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

BMJ Open. 2021 Aug 12;11(8):e046588. doi: 10.1136/bmjopen-2020-046588.


Introduction: Limited 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 analysis: EMBARK 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 dissemination: The 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 number: NCT02319837.

Keywords: clinical trials; genitourinary medicine; prostate disease.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / therapeutic use
  • Benzamides
  • Humans
  • Leuprolide / therapeutic use
  • Male
  • Neoplasm Recurrence, Local / drug therapy
  • Nitriles
  • Phenylthiohydantoin
  • Prostate-Specific Antigen*
  • Prostatic Neoplasms* / drug therapy


  • Androgen Antagonists
  • Benzamides
  • Nitriles
  • Phenylthiohydantoin
  • enzalutamide
  • Prostate-Specific Antigen
  • Leuprolide

Associated data

  • ClinicalTrials.gov/NCT02319837