On August 27, 2025 Merck reported that the first patient has been dosed in the HERTHENA-Breast04 phase 3 trial evaluating the efficacy and safety of investigational patritumab deruxtecan (HER3-DXd) versus investigator’s choice of treatment in patients with unresectable locally advanced or metastatic hormone receptor (HR) positive, HER2 negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer with disease progression following endocrine and CDK4/6 inhibitor therapy in either the adjuvant or first-line metastatic settings (Press release, Merck & Co, AUG 27, 2025, View Source [SID1234655516]).

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Patritumab deruxtecan is a specifically engineered HER3 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being developed jointly by Daiichi Sankyo and Merck (known as MSD outside of the United States and Canada).

While survival rates are high for those diagnosed with early-stage breast cancer, only about 30% of patients initially diagnosed with advanced disease or having metastatic progression are expected to live five years following diagnosis.1 Patients with HR positive, HER2 negative metastatic breast cancer experience poor outcomes if they progress following initial treatment, highlighting the need for additional options.2

"Despite significant development in the treatment landscape, HR positive, HER2 negative metastatic breast cancer is a highly complex and challenging disease with an overall poor prognosis," said Mark Rutstein, MD, Head, Therapeutic Area Oncology Development, Daiichi Sankyo. "The promising clinical activity observed in our early phase studies including ICARUS-Breast01 suggest that patritumab deruxtecan has the potential to become a meaningful new treatment option for this specific type of breast cancer."

"The initiation of HERTHENA-Breast04 demonstrates our ongoing commitment to researching innovative approaches that may help treat some of the most challenging cancers," said Marjorie Green, MD, Senior Vice President and Head of Oncology, Global Clinical Development, Merck Research Laboratories. "These patients need new options, and we continue to pursue cutting-edge science to develop therapies that may lead to improved treatment outcomes."

The initiation of HERTHENA-Breast04 is based on results from ICARUS-Breast01 and a phase 1/2 breast cancer trial previously published in Journal of Clinical Oncology in June 2022, where patritumab deruxtecan showed promise in patients with metastatic breast cancer.

About HERTHENA-Breast04

HERTHENA-Breast04 is an open-label, randomized, phase 3 trial evaluating the safety and efficacy of patritumab deruxtecan (5.6 mg/kg) monotherapy versus physician’s choice of treatment in adult patients with unresectable locally advanced or metastatic HR positive, HER2 negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer previously treated with endocrine and CDK4/6 inhibitor therapy. Patients in the trial should not be eligible to receive additional endocrine therapy and should not have received chemotherapy or an ADC for advanced or metastatic disease. Further, patients must have experienced disease progression on first-line endocrine and CDK4/6 inhibitor therapy in the advanced or metastatic setting or relapse on or within 24 months of adjuvant endocrine and CDK4/6 inhibitor therapy.

Patients will be randomized 1:1 to receive patritumab deruxtecan or physician’s choice of treatment, consisting of either chemotherapy (paclitaxel, nab-paclitaxel, capecitabine, liposomal doxorubicin) or HER2 directed ADC (trastuzumab deruxtecan). Randomization will be stratified by HER2 expression and treatment intent (chemotherapy versus trastuzumab deruxtecan), HER3 expression (low versus high per IHC) and presence of visceral disease.

The dual primary endpoints of HERTHENA-Breast04 are progression-free survival by blinded independent central review and overall survival. Secondary endpoints include objective response rate, duration of response and safety.

HERTHENA-Breast04 will enroll approximately 1,000 patients across Asia, Europe, North America, and South America. For more information, please visit ClinicalTrials.gov.

About Hormone Receptor Positive, HER2 Negative Breast Cancer

More than 2 million cases of breast cancer were diagnosed in 2022, with approximately 670,000 deaths globally.3 While survival rates are high for those diagnosed with early-stage breast cancer, only about 30% of patients initially diagnosed with advanced disease or having metastatic progression are expected to live five years following diagnosis.1

Approximately 70% of diagnosed cases are considered what has been historically called HR positive, HER2 negative breast cancer (as measured as HER2 score of IHC 0, IHC 1+ or IHC 2+/ISH-).4,5 Patients with HR positive, HER2 negative metastatic breast cancer experience poor outcomes if they progress following initial treatment, highlighting the need for additional options.2

About HER3

HER3 is a member of the HER family of receptor tyrosine kinases.6 HER3 is broadly expressed in about 90% of breast tumors.7,8,9 HER3 is associated with poor treatment outcomes, including shorter relapse-free survival and significantly reduced survival.10,11 There is currently no HER3 directed therapy approved for the treatment of any cancer.

About Patritumab Deruxtecan

Patritumab deruxtecan (HER3-DXd) is an investigational HER3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, patritumab deruxtecan is composed of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

About the Patritumab Deruxtecan Clinical Development Program

A comprehensive global clinical development program is underway evaluating the efficacy and safety of patritumab deruxtecan across multiple cancers. Trials in combination with other anticancer medicines also are underway.