FDA Approves Datopotamab Deruxtecan for TNBC

The FDA has approved the antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd; Datroway) for adult patients with unresectable or metastatic triple-negative breast cancer (TNBC) who are not candidates for PD-1/PD-L1 inhibitor therapy.¹

The approval of the TROP2-directed ADC is supported by results from the phase 3 TROPION-Breast02 trial in which datopotamab deruxtecan met both co-primary endpoints, delivering statistically significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) versus investigator's choice of chemotherapy (paclitaxel, nab-paclitaxel, capecitabine, carboplatin, or eribulin).

The median OS was 23.7 months with Dato-DXd compared with 18.7 months with chemotherapy, a 5.0-month improvement translating to a 21% reduction in the risk of death (HR, 0.79; 95% CI, 0.64-0.98; P = .0290).² The PFS benefit was more pronounced: median PFS by blinded independent central review (BICR) was 10.84 months (95% CI, 8.57-12.98) with Dato-DXd vs 5.55 months (95% CI, 4.96-6.97) with chemotherapy—a difference of approximately 5.3 months, representing a 43% reduction in the risk of progression or death (HR, 0.57; 95% CI, 0.47-0.69; P < .0001). Investigator-assessed PFS (HR, 0.56) was consistent with the BICR result, strengthening confidence in the primary finding. At 12 months, the PFS rate was 46% with Dato-DXd vs 26% with chemotherapy; at 18 months, 33% vs 17%.

Response outcomes also strongly favored the ADC. The confirmed objective response rate (ORR) was 64% with Dato-DXd vs 30% with chemotherapy. The median duration of response was 12.3 months with datopotamab deruxtecan compared with 7.1 months with chemotherapy.²

PFS and ORR improvements were consistent across all prespecified subgroups, including by PD-L1 status, geographic region, disease-free interval, HER2 expression level, presence of liver metastases, and presence of brain metastases. Approximately one-third of enrolled patients had de novo metastatic disease, and 15% had a disease-free interval of 0 to 6 months, a subgroup historically excluded from trials and known to carry particularly poor outcomes.

“Datopotamab deruxtecan is the first and only medicine to significantly prolong overall survival in the 1st-line setting compared to chemotherapy in patients with metastatic triple-negative breast cancer who are not candidates for immunotherapy. This approval will bring a much-needed treatment option for these patients,” Tiffany A. Traina, MD, FASCO, section head, Triple-Negative Breast Cancer Clinical Research Program, Memorial Sloan Kettering Cancer Centre and investigator for TROPION-Breast02, stated in a news release.¹

Safety in TROPION-Breast02

Among 319 safety-evaluable patients in the Dato-DXd arm, 93% experienced any-grade treatment-related adverse events (TRAEs) and 33% had grade 3 or higher TRAEs, which was comparable to the 29% rate of grade 3 or higher TRAEs observed in the chemotherapy arm, despite a median treatment duration for Dato-DXd that exceeded double that of chemotherapy. Discontinuation due to TRAEs was lower with datopotamab deruxtecan (4%) than chemotherapy (7%).²

The most common any-grade TRAEs with Dato-DXd included stomatitis (57%), nausea (45%), dry eye (24%), constipation (23%), vomiting (20%), and decreased appetite (15%). These events reflect TROP2 expression on normal tissues including the oral mucosa, esophagus, stomach, and corneal epithelium. The most notable grade 3 or higher TRAEs with datopotamab deruxtecan versus chemotherapy were neutropenia (3% vs 13%), stomatitis (8% vs 0%), fatigue (3% vs 3%), anemia (2% vs 3%), and vomiting (1% vs <1%). Interstitial lung disease (ILD) and ocular surface events were generally low grade and manageable. One grade 5 ILD event was adjudicated as drug-related by an independent committee; however, the treating investigator attributed that patient's cause of death to disease progression.

Trial Design and Patient Population

TROPION-Breast02 was a global, multicenter, randomized, open-label Phase 3 trial that enrolled 644 patients across 229 centers in 23 countries between May 2022 and June 2024. Patients were randomized 1:1 to Dato-DXd 6 mg/kg intravenously every 3 weeks or investigator's choice chemotherapy, stratified by geographic location, PD-L1 status, and disease-free interval history (de novo vs DFI 0–12 months vs DFI >12 months). Eligible patients were adults with an ECOG performance status of 0 or 1, histologically or cytologically confirmed locally recurrent inoperable or metastatic TNBC, no prior systemic therapy in the metastatic setting, and at least one measurable lesion per RECIST v1.1. The trial included patients with poor prognostic features such as de novo disease, short disease-free intervals, and stable brain metastases.

Based on TROPION-Breast02 results, datopotamab deruxtecan has been designated a Category 1 Preferred first-line option in the NCCN Clinical Practice Guidelines for patients with metastatic TNBC ineligible for immunotherapy.

"For 7 out of 10 patients with metastatic triple-negative breast cancer who are not candidates for immunotherapy, chemotherapy has remained the only treatment option. Today's approval of [Dato-DXd] means that for the first time, these patients will have a new standard of care beyond traditional chemotherapy at the outset of their treatment," Arlene Brothers, executive director of the Triple Negative Breast Cancer Foundation, stated in the news release.¹

REFERENCES

1. AstraZeneca. Datroway approved in the US as first TROP2-directed antibody drug conjugate for 1st-line treatment of patients with metastatic triple-negative breast cancer who are not PD-1/PD-L1 inhibitor candidates. Press release. May 22, 2026. Accessed May 22, 2026. https://tinyurl.com/5y8vbvz5

2. Dent R, Shao Z, Schmid P, et al. Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial. Ann Oncol. Published online April 3, 2026. doi:10.1016/j.annonc.2026.03.008