EMBARK

Background

Phase III, double-blind, placebo-controlled RCT. 1068 patients with biochemically recurrent (BCR) prostate cancer after radical prostatectomy or radiation therapy, PSA doubling time ≤9 months, PSA ≥2 ng/mL (post-prostatectomy) or ≥5 ng/mL (post-radiation), no evidence of distant metastases on conventional CT and bone scan.

Interventions and follow up

Arm A: Enzalutamide 160mg/day orally + leuprolide 22.5mg SC q12wk (combination)
Arm B: Enzalutamide 160mg/day orally + placebo injection (enzalutamide monotherapy)
Arm C: Placebo oral + leuprolide 22.5mg SC q12wk (ADT alone, control)
Primary endpoint: Metastasis-free survival (MFS)
mFollow up: 63.2 mo

Results

MFS (Arm A vs Arm C): Not reached vs 36.2 mo, HR 0.42, P<.001
MFS (Arm B vs Arm C): Not reached vs 36.2 mo, HR 0.63, P<.001
PSA undetectable at 36 wks (Arm A): 86.8% vs 54.2% (Arm C)
PSA-PFS (Arm A vs Arm C): HR 0.30

Adverse events

Overall grade ≥3 AEs: Arm A 42.2%, Arm B 34.2%, Arm C 17.6%
Constitutional: Fatigue (any grade) Arm A 53.4%, Arm B 51.6%, Arm C 28.7%; hot flush Arm A 36.7%, Arm B 37.8%, Arm C 28.4%
Cardiovascular: Hypertension grade ≥3 Arm A 5.2%
Neurologic: Seizure Arm A 0.3%, Arm B 0.3%
Discontinuation due to AEs: Arm A 13.7%, Arm B 11.5%, Arm C 8.3%

Conclusions

Enzalutamide combined with leuprolide significantly prolonged MFS versus leuprolide alone in high-risk BCR prostate cancer, with enzalutamide monotherapy also demonstrating superiority to ADT alone. Both enzalutamide-containing strategies provide clinically meaningful MFS benefit in the pre-metastatic setting.

Key Limitations

Key Limitations: MFS is a surrogate endpoint; OS data were immature at primary analysis. Metastatic status was defined by conventional imaging without PSMA PET, which would reclassify a substantial proportion of enrolled patients as having micrometastatic disease. The 3-arm design does not allow a direct superiority comparison of combination versus monotherapy. PSA DT ≤9 months may not translate perfectly across staging eras, particularly with modern PSMA PET restaging now standard in BCR.

Clinical Context

EMBARK established enzalutamide (with or without ADT) as active therapy in the high-risk BCR setting, leading to FDA approval in 2023. The monotherapy arm provides an option to defer ADT-related side effects. Ongoing integration of PSMA PET into BCR staging may narrow the population truly eligible for this trial design. Guidelines support considering intensified systemic therapy for high-risk BCR (PSA DT ≤9–12 months) after local therapy failure.

References

References: Freedland SJ et al, NEJM 2023