New Study Evaluates Neoadjuvant HER3-Targeted ADC in Early Triple-Negative Breast Cancer

Researchers are investigating whether the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd) can improve outcomes for patients with high-risk, early stage triple-negative breast cancer (TNBC) and hormone receptor (HR)-low positive/HER2-negative breast cancer when added to pembrolizumab-based therapy.¹

The phase 2 HERTHENA-breast03 trial (NCT06797635) was presented at the European Society for Medical Oncology (ESMO) Congress 2025 in Berlin. Researchers aim to enhance pathologic complete response (pCR) rates while avoiding the long-term toxicities commonly associated with chemotherapy.²

Addressing Unmet Needs in Early-stage TNBC

Among patients with high-risk, early-stage TNBC, neoadjuvant chemotherapy plus immunotherapy is the standard of care. This treatment regimen often causes serious long-term medical issues including secondary cancers and cardiomyopathy. Even more worrisome for patients, those who fail to achieve pCR face approximately a 3-fold risk of their breast cancer recurring.³

HER-DXd is an experimental drug designed to seek out human epidermal growth factor receptor 3 (HER3), a protein often found in breast tumors, and deliver chemotherapy without affecting surrounding healthy cells and with fewer side effects.

Trial Design and Treatment Arms

Researches designed the trial to have 2 parts: a safety lead-in to determine optimal dosage (n = 10-30), and a randomized phase with a control group (n = 342).

For the safety lead-in, between 10 and 30 patients will receive either 5.6, 4.8, or 3.2 mg/kg of HER3-DXd, plus 200 mg of pembrolizumab for 4 cycles (with each cycle lasting 3 weeks), followed by carboplatin plus paclitaxel plus pembrolizumab for another 4 cycles, followed by surgery.

In the randomized phase of the trial, researchers plan to enroll approximately 342 patients into 3 arms on a 1:1:1: basis and will administer 2 cycles of therapy for 4 cycles each. Arm A will receive HER3-DXd plus pembrolizumab followed by carboplatin plus paclitaxel plus pembrolizumab. Arm B will receive carboplatin plus paclitaxel plus pembrolizumab, followed by HER3-DXd plus pembrolizumab. Arm C will receive carboplatin plus paclitaxel plus pembrolizumab, followed by either doxorubicin or OR epirubicin plus cyclophosphamide plus + pembrolizumab.

All participants will receive surgery after their neoadjuvant therapies, followed by adjuvant pembrolizumab every 6 weeks for 5 more cycles and further chemotherapy for patients with residual disease.

The trial's primary end points are to determine safety and improve pCR rates. Enrollment began in the first quarter of 2025.¹

Implications for Patients and Pharmacists

If HERTHENA-breast03 researchers meet the study's end points, it could change how patients with high-risk early breast cancer are treated. Therapies could shift away from powerful chemotherapy drugs that have been used for decades but often cause secondary and long-lasting health issues without sacrificing efficacy or patient survival. This could be especially meaningful for younger patients diagnosed with breast cancer; the median age for first diagnosis has been trending younger in recent years (under 50 years of age).⁴ Precision-guided therapies like HER-DXd address a substantial unmet need for patients who do not reach pCR on chemotherapies alone.

Pharmacists will play a key role in helping patients understand the benefits of targeted ADCs like HER-DXd and monitoring patients for overlapping toxicities between ADCs and immunotherapy agents.

REFERENCES

1. Danso MA, Collins JM, Yao L, et al. HERTHENA-breast03: A phase 2, randomized, open-label study evaluating neoadjuvant patritumab deruxtecan + pembrolizumab before or after pembrolizumab + chemotherapy for early-stage TNBC or HR-low+/HER2− breast cancer. Presented at: European Society for Medical Oncology (ESMO) Congress 2025; October 2025; Berlin, Germany. Abstract 463eTiP.

2. ClinicalTrials.gov. Study of patritumab deruxtecan with pembrolizumab before or after pembrolizumab with chemotherapy for early-stage TNBC or HR-low+/HER2- breast cancer (HERTHENA-breast03). NCT06797635. Updated 2025. Accessed October 29, 2025. https://clinicaltrials.gov/study/NCT06797635

3. Spring LM, Fell G, Arfe A, et al. Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis. Clin Cancer Res. 2020;26(12):2838-2848. doi:10.1158/1078-0432.CCR-19-3492

4. American Cancer Society. Breast Cancer Facts & Figures 2024-2025. Atlanta, GA: American Cancer Society; 2024.