Abstract PS2-04-06: Real-world outcomes of trastuzumab deruxtecan with or without endocrine therapy in her2-low, hormone receptor-positive metastatic breast cancer: a propensity-matched analysis

Background: Combination therapy involving anastrozole or fulvestrant with fam-trastuzumab deruxtecan-nxki (TDX-d) has demonstrated promising antitumour activity in chemotherapy-naïve, HER2-low, hormone receptor-positive (HR+) metastatic breast cancer (mBC) patients, as evidenced by the phase 1b DESTINY-Breast08 trial (NCT04556773). Although this regimen is not currently established as a standard of care, it is being utilized in several oncology centers. However, real-world evidence supporting this strategy remains limited. Methods: Applying the TriNetX Global Collaborative Network, we retrospectively identified two cohorts comprising 658 mBC patients, stratified by receipt of TDX-d monotherapy or TDX-d in combination with endocrine therapy (ET). Propensity score matching (1:1) was performed to balance the cohorts (TDX-d plus ET, n=85; TDX-d alone, n=85) for age, race, and body mass index, all of whom had prior exposure to CDK4/6 inhibitors and chemotherapy. Hazard ratios (HRs) were calculated to compare overall survival (OS) between groups. Results: Following matching, the median age was 57.3 years (±13.9) in the TDX-d plus ET group and 56.7 years (±14.1) in the TDX-d monotherapy group. Median follow-up was 87.9 months for the combination cohort and 46.1 months for the monotherapy cohort. The combination group demonstrated a trend towards improved overall survival compared to TDX-d alone (HR=0.79; 95% CI, 0.465-1.344; p=0.384), although statistical significance was not achieved. Conclusions: This represents the first large-scale real-world cohort analysis evaluating the addition of endocrine therapy to TDX-d in patients with HER2-low, HR+ mBC. While these preliminary findings suggest a potential survival benefit with the combination approach, the limited follow-up duration preclude definitive conclusions. Further prospective studies are warranted to elucidate the clinical utility of combining TDX-d with ET in this patient population. Our research aims to perform ongoing follow-up of these patients to generate more robust data, thereby further clarifying the clinical benefit of combining TDX-d with ET in this population. Key-words (max 5): Trastuzumab deruxtecan; metastatic breast cancer; endocrine therapies; TrineTX; real world evidence Citation Format: M. Palleschi, A. Farolfi, C. Gianni, G. Miserocchi, M. Corianò, N. Gentili, M. Mariotti, G. Di Menna, O. Serra, C. Casadei, F. Rusconi, A. Andalò, S. Sabbioni, A. Carlini, D. Montanari, M. Sirico, R. Maltoni, L. Cecconetto, S. Sarti, F. Merloni, A. Musolino. Real-world outcomes of trastuzumab deruxtecan with or without endocrine therapy in her2-low, hormone receptor-positive metastatic breast cancer: a propensity-matched analysis [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 PS2-04-06.