Dato-DXd Shows Promise as First-Line Therapy in Metastatic TNBC

A new study shows datopotamab deruxtecan (Dato-DXd; Datroway; AstraZeneca) offers a meaningful survival advantage in a subgroup of patients with metastatic triple-negative breast cancer (mTNBC) who are not eligible for immunotherapy, according to recent data from the TROPION-Breast02 trial (NCT05374512).^1,2

Antibody-drug conjugates (ADCs) continue to reshape the therapeutic landscape in oncology, offering targeted delivery of cytotoxic payloads to tumor cells. Dato-DXd is being investigated in multiple malignancies, including breast cancer.

The TROPION-Breast01 trial (NCT05104866) is a phase 3, open-label, randomized study that is designed to assess the efficacy of datopotamab deruxtecan relative to the investigator's choice of single-agent chemotherapy (such as eribulin, capecitabine, vinorelbine, or gemcitabine) in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer post 1 or 2 lines of chemotherapy. The major endpoints are progression-free survival (PFS) and overall survival (OS), while the study also gathers data on safety and quality of life as secondary objectives.³ The estimated date of completion is December 2025.³

Although TROPION-Breast01 concentrates on HR+ conditions, the TROPION-Breast02 trial is an entirely different, first-line metastatic TNBC study, which aims to compare datopotamab deruxtecan (6 mg/kg) with the investigator’s choice of chemotherapy in patients with previously untreated, inoperable, or mTNBC.⁴

TROPION-Breast02 results have already been made public through an AstraZeneca press release, which indicates a statistically significant and clinically meaningful increase in overall survival (OS) in the subgroup of patients who were immunotherapy non-candidates.⁴ Traditionally, it has been difficult to find benefits of overall survival in the first line of TNBC, especially in the group of patients who are not suitable for immunotherapy.²

According to AstraZeneca, datopotamab deruxtecan produced a survival advantage compared to standard chemotherapy in this first-line mTNBC population unable to receive immunotherapy.² Datopotamab deruxtecan is reported as the first ADC and the only therapy to significantly improve OS in patients with metastatic TNBC for whom immunotherapy is not an option. The safety profile in TROPION-Breast02 was consistent with earlier trials of datopotamab in breast cancer, with no unexpected safety signals. Detailed hazard ratios and Kaplan–Meier survival curves are expected to be presented at an upcoming medical meeting.²

In the TROPION-Breast01 trial, datopotamab deruxtecan met its dual primary endpoint of PFS: datopotamab deruxtecan reduced the risk of disease progression or death by 37% compared to chemotherapy in patients with inoperable or metastatic HR+/HER2– disease.⁵ However, in a subsequent final OS analysis, the drug did not achieve statistical significance in overall survival versus chemotherapy.⁴ No new safety concerns emerged, and rates of treatment-related adverse events and interstitial lung disease (ILD) remained low. The failure to meet OS in Breast01 underscores the challenges of demonstrating life-extension benefits when subsequent lines of therapy may confound survival.⁴

Because TROPION-Breast01 and TROPION-Breast02 are linked, this underscores the importance of understanding how regulatory decision-makers view surrogate endpoints vs. OS in ADC trials for breast cancer. AstraZeneca has filed a biologics license application for datopotamab deruxtecan in HR+/HER2– metastatic breast cancer, supported by the PFS data from TROPION-Breast01.⁴

The TROPION-Breast02 trial results suggest that datopotamab deruxtecan may establish a new standard for first-line therapy in mTNBC patients who cannot receive immunotherapy by demonstrating an OS benefit compared to chemotherapy. These findings build on the PFS success in the HR+ setting TROPION-Breast01, albeit tempered by the lack of OS statistical significance in that earlier trial. As the oncology field digests the full data, pharmacists will play an essential role in safe implementation, monitoring, formulary decision-making, and patient education.

REFERENCES

1. Dent RA, Cescon DW, Bachelot T, et al. TROPION-Breast02: Datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer. Future Oncol. 2023;19(35):2349-2359. doi:10.2217/fon-2023-0228

2. Datroway demonstrated statistically significant and clinically meaningful improvement in overall survival as 1st-line therapy for patients with metastatic triple-negative breast cancer for whom immunotherapy was not an option in TROPION-Breast02. Astrazeneca.com. Published October 6, 2025. Accessed October 6, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/datroway-improved-os-and-pfs-in-tropion-breast02.html

3. Clinicaltrials.gov. Published 2025. https://clinicaltrials.gov/study/NCT05104866

4. Press Releases. DSI. Published 2023. Accessed October 6, 2025. https://daiichisankyo.us/press-releases/-/article/tropion-breast02-phase-3-trial-of-datopotamab-deruxtecan-initiated-in-patients-with-previously-untreated-metastatic-triple-negative-breast-cancer

5. Aditya Bardia, Jhaveri K, Im SA, 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. Journal of Clinical Oncology. Published online September 12, 2024. doi:10.1200/jco.24.00920