Outcomes of men with high-risk biochemically recurrent prostate cancer who suspended enzalutamide monotherapy treatment in the phase 3 EMBARK study.
Authors: Shore Neal D. , Sieber Paul R. , Gleave Martin , De Giorgi Ugo , Mehlhaff Bryan Allyn , Danila Daniel Costin , Dunshee Curtis , Lallas Costas D. , Pliskin Marc , Tang Yiyun , Haas Gabriel P. , Rosales Matt , Tarazi Jamal Christo Christo , Zohren Fabian , Russell David , Freedland Stephen J. 
Published: January 2024

15 Background: In the 3-arm EMBARK trial, enzalutamide (enza) + leuprolide acetate (leuprolide) and enza monotherapy (mono) showed statistically superior and clinically meaningful improvements in metastasis-free survival (MFS) vs placebo + leuprolide (alone) in patients (pts) with high-risk biochemically recurrent (BCR) prostate cancer. Based on serum prostate-specific antigen (PSA) response, treatment (tx) was suspended at week 37 in 304 (85.9%) pts in the enza mono arm and 240 (67.8%) in the leuprolide-alone arm; pts who did not meet suspension criteria continued tx. Outcomes with enza mono vs leuprolide alone by tx suspension status are presented. Methods: EMBARK is a double-blind phase 3 study of pts with high-risk BCR (i.e., PSA doubling time (PSADT) ≤9 months and PSA ≥2 ng/mL above nadir post-radiotherapy [RT] or ≥1 ng/mL after radical prostatectomy [RP] ± postoperative RT). Pts were randomized (1:1) to enza mono (160 mg/day, open-label) or leuprolide alone (22.5 mg every 12 weeks). PSA <0.2 ng/mL at week 36 triggered tx suspension at week 37; tx restarted when PSA reached ≥2 ng/mL or ≥5 ng/mL for pts with or without primary RP, respectively. The proportion of pts with undetectable PSA 2 years after tx suspension was a secondary endpoint. MFS (by blinded independent central review) was analyzed descriptively in each tx arm by suspension status. P-values were nominal. Results: In the suspension group, the 3-year MFS rate (95% CI) was 88.1% (83.8–91.4%) for enza mono and 90.0% (85.3–93.2%) for leuprolide alone; there was no difference in MFS (hazard ratio [HR] 0.840, 95% CI 0.575–1.226; P=0.3659). In the no suspension group, 3-year MFS rates were 88.5% (68.5–96.2%) and 66.9% (55.4–76.1%), respectively; MFS was longer with enza mono vs leuprolide alone (HR 0.340, 95% CI 0.118–0.985; P=0.0378). In the suspension group vs the no suspension group, a greater proportion had received prior RP (enza mono: 78.9 vs 41.9%; leuprolide alone: 78.3 vs 52.2%) or RP and RT (enza mono: 50.7 vs 16.1%; leuprolide alone: 55.0 vs 38.0%), while baseline median PSADT was similar (enza mono: 4.9 vs 5.9 months; leuprolide alone: 5.0 vs 4.8 months). The proportion (95% CI) of pts with undetectable PSA 2 years after tx suspension was 4.6% (2.5–7.6%) for enza mono and 9.6% (6.2–14.0%) for leuprolide alone ( P=0.0326). Conclusions: In pts with high-risk BCR who suspended tx, the tx effect on MFS with enza mono was not different compared with leuprolide alone, though more pts reached tx suspension criteria with enza mono. However, in the no suspension group, enza mono prolonged MFS vs leuprolide alone, though the number of MFS events was limited (n=4). Pts with prior RP were also more likely to reach the PSA threshold for tx suspension. Few pts who suspended tx had undetectable PSA after 2 years, regardless of tx. Clinical trial information: NCT02319837 .