The EMBARK Trial: Enzalutamide Plus ADT Achieves Unprecedented OS in nmCSPC

Patients with nonmetastatic castration-sensitive prostate cancer (nmCSPC) who have high-risk biochemical recurrence have an increased risk of disease progression, including metastasis and mortality.¹ The phase 3 EMBARK trial (NCT02319837) sought to address this need by evaluating the efficacy and safety of the androgen receptor inhibitor enzalutamide (Xtandi) in combination with androgen-deprivation therapy (ADT) of leuprolide acetate, as well as monotherapy, in patients with patients with nmCSPC at high risk of biochemical recurrence.²

Enzalutamide’s journey has been marked by numerous FDA approvals across prostate cancer indications, such as late-stage metastatic castration-resistant prostate cancer as its first approved indication in 2012³ and metastatic castration-sensitive prostate cancer. Pertaining to the EMBARK trial, positive data published in The New England Journal of Medicine in 2023¹ paved the way for the FDA approval of enzalutamide in the same year in patients with high-risk, biochemically recurrent nmCSPC.

Results of the EMBARK trial’s final overall analysis were recently presented at the 2025 European Society for Medical Oncology (ESMO) Congress and simultaneously published in The New England Journal of Medicine.⁵ These data show a 40% reduction in risk of death when treated with the combination compared with ADT alone along with a manageable safety profile, reaffirming enzalutamide’s position as a robust standard of care for this patient population.

In an interview with Targeted Oncology, Stephen Freedland, MD, 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, and Warschaw, Robertson, Law Families Chair in prostate cancer and professor in the Department of Urology at Cedars-Sinai Medical Center, delves into the pivotal new findings from the EMBARK trial and its implications for patients.

Targeted Oncology: What was the unmet need in the patient population that prompted the EMBARK trial?

Stephen Freedland, MD: Patients with high-risk, biochemically recurrent, conventional imaging-negative prostate cancer have presented a dilemma for clinicians for many years in terms of when to do something and what to do. We know these patients are at high risk of developing metastatic disease and ultimately dying from prostate cancer, and yet we're left with not knowing what to do for these patients. So that was the unmet need––we have a group that we know is going to be in trouble, we want to do something about it, and we didn't know what to do.

[The trial] is trying to answer an important question: When is the right time to start systemic therapy? How do we do that? We still haven't 100% answered the “when to start,” but we went after the “how to start.” We know in the metastatic space, based on conventional imaging, that adding an androgen receptor pathway inhibitor like enzalutamide to standard ADT delays progression, improves survival, and preserves quality of life. Could we apply that 1 step earlier in the disease and get similar outcomes?

What were the characteristics of patients in the EMBARK trial?

We focused on patients with high-risk, biochemically recurrent, conventional imaging-negative prostate cancer. Conventional imaging-negative [was defined as] no evidence of metastatic disease based upon the standard of care at the time, which were computed tomography [CT], bone scan, or magnetic resonance imaging [MRI].

High risk [was] defined as prostate-specific antigen [PSA] doubling time [of] less than 9 months and no longer candidates for any further salvage local therapies. PSA needed to be greater than 1 for those who had surgery or greater than 8 or plus 2 for those who had radiation. We ended up with a cohort where the median PSA doubling time was about 5. Half of patients had surgery and radiation, a quarter surgery only, and another quarter radiation only.

What were the major efficacy and safety findings, and what is the overall significance of these findings?

We previously reported 2 years ago in The New England Journal of Medicine that adding enzalutamide to ADT, or enzalutamide by itself, for the first time ever in a phase 3 clinical trial, delayed progression for these patients, defined as metastasis or death––both bad things that we want to avoid in our patients, both highly statistically, clinically significant. Delays in those events met many of the secondary outcomes and preserved quality of life. That's what we knew 2 years ago led to FDA approval, EMA in Europe, and incorporation and guidelines in many other countries around the world.

What we're finding here is that, with continued follow up, the delay in metastasis or death for the combination of enzalutamide plus ADT translated into an over 40% reduction in the risk of death––a profound, unprecedented risk reduction in a global phase 3 clinical trial focused on the entire patient population, not cherry-picking a small subset of patients, while meeting many of the secondary outcomes and preserving quality of life. For monotherapy, while it did not reach statistical significance, there was a slight suggestion of improved survival, and it met many of the secondary outcomes as well.

With 2.5 years of follow-up, [there were] no new safety signals, [indicating] that we have 2 great options for our patients, 1 of which has an unprecedented survival advantage––really saying that enzalutamide plus ADT is the standard of care for these high-risk patients.

What do you see as the next steps in this research? What questions do you still have?

Whenever you have a successful phase 3 clinical trial, there [are] 2 ways of looking at it. One is, how do we make the treatment better? And then, how do we make it with less [adverse effects]? I think, given the unprecedented, incredible survival advantage, it's going to be hard to do better. I'm certainly supportive of trying to do better, but it took us 11 years to show that this worked. If we want to do better, the next study is going to [take] 12 to 15 years to show that.

So, for the combination, I think the focus is on how do we [lessen adverse effects]? That's where I think bringing in metastasis-directed therapy [comes into play]. The world has changed with prostate-specific membrane antigen [PSMA] imaging and multiple rounds of treatment suspension––I didn't mention patients were treated for 9 months, and if they responded, we stopped treatment, but once they went back on treatment, they stayed on treatment until they progressed. So, can we do multiple rounds of treatment suspension, all in an effort to prolong the time off therapy while maintaining the same cancer benefits?

On the flip side for the monotherapy, we did not have a significant survival advantage relative to ADT. So, the question is, how do we make it more effective? One of the thoughts is, maybe at that 9-month mark, if [the patient is] doing well, we shouldn't stop therapy. Let's just keep going with therapy, because anecdotally, it tends to be well tolerated, perhaps better than with the ADT, just because ADT itself has [adverse] effects that we can avoid. I think there's an opportunity there to try and make that a little bit more effective while focus[ing] on the combination of enzalutamide plus ADT to try and reduce the length of hormonal therapy that patients would receive.

Are there any final takeaways from this research that you wish to reiterate?

We’ve seen a lot of advancements in prostate cancer. We've seen a lot of drugs move earlier and earlier, and we kind of take it as second nature that if a drug works late, it's going to work early. It takes time to prove that, but I think it's important to just pause and realize what this has shown here. We have a drug that’s 13 years on the markets, and we're seeing how powerful of a drug it is when used in the right patient population, really early, with again, an unprecedented 40% reduction of risk of death and [manageable adverse effects]. What a great day this is for our patients that we can find them this early and get such a profound benefit––it's incredible and a testament to modern medicines of what we can accomplish.

REFERENCES:

1. 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

2. Safety and Efficacy Study of Enzalutamide Plus Leuprolide in Patients With Nonmetastatic Prostate Cancer (EMBARK). ClinicalTrials.gov. Updated July 8, 2025. Accessed October 20, 2025. https://clinicaltrials.gov/study/NCT02319837

3. U.S. FDA Approves XTANDI® (enzalutamide) for the Treatment of Men with Non-Metastatic Castration-Resistant Prostate Cancer (CRPC). News release. Pfizer. July 13, 2018. Accessed October 20, 2025. https://tinyurl.com/2hwn6uf4

4. Shore ND, de Almeida Luz M, De Giorgi U, et al. Improved survival with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2025; Published October 19, 2025. doi:10.1056/NEJMoa2510310