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.
Pages like this
not linked directly; found by shared links- Key paperDESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group
Shares Seock-Ah Im, Binghe Xu, Immunohistochemistry (IHC), Payload-class switching as the rule for ADC sequencing.
- Key paperDESTINY-Breast06: trastuzumab deruxtecan before any chemotherapy in hormone-receptor-positive, HER2-low or ultralow breast cancer
Shares Carlos Barrios, Seock-Ah Im, Immunohistochemistry (IHC), Daiichi Sankyo.
- Key paperDESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer
Shares Seock-Ah Im, Binghe Xu, Payload-class switching as the rule for ADC sequencing, ADC sequencing.
- RoadmapTROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET
Shares TROPION-Breast01, TROPION-Breast02, TROP2 PET to choose and sequence TROP2 ADCs, ADC sequencing.
- IdeaUse SLFN11 status to decide which antibody-drug payload to give next
Shares Payload-class switching as the rule for ADC sequencing, ADC sequencing, Topoisomerase-I inhibitors (and ADC payloads), Biomarkers are not validated or standardised.
- PersonSara M. Tolaney
Shares TROPION-Breast01, Datopotamab deruxtecan, TROP2, Antibody-drug conjugate (ADC).
- PairingCaution: TOP1 ADC immediately after TOP1 ADC
Shares Payload-class switching as the rule for ADC sequencing, ADC sequencing, Datopotamab deruxtecan, HR-positive / HER2-negative breast cancer.
- TechnologyTROP2 PET
Shares TROP2 PET to choose and sequence TROP2 ADCs, Datopotamab deruxtecan, TROP2, Biomarkers are not validated or standardised.