Abstract PS3-09-08: Five-year analysis of distant disease-free survival (DDFS) across key subgroups from the phase 3 NATALEE trial of ribociclib (RIB) plus a nonsteroidal aromatase inhibitor (NSAI) in patients with HR+/HER2− early breast cancer (EBC)

Abstract Background: Despite improvements in outcomes in patients with HR+ EBC, distant recurrence remains a major concern given that there is no cure for metastatic breast cancer. The NATALEE trial has shown invasive disease-free survival and DDFS benefits with RIB + NSAI in patients with stages II and III HR+/HER2− EBC. We present updated DDFS data from the prespecified 5-y landmark analysis of NATALEE across clinically relevant subgroups. Methods: In NATALEE, patients were randomized 1:1 to receive either RIB (400 mg/d, 3 wk on/1 wk off for 3 y) + NSAI (anastrozole 1 mg/d or letrozole 2.5 mg/d for ≥5 y) or NSAI alone; men and premenopausal women also received goserelin. Patients with anatomic stage IIA (either node-negative [N0] with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III disease per AJCC (8th edition) were included in the trial. DDFS, a secondary endpoint, was defined as the time from randomization to the first event of distant recurrence, second primary non-breast invasive cancer (except for basal and squamous cell skin carcinomas), or death from any cause. Kaplan-Meier analysis was used to estimate survival rates at each time point, and a Cox proportional hazards model was applied to calculate hazard ratios (HRs) for RIB + NSAI vs NSAI alone, stratified based on study stratification factors. DDFS was analyzed across clinically relevant subgroups, including anatomic stage and nodal status. Results: At the updated data cutoff of May 28, 2025, with a median duration of follow-up for DDFS of 55.5 months, RIB + NSAI continued to show a DDFS benefit (HR, 0.709 [95% CI: 0.608-0.827]; nominal 1-sided P<.0001) and a distant recurrence-free survival benefit (HR, 0.699 [95% CI: 0.594-0.824]; nominal 1-sided P<.0001) over NSAI alone in the intent-to-treat population. The most common sites of distant recurrence were bone, liver, lung/pleura, and lymph nodes with fewer events observed with RIB + NSAI vs NSAI alone across all sites. The DDFS benefit was observed irrespective of anatomic stage (stage IIA [n=1001]: HR, 0.374 [95% CI: 0.218-0.644]; stage IIB [n=1045]: HR, 0.863 [95% CI: 0.580-1.285]; stage IIIA [n=1830]: HR, 0.735 [95% CI: 0.569-0.951]; stage IIIB [n=317]: HR, 0.644 [95% CI: 0.390-1.063]; stage IIIC [n=892]: HR, 0.785 [95% CI: 0.594-1.037]). Likewise, a consistent improvement in DDFS with RIB + NSAI vs NSAI alone was observed irrespective of nodal status (N0 [n=614]: HR, 0.539 [95% CI: 0.318-0.913]; node-positive [N+] [n=4479]: HR, 0.723 [95% CI: 0.615-0.849]). The DDFS benefit with RIB + NSAI vs NSAI alone was similar across other clinically relevant subgroups, which included subgroups based on menopausal status, age, prior endocrine therapy duration, and Ki-67 status. Conclusions: In this prespecified 5-y analysis, with all patients off RIB treatment for a median of 2 y, the DDFS benefit with RIB + NSAI was sustained or improved compared with prior NATALEE analysis. This benefit was observed across all key subgroups, including N0 disease. These findings support the use of adjuvant RIB + NSAI to reduce distant recurrence risk in the NATALEE-eligible high-risk HR+/HER2− EBC population. Citation Format: S. Hurvitz, M. Jarzab, A. Ring, P. Sharma, I. Temciuc, H. Hu, M. Akdere, J. Pablo Zarate, D. Yardley. Five-year analysis of distant disease-free survival (DDFS) across key subgroups from the phase 3 NATALEE trial of ribociclib (RIB) plus a nonsteroidal aromatase inhibitor (NSAI) in patients with HR+/HER2− early breast cancer (EBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-09-08.