A phase 3 randomised study of enzalutamide plus leuprolide and enzalutamide monotherapy in high-risk non-metastatic hormone-sensitive prostate cancer with rising PSA after local therapy: EMBARK study design

Abstract

IntroductionLimited data from controlled clinical trials are available for men who experience biochemical recurrence after definitive therapy for prostate cancer. In the absence of overt metastases, patients with non-metastatic castration-sensitive prostate cancer (nmCSPC) often receive androgen deprivation therapy (ADT). There is no standard-of-care consensus on optimal ADT timing, although most men are treated prior to metastases, especially those with high-risk features (Gleason score 8–10 or prostate-specific antigen doubling time (PSADT) <9–12 months). Given data that ADT plus novel hormonal agents improve survival in men with metastatic CSPC, there is a desire to evaluate these agents earlier in the disease course. The main objective of EMBARK is the comparative assessment of enzalutamide plus leuprolide (luteinising hormone-releasing hormone agonist (LHRHa)) or enzalutamide monotherapy versus monotherapy LHRHa to improve metastasis-free survival (MFS) in patients with high-risk nmCSPC PSA recurrence after definitive therapy.Methods and analysisEMBARK is a randomised, phase 3 study of high-risk patients with nmCSPC, a PSADT of ≤9 months and a screening PSA of ≥2 ng/mL above the nadir after radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) with or without postoperative RT. Men (n=1050) are randomised 1:1:1 to enzalutamide 160 mg/day plus LHRHa or placebo plus LHRHa (double-blind arms) or enzalutamide monotherapy (open-label arm). Treatment is suspended at week 37 if PSA concentrations are <0.2 ng/mL and reinstated if levels rise to ≥2.0 ng/mL with RP or ≥5.0 ng/mL without RP. Patients with PSA ≥0.2 ng/mL at week 37 continue until treatment discontinuation criteria are met. The primary endpoint is MFS comparing enzalutamide plus LHRHa versus placebo plus LHRHa.Ethics and disseminationThe study is conducted under the guiding principles of the World Medical Association Declaration of Helsinki. The results will be disseminated at research conferences and in peer-reviewed journals.Trial registration numberNCT02319837.

PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19)

“…Intensification of ADT in the biochemically recurrent castration-sensitive disease setting is further supported by the recently reported phase III EMBARK study. 25 In this study, both ADT plus enzalutamide as well as enzalutamide monotherapy prolonged metastasis-free survival and PSA PFS compared with ADT alone. 26 There were important differences in the study population and design of EMBARK, which hinder cross-trial comparisons with the current study, including the allowance of either postradiation or postprostatectomy patients in EMBARK, metastasis-free survival as the primary study end point, the inclusion of a re-treatment period and overall longer duration of treatment compared with the current study, differing definition of PSA PFS, and the addition of a noncastrating treatment arm with enzalutamide monotherapy.…”

Recent advances in the treatment of advanced prostate cancer: maximizing existing therapies while searching for novel solutions

“…No significant difference was noted in PSA growth rate between the two treatment arms, but median PSA decline in all participants was more than 99% and median time to PSA recovery to baseline after completion of therapy was 224 days, suggesting significant activity for such short course AR inhibitor [16]. A larger randomized trial of ADT monotherapy versus enzalutamide monotherapy versus ADT and enzalutamide in men with biochemically recurrent prostate cancer is accruing [17].…”

Salvage Therapy for Prostate Cancer: AUA/ASTRO/SUO Guideline Part II: Treatment Delivery for Non-metastatic Biochemical Recurrence After Primary Radical Prostatectomy

“…41 The EMBARK trial (NCT02319837) compares three arms: enzalutamide with ADT versus placebo with ADT versus enzalutamide monotherapy for BCR after primary RP or RT, but this study does not require salvage RT. 42 The phase 3 ECOG/ACRIN EA8191 (INDICATE, NCT04423211) study contains four arms, two of which (arms A and B) are comparing apalutamide with ADT versus ADT without apalutamide in conjunction with salvage RT or salvage RT with metastases-directed RT in patients with BCR after primary RP.…”