The recent FDA approval of datopotamab deruxtecan (Datroway®; Daiichi Sankyo and AstraZeneca) introduces the first TROP2-directed antibody-drug conjugate (ADC) for adults with unresectable or metastatic triple-negative breast cancer (mTNBC) who are not candidates for PD-1/PD-L1 inhibitor therapy. This article reviews the pivotal TROPION-Breast02 phase 3 trial results, clinical implications, safety profile, and the potential of Datroway to become a new standard of care in this challenging patient population.
Triple-negative breast cancer (TNBC) is an aggressive subtype, representing approximately 15% of all breast cancer cases, and is characterized by the absence of estrogen and progesterone receptors, as well as HER2 expression. Patients diagnosed with mTNBC who are ineligible for immunotherapy have faced limited treatment options, with chemotherapy as the historical first-line standard. The approval of datopotamab deruxtecan, a TROP2-directed ADC, marks a significant therapeutic advance.
FDA Approval and Indication
On May 22, 2026, the U.S. Food and Drug Administration (FDA) approved datopotamab deruxtecan for adult patients with unresectable or mTNBC who are not candidates for PD-1/PD-L1 inhibitor therapy. The approval follows Priority Review by the U.S. Food and Drug Administration (FDA) based on results from the TROPION-Breast02 phase 3 trial, which were presented at the 2025 European Society for Medical Oncology Congress (ESMO) and published in Annals of Oncology.[1]
Datopotamab deruxtecan is the first agent in this setting to demonstrate a statistically significant survival advantage over chemotherapy, offering new hope to a population with historically poor outcomes.
Datopotamab deruxtecan is a specifically engineered ADC targeting TROP2, a protein broadly expressed in solid tumors and associated with poor prognosis in breast cancer. The molecule consists of a humanized anti-TROP2 IgG1 monoclonal antibody, conjugated via a cleavable tetrapeptide linker to a topoisomerase I inhibitor payload (DXd). Upon binding to TROP2-expressing tumor cells, Datroway is internalized, releasing the cytotoxic payload and inducing cell death.
Efficacy: TROPION-Breast02 Phase 3 Trial
The approval of datopotamab deruxtecan was based on data from the global, multicenter, randomized, open-label phase 3 TROPION-Breast02 trial (NCT07092254), which enrolled 644 patients with previously untreated, locally recurrent inoperable or mTNBC, ineligible for immunotherapy. Patients were randomized to receive datopotamab deruxtecan (6 mg/kg) or the investigator’s choice of chemotherapy.
- Overall Survival (OS): Datroway significantly improved median OS to 23.7 months compared to 18.7 months with chemotherapy (hazard ratio [HR]=0.79; 95% CI: 0.64–0.98; p=0.0290).
- Progression-Free Survival (PFS): Median PFS was 10.8 months with Datroway versus 5.6 months for chemotherapy (HR=0.57; 95% CI: 0.47–0.69; p<0.0001), representing a 43% reduction in risk of progression or death.
- Objective Response Rate (ORR): Datroway achieved an ORR of 64%, more than double the 30% observed with chemotherapy.
These results represent the first demonstration that a TROP2-directed ADC prolongs overall survival compared with chemotherapy in this patient population.
Safety Profile
The safety of datopotamab deruxtecan (6 mg/kg every 3 weeks) was evaluated in 319 patients with TNBC in TROPION-Breast02. The most common adverse reactions (≥20%) included stomatitis, increased amylase, nausea, alopecia, decreased hemoglobin and white blood cells, constipation, decreased calcium and lymphocytes, fatigue, decreased neutrophils, elevated transaminases, dry eye, keratitis, decreased albumin, vomiting, musculoskeletal pain, decreased sodium, and increased blood alkaline phosphatase.
Serious adverse reactions occurred in 17% of patients, with the most frequent being pneumonia, vomiting, COVID-19, and anemia. One patient fatality was attributed to interstitial lung disease/pneumonitis. Ocular adverse reactions, stomatitis, and embryo-fetal toxicity were also observed and are highlighted in the prescribing information. Monitoring and management strategies are recommended for these events.
Clinical Implications and Guidelines
The unprecedented median OS of nearly two years with datopotamab deruxtecan, together with its significant PFS and ORR benefits, positions it as a potential new standard of care for first-line treatment of mTNBC patients ineligible for immunotherapy.
Datopotamab deruxtecan is now included as a Category 1 Preferred first-line option in the NCCN Clinical Practice Guidelines in Oncology for this population.
Patient Population and Unmet Need
Metastatic TNBC accounts for approximately 15% of all breast cancer cases, with an estimated 345,000 diagnoses globally each year.[2][3] TNBC is diagnosed more frequently in younger and premenopausal women, and is more prevalent in Black and Hispanic women.[4][5][6] mTNBC is the most aggressive type of breast cancer and has one of the worst prognoses, with median OS of just 12 to 18 months and only about 14% of patients living five years following diagnosis.[4][7][8]
While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of HER2, TNBC tests negative for all three.3 Due to its aggressive nature and absence of common breast cancer receptors, TNBC is characteristically difficult to treat.3 For patients with metastatic disease with PD-L1-expressing tumors, the addition of immunotherapy to chemotherapy has improved outcomes in the first-line setting.[9][10] However, for approximately 70% of patients with metastatic TNBC who are not candidates for immunotherapy, chemotherapy remains the first-line standard of care.[11][12] TROP2 is a protein broadly expressed in several solid tumors, including TNBC.[13] TROP2 is associated with increased tumor progression and poor survival in patients with breast cancer.[14][15]
Ongoing and Future Research
Datopotamab deruxtecan is being studied in more than 20 clinical trials across multiple tumor types, including NSCLC, TNBC, and urothelial cancer, both as monotherapy and in combination regimens. The robust clinical development program includes several phase 3 studies in breast and lung cancer, with a focus on expanding Datroway’s role across disease stages and settings.
Datopotamab deruxtecan represents a major advance in the first-line management of mTNBC for patients ineligible for immunotherapy, offering unprecedented survival and response benefits. Its approval establishes a new therapeutic paradigm for this challenging disease and underscores the evolving promise of antibody-drug conjugates in oncology.
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Clinical Trials
Patterns of Care and Outcomes in Locally Recurrent Inoperable or Metastatic Triple-Negative Breast Cancer
ClinicalTrials.gov ID NCT07092254
Highlights of Prescribing Information
Datopotamab deruxtecan (Datroway®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Reference
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