Setting New Standards in Prostate Cancer Management With EMBARK With Stephen Freedland, MD

What Did EMBARK Investigate?

EMBARK enrolled patients with BCR after surgery or radiation and high risk by prostate-specific antigen (PSA) doubling time, with negative conventional imaging. Patients were randomized to receive:

• Androgen deprivation therapy (ADT) alone
• ADT plus enzalutamide
• Enzalutamide monotherapy

The primary end point was metastasis-free survival (MFS), with overall survival (OS) assessed with longer follow-up.

“We’ve known for a long time that patients who have BCR after surgery or radiation and a short PSA doubling time, where the PSA is rising very rapidly, are at high risk for developing metastatic disease and dying of their cancer,” explained Dr. Freedland. “The question has always been about what to do for these patients. That’s where EMBARK stepped in.”

Earlier results showed significant MFS improvement with both enzalutamide combination therapy and monotherapy, enabling FDA approval, guideline inclusion, and regulatory label expansion.

What’s New in the Latest Analysis?

The new analysis demonstrates a highly significant OS advantage for ADT plus enzalutamide, with more than 40% relative reduction in risk of death across the intent-to-treat population. The OS hazard ratio with monotherapy was 0.83 but did not reach statistical significance, though it continued to meet many secondary end points.

“ADT plus enzalutamide had an unprecedented survival advantage in this population,” Dr. Freedland shared. “It’s the greatest survival advantage we have ever seen in a global phase 3 trial in prostate cancer.”

How These Results Impact Practice

Enzalutamide combination therapy is poised to move from National Comprehensive Cancer Network (NCCN) Category 2A to Category 1 in high-risk BCR prostate cancer after local therapy failure, establishing it as standard of care based on OS. Monotherapy remains a reasonable option for selected patients, prioritizing preservation of sexual function and quality of life, while recognizing the lack of statistically significant OS benefit.

“If you really want that OS benefit, it’s with the combination,” Dr. Freedland underscored. “With data like this, it’s really hard to ignore a 40% reduction in risk of risk of death—really an unprecedented benefit. It’s a great day for our patients when we can really halt the natural history and dramatically cut the risk of death from this disease.”

Patient Selection and Toxicity Management

Quality of life was preserved overall, with expected ADT-related adverse effects:

• Fatigue, hot flashes, increased risk of falls
• Rare seizures (~1%): discontinue therapy if they occur
• With monotherapy, gynecomastia can be mitigated with breast irradiation and/or low-dose tamoxifen

“Enzalutamide has side effects, and we need to be cautious of that,” Dr. Freedland elaborated. “It’s not for every patient, so we’ve got to pick the right patients.

PSA doubling time is central to patient selection:

• Doubling time <3 months: monotherapy showed no advantage over ADT alone (hazard ratio ~1.0); favor combination
• Doubling time 3-9 months: combination strongly favored; monotherapy may be considered in selected cases

Supportive measures include exercise, rest, nutrition, and dose adjustments as needed. “There are some side effects that we need to be aware of and manage, but the vast majority of patients are able to stay on the drug, get the full dose, or maybe get a little bit of a reduction get still see those benefits that we saw in the trial,” Dr. Freedland explained.

Treatment Suspension and Ongoing Analyses

EMBARK included protocolized treatment suspension after 37 weeks for patients achieving robust PSA response. Ongoing work aims to quantify “time off therapy” across all randomized patients, including those never eligible for suspension, and to explore whether avoiding suspension could enhance monotherapy outcomes. The recent publication of the data in the New England Journal of Medicine includes a discussion exploring these future directions and analyses.

Final Advice for Clinicians

“The data are clear: adding enzalutamide to ADT, once local therapies have failed, has a dramatic survival advantage,” Dr. Freedland concluded. “Side effects are manageable for the most part, and quality of life is preserved. It’s really impressive data that cannot be ignored for the sake of our patients.”

Key Takeaways

• ADT plus enzalutamide yields a >40% relative reduction in mortality in high-risk BCR prostate cancer, establishing a new standard of care.
• Enzalutamide monotherapy improves several secondary outcomes but did not achieve statistically significant OS; it can be considered for select patients where quality of life and sexual function are a priority and disease kinetics are less extreme.
• Expect and manage androgen-axis toxicities; counsel on fatigue, falls, hot flashes; address gynecomastia with monotherapy.
• PSA doubling time drives selection: doubling time <3 months strongly favors combination therapy and 3-9 months supports combination, with selective use of monotherapy.
• Treatment suspension after response is feasible and common; analyses continue to refine on/off strategies.

About the Speaker

Stephen Freedland, MD, is a Professor of Urology and the Warschaw Robertson Law Families Chair in Prostate Cancer at Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center. He is also the Director of the Center for Integrated Research in Cancer and Lifestyle and the Associate Director for Education and Training at Samuel Oschin, and he holds a Staff Physician appointment at the Durham VA Medical Center in Durham, North Carolina. Dr. Freedland has published over 700 articles and served on numerous AUA and ASCO guideline panels for prostate cancer. His research interests include cancer health disparities, risk stratification, and the role of diet, lifestyle, and obesity in cancer.