Abstract PS5-01-30: Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): Final analysis from DESTINY-Breast03

Abstract Background In DESTINY-Breast03 (NCT03529110), T-DXd showed statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) vs T-DM1 in pts with HER2+ mBC previously treated with trastuzumab and a taxane. We report the 5-year follow-up efficacy and safety analysis. Methods DESTINY-Breast03 was a randomized, multicenter, open-label, phase 3 trial. Pts were assigned 1:1 to T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg intravenously/3 wk. Exploratory analyses at 5 years included PFS, PFS2 (time from randomization to disease progression on the next line of therapy or death), OS, confirmed objective response rate (cORR), duration of response (DOR) (all investigator assessed), and safety. Results Overall, 524 pts were randomized (261 to T-DXd; 263 to T-DM1), with the last pt enrolled on June 23, 2020. At the data cutoff (DCO), June 27, 2025, median (m; range) duration of follow-up was 50.9 mo (0.0-80.6) for T-DXd and 35.4 mo (0.0-80.4) for T-DM1; 24 pts (9.3%) in the T-DXd group and 2 pts (0.8%) in the T-DM1 group remained on treatment. The most common reasons pts discontinued were progressive disease (44.7% T-DXd, 70.9% T-DM1) and adverse events (AEs; 26.8% T-DXd, 10.0% T-DM1). Among pts who discontinued, 161/233 (69.1%) in the T-DXd group and 203/259 (78.4%) in the T-DM1 group received subsequent systemic anticancer therapy. Median (range) treatment duration was 18.2 mo (0.7-76.0) with T-DXd and 6.9 mo (0.7-65.1) with T-DM1. Estimated mPFS (95% CI) was 29.0 mo (23.7, 42.7) with T-DXd vs 7.8 mo (6.8, 8.3) with T-DM1 (hazard ratio HR, 0.33 95% CI, 0.26, 0.41). The estimated PFS (95% CI) rate at 5 years was 37.6% (30.8, 44.4) with T-DXd vs 10.0% (6.1, 15.0) with T-DM1. Estimated mOS (95% CI) was 56.4 mo (49.4, 67.0) with T-DXd vs 42.7 mo (35.4, 52.6) with T-DM1 (HR, 0.74 95% CI, 0.59, 0.94, using a stratified Cox regression model). The estimated OS (95% CI) rate at 5 years was 48.1% (41.7, 54.2) with T-DXd vs 36.9% (30.8, 43.1) with T-DM1. Rates of treatment-emergent adverse events (TEAEs) were consistent with the prior DCO. Exposure-adjusted incidence rates for any-grade, grade ≥3, and serious TEAEs were lower with T-DXd than T-DM1. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 17.5% of pts treated with T-DXd (2 new events grade 1 and 3 since last DCO) and 3.1% of pts with T-DM1, with 3 (1.2%) and 1 (0.4%) grade 3 events, respectively, and no grade 4 or 5 in either group. Updated data are shown in the Table. Conclusions The final analysis of DESTINY-Breast03 confirms the superior efficacy of T-DXd over T-DM1 in pts with HER2+ mBC whose disease had progressed following prior treatment with trastuzumab and a taxane. The safety profile of T-DXd was similar to previous reports, with no new safety signals observed with longer follow-up. Citation Format: S.-A. Im, J. Cortes, S.-B. Kim, G. Curigliano, G. Buscacio de Sousa, S. E. Nagai, T. Sun, J. Ignacio Delgado Mingorance, V. Kaklamani, F. Puglisi, C. Levy, H. Iwata, S. A. Hurvitz, S. Nakatani, Z. Liang, S. Ashfaque, A. Egorov, E. P. Hamilton. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): Final analysis from DESTINY-Breast03 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 PS5-01-30.