Abstract RF6-06: Patient-reported outcomes (PROs) in DESTINY-Breast11: neoadjuvant treatment (NAT) with trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) vs dose-dense doxorubicin + cyclophosphamide follo

Abstract Background: In the DESTINY-Breast11 Phase 3 study, NAT with T-DXd-THP showed a statistically significant and clinically meaningful improvement in pathologic complete response rate and improved safety profile vs ddAC-THP in high-risk, HER2+ eBC. We report physical functioning (PF) and patient-reported tolerability during NAT. Methods: Patients with high-risk (≥T3, node positive [N1-3], or inflammatory), HER2+ eBC were randomized to NAT T-DXd (8 cycles), T-DXd-THP (4+4 cycles), or ddAC-THP (4+4 cycles). PF was measured on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire Core 30 (QLQ-C30) PF subscale. Twenty symptomatic adverse events (AEs) were measured using select items from the PRO version of the Common Terminology Criteria for Adverse Events, EORTC-QLQ-C30, and EORTC item library. The Patient Global Impression of Treatment Tolerability measured overall side-effect bother. Descriptive PRO analyses included all patients who received ≥1 dose of study intervention. Results: In the T-DXd, T-DXd-THP, and ddAC-THP arms, respectively, 283, 320, and 312 patients began treatment. More patients had maintained or improved PF during NAT with T-DXd and T-DXd-THP vs ddAC-THP (range across weeks, respectively: 42.7-75.5%, 43.7-75.7%, and 24.0-62.4%; Table). Overall side-effect bother during NAT was generally lower with T-DXd and T-DXd-THP than ddAC-THP, with a numerically lower proportion of patient-weeks with high side-effect bother (T-DXd 45.8%; T-DXd-THP 43.0%; ddAC-THP 49.5%). Of the 20 symptomatic AEs measured, 14 and 13 AEs, respectively, were generally better with T-DXd and T-DXd-THP than ddAC-THP (both: diarrhea, appetite loss, taste changes, mouth/throat sores, numbness/tingling, muscle pain, joint pain, chest pain, cough, dyspnea, rash, hot flashes, insomnia; T-DXd: nosebleed). Although present in all arms, five AEs were generally worse with T-DXd and/or T-DXd-THP vs ddAC-THP (both: hair loss, headache, nausea, vomiting; T-DXd: constipation; T-DXd-THP: nosebleed). For symptomatic AEs for which impact on daily activities was assessed (headache, insomnia, joint pain, mouth/throat sores, muscle pain, numbness/tingling), limited interference on daily activities was observed across all arms. Conclusion: More patients had maintained or improved PF with T-DXd or T-DXd-THP vs ddAC-THP. T-DXd and T-DXd-THP demonstrated a lower patient-reported treatment burden (tolerability, symptomatic AEs) than ddAC-THP. These findings, together with the favorable safety and efficacy profile of T-DXd-THP vs ddAC-THP, support T-DXd-THP as a tolerable therapy in high-risk HER2+ eBC. Citation Format: S. Modi, J. Boileau, J. Wu, L. Pusztai, S. Ohno, G. Curigliano, C. Kelly, J. Asselah, S. Im, L. Coltelli, M. Chaudhari, S. Blau, A. Martínez Bueno, B. Czartoryska-Arlukowicz, J. Pedrini, C. Zhang, S. Safdar, S. Mannix, N. Harbeck. Patient-reported outcomes (PROs) in DESTINY-Breast11: neoadjuvant treatment (NAT) with trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) vs dose-dense doxorubicin + cyclophosphamide followed by THP (ddAC-THP) in high-risk, HER2+ early-stage 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 RF6-06.