Abstract CT256: EmpowHER-303: A phase 3 study of zanidatamab vs trastuzumab with physician’s choice of chemotherapy in patients with HER2+ metastatic breast cancer whose disease progressed on trastuzumab deruxtecan

Abstract Background: HER2-targeted therapies have revolutionized the treatment of HER2+ breast cancer (BC). However, there is a need for novel treatment options after progression on available therapies, including trastuzumab deruxtecan (T-DXd). Zanidatamab (zani) is a dual HER2-targeted bispecific antibody that binds 2 HER2 domains in a trans configuration, leading to multiple mechanisms of action, including enhanced HER2 internalization and downregulation, complement-dependent cytotoxicity, and antibody-dependent cellular cytotoxicity and phagocytosis. Zani, as a monotherapy and combination therapy, has shown antitumor activity against multiple HER2+ metastatic tumors, including metastatic BC (mBC). Methods: EmpowHER-303 (NCT06435429) is a phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of zani vs trastuzumab (T) both in combination with physician’s choice of chemotherapy in patients (pts; ≥18 years old) with histologically confirmed HER2+ mBC (per ASCO-CAP guidelines) and measurable disease (per RECIST version 1.1). Eligible pts must have progressed on, or be intolerant to, prior T-DXd and have received ≥2 but ≤4 lines of prior HER2-directed therapies for mBC. Based on physician’s choice, pts’ eligibility, and institutional/local guidelines, pts may have received post-T-DXd therapy (eg, a tucatinib-based regimen and/or trastuzumab emtansine). Pts must be eligible to receive the physician’s choice of chemotherapy (eribulin, gemcitabine, vinorelbine, or capecitabine). Pts with CNS metastases are eligible if their CNS metastases have been treated or are clinically inactive. Pts must have adequate hematologic parameters, hepatic function (LVEF ≥50%), renal function (creatine clearance of ≥30 mL/min), and ECOG PS ≤1, and a life expectancy of ≥6 months. Exclusion criteria include known or suspected leptomeningeal disease, uncontrolled or significant cardiovascular disease, uncontrolled infection, history of hypersensitivity to monoclonal antibodies, or inability to receive zani or T. An estimated 550 pts will be randomized 1:1 to zani (1800 mg [pts <70 kg] or 2400 mg [pts ≥70 kg] IV) or T (8 mg/kg IV loading dose, then 6 mg/kg), plus physician’s choice of chemotherapy in 3-week cycles. Randomization will be stratified by number of prior lines of HER2-directed therapies, prior tucatinib use, geographic region, CNS metastases, and chemotherapy choice. Pts randomized to zani will receive mandatory prophylaxes for diarrhea and infusion-related reactions. The primary endpoint is progression-free survival (PFS) by blinded independent central review; overall survival is the key secondary endpoint. Other secondary endpoints include confirmed objective response rate, duration of response, investigator-assessed PFS, safety, and pt-reported outcomes. Citation Format: Sara M. Tolaney, Javier Cortes, Erika Hamilton, Hiroji Iwata, Yeon Hee Park, Debasish Tripathy, Romualdo Barroso-Sousa, Giuseppe Curigliano, Nadia Harbeck, Hope S. Rugo, Shanu Modi, Joshua Drago, Stephanie L. Graff, Carlos Barrios, Hartmut Kristeleit, Barbara Pistilli, Philippe Aftimos, Shigehira Saji, Angelos Koutras, Debasis Chakrabarti, Kamalnayan Bhatt, George Cai, Xiaoyan Wang, Sara Hurvitz. EmpowHER-303: A phase 3 study of zanidatamab vs trastuzumab with physician’s choice of chemotherapy in patients with HER2+ metastatic breast cancer whose disease progressed on trastuzumab deruxtecan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT256.