Datopotamab Deruxtecan Wins First-Line FDA Approval for Immunotherapy-Ineligible Triple-Negative Breast Cancer

The FDA has approved datopotamab deruxtecan (Datroway; AstraZeneca/Daiichi Sankyo) as the first trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC) for first-line treatment of adults with unresectable or metastatic triple-negative breast cancer (TNBC) who are not candidates for PD-1 or PD-L1 inhibitor therapy.¹ The approval, granted May 22, 2026, marks the first time a targeted therapy has demonstrated a significant overall survival (OS) advantage over chemotherapy in this difficult-to-treat population, filling a therapeutic void that has persisted for years.

What Makes This Population So Difficult to Treat?

TNBC is defined by the absence of estrogen receptors and progesterone receptors, as well as human epidermal growth factor receptor 2 (HER2) overexpression. This biological profile has historically excluded patients from the hormone- and HER2-targeted treatments that have transformed outcomes in other breast cancer subtypes. TNBC accounts for approximately 15% of all breast cancer diagnoses and disproportionately affects younger and premenopausal women, as well as Black and Hispanic women.¹ In the metastatic setting, median OS with conventional chemotherapy has ranged from 12 to 18 months, and only about 15% of patients survive 5 years following diagnosis.¹

The challenge is compounded by the fact that immunotherapy, which is now a cornerstone for PD-L1–positive metastatic TNBC, is not an option for the approximately 70% of patients whose tumors do not express PD-L1 at sufficient levels or who are otherwise ineligible for immune checkpoint inhibitors.² For this majority, chemotherapy alone has remained the standard of care in the first-line metastatic setting—until now. The January 2025 FDA approval of Datroway for previously treated hormone receptor (HR)-positive, HER2-negative metastatic breast cancer established an early proof of concept for the drug across breast cancer subtypes, but no targeted option had reached regulatory clearance for immunotherapy-ineligible TNBC in the front line.³

What the Phase 3 Data Revealed

The approval was based on results from TROPION-Breast02 (NCT05374512), a global, randomized, open-label phase 3 trial that enrolled 644 patients across 229 centers in 23 countries between May 2022 and June 2024.² Patients with previously untreated, locally recurrent, inoperable, or metastatic TNBC for whom immunotherapy was not an option were randomly assigned 1:1 to receive datopotamab deruxtecan (6 mg/kg intravenously every 3 weeks) or investigator's choice of chemotherapy. The trial included patients regardless of disease-free interval, and notably enrolled patients with brain metastases and early relapsers, which are populations typically excluded from clinical trials and with particularly poor prognoses.

The dual primary end points were progression-free survival (PFS) by blinded independent central review and OS. Median PFS was 10.8 months vs 5.6 months with chemotherapy, representing a 43% reduction in the risk of disease progression or death (HR, 0.57; 99% CI, 0.44-0.73; P < .0001). Median OS reached 23.7 months with datopotamab deruxtecan compared with 18.7 months with chemotherapy, representing a clinically meaningful 5-month improvement (HR, 0.79; 95.01% CI, 0.64-0.98; P = .029). The objective response rate (ORR) with datopotamab deruxtecan was 63%, which is more than double the 29% seen in the chemotherapy arm, and the median duration of response was 12.3 months vs 7.1 months.

The PFS and ORR benefits were consistent across all prespecified patient subgroups. OS was consistent across most subgroups, with the authors noting that heterogeneity observed in the US/Canada/Europe subgroup was likely confounded by imbalances in baseline prognostic characteristics and higher rates of subsequent ADC use in the chemotherapy arm in that region.

On the safety front, treatment-related adverse events (TRAEs) of grade 3 or higher were reported in 33% of Datroway-treated patients vs 29% of those receiving chemotherapy. This marginal difference persisted despite patients in the datopotamab deruxtecan arm remaining on treatment for nearly twice as long (median 8.5 vs 4.1 months). TRAEs led to discontinuation in just 4% of datopotamab deruxtecan–treated patients compared with 7% in the chemotherapy arm, and there were no treatment-related deaths in either group. The most common TRAEs with datopotamab deruxtecan were mostly grade 1 or 2 and generally manageable and included stomatitis, nausea, and alopecia.

References

1. 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. News release. AstraZeneca. May 22, 2026. Accessed May 22, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/datroway-approved-in-us-for-1l-triple-negative-bc.html
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
3. Steinzor P. FDA approves datopotamab deruxtecan for HR-positive/HER2-negative metastatic breast cancer. AJMC^®. January 17, 2025. Accessed May 22, 2026. https://www.ajmc.com/view/fda-approves-datopotamab-deruxtecan-for-hr-positive-her2-negative-metastatic-breast-cancer