, during the trial, if patients had an adequate PSA response, defined as a PSA level <0.2 ng/mL at week 37, then treatment was suspended. Treatment was restarted when the PSA level rose to at least 5.0 ng/mL if the patient had not undergone radical prostatectomy, or 2.0 ng/mL if the patient had undergone prostatectomy (3).

At initial publication, EMBARK’s primary endpoint of metastasis-free survival favored the combination of enzalutamide and leuprolide over leuprolide monotherapy [hazard ratio (HR) 0.42; 95% confidence interval (CI): 0.30–0.61; P<0.001] (4). This relationship continued in time to event analyses of first use of new antineoplastic therapy, distant metastasis, and symptomatic progression. Additionally, while enzalutamide monotherapy was superior to leuprolide monotherapy (HR 0.63; 95% CI: 0.46–0.87; P=0.005), there was no difference in metastasis-free survival between enzalutamide plus leuprolide and enzalutamide monotherapy at the initial readout.

Recently, the secondary endpoint of OS was reported by Shore et al., showing that OS was significantly longer in the leuprolide-enzalutamide combination group compared to leuprolide monotherapy [8-year overall survival (OS) 78.9% vs. 69.5%] and was associated with a decreased risk of mortality [HR (95% CI): 0.60 (0.44–0.80), P<0.001] (3). However, enzalutamide monotherapy was not associated with a decreased risk of mortality compared to patients receiving leuprolide monotherapy [HR (95% CI): 0.83 (0.63–1.10), P=0.19] (3). Enzalutamide monotherapy did show benefit in other prespecified secondary and exploratory end points such as time to first use of new antineoplastic therapy [HR (95% CI): 0.57 (0.45–0.72)] or first symptomatic skeletal event [HR (95% CI): 0.49 (0.28–0.86)] (3), but did have better preservation of sexual activity in health-related quality of life assessments (5).

Another major analysis performed in EMBARK related to medication side effects. A total of 98% of patients involved in the trial experienced an adverse event, and most involved fatigue, hot flashes, and gynecomastia (3). Of the breast-related adverse events, such as gynecomastia, nipple pain, and breast tenderness, the incidence was highest in the enzalutamide monotherapy group (3). Although the different side effect profiles require shared decision-making, the results suggest that if enzalutamide is to be used, optimum outcomes are achieved in combination with leuprolide.

EMBARK stands out due to the inclusion criteria. Enrolling patients that have already undergone definitive therapy and have a rapid PSA doubling time ensures that participants have truly aggressive disease (6). For example, treatment goals and regimens would differ significantly between a patient with a stable, albeit moderately elevated PSA, compared to a patient whose disease PSA is increasing at a high rate. Prostate cancer can have an indolent course, even when biochemically recurrent (7). While it is important to acknowledge the stage of a patient’s disease when considering treatment regimen, it is imperative to also consider the growth and change of the disease. Selection of patients at the highest risk of cancer progression and death is imperative in order to identify a therapeutic effect in clinically meaningful endpoints, such as development of metastasis or death.

While the EMBARK trial provides data supporting combination treatment in patients with biochemically recurrent localized disease, the cohort selection should be interpreted based on modern imaging methods. Patients enrolled in EMBARK had localized disease based on conventional imaging, such as computed tomography (CT) and nuclear medicine bone scans. However, as discussed by Shore et al., conventional imaging for disease staging is less sensitive than modern imaging methods such as PSMA-PET. A meaningful proportion of patients would have metastatic disease on PSMA PET (8,9), even when using a lower PSA threshold of <1 ng/mL (9). Therefore, this population could be considered for treatment of metastatic APMN with enzalutamide, similar to the ARCHES and ENZAMET trials (Figure 1) (10,11).

Figure 1 Comparison of trials of enzalutamide over disease states: the only trial that did not meet its primary endpoint was ENZARAD, which included patients with the lowest risk of prostate cancer (highlighted in red). Studies with positive findings have major findings are highlighted in green. ARCHES: name of the phase III enzalutamide trial in metastatic hormone-sensitive prostate cancer. EMBARK: name of the phase III trial of enzalutamide in biochemically recurrent prostate cancer. ENZAMET: name of the phase III enzalutamide trial in metastatic hormone-sensitive prostate cancer. ENZARAD: name of the phase III trial of enzalutamide with radiation therapy for localized prostate cancer. PROSPER: name of the phase III enzalutamide trial in non-metastatic castration-resistant prostate cancer. ADT, androgen deprivation therapy; CI, confidence interval; CT, computed tomography; EBRT, external beam radiation therapy; HR, hazard ratio; MFS, metastasis-free survival; mHSPC, metastatic hormone-sensitive prostate cancer; MRI, magnetic resonance imaging; N1, regional lymph node-positive disease; NSAA, nonsteroidal antiandrogen; OS, overall survival; PSA, prostate specific antigen.

The magnitude of benefit of enzalutamide in patients with relapsed localized disease and no evidence of distant metastatic disease by PSMA-PET is less certain. These patients would be at a lower risk and while there are no trials with this inclusion criteria, data from studies with earlier disease states can give some guidance. There is evidence of improved metastasis-free survival with abiraterone in patients with newly diagnosed non-metastatic prostate cancer at diagnosis in STAMPEDE, who were mainly treated with radiotherapy (12). However, the recently announced ENZARAD trial did not show benefit of enzalutamide with radiation in newly diagnosed localized disease (13), the earliest disease state tested in a large trial of enzalutamide (Figure 1). The lack of benefit of enzalutamide in this setting is surprising. Data from EMBARK, STAMPEDE, and other trials with enzalutamide would suggest similar efficacy, and in meta-analyses of clinical trials and real-world data in other disease settings, enzalutamide has superior or similar effectiveness compared to abiraterone (14-16). It is important to consider the characteristics of patients enrolled in ENZARAD. In STAMPEDE, 39% of patients were node positive while only 11% in ENZARAD. In a pre-specified analysis of the ENZARAD population that was node positive or had planned pelvic radiation, there was a benefit of enzalutamide on metastasis-free survival (13). Enzalutamide combination therapy could be considered in patients with newly diagnosed localized disease (ENZARAD) or relapsed disease with doubling time <9 months (EMBARK) and more aggressive features, such as lymph-node positive disease on PSMA-PET.

Importantly, EMBARK implemented intermittent therapy. If patients had a PSA level <0.2 ng/mL at week 37 of treatment, treatment was suspended. It would be reinitiated if PSA rose to at least 5.0 ng/mL if the patient had not undergone radical prostatectomy, or 2.0 ng/mL if that patient had a prostatectomy (3). The concept of intermittent therapy deserves attention as it uses response to guide treatment and reduce therapeutic burden. As it is important to treat patients who are high risk, patients with excellent response should be considered for intermittent therapy, similar to EMBARK. Additional trials of enzalutamide and androgen deprivation therapy (ADT), such as leuprolide, were able to achieve a PSA <0.2 ng/mL at a higher rate than those treated with placebo and ADT (17). The use of intermittent therapy similar to EMBARK could be considered in some patients with metastatic disease based on PSMA-PET if further studies identify which patient populations can safely suspend treatment in prospective trials.

The EMBARK trial has informed treatment of patients with high-risk prostate cancer and helped advance trial design by enrolling patients based on PSA kinetics. Patients with biochemical recurrence and PSA doubling time of <9 months benefit from enzalutamide and leuprolide combination therapy. Given the limitations of conventional imaging in EMBARK, prospective trials are needed in ‘EMBARK-like’ patients with low-volume metastatic disease based on PSMA-PET to evaluate the role of intermittent therapy. EMBARK also emphasizes the importance of selecting the highest risk patients for combination therapies in clinical practice and therapeutic trials. The longitudinal assessment of PSA doubling time increases the likelihood of finding a therapeutic benefit by selecting more aggressive cancers. Lastly, EMBARK establishes intermittent therapy as a promising tactic for treating patients with aggressive disease while reducing burden and opens the possibility of adaptive therapy that can be optimized in future trials.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0475/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0475/coif). M.W.S. reports consulting for ConcertAI; and research funding from Astellas, Johnson and Johnson, Pfizer, Prostate Cancer Foundation, Congressional Directed Medical Research Program, and Veterans Affairs Office of Research and Development to his institution. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 2005;294:433-9. [Crossref] [PubMed]
2. Freedland SJ, Humphreys EB, Mangold LA, et al. Death in patients with recurrent prostate cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their associated contributions to all-cause mortality. J Clin Oncol 2007;25:1765-71. [Crossref] [PubMed]
3. Shore ND, Luz MA, De Giorgi U, et al. Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med 2026;394:563-75. [Crossref] [PubMed]
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;389:1453-65. [Crossref] [PubMed]
5. Freedland SJ, Mulhall JP, Gleave M, et al. 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. Eur Urol 2025;87:507-11. [Crossref] [PubMed]
6. Eastham JA. Prostate-specific antigen doubling time as a prognostic marker in prostate cancer. Nat Clin Pract Urol 2005;2:482-91. [Crossref] [PubMed]
7. Martin NE, Chen MH, Beard CJ, et al. Natural history of untreated prostate specific antigen radiorecurrent prostate cancer in men with favorable prognostic indicators. Prostate Cancer 2014;2014:912943. [Crossref] [PubMed]
8. Holzgreve A, Armstrong WR, Clark KJ, et al. PSMA-PET/CT Findings in Patients With High-Risk Biochemically Recurrent Prostate Cancer With No Metastatic Disease by Conventional Imaging. JAMA Netw Open 2025;8:e2452971. [Crossref] [PubMed]
9. Droghetti M, Pirelli V, Ceci F, et al. PSMA-PET imaging in prostate cancer patients with high-risk biochemical recurrence: implications from an "EMBARK-Like" cohort. Prostate Cancer Prostatic Dis 2026; Epub ahead of print. [Crossref]
10. Armstrong AJ, Petrylak DP, Shore ND, et al. ARCHES 5-year Survival with Enzalutamide Plus Androgen-deprivation Therapy in Metastatic Hormone-sensitive Prostate Cancer Patients. Eur Urol 2026;89:396-403. [Crossref] [PubMed]
11. Sweeney CJ, Martin AJ, Stockler MR, et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol 2023;24:323-34. [Crossref] [PubMed]
12. Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Lancet 2022;399:447-60. [Crossref] [PubMed]
13. Nguyen PL, Sweeney C, Stockler MR, et al. LBA86 Randomised phase III trial of androgen deprivation therapy (ADT) with radiation therapy with or without enzalutamide for high risk, clinically localised prostate cancer: ENZARAD (ANZUP 1303). Ann Oncol 2025;36:S1628-S1629.
14. Schoen MW, Carson KR, Eisen SA, et al. Survival of veterans treated with enzalutamide and abiraterone for metastatic castrate resistant prostate cancer based on comorbid diseases. Prostate Cancer Prostatic Dis 2023;26:743-50. [Crossref] [PubMed]
15. Fisher DJ, Vale CL, Rydzewska LH, et al. Which patients with metastatic hormone-sensitive prostate cancer (mHSPC) benefit more from androgen receptor pathway inhibitors (ARPIs)? STOPCAP meta-analyses of individual participant data (IPD). J Clin Oncol 2025;43:20.
16. Leuva H, Zhou M, Teply BA, et al. Abiraterone vs Enzalutamide Among US Veterans With Metastatic Hormone-Sensitive Prostate Cancer. JAMA Netw Open 2025;8:e2540730. [Crossref] [PubMed]
17. Azad AA, Petrylak DP, Iguchi T, et al. Enzalutamide and Prostate-Specific Antigen Levels in Metastatic Prostate Cancer: A Secondary Analysis of the ARCHES Randomized Clinical Trial. JAMA Netw Open 2025;8:e258751. [Crossref] [PubMed]