Abstract Background: T-DXd demonstrated substantial and durable overall and intracranial clinical activity in DESTINY-Breast12. In pts with BM, 12-month progression-free survival (PFS) and central nervous system (CNS) PFS rates were 61.6% and 58.9%, respectively, and CNS objective response rate (ORR) was 71.7% (79.2% in pts with stable and 62.3% in pts with active BM). In the cohort of pts without BM, efficacy of T-DXd was in line with previous data, and there were no new safety signals. To date, T-DXd has shown clinical benefit irrespective of HR status, most recently in first-line HER2+ mBC in DESTINY-Breast09. In a post-hoc analysis of DESTINY-Breast12, outcomes by HR status in pts with BM were explored. Methods: Pts ≥18 years old with HR-positive (HR+) or HR-negative (HR−) HER2+ mBC whose disease had progressed after ≤2 previous lines of therapy were eligible; BM were required to be stable or active (untreated/treated progressing) and not in need of immediate local therapy. All pts received intravenous T-DXd 5.4 mg/kg every 3 weeks. Efficacy outcomes were analyzed by baseline HR status using the Kaplan-Meier technique for PFS. Results: In total, 262 pts with baseline BM were included in this analysis, of whom 165 (63.0%) had HR+ disease. Among pts with BM, the median age (range) was 52.0 (30-80) years in the HR+ subgroup and 54.0 (28-86) years in the HR− subgroup (n=97). Median follow up for PFS at data cutoff (February 8, 2024) was 13.1 months in both subgroups. Median PFS was not calculable for either HR subgroup. The 12-month PFS and CNS PFS, as well as CNS ORR, were indicative of consistent responses with T-DXd regardless of HR subgroup; confirmed ORRs, including in pts with measurable disease at baseline, indicated activity of T-DXd in pts with HR+ and HR− tumors (Table). The median total treatment duration (range) was 12.0 (0.7-26.9) months in the HR+ subgroup and 11.1 (0.1-26.8) months in the HR− subgroup. Adverse events of any grade in pts occurred with a similar overall incidence in both HR subgroups; the most common Grade ≥3 events were neutropenia (12.1%), anemia (7.3%), and fatigue (6.7%) in the HR+ subgroup, and neutropenia (11.3%), decreased neutrophil count (8.2%), and anemia (7.2%) in the HR− subgroup. Interstitial lung disease / pneumonitis occurred in 26 (Grade 5, n=3) and 16 (Grade 5, n=3) pts in the HR+ and HR− subgroups, respectively. Results by HR subgroup in the cohort without BM (data not presented) were consistent with those from the cohort with BM. Conclusion: T-DXd demonstrated consistent intracranial activity and safety in pts with BM, regardless of HR status. These data reinforce the utility of T-DXd as a second-line treatment regardless of HR status in pts with HER2+ mBC. Citation Format: H. Wildiers, N. Harbeck, E. Ciruelos, G. Jerusalem, V. Müller, N. Niikura, G. Viale, R. Bartsch, C. Kurzeder, M. Higgins, R. Connolly, S. Baron-Hay, M. Gión, V. Guarneri, G. Bianchini, S. Escrivá-de-Romaní, M. Prahladan, S. Anand, N. Toms, R. Antony, N. Lin. Outcomes by hormone receptor (HR) status in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) with brain metastases (BM) treated with trastuzumab deruxtecan (T-DXd): a post-hoc subgroup analysis of DESTINY-Breast12 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 PS5-01-27.
Wildiers et al. (2026) studied this question.
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