Efficacy and safety of elinzanetant for vasomotor symptoms associated with adjuvant endocrine therapy: Phase 3 OASIS 4 trial.

508 Background: Vasomotor symptoms (VMS) associated with adjuvant endocrine therapy (AET) impact quality of life and decrease treatment adherence, worsening breast cancer outcomes. There are few effective treatment options and none approved for this indication. Methods: The 52-week randomized phase 3 trial OASIS 4 (NCT05587296) evaluated the safety and efficacy of elinzanetant (EZN), a dual neurokinin-1 and -3 receptor antagonist, in women aged 18–70 years being treated for, or at high risk of developing, hormone receptor-positive (HR+) breast cancer and experiencing ≥35 moderate-to-severe VMS/week associated with AET. Women were randomized 2:1 to receive once-daily EZN 120 mg for 52 weeks or placebo (P) for 12 weeks followed by EZN for 40 weeks. Primary endpoints were mean change in moderate-to-severe VMS frequency from baseline to weeks 4 and 12 analyzed using mixed model with repeated measures (one-sided p-values). Secondary endpoints were mean changes from baseline in moderate-to-severe VMS frequency to week 1 and moderate-to-severe VMS severity to weeks 4 and 12. Treatment-emergent adverse events (TEAEs) were reported throughout the study. Results: Mean (standard deviation [SD]) baseline daily VMS frequency was 11.4 (6.9) in the EZN group (n=316) and 11.5 (6.4) in the P group (n=157). Reductions from baseline in VMS frequency were observed from week 1 (EZN: -4.0 [5.1]; P: -1.8 [3.8]). At week 4, mean (SD) VMS frequency reduced by -6.5 (6.1) with EZN and -3.0 (5.0) with P, with statistical significance between EZN and P (least squares [LS] mean difference [95% confidence interval (CI)]: -3.5 [-4.4, -2.6]; p<0.0001). At week 12, reductions in VMS frequency were -7.8 (6.2) with EZN and -4.2 (6.1) with P, with statistical significance between EZN and P (LS mean difference [95% CI]: -3.4 [-4.2, -2.5]; p<0.0001). Reductions in VMS severity were greater with EZN vs. P (week 4: -0.7 [0.6]; -0.4 [0.4], week 12: -1.0 [0.7]; -0.5 [0.6]). During the placebo-controlled period, 220 (69.8%) and 98 (62.0%) patients reported TEAEs in the EZN and P groups, respectively. Somnolence, fatigue, and diarrhea were more frequently reported with EZN (Table). Fewer TEAEs were reported in both groups during weeks 13–52. Conclusions: EZN was efficacious with a fast onset and well tolerated for the treatment of VMS associated with AET. TEAE frequency was as expected for this type of trial. Adequate VMS management can improve adherence to AET and, therefore, improve cancer outcomes and quality of life. Clinical trial information: NCT05587296 . n (%) EZNWeek 1–12n=315 PWeek 1–12n=158 Total EZNWeek 1–52N=465 Any TEAE 220 (69.8%) 98 (62.0%) 368 (79.1%) Headache 30 (9.5%) 20 (12.7%) 56 (12.0%) Arthralgia 20 (6.3%) 10 (6.3%) 52 (11.2%) Fatigue 30 (9.5%) 8 (5.1%) 43 (9.2%) Somnolence 34 (10.8%) 6 (3.8%) 42 (9.0%) Diarrhea 16 (5.1%) 3 (1.9%) 32 (6.9%) Back pain 10 (3.2%) 7 (4.4%) 29 (6.2%) Nausea 19 (6.0%) 10 (6.3%) 29 (6.2%) Any serious TEAE 8 (2.5%) 1 (0.6%) 33 (7.1%)