Background
Phase 3, global, open-label, randomized. Inoperable/metastatic HR+/HER2- breast cancer, progression on endocrine therapy and 1-2 prior chemo lines in the advanced setting. Datopotamab deruxtecan (Dato-DXd) is a TROP2-directed ADC with a topoisomerase I inhibitor payload. N=732 (Dato-DXd 365 vs ICC 367).
Results
Interventions and follow up: Arm A: datopotamab deruxtecan 6 mg/kg IV q3wk (n=365).
Arm B: investigator's choice chemotherapy — eribulin, vinorelbine, capecitabine, or gemcitabine (n=367).
Primary endpoint: dual primary PFS by BICR and OS.
mFollow up: 10.8 mo at primary PFS analysis.
Results: PFS (BICR): 6.9 vs 4.9 mo, HR 0.63, 95% CI 0.52–0.76, P<.001 (favors Dato-DXd); consistent across subgroups.
ORR: 36.4% vs 22.9%.
OS (immature, primary analysis): HR 0.84, 95% CI 0.62–1.14 (trend, NS).
OS (final, Ann Oncol 2025): 18.6 vs 18.3 mo, HR 1.01, 95% CI 0.83–1.22, P=.94 (NOT significant).
Arm B: investigator's choice chemotherapy — eribulin, vinorelbine, capecitabine, or gemcitabine (n=367).
Primary endpoint: dual primary PFS by BICR and OS.
mFollow up: 10.8 mo at primary PFS analysis.
Results: PFS (BICR): 6.9 vs 4.9 mo, HR 0.63, 95% CI 0.52–0.76, P<.001 (favors Dato-DXd); consistent across subgroups.
ORR: 36.4% vs 22.9%.
OS (immature, primary analysis): HR 0.84, 95% CI 0.62–1.14 (trend, NS).
OS (final, Ann Oncol 2025): 18.6 vs 18.3 mo, HR 1.01, 95% CI 0.83–1.22, P=.94 (NOT significant).
Adverse events
Grade ≥3 TRAEs: 20.8% (Dato-DXd) vs 44.7% (ICC).
Dato-DXd most common (any grade): nausea 51.1% (grade ≥3 1.4%), stomatitis 50% (grade ≥3 6.4%); ocular surface events mostly low grade.
Dato-DXd ILD: adjudicated drug-related ~3%, mostly low grade.
ICC: grade ≥3 neutropenia 30.8%.
Dato-DXd most common (any grade): nausea 51.1% (grade ≥3 1.4%), stomatitis 50% (grade ≥3 6.4%); ocular surface events mostly low grade.
Dato-DXd ILD: adjudicated drug-related ~3%, mostly low grade.
ICC: grade ≥3 neutropenia 30.8%.
Conclusions
Dato-DXd produced a statistically significant, clinically meaningful PFS improvement over investigator's choice chemotherapy with a more favorable grade ≥3 toxicity profile in pretreated HR+/HER2- mBC. However, the final OS analysis was negative (HR 1.01), so the PFS gain did not translate into a survival benefit.
Key Limitations
The PFS gain was modest in absolute terms (~2 mo) and did not yield an OS benefit; final OS curves were essentially superimposed. Open-label design plus imbalanced subsequent ADC use (12.3% Dato-DXd vs 24.0% ICC) confounds the OS data. Distinctive toxicities (stomatitis, ocular surface events, ILD) require active monitoring and supportive management.
Clinical Context
Supported FDA approval (Jan 2025) of datopotamab deruxtecan for pretreated HR+/HER2- metastatic breast cancer, on the PFS endpoint. Adds a TROP2-directed ADC to a crowded later-line landscape that includes sacituzumab govitecan and, for HER2-low, trastuzumab deruxtecan; ESMO/ASCO position ADC sequencing here as evolving. The PFS-versus-OS discordance, driven by crossover and subsequent ADC use, tempers enthusiasm, though the gentler toxicity vs chemotherapy is a practical advantage.