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Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in Men with High-Risk Biochemically Recurrent Prostate Cancer and Prior Radiotherapy: EMBARK Subgroup Analysis

Purpose/Objective(s): The primary analysis of EMBARK demonstrated that after a median follow-up of 60.7 months metastasis-free survival (MFS) for enzalutamide (enza) + leuprolide acetate (LA; hazard ratio [HR] 0.42; 95% confidence interval [CI], 0.30–0.61; p<0.0001) and enza monotherapy (mono; HR 0.63; 95% CI, 0.46–0.87; p=0.0049) was clinically meaningful and statistically superior to placebo + LA. Here, we present a subgroup analysis of MFS by prior radiotherapy (RT).

Materials/Methods: EMBARK (NCT02319837) is a phase 3 study of patients with high-risk biochemical recurrence (BCR): prostate-specific antigen (PSA) doubling time ≤9 months and PSA ≥2 ng/mL above nadir post-RT or ≥1 ng/mL after radical prostatectomy (RP) ± postoperative RT. Patients were randomized (1:1:1) to enza 160 mg/day + LA (double-blind), placebo + LA (double-blind), or enza mono (open-label). LA 22.5 mg was administered every 12 weeks. If PSA was <0.2 ng/mL at Week 36, treatment was suspended at Week 37 and restarted when PSA was ≥2 ng/mL for patients with primary RP, and ≥5 ng/mL for patients without RP. The primary endpoint, determined by blinded, independent central review (BICR), was MFS with enza + LA vs placebo + LA. MFS of enza mono vs placebo + LA was a key secondary endpoint. Subgroup analysis of MFS by prior RT (yes/no) was pre-specified and considered descriptive.

Results: Overall, 804 patients received prior RT (enza + LA, n=265; placebo + LA, n=283; enza mono, n=256). External beam RT was the most common prior RT received (enza + LA, n=253 [71.3%]; placebo + LA, n=267 [74.6%]; enza mono, n=240 [67.6%]). For patients with prior RT, MFS per BICR for enza + LA and for enza mono were each superior to placebo + LA (Table 1). For patients without prior RT, MFS per BICR for enza + LA was superior to placebo + LA; there was no difference between the enza mono and placebo + LA cohorts (Table 1).

Conclusion: In patients with high-risk BCR and prior RT, both enza + LA and enza mono demonstrated a clinically meaningful improvement in MFS vs placebo + LA. In patients without prior RT, the number of MFS events was too low to draw any conclusions. If approved, enza combination therapy may represent a new standard of care for patients with high-risk BCR and prior RT.

S. Sridharan,1 N. Shore,2 B. Venugopal,3 M. Gleave,4 U. De Giorgi,5 Y. Tang,6 G.P. Haas,7 M. Rosales,7 F. Zohren,8 S.J. Freedland9

  1. Calvary Mater Newcastle Hospital, Waratah, NSW, Australia
  2. Carolina Urologic Research Center, Myrtle Beach, SC; GenesisCare US, Myrtle Beach, SC
  3. University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
  4. Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
  5. IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Medola, Italy
  6. Pfizer, Inc., San Francisco, CA
  7. Astellas Pharma, Inc., Northbrook, IL
  8. Pfizer, Inc., Cambridge, MA
  9. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Durham VA Medical Center, Durham, NC
Source: Sridharan S, Shore N, Venugopal B, et al. Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in Men with High-Risk Biochemically Recurrent Prostate Cancer and Prior Radiotherapy: EMBARK Subgroup Analysis. International Journal of Radiation Oncology Biology Physics. 2023. DOI:https://doi.org/10.1016/j.ijrobp.2023.08.030