Abstract PS5-07-21: TROPION-Breast06: Multicenter, multinational, open-label, single-arm, phase 3b study of datopotamab deruxtecan (Dato-DXd) in patients (pts) with locally advanced inoperable or metastatic HR+/HER2 IHC 0 breast cancer (BC) refractor

Abstract Background: Chemotherapy (CT) is the main treatment in endocrine-refractory HR+/HER2− metastatic BC but has limited efficacy and substantial toxicities. Dato-DXd is a TROP2-directed antibody-drug conjugate (ADC) that consists of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a plasma-stable cleavable linker. It is approved in multiple countries for adult pts with unresectable or metastatic HR+/HER2− (IHC 0, IHC 1+, or IHC 2+/ISH−) BC who have received prior endocrine therapy and CT for advanced disease, based on the findings of the TROPION-Breast01 study (NCT05104866). In the endocrine-refractory setting, the HER2-directed ADC trastuzumab deruxtecan significantly improved outcomes vs CT in pts with HR+/HER2-low (IHC 1+ or IHC 2+/ISH−) or HER2-ultralow (IHC 0 with membrane staining) unresectable or metastatic BC who had received ≥1 line of endocrine-based therapy and no prior CT in the advanced setting (DESTINY-Breast06; NCT04494425). TROPION-Breast06 aims to assess the efficacy and safety of Dato-DXd in the pre-CT endocrine-refractory setting for pts with HR+/HER2 IHC 0 (defined as no staining or incomplete and faint/barely perceptible membrane staining in ≤10% of tumor cells) inoperable or metastatic BC. Adverse events of special interest including Dato-DXd-related oral mucositis/stomatitis (OM/S) and ocular surface events (OSE) will be assessed. Trial Design: TROPION-Breast06 (EudraCT 2025-521904-23-00) is an open-label, single-arm, phase 3b study of Dato-DXd in adults (aged ≥18 years) with locally advanced inoperable or metastatic HR+, HER2 IHC 0 (per ASCO/CAP guidelines) BC who have not received any prior ADC or CT in the inoperable/metastatic setting, with progression on and not suitable for further endocrine therapy per investigator assessment. HER2 status will be determined on the most recent biopsy (collected within 6 weeks of treatment start) by local testing, and may include central confirmation. At time of enrolment, eligible pts must have an ECOG performance status of 0 or 1 and measurable disease per RECIST v1.1 or evaluable disease. Pts with clinically stable brain metastases are permitted. Sample size estimation is based on achieving a planned precision in the 95% confidence interval for median PFS, not hypothesis testing, with 100 participants chosen. Eligible pts from approximately 35 sites in North America, Europe and the Asia Pacific region will receive Dato-DXd (6 mg/kg IV) every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent or other discontinuation criteria are met. A prophylactic oral care plan will be started prior to study drug initiation and throughout treatment, including daily use of steroid-containing mouthwash and consideration of prophylactic cryotherapy; adherence to these measures and reports of mouth and throat symptoms will be captured daily in a digital tracker. Scanning/tumor assessments will be performed every 8 weeks from the first dose of study drug for 48 weeks and then every 12 weeks until RECIST v1.1-defined radiological progression by investigator assessment. Ophthalmologic assessments are mandated at regular intervals and daily use of artificial tears (4-8 times daily) and avoidance of contact lenses is recommended. The primary endpoint is investigator-assessed PFS per RECIST v1.1. Key secondary endpoints are the proportion of pts with OM/S, OSE, and treatment-related Grade ≥3 adverse events. Other secondary endpoints include clinical benefit rate, objective response rate, duration of response, overall survival, and safety/tolerability. Tumor tissue and blood samples will be collected for exploratory analyses. Citation Format: K. Jhaveri, A. C. Garrido-Castro, A. Decque, F. Lujan, M. Prahladan, R. Taylor, N. Toms, F. Bidard. TROPION-Breast06: Multicenter, multinational, open-label, single-arm, phase 3b study of datopotamab deruxtecan (Dato-DXd) in patients (pts) with locally advanced inoperable or metastatic HR+/HER2 IHC 0 breast cancer (BC) refractory to endocrine therapy [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 PS5-07-21.