TROPION-Breast01: Redefining Treatment for HR+/HER2– Metastatic Breast Cancer

The TROPION-Breast01 trial introduces datopotamab deruxtecan (Dato-DXd) as a promising new option for HR+/HER2– metastatic breast cancer patients resistant to endocrine therapy. This Phase 3 study showed superior progression-free survival and reduced toxicity compared to standard chemotherapy. The findings support Dato-DXd as a potential new standard of care, marking a significant shift in treatment strategies.

---

By Dr. Elvina Almuradova, MD, Assoc. Prof. of Oncology

Can Hospital - LinkedIn Profile

---

Click the picture to view the PDF version: Pg 33-36.

Hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC) is the first tumor type where targeted therapies were introduced. These targeted agents included aromatase inhibitors and tamoxifen. Over time, the efficacy of these agents has increased with the development of CDK 4/6, PIK3CA, and AKT inhibitors. 

However, it is well known that this type of breast cancer gradually loses its hormone sensitivity. For many years, the only available option in this scenario was chemotherapy agents. Traditional chemotherapy is associated with limited clinical benefit and significant toxicity. 

Therefore, there is a need for more effective and better-tolerated treatment options, and in recent years, the development of targeted therapies such as antibody-drug conjugates (ADCs) has significantly altered these strategies.
One of the promising drugs in this field is datopotamab deruxtecan (Dato-DXd), an ADC targeting TROP2. The global, phase 3, open-label, randomized clinical trial na-med TROPION-Breast01 compared Dato-DXd with investigator’s choice of chemotherapy (ICC). Patients who were endocrine therapy-resistant and had received one or two lines of chemotherapy in the metastatic setting were included in the study.

The results of this study, published in the Journal of Clinical Oncology, strongly support considering Dato-DXd as a new standard-of-care option for this patient population. The development of ADCs such as trastuzumab deruxtecan (Enhertu) for HER2-low patients and sacituzumab govitecan for triple-negative breast cancer (TNBC) represents important steps toward addressing this need. Dato-DXd, which targets TROP2, emerges as a strong alternative to chemotherapy for endocrineresistant HR+/HER2– MBC.

The TROPION-Breast01 trial included 732 patients diagnosed with HR+/HER2– breast cancer who were endocrine therapy-resistant and had received one or two lines of chemotherapy in the inoperable or metastatic setting. Patients were randomized 1:1 to receive one of the following treatments: Dato-DXd: 6 mg/kg IV every three weeks; ICC: eribulin, vinorelbine, capecitabine, or gemcitabine. 

The primary endpoints of the study were progression-free survival (PFS) assessed by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), time to first subsequent therapy, safety, and tolerability.

Progression-free survival (PFS) was significantly prolonged in patients receiving Dato-DXd compared to ICC (6.9 months vs. 4.9 months). Dato-DXd reduced the risk of disease progression or death by 37% (HR: 0.63; 95% CI: 0.52-0.76; p < .0001). 
Similar benefits were observed across all subgroups, regardless of variables such as prior CDK4/6 inhibitor use, geographic region, or previous chemotherapy treatment. Although overall survival (OS) data are not yet mature, a favorable trend in favor of Dato-DXd has been observed (HR: 0.84; 95% CI: 0.62-1.14).

One of the most striking findings of the TROPION-Breast01 trial is that Dato-DXd had a significantly lower rate of severe adverse events compared to ICC. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 20.8% of the Dato-DXd group, compared to 44.7% in the chemotherapy arm. 

As with other ADCs, the most concerning adverse event, drug-related interstitial lung disease (ILD), was observed in 3.3% of patients, with one patient experiencing a Grade 5 event. These results demonstrate that Dato-DXd offers lower severe hematologic toxicity and better tolerability compared to chemotherapy. 

The TROPION-Breast01 study strongly supports that Dato-DXd could become a new standard of care in the post-chemotherapy treatment of HR+/HER2– metastatic breast cancer. This study, which highlights the potential of ADCs to replace traditional chemotherapy, signals a significant shift in clinical practice.

References:

1. W A Phase-3, Open-Label, Randomized Study of Dato-DXd Versus Investigator’s Choice of Chemotherapy (ICC) in Participants With Inoperable or Metastatic HR-Positive, HER2-Negative Breast Cancer Who Have Been Treated With One or Two Prior Lines of Systemic Chemotherapy (TROPION-Breast01)
2. Aditya Bardia et al. Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor–Positive Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer: Primary Results From TROPION-Breast01. JCO 43, 285-296(2025). DOI:10.1200/JCO.24.00920.