TROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival
The TROP2-directed antibody-drug conjugate Dato-DXd delayed progression by about two months compared with chemotherapy, but patients did not live longer, which stalled its approval in breast cancer.
Open-label phase 3 trial of 732 patients with hormone-receptor-positive, HER2-negative metastatic breast cancer after one or two lines of chemotherapy, randomised to datopotamab deruxtecan (Dato-DXd, 6 mg/kg) or investigator's choice chemotherapy (eribulin, vinorelbine, capecitabine or gemcitabine). Dual primary endpoints were PFS by blinded review and overall survival.
PFS was improved (6.9 vs 4.9 months, HR 0.63) with fewer high-grade adverse events, but the final overall survival analysis showed no difference. The trial is a cautionary example that a TROP2 ADC can beat chemotherapy on PFS in an unselected population without changing survival.
- Median PFS by blinded central review 6.9 vs 4.9 months; HR 0.63 (95% CI 0.52-0.76).
- Objective response rate 36.4% vs 22.9%.
- Grade 3 or higher treatment-related adverse events about 21% vs 45%; stomatitis and ocular surface events were the characteristic Dato-DXd toxicities.
- Final overall survival analysis (2024): no significant difference (HR close to 1.0).
- TROP2 expression by immunohistochemistry did not select responders.
For hormone-receptor-positive metastatic breast cancer that has already had chemotherapy, Dato-DXd controls the disease for longer with fewer severe side effects than chemotherapy, but does not help patients live longer, so it is not a standard option here. The result is a reminder that progression-free survival is a surrogate; regulators and clinicians should wait for survival data before adopting an ADC in a setting where later therapies are effective.
- Open-label; PFS assessed by blinded review but subsequent therapy was at physician discretion.
- Post-progression therapy, including other ADCs, likely diluted any survival effect.
- The population was chemotherapy-pretreated and heterogeneous; a first-line or biomarker-selected trial might behave differently.
- Immunohistochemistry for TROP2 was not predictive, leaving no validated way to choose patients.