TPS1149 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 (CDK4/6i) 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 HR+/HER2− breast cancer and is associated with poor prognosis and drug resistance. Patritumab deruxtecan (HER3-DXd) is a novel ADC 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 and manageable safety in patients with HR+/HER2− advanced breast cancer who progressed on CDK4/6i treatment and 1 line of chemotherapy. The phase 3, multicenter, open-label, HERTHENA-Breast04 study (NCT07060807) evaluates efficacy and safety of HER3-DXd monotherapy vs treatment of physician’s choice (TPC) in participants with HR+/HER2− advanced breast cancer after progression on 1 line of CDK 4/6i 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 CDK4/6i and ET and must be eligible for at least 1 TPC option, as determined by the investigator. Participants must have measurable disease per RECIST v1.1 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 ~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: paclitaxel, nab-paclitaxel, capecitabine, liposomal doxorubicin, or trastuzumab deruxtecan. Treatment will continue until disease progression, unacceptable toxicity, or participant withdrawal. The dual primary endpoints are PFS per RECIST v1.1 by BICR and OS. Secondary endpoints are ORR and DOR per RECIST v1.1 by BICR, safety, and patient-reported outcomes. Imaging assessments occur Q6W from randomization through week 60 and Q12W thereafter. Enrollment began in 2025. Clinical trial information: NCT07060807 .
Pistilli et al. (Thu,) studied this question.