HERTHENA-Breast04 Is Set to Delineate the Role of HER3-Targeted Therapy in Advanced HR+ Breast Cancer

As the development of patritumab deruxtecan (HER3-DXd) propels into the phase 3 setting in patients with hormone receptor (HR)–positive, HER2-negative advanced breast cancer, the treatment paradigm for patients who have progressed or recurred on standard first-line regimens may become better tailored to manage further disease progression with a relatively more tolerable safety profile.

The standard-of-care (SOC) first-line therapy for patients with HR-positive, HER2-negative advanced breast cancer is endocrine therapy plus a CDK4/6 inhibitor.¹ After disease progression or recurrence in this setting, patients who are not considered eligible for additional endocrine-based therapy or targeted therapies typically receive cytotoxic therapy via chemotherapy or antibody-drug conjugates (ADCs). However, the development of ADCs with novel antigen targets may improve the safety profile of this class of agents in this patient population.

The overexpression of HER3, which occurs in approximately 50% to 70% of patients with breast cancer; it has highest expression in HR-positive, HER2-negative disease, and is associated with drug resistance and poor treatment outcomes.² HER3-DXd is a novel HER3-directed ADC comprising a fully human anti-HER3 IgG1 antibody linked to a cytotoxic topoisomerase I inhibitor.¹ This agent has a drug-to-antibody ratio of approximately 8 and is being evaluated in the ongoing phase 3 HERTHENA-Breast04 trial (NCT07060807) in patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer.

“When you look at the landscape of HR-positive metastatic disease, we have several endocrine therapies, targeted agents, PI3K inhibitors, AKT inhibitors, oral selective estrogen receptor degraders, and so forth. However, we know that these tumors sooner or later become endocrine resistant.” Virginia Kaklamani, MD, DSc, said in an interview with OncLive®. “[Data from HERTHENA-Breast04] will help inform a small but extremely important patient population, where we likely don't have a lot of options because of the aggressiveness of their disease.”

Kaklamani is a professor of medicine in the Division of Hematology-Medical Oncology at The University of Texas (UT) Health Science Center San Antonio and leader of the breast cancer program at the Mays Cancer Center, UT Health San Antonio MD Anderson Cancer Center.

What data have been previously reported with HER3-DXd in patients with breast cancer?

Previously, the phase 2 ICARUS-Breast01 trial (NCT04965766) demonstrated that HER3-DXd generated clinically meaningful antitumor activity and a manageable safety profile in patients with HR-positive, HER2-negative advanced breast cancer who had progressed on a CDK4/6 inhibitor and 1 line of chemotherapy.^1,3 The overall response rate (ORR) was 53.5% (90% CI, 44.8%-62.1%), and the median progression-free survival (PFS) was 9.2 months (95% CI, 8.0-12.8%).³ Additionally, preliminary evidence showed a correlation between HER3 expression and HER3-DXd efficacy outcomes.

“Preliminary results that we've had with the efficacy of HER3-DXd in breast cancer have been impressive,” Kaklamani noted. “[It has shown] good efficacy in both estrogen receptor–positive and –negative metastatic disease. The toxicity profile seems to be favorable with lower rates of pneumonitis compared with other HER2-directed antibodies. [These data are] make it ideal for us to try it in combinations, [as a] single agent, and in different settings [such as] HR-positive metastatic disease,” Kaklamani added.

What is the design of the HERTHENA-Breast04 trial?

The trial is enrolling patients at least 18 years of age with HR-positive, HER2-negative invasive breast carcinoma that is locally advanced and not amenable to curative-intent resection, or is metastatic and not suited for curative-intent treatment.^1,4 Patients need to be evaluable for HER3 expression via a biopsy of a distant metastatic site collected during or after their most recent line of therapy.

Patients also need to have radiographic disease progression on first-line endocrine therapy plus a CDK4/6 inhibitor for advanced HR-positive, HER2-negative breast cancer (must be the only line of therapy received in the advanced setting), or radiographic and/or histologically confirmed disease recurrence during adjuvant treatment with endocrine therapy plus a CDK4/6 inhibitor or within 24 months from the last dose of an adjuvant CDK4/6 inhibitor. Additionally, patients must be candidates for at least 1 treatment of physician’s choice, have measurable disease per RECIST 1.1 criteria, have an ECOG performance status of 0 or 1, and have adequate organ function.

Patients are being excluded if they have breast cancer that is amenable to treatment with curative intent, are eligible to receive additional adjuvant endocrine-based therapies, or have known deleterious or suspected deleterious germline BRCA mutations where PARP inhibitors are a potential treatment option. Additionally, patients cannot have previously received chemotherapy for unresectable locally advanced or metastatic breast cancer, a HER3-directed antibody and/or ADC that is composed of a topoisomerase I inhibitor, any other topoisomerase I inhibitor therapy, systemic anticancer therapy within 4 weeks or 5 half-lives (whichever is shorter) before random assignment, or radiotherapy for non–central nervous system disease or required corticosteroids for radiation-related toxicities within 14 days of the first dose of study treatment. Patients will also be excluded if they have current visceral crisis or are at risk for visceral crisis that has caused or may cause imminent organ compromise and/or other life-threatening complications.

Patients will be stratified by HER2 expression and treatment intent (HER2-null and intent to give chemotherapy vs HER2-ultralow/low and intent to give chemotherapy vs HER2-ultralow/low and intent to give fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu]), HER3 expression (low vs high), and the presence of visceral disease (yes vs no).

An estimated 1000 patients will be randomly assigned 1:1 to receive intravenous HER3-DXd at 5.6 mg/kg every 3 weeks, or treatment of physician’s choice consisting of paclitaxel, nab-paclitaxel (Abraxane), capecitabine, liposomal doxorubicin, or T-DXd (where approved and available).

PFS per RECIST 1.1 criteria by blinded independent review and overall survival (OS) will serve as the co-primary end points. Secondary end points include ORR, duration of response, change from baseline and time to deterioration in health-related quality of life per the EORTC QLQ-C30, and safety.

The trial was initiated on July 21, 2025, and the estimated primary completion date is July 14, 2033.⁴ The trial is currently enrolling.

“[Locally advanced or metastatic HR-positive, HER2-negative breast cancer] is a crowded field where we have a lot of clinical trials [that are] ongoing, but we need to understand the disease better. We need to understand what we call endocrine resistance and what the mechanism of endocrine resistance is in each setting,” Kaklamani concluded. “We need to understand this in real time so that we can treat patients better.”

References

1. Pistilli B, Hou S, Collins JM, Sudheendra PK, Kaklamani VG, et al. 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. J Clin Oncol. 2026;44(suppl 16):TPS1149. doi:10.1200/JCO.2026.44.16_suppl.TPS1149
2. Lyu H, Han A, Polsdofer E, Liu S, Liu B. Understanding the biology of HER3 receptor as a therapeutic target in human cancer. Acta Pharm Sin B. 2018;8(4):503-510. doi:10.1016/j.apsb.2018.05.010
3. Pistilli B, Mosele F, Corcos N, et al. Patritumab deruxtecan in HR⁺HER2^- advanced breast cancer: a phase 2 trial. Nat Med. 2025;31(10):3492-3503. doi:10.1038/s41591-025-03885-3
4. A clinical study of patritumab deruxtecan to treat breast cancer (MK-1022-016). ClinicalTrials.gov. Updated June 1, 2026. Accessed June 3, 2026. https://clinicaltrials.gov/study/NCT07060807