261TiP TROPION-Breast05: Phase (Ph) III study of datopotamab deruxtecan (Dato-DXd) ± durvalumab (D) vs chemotherapy (CT) + pembrolizumab (pembro) in patients (pts) with PD-L1+ locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC)

Standard of care for pts with metastatic PD-L1+ (Combined Positive Score CPS ≥10) TNBC is pembro + CT, but prognosis remains poor. Dato-DXd comprises a humanised, anti-TROP2 IgG1 mAb conjugated to a potent topoisomerase I (Topo-I) inhibitor via a plasma-stable, tetrapeptide-based, tumour-selective cleavable linker. D is a high-affinity, human IgG1 mAb that blocks interaction of PD-L1 with PD-1 and CD80 by binding to PD-L1. In the Ph1 TROPION-PanTumor01 study, Dato-DXd demonstrated a manageable safety profile and encouraging efficacy in heavily pretreated metastatic TNBC. In the PhIb/2 BEGONIA study, Dato-DXd + D showed durable responses in unresectable advanced TNBC. TROPION-Breast05 (NCT06103864) will evaluate Dato-DXd ± D vs investigator's choice of CT (ICC) + pembro in PD-L1+ locally recurrent inoperable or metastatic TNBC. The Ph3, randomized, open-label, 3-arm, multicentre TROPION-Breast05 study will randomise ∼625 pts (≥18 years) with histologically/cytologically documented, locally recurrent inoperable or metastatic PD-L1+ (CPS ≥10) TNBC not previously treated with CT or targeted systemic anticancer therapy. Pts with active brain metastases, or prior exposure to Topo-I ADC or TROP2-targeted therapy will be excluded. Pts will be randomised 1:1 to Arm 1 (Dato-DXd 6 mg/kg IV every 3 weeks Q3W + D 1120 mg IV Q3W) or Arm 2 (ICC paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin + pembro), or in selected countries, 1:1:1 to Arms 1, 2, or 3 (Dato-DXd alone). Once ∼75 pts have been randomised to Arm 3, it will close and all countries will continue with 1:1 randomisation. Primary endpoint: progression-free survival (PFS) by blinded independent central review per RECIST v1.1. Secondary endpoints: overall survival, objective response rate, duration of response, investigator-assessed PFS, PFS2, clinical benefit rate at 24 weeks, patient-reported outcomes, pharmacokinetics, immunogenicity, safety. Enrolment is planned in 20 countries/regions; recruitment is active in the UK, South Korea and Taiwan at the time of abstract submission. NCT06103864. Medical writing support for the development of this abstract, under the direction of the authors, was provided by Helen Kitchen of Ashfield MedComms (Macclesfield, UK), an Inizio company. AstraZeneca PLC in collaboration with Daiichi Sankyo. Pharmaceutical, biotech, or other commercial company; AstraZeneca PLC in collaboration with Daiichi Sankyo.