The EMBARK Trial: An Interview With Neal D. Shore, MD

The phase 3 EMBARK trial involved more than 200 global sites and had 8 years of follow-up.

During a plenary session at the American Urological Association’s 2023 Annual Scientific Meeting, Neal D. Shore, MD, FACS, Director, CPI, of Carolina Urologic Research Center, and a CMO with GenesisCare, US in Myrtle Beach, South Carolina, presented findings from the phase 3 EMBARK trial demonstrating a strong oncologic benefit of using enzalutamide alone or in combination with androgen deprivation therapy (ADT) in treating patients with high-risk biochemical recurrence (BCR) after interventional therapy (prostatectomy and/or radiation therapy). Renal & Urology News spoke with Dr Shore recently to discuss the 8-year trial and trends in prostate cancer treatment.

In your study, enzalutamide alone or in combination with leuprolide significantly decreased the risk for metastasis and PSA progression compared with placebo plus ADT (leuprolide). Do these findings, by themselves or combined with the findings of other studies, make a case for a new standard of care for patients with high-risk prostate cancer?

Dr Shore: I think they do. This was a global phase 3 trial that addressed the issue for patients who had high-risk BCR based upon a rapid PSA doubling time. There has been a lack of level 1 evidence as to how to best approach these patients. We know that they are at high risk for metastasis. Once they develop metastasis, by conventional imaging, they are going to be at risk for developing symptoms and then they begin the cascade of approved metastatic prostate cancer therapies. Achieving a phase 3 trial that could prospectively assess the best approach towards addressing patients with high-risk BCR was our goal. Historically, these patients were receiving intermittent ADT or continuous ADT, with or without a first-generation androgen receptor (AR) blocker, which are much less potent AR inhibitors.

When you observe that the combination arm of ADT plus enzalutamide versus ADT and a placebo, after a median follow-up of 5 years, had a 58% improvement in metastasis-free survival, and with a p value which was highly statistically significant, this is extremely clinically significant for patients. These patients’ biology can take years to evolve, which explains why this was an 8-year trial. The survival curves favor a survival benefit, but haven’t reached statistical significance yet. We will continue to closely follow EMBARK patients for overall survival (OS). Even before we have the final OS analysis, I believe that the results are already practice changing.

Was the trial challenging to conduct?

The EMBARK trial completion undertook a Herculean effort of over 200 sites globally during an 8-year follow up. The first patient was enrolled on January 2015. The last patient enrolled in August 2018. It required an enormous amount of dedication to obtain the PSAs, imaging, and careful follow-up.  An interesting aspect of this trial is that we allowed for treatment holidays to improve patients’ quality of life upon achieving steep declines in PSA response. We’re still pouring over a lot of the data. We had our top-line readout on March 15, and we were fortunate to have the AUA allow for our plenary presentation on April 29.

Do you currently use enzalutamide for high-risk localized prostate cancer in your practice?

No, I don’t. I would only use it within the parameters of a clinical trial. If it’s a patient who is asking about it, prior to this, there may be some very rare exceptions, but I tend to follow our guidelines and level 1 evidence. Certainly, right now, we have level 1 evidence to recommend the combination, but I would prefer that we wait until we go through regulatory review with the FDA and other important international regulatory agencies.

Are there any downsides to using enzalutamide so early in the disease process?

We don’t have evidence to suggest that there’s a downside. We do see some increase in some side effects, but we documented no new safety signals for enzalutamide. If you’re giving enzalutamide plus a testosterone-lowering agent, and any time you go from a monotherapy to doublet therapy, you are going to see some additional side effects. We did not see any new safety signals that hadn’t already been well characterized with numerous phase 3 trials with enzalutamide. There has been a decade of robust experience for combining enzalutamide and ADT.

Would apalutamide and darolutamide exert the same oncologic benefit as enzalutamide in this patient population?

Dr Shore: I don’t think we could answer that until those trials are done. I certainly am very experienced with both apalutamide and darolutamide. I think they are both excellent drugs. But [as for] the data right now, the level 1 evidence only exists for enzalutamide. We have a luxury of multiple androgen-receptor pathway inhibitors, including an androgen biosynthesis inhibitor — abiraterone. But I tend to favor using drugs for indications established by level 1 evidence. That’s why we do trials, to change and improve clinical practice and patient outcomes.

Given that metastatic disease is incurable despite a widening array of novel treatments, should the emphasis be on treating high-risk localized prostate cancer as early and as hard as possible to prevent progression as long as possible?

I think there is a lot of wisdom in that approach, assuming the patient has a good performance status and doesn’t have any significant comorbidities. But more importantly, what does the patient want? I think learning a patients’ preference values as to how risk-averse or risk-tolerant they are is an important tenet of shared decision-making. Patients, when they first present with metastatic disease, are typically younger than patients who have resistant disease. Their performance status is usually better, and they oftentimes will tolerate therapies better. That said, that’s why there is still the art of medicine and the importance of having shared decision-making discussions with patients and their caregivers.

Ultimately, what type of therapy or therapies will be needed to cure metastatic prostate cancer?

Advanced disease really begins when the cancer cells move outside the prostate. Sometimes, we have patients who can be cured with combination therapies when they have local metastases. It’s very uncommon to achieve that with a patient who has bone lesions and/or visceral metastases. I think earlier administration of drug combinations with novel mechanisms of action in a judicious way, as well as sequentially, is important for our attempts to potentially achieve cure, while always hoping for super-responder outcomes.

The word “cure” has different meanings to clinicians and patients. Ostensibly, a patient might be considered ‘cured’ if we can effect a prolonged state of remission such that the patient ultimately succumbs with the disease and not from the disease.

This article originally appeared on Renal and Urology News