15th Shanghai Urological Oncology Academic Conference
In the treatment pathway of prostate cancer, biochemical recurrence (BCR) represents a critical turning point. Especially for high-risk BCR patients with a short PSA doubling time, how to delay disease progression and improve overall survival (OS) has long been a major clinical concern. At the recent 15th Shanghai Urological Oncology Academic Conference, Oncology Frontier – UroStream invited Professor Stephen J. Freedland from Cedars-Sinai Medical Center to provide an in-depth interpretation of the EMBARK study, including its study rationale, clinical benefits, and individualized treatment strategies for high-risk BCR patients.01
Professor Stephen J. Freedland: The EMBARK study (NCT02314442) is a global, multicenter, randomized Phase III clinical trial designed to evaluate the application of enzalutamide in patients with high-risk biochemical recurrence (BCR).
Study Background and Inclusion Criteria: Based on the proven survival benefits of enzalutamide in metastatic prostate cancer, we explored whether its use could be moved “upstream” to the non-metastatic stage. The study enrolled patients with no metastatic lesions detected by conventional imaging (CT or bone scan) but who exhibited a high risk of biochemical recurrence, defined as a PSA doubling time (PSADT) ≤ 9 months.
Study Design: Patients were randomized into three arms: enzalutamide plus androgen deprivation therapy (ADT), ADT alone, and enzalutamide monotherapy (marking the first time an ARPI has been evaluated as a monotherapy in a Phase III trial). A unique “intermittent treatment strategy” was employed: after 9 months of initial treatment, if PSA dropped below 0.2 ng/mL, treatment was suspended; treatment resumed with the original assigned regimen only when PSA levels rose again.
Key Efficacy Data: Combination Group (Enzalutamide + ADT): Compared to ADT alone, the combination therapy significantly delayed disease progression. The primary endpoint, Metastasis-Free Survival (MFS), showed a 58% reduction in risk, a highly significant result. More importantly, the combination regimen led to a reduction in the risk of all-cause death by over 40%. Such a significant OS benefit in a Phase III trial for the non-metastatic stage is unprecedented.
Monotherapy Group (Enzalutamide alone): Compared to ADT alone, the monotherapy group showed a 37% reduction in the risk of disease progression (metastasis or death). While the Hazard Ratio (HR) for OS was 0.83, indicating a positive trend, it did not reach statistical significance.
The EMBARK results provide robust evidence for the management of high-risk BCR prostate cancer. Specifically, the dual breakthrough in MFS and OS achieved by the enzalutamide plus ADT regimen establishes the role of intensified endocrine therapy in this disease stage. In clinical practice, physicians should develop refined, individualized plans based on a patient’s risk stratification, quality-of-life expectations, and tolerability, while maintaining vigilant monitoring and management of adverse effects throughout the treatment course.
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Professor Stephen J. Freedland: By synthesizing findings from the EMBARK, PRESTO, and STAMPEDE trials, we can derive several conclusions vital to clinical practice:
1. ARPIs are not “the more, the better”: Multiple studies indicate that combining two different androgen receptor pathway inhibitors (ARPIs) simultaneously is not superior to using a single ARPI. Such combinations only increase toxicity without providing additional oncological benefits. Therefore, dual ARPI therapy is not recommended.
2. Continuity and Consistency of Intensified Therapy: In the PRESTO study, patients stopped treatment after 52 weeks and restarted with ADT monotherapy upon progression. However, in EMBARK, patients who restarted treatment returned to their original intensified regimen (e.g., enzalutamide + ADT). While PRESTO did not observe a significant MFS benefit, EMBARK demonstrated clear survival advantages. This suggests that not only should the initial treatment be intensified, but the regimen used upon restart after biochemical progression should also maintain the same level of intensification.
3. Individualized Selection: Most High-Risk Patients: Intensified combination therapy (ARPI + ADT) is recommended to achieve optimal survival protection. Specific Populations: For patients with relatively less aggressive disease (high-risk but not “ultra-high” risk) who highly prioritize the preservation of sexual function, enzalutamide monotherapy serves as a viable alternative.
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Professor Stephen J. Freedland: As the window for ARPI application moves earlier in the disease course, patients remain on treatment for longer durations, making the management of long-term side effects particularly critical.
Enzalutamide Monotherapy Specifics: The advantage of monotherapy is a significant reduction in hot flashes; however, gynecomastia (breast enlargement) is very common. Management: We typically consider prophylactic breast irradiation before starting treatment or the administration of Tamoxifen. Regarding Tamoxifen dosing, clinical practices vary from 10 mg daily to 10 mg weekly; while there is no consensus on the “optimal” standard, clinicians must proactively address this issue.
Combination Therapy Side Effects: Enzalutamide plus ADT can essentially be viewed as “intensified ADT”. Consequently, the side effect profile is similar to ADT alone—including fatigue and hot flashes—though the severity may be more pronounced. Management: Lifestyle interventions are emphasized. Ensure patients maintain a healthy diet, adhere to regular exercise, and get sufficient sleep. Proper exercise can significantly reduce the risks of falls, fractures, and fatigue. While the vast majority of patients can tolerate full-dose therapy, clinicians should not hesitate to implement dose adjustments if lifestyle interventions are insufficient to balance efficacy with quality of life.
Stephen J. Freedland
