Abstract Background: According to recent findings from the DESTINY-06 trial, HR-positive (HR+)/HER2-low metastatic breast cancer (mBC) patients (pts) who received trastuzumab deruxtecan (T-Dxd) following ≥1 line of endocrine therapy (ET) experienced improved progression-free survival (PFS) compared to those who received chemotherapy (chemo) in a second-line (2L) setting. To assess whether similar benefits are seen in a real-world setting, we evaluated overall survival (OS) and time to next treatment (TTNT). TTNT was used as a surrogate measure for PFS. Methods: We used the IntegraConnect PrecisionQ de-identified electronic health record database of 3 million cancer pts across 500 care sites, to identify pts. Eligible pts for the study were adults with a confirmed diagnosis of HR+/HER2-low mBC who had ≥2 documented visits and a CDK4/6 inhibitor(i) +/- ET in the first-line metastatic setting. Pts with a subsequent treatment (2L) with T-Dxd or chemo were identified and observed between 6-1-2022 and 4-30-2025. TTNT was defined as time from the 2L start to either the initiation of a subsequent line of therapy or death. We did not assess for the reason pts discontinued (e.g., toxicity or disease progression). TTNT and OS were analyzed using Kaplan-Meier analysis. Hazard ratios (HR) adjusting for age at treatment and race were estimated using Cox proportional hazard models. Results: Among 340 eligible pts, 82 received TDxd and 248 received chemo in the 2L setting. The median age at treatment was 64 (interquartile range 55, 70) years old with a composition of 70.0% White, 10.6% African American. Among pts with a reported Eastern Cooperative Oncology Group (ECOG) status at treatment, 91.5% had an ECOG score of ≤1. Median OS was not significantly different for pts who received T-Dxd compared to chemo (Table), but median TTNT was significantly longer for pts who received T-Dxd (10.1 months, 95% CI: 7.8, 13.1) compared to chemo (6.0 months, 95% CI: 5.1, 6.5). Pts using T-Dxd were significantly less likely to change treatment compared to chemo after adjusting for age, and race HR (95% CI): 0.45 (0.30, 0.66), P0.01). Treatment crossover occurred in both cohorts: 28% of pts in the chemo group utilized T-Dxd in a later line of therapy, and 19% of pts in the T-Dxd group utilized chemo in a later line of therapy. Conclusions: Consistent with findings from a subset of the Destiny-06 trial, HR+/HER2-low mBC pts previously treated with a CDK4/6i who then utilized T-Dxd in the 2L setting were associated with a significantly improved TTNT compared to 2L chemo utilization. OS was not statistically different between T-Dxd and Chemo. These results may be impacted by unmeasured factors such as, tumor burden, endocrine resistance, and access to care. Further studies are needed to confirm the optimal sequencing of TDxd in the real-world setting. Citation Format: R. Mahtani, R. Choksi, F. Kudrik, D. Patt, S. Reddy, S. Reganti, S. Rosenfeld, S. W. Champaloux, D. Parris, A. Rui, A. Sharma, M. Gart, C. Wall, B. Wang, P. Varughese, J. Donegan, L. Morere, R. Geller, J. Scott, V. Gorantla. Real-world comparison of time to next treatment for patients with HR-positive, HER2-low metastatic breast cancer treated with either chemotherapy or trastuzumab deruxtecan in the second-line 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 PS1-11-17.
Mahtani et al. (2026) studied this question.