Abstract PS5-07-22: Herthena-breast04: a phase 3, randomized, open-label study evaluating the efficacy and safety of patritumab deruxtecan (HER3-DXd) versus treatment of physician’s choice in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) unresectable locally advanced or metastatic breast cancer

Abstract Background: There is an unmet therapeutic need for patients with HR+/HER2− metastatic breast cancer who experience disease progression and recurrence after first-line standard of care treatment with a CDK4/6 inhibitor and endocrine therapy (ET). The main therapy options, for those patients who are not considered suitable for additional ET-based therapy, are chemotherapy and antibody-drug conjugates (ADCs). Human epidermal growth factor receptor 3 (HER3) is overexpressed in 50-70% of breast cancers, with highest expression in HR+/HER2− breast cancer, and its overexpression is associated with poor prognosis and drug resistance. Patritumab deruxtecan (HER3-DXd), a novel ADC that selectively binds HER3, is composed of a fully human anti-HER3 IgG1 antibody linked to a cytotoxic topoisomerase I inhibitor via a stable tetrapeptide-based linker that is selectively cleaved within tumor cells. In the phase 2 ICARUS-Breast01 study, HER3-DXd showed clinically meaningful antitumor activity (ORR, 53.5% [95% CI, 43.2-63.6]; median PFS, 9.4 months [95% CI, 8.1-13.4]) and manageable safety in patients with HR+/HER2− advanced breast cancer who progressed on CDK4/6 inhibitor treatment, and 1 line of chemotherapy. The phase 3, multicenter, open-label, HERTHENA-Breast04 study (NCTXXXXXXXX) evaluates efficacy and safety of HER3-DXd monotherapy vs treatment of physician’s choice (TPC) in participants with HR+/HER2− unresectable locally advanced or metastatic breast cancer after progression on one line of CDK 4/6 inhibitor treatment. Methods: Participants must be aged ≥18 y and have centrally confirmed HR+/HER2− (per most recent ASCO/CAP guidelines: HER2 IHC 0 or 1+ or IHC 2+/in situ hybridization negative) unresectable locally advanced or metastatic breast cancer. Participants must have experienced disease progression or recurrence following prior treatment with a CDK4/6 inhibitor and ET and must be eligible for at least 1 TPC option, as determined by the investigator. Participants must have measurable disease per RECIST version 1.1 and ECOG PS of 0 or 1. Participants who have received prior chemotherapy or are candidates for an additional line of ET-based therapy in the advanced setting are ineligible for the study. Participants are randomized 1:1 to Arm 1 or 2, with approximately 500 participants assigned to each arm. Participants in Arm 1 will receive HER3-DXd 5.6 mg/kg IV on day 1 Q3W, and participants in Arm 2 will receive TPC consisting of 1 of the following options: 1) paclitaxel 80 mg/m2 IV on days 1, 8, 15, and 22 Q4W; 2) paclitaxel 90 mg/m2 IV on days 1, 8, and 15 Q4W; 3) nab-paclitaxel 100 mg/m2 IV on days 1, 8, and 15 Q4W; 4) capecitabine 1000 mg/m2 orally twice daily on days 1 to 14 Q3W; 5) liposomal doxorubicin 50 mg/m2 IV on day 1 Q4W; or 6) trastuzumab deruxtecan 5.4 mg/kg IV on day 1 Q3W. Treatment will continue until radiographic disease progression, unacceptable toxicity, or participant withdrawal. The dual primary endpoints are PFS per RECIST version 1.1 by BICR and OS. Secondary endpoints are ORR and DOR per RECIST version 1.1 by BICR, safety, and patient-reported outcomes. AEs are graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Imaging assessments occur Q6W from randomization through week 60 and Q12W thereafter. Enrollment is planned to begin in Q3 2025 across North America, Latin America, Europe, and Asia Pacific. Citation Format: B. Pistilli, S. Hou, J. M. Collins, P. K. Sudheendra, V. Kaklamani. Herthena-breast04: a phase 3, randomized, open-label study evaluating the efficacy and safety of patritumab deruxtecan (HER3-DXd) versus treatment of physician’s choice in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) unresectable locally advanced or metastatic breast cancer [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 PS5-07-22.