Dalpiciclib (Dalp) plus endocrine therapy (ET) as adjuvant treatment for HR+/HER2– early breast cancer (BC): The randomized, phase 3, DAWNA-A trial.

515 Background: Dalp, a potent CDK4/6 inhibitor, has demonstrated significant improvements in PFS when combined with ET in both first-line and later-line settings for HR+/HER2– advanced BC. We conducted a randomized, double-blind, phase 3 trial (DAWNA-A) to further evaluate Dalp with ET as adjuvant therapy for high-risk, early HR+/HER2– BC and here present findings from the pre-specified first interim analysis (IA1). Methods: Women aged 18-75 y, with stage II-III, HR+/HER2– BC, who had completed definitive local therapy (surgery and/or radiotherapy) and had pathologically confirmed ipsilateral axillary lymph node involvement, were enrolled. Patients (pts) were randomized (1:1) to receive oral Dalp (125 mg QD; 3-wk on/1-wk off, for 2 y) + ET (letrozole 2.5 mg/anastrozole 1 mg/tamoxifen 10 mg/toremifene 60 mg QD, for 5 y) or placebo + ET. Pre/peri-menopausal pts received LHRH agonists (perimenopausal use at investigator’s discretion). Stratification factors were menopausal status (pre/peri vs post), clinical stage (II vs III), number of involved nodes (<4 vs ≥4), and adjuvant chemo (y vs n). The primary endpoint was invasive disease-free survival (iDFS). IA1 was pre-planned at ~254 iDFS events (~50% of total expected). As of Oct 25, 2024, 268 iDFS events occurred and IA1 was performed; the actual superiority boundary was a 1-sided p <0.00205 (Lan-DeMets [O’Brien-Fleming] boundary). Results: Between Apr. 30, 2021 and Jul. 19, 2024, 5274 pts were randomized (Dalp, n=2640; placebo, n=2634). As of data cutoff, median follow-up was 20.3 mo (range 0.0–41.9). Dalp + ET significantly prolonged iDFS vs placebo + ET (HR 0.56, 95% CI 0.43–0.71; 1-sided p <0.0001); iDFS benefits with Dalp were generally consistent across stratification factors and other baseline subgroups. DFS and distant DFS (DDFS) also favored Dalp + ET over placebo + ET (Table). TRAEs led to discontinuation of Dalp in 2.1% of treated pts in Dalp arm and of placebo in 0.8% in placebo arm. Tr-SAE occurred in 3.7% and 1.5%, respectively. There was no death due to TRAEs. Conclusions: Addition of Dalp to ET as adjuvant treatment significantly improved iDFS, with a tolerable safety profile. These data support the use of Dalp for treating HR+/HER2- early BC. Clinical trial information: NCT04842617 . Efficacy outcomes. Dalp + ET (n=2640) Placebo + ET (n=2634) iDFS Event, n (%) 98 (3.7) 170 (6.5) 3-y rate * , % (95% CI) 89.1 (85.8–91.7) 86.2 (83.3–88.6) HR † (95% CI); p value ‡ 0.56 (0.43–0.71); p <0.0001 DFS Event, n (%) 108 (4.1) 195 (7.4) 3-y rate * , % (95% CI) 88.0 (84.5–90.7) 83.8 (80.5–86.6) HR † (95% CI); p value ‡ 0.53 (0.42–0.67); p <0.0001 DDFS Event, n (%) 93 (3.5) 149 (5.7) 3-y rate * , % (95% CI) 90.2 (87.2–92.6) 88.7 (86.2–90.8) HR † (95% CI); p value ‡ 0.60 (0.46–0.78); p<0.0001 * Kaplan–Meier method. † Stratified Cox proportional hazards model. ‡ Stratified Log-rank test (1-sided).