First-line datopotamab deruxtecan (Dato-DXd) not only improved survival outcomes vs chemotherapy but also delivered sustained quality-of-life benefits (QoL) for patients with locally recurrent, inoperable, or metastatic triple-negative breast cancer (TNBC) who were not candidates for immunotherapy in the TROPION-Breast02 study.

Compared with chemotherapy, Dato-DXd delayed deterioration in global health status (GHS)/QoL, physical functioning, pain, and breast and arm symptoms, while patient-reported adverse events were generally manageable in the phase 3 trial.

The new patient-reported outcome (PRO) data from the trial “further support Dato-DXd as a potential new first-line standard of care” in patients with locally recurrent, inoperable, or metastatic TNBC who aren’t candidates for immunotherapy, said Peter Schmid, MD, PhD, of Barts Cancer Institute, Queen Mary University of London in England, while presenting the study results at ESMO Breast Cancer 2026.

Longer Time Spent Well 

Dato-DXd is a TROP2-directed antibody-drug conjugate jointly developed by AstraZeneca and Daiichi Sankyo. 

TROPION-Breast02 was a randomized, global phase 3 trial evaluating Dato-DXd against the investigator’s choice chemotherapy in patients with unresectable, locally recurrent, or metastatic TNBC who had not received prior systemic therapy in the advanced setting and for whom immunotherapy was not considered an option. 

A total of 644 patients were randomly assigned (1:1) to receive either Dato-DXd or chemotherapy (paclitaxel, nab-paclitaxel, capecitabine, eribulin, or carboplatin). None had received prior chemotherapy or targeted systemic therapy in the metastatic setting and had an ECOG Performance Status of 0-1.

Earlier efficacy results, reported previously by Medscape Medical News, showed statistically significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) with Dato-DXd compared with chemotherapy.

Median OS was 23.7 months with Dato-DXd vs 18.7 months with chemotherapy (hazard ratio [HR], 0.79; P = .0291), while median PFS by blinded independent central review was 10.8 months vs 5.6 months, respectively (HR, 0.57; P < .0001).

Despite more than double the median treatment duration time (8.5 vs 4.1 months), rates of grade ≥ 3 and serious treatment-related adverse events were similar, and discontinuations were lower with Dato-DXd vs chemotherapy, noted Schmid.

Based on the TROPION-Breast02 efficacy results, the US FDA granted Dato-DXd priority review as a first-line treatment of patients with unresectable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy. 

As part of the trial, PROs — including how treatment affected symptoms, physical functioning, and QoL — were assessed at baseline and throughout the study using validated electronic PRO questionnaires. 

Across key secondary PRO endpoints, Dato-DXd consistently delayed worsening of symptoms and functioning compared with chemotherapy, Schmid reported. 

Median time to first deterioration in GHS/QoL was 23.5 months with Dato-DXd vs 8.3 months with chemotherapy (HR, 0.64). For confirmed deterioration, the median was not calculable with Dato-DXd and was 29.0 months with chemotherapy (HR, 0.61). 

Median time to deterioration in physical functioning was 10.4 months with Dato-DXd vs 4.1 months with chemotherapy (HR, 0.67), with confirmed deterioration at 24.9 months vs 9.0 months (HR, 0.59). 

Dato-DXd also showed numerically greater improvements from baseline on separate QoL and functioning scales, as well as in pain, breast symptoms, and arm symptoms, than chemotherapy.

Patient-reported symptomatic adverse events were generally consistent with clinician-reported safety findings from the primary analysis. Compared with chemotherapy, fewer patients receiving Dato-DXd reported any abdominal pain, shortness of breath, hair loss, numbness or tingling, and general pain, although higher rates of dry mouth, vomiting, constipation, fatigue, and dry eye were reported.

Interference with daily activities was limited for both treatments, with most patients describing side effects as “not at all” or “a little bit” bothersome, Schmid said.

Early Supportive Care Key

Study discussant Ines Vaz-Luis, MD, PhD, said the TROPION-Breast02 results are particularly meaningful in an increasingly crowded treatment landscape because they demonstrate not only longer OS but also “better-lived time” for patients. 

“In a crowded therapy landscape, efficacy is only the first anchor — does it add time. The second anchor is better-lived time — does it preserve how patients feel and function,” commented Vaz-Luis, who is a medical oncologist at Gustave Roussy and the University of Paris-Saclay in Villejuif, France.

The OS benefit seen with Dato-DXd is a “milestone for our patients” who are not candidates for immunotherapy, Vaz-Luis said.

She noted that while QoL was maintained with Dato-DXd, the toxicity profile shifts from the traditional chemotherapy-related burden of neutropenia and peripheral neuropathy toward antibody-drug conjugate-specific adverse events such as stomatitis, dry eye, and nausea, with interstitial lung disease/pneumonitis remaining a rare but serious risk. 

Vaz-Luis said the PRO data underscore the importance of early and proactive supportive care beginning on “day one” of treatment, including oral and eye care, strong nausea prevention, and rapid evaluation of respiratory symptoms.

The study was funded by AstraZeneca and Daiichi Sankyo. Disclosures for study authors are available with the original presentation materials. Vaz-Luis reported having relationships with Amgen, AstraZeneca, Pfizer/Edimark, Novartis, Sandoz, Chugai Pharmaceutical, Servier Monde, the Servier International Research Institute, and Doctaforum Medical Marketing Specialists.