Abstract RF6-07: Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with HER2-positive (HER2+) advanced/metastatic breast cancer (a/mBC): patient-reported outcomes (PROs) from the DESTINY-Breast09 study

Abstract Background: In the Phase 3 randomized trial, DESTINY-Breast09 (NCT04784715), T-DXd + P significantly improved progression-free survival (PFS) compared with standard-of-care THP as 1L therapy for pts with HER2+ a/mBC, with no new safety signals. Here, we present PROs for the T-DXd + P and THP arms. The T-DXd monotherapy arm remains blinded until the final PFS analysis. Methods: Eligible pts had HER2+ a/mBC and no prior systemic therapy for a/mBC (1 line of endocrine therapy ET allowed). (Neo)adjuvant HER2-directed therapy/chemotherapy with a disease-free interval of 6 months was permitted. Pts were randomized 1:1:1 to T-DXd 5.4 mg/kg once every 3 weeks (= one cycle), T-DXd + P, or THP. Pts with hormone receptor-positive disease could add ET after taxane discontinuation or six cycles of T-DXd. PRO secondary endpoints included: time to deterioration (TTD) in pain via the EORTC QLQ-C30; the proportion of pts experiencing treatment-related symptoms via selected scales/items of the QLQ-C30, EORTC QLQ-BR45, and PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE); the proportion of pts with ‘maintained or improved’ physical function via the QLQ-C30; and side effect burden via the Patient Global Impression of Treatment Tolerability (PGI-TT). PROs were assessed on Day 1 of each cycle until Cycle 9, with the QLQ-C30/-BR45 assessed every second cycle thereafter until progression. Results: In total, 383 pts were randomized to T-DXd + P and 387 to THP. Median TTD in pain was not reached in either arm; the risk of pain deterioration was similar in both arms (hazard ratio 0.95; 95% CI 0.74, 1.21; maturity 35%). On the QLQ-C30/-BR45, more pts in the T-DXd + P arm reported deterioration in nausea/vomiting, constipation, and appetite loss, whereas fewer pts reported deterioration in skin/mucosal symptoms compared with THP ( Table ). On the PRO-CTCAE, fewer pts in the T-DXd + P arm experienced nosebleeds and extremity swelling vs those in the THP arm. PGI-TT outcomes were comparable between arms. Most pts had ‘maintained or improved’ physical function: 82.9% with T-DXd + P vs 82.4% with THP at Cycle 2; and 75.4% vs 77.7%, respectively, at Cycle 27 (∼18.7 months, the expected median PFS in the THP arm). Conclusions: T-DXd + P was associated with more gastrointestinal symptoms but fewer skin/mucosal, nosebleed, and extremity swelling symptoms vs THP. Pain, fatigue, physical function, and overall patient-reported treatment impact were similar between regimens. Complementing the efficacy and safety results, PRO data support T-DXd + P as a new 1L treatment in HER2+ a/mBC providing durable pain control and maintenance of physical function, with distinct quality of life advantages compared with THP. Citation Format: M. Rimawi, S. Loibl, Z. Jiang, R. Barroso-Sousa, Y. Park, C. Saura, A. Schneeweiss, M. Toi, Ç. Arslan, W. Chen, J. Sohn, W. Li, H.-C. Wang, M. Şendur, J. Asselah, A. Roborel de Climens, J. Liu, D. Huang, J. Shetty, S. Tolaney. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with HER2-positive (HER2+) advanced/metastatic breast cancer (a/mBC): patient-reported outcomes (PROs) from the DESTINY-Breast09 study 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 RF6-07.