For years, patients with triple negative breast cancer (TNBC) have had limited treatment options beyond chemotherapy. Now, findings from the landmark TROPION-Breast02 trial (NCT05374512) led by MSK researchers have established a new standard of care for this hard-to-treat breast cancer subtype.
The international, open-label phase3 trial showed superiority of Datopotamab deruxtecan (Dato-DXd) compared to standard chemotherapy as first-line therapy in patients with metastatic TNBC who are not candidates for immunotherapy. Results were presented at the European Society for Medical Oncology Congress in October 2025 and published in the Annals of Oncology on April 3, 2026.
“Dato-DXd significantly improved overall survival for this challenging subtype of breast cancer, where historic median overall survival has been about 12 months,” said MSK Breast Medical Oncologist Tiffany Traina, MD. Dr. Traina was U.S. lead and senior author of the study and is Section Head of the Triple Negative Breast Cancer Clinical Research Program at MSK.
TNBC is an aggressive cancer found in 10% to 20% of people diagnosed each year with breast cancer. For about 70% of these patients, immunotherapy is not an option. Chemotherapy has been the mainstay as first-line treatment and has had only modest benefit.
Novel Therapeutic for the Treatment of TNBC
Dato-Dxd is an antibody-drug conjugate composed of a monoclonal antibody targeted at the TROP-2 protein that is overexpressed in epithelial cancers like breast cancer and non-small cell lung cancer (NSCLC), which is linked to DXd chemotherapy. In January, 2025, Dato-Dxd was FDA approved for the treatment of patients with advanced HER2 negative breast cancer who have already received endocrine-based therapy and chemotherapy, based on results from the phase 3 TROPION-Breast 01 trial (NCT05104866). In June 2025, Dato-DxD gained accelerated FDA approval in the treatment of EGFR-mutated non-small cell lung cancer, based on results from TROPION-Lung05 (NCT04484142) and TROPION-Lung01 (NCT04656652).
Study Design
The TROPION-Breast02 trial was a randomized, open-label phase 3 trial that took place in 229 centers across 23 countries. The trial compared Dato-Dxd monotherapy to investigators’ choice of chemotherapy in patients with previously untreated, locally recurrent inoperable or metastatic TNBC who were not candidates for immunotherapy. It included a total of 644 participants who were randomly assigned either to Dato-DXd (n=323, median age 56 years) or chemotherapy (n=321, median age 57 years). Study participants had very short disease-free intervals: up to 20% had disease recurrence less than 12 months after receiving adjuvant therapy, and 15% recurred less than 6 months after adjuvant therapy. Additionally, about 10% had brain metastases, indicating a subgroup that is very difficult to treat.
The two primary endpoints were progression-free survival (PFS; time from randomization until progression per RECIST version 1.1 or death due to any cause) by blinded independent central review (BICR), and overall survival (OS; time from randomization until death due to any cause).
Findings
The median follow-up was 27.5 (range 13.3-38.7) months, at which point 14% (n=45/319) of patients in the Dato-DXd group and 3% (n=8/309) of patients in the chemotherapy group were still on treatment.
Results showed that Dato-DXd was associated with significant improvement in both PFS and OS, which were both about 5 months longer compared to chemotherapy:
- Median PFS: 10.8 months [95% confidence interval (CI) 8.6-13.0] with Dato-DXd vs. 5.6 months (95% CI 5.0-7.0) = with chemotherapy,[HR 0.57 (99% CI 0.44-0.73); P < 0.0001].
- Median OS: 23.7 months (95% CI 19.8-25.6) with Dato-DXd vs. 18.7 months (95% CI 16.0-21.8) with chemotherapy[hazard ratio 0.79 (95.01% CI 0.64-0.98); P = 0.029].
The Dato-DXd group also had a higher confirmed objective response rate (ORR) compared to chemotherapy (63% [n=202] vs. 29% [n=94]). Nine percent (n=29) of the DatoDXd group showed complete response compared to 2% (n=8) of those who received chemotherapy. The Dato-DXd group had a median duration of response (DoR) of 12.3 months (95% CI 9.1-15.9), compared to 7.1 months (95% CI 5.6-8.9) with chemotherapy. The median duration of treatment was 8.5 months (range 0.7-38.0) with Dato-DXd, compared to 4.1 months (range 0.1-32.0) with chemotherapy.
Rates of serious and grade 3 or higher treatment-related adverse events (TRAEs) were similar between the two groups. The Dato-DXd group had lower rates of discontinuation due to TRAES, compared to chemotherapy (4% [n=14] vs 7% [n= 23]). Neither group had treatment-related deaths.
Patient-reported outcomes showed a benefit for Dato-DXd compared with chemotherapy in time to deterioration in pain, physical functioning, global health status/quality of life, and breast and arm symptoms.
Clinical Implications
Based on results from the TROPION-Breast02 trial, Dato-DXd was FDA approved on May 22, 2026 as first-line therapy for adults with unresectable or metastatic TNBC who are not eligible for immunotherapy, making it the first TROP2-directed ADC to gain FDA approval as first-line in this patient population. DatoDXd has also been incorporated into the National Comprehensive Cancer Network Guidelines as a Category 1 preferred first-line treatment option for patients with metastatic TNBC who are not candidates for checkpoint inhibitors.
“This has been really practice changing,” said Dr. Traina. “It highlights truly impactful work for a subset of breast cancer that has the poorest survival outcomes. It underscores the rapid translation of this important work from clinical investigation to routine patient care.”
The study showcases the work of the Breast Medicine Service at MSK as they continue to advance practice-changing research in metastatic TNBC.
Disclosures
Dr. Traina reports professional services and activities with Aktis Oncology, Inc., AstraZeneca, BioNTech, Curio Science LLC, Daiichi Sankyo, Ellipses Pharma, Exact Sciences Corporation, Genentech, Gilead Sciences, Inc., Medscape, Pfizer, Inc., Physicians’ Education Resource, Research to Practice, Roche, and Veracyte, Inc.
