AstraZeneca breast cancer drug splits EU and US regulators: divergent advisory votes leave clinicians watching
Datopotamab deruxtecan (Datroway), developed jointly by AstraZeneca and Daiichi Sankyo, has produced a rare disagreement between regulators over its use in HER2-low breast cancer. The European Medicines Agency's human-use committee (CHMP) issued a positive opinion on Thursday, while the US Food and Drug Administration's Oncology Drug Advisory Committee (ODAC) voted 6-2 against approval for the same indication. The FDA's formal decision is due by 14 July.
Datopotamab deruxtecan is a TROP2-directed antibody-drug conjugate (ADC). It is under review in patients with HER2-low (i.e. HER2 IHC 1+ or IHC 2+/FISH-negative) and hormone-positive metastatic breast cancer who have already received two or more prior treatment regimens. The TROPION-Breast01 Phase 3 trial showed an overall survival of 18.6 months versus 18.3 months for chemotherapy comparator arm, and a progression-free survival of 6.9 versus 4.9 months.
The FDA ODAC's 6-of-8 vote against approval centred on a discrepancy between blinded independent committee review of tumour assessments and investigator assessments in the Phase 3, together with the absence of statistically significant overall survival benefit. ODAC member Dr Daniel Spratt of University Hospitals Seidman Cancer Center in Cleveland said: 'We cannot conclude on overall survival without seeing the meta-analysis, and the risk-benefit balance in this case is less clear.' One of the two yes votes, Dr Christopher Lieu of the University of Colorado Cancer Center, cited the heavier side-effect profile of the chemotherapy comparator arm.
The CHMP read the same data differently. Despite working from identical trial results, the committee weighed the roughly two-month progression-free survival advantage and favourable quality-of-life signals and issued a positive opinion. CHMP vice-chair Dr Bruno Sepodes explained: 'Treatment options for these patients are limited; the risk-benefit balance is positive.' The European Commission's formal authorisation typically follows the CHMP opinion by about 67 days, suggesting an end-of-July decision.
From AstraZeneca, oncology unit head Dr Susan Galbraith addressed the regulator divergence by saying that the two agencies are 'reading the statistical results through different frames'. The company also outlined a plan to submit further Phase 3 data should the FDA decision be unfavourable; the TROPION-Breast02 and -Breast05 trials are expected to read out at the end of 2026 and early 2027.
Breast cancer specialists say the regulatory split risks creating confusion in the clinic. Dr Sara Tolaney of Dana-Farber Cancer Institute told STAT News: 'A drug that's available in Europe but not in the US makes patient referral and clinical-trial enrolment more complicated.'
The financial stakes are material. AstraZeneca's ADC portfolio is led by trastuzumab deruxtecan (Enhertu), which generated $3.8 billion in sales in 2024 in the HER2-positive indication. Datopotamab deruxtecan's HER2-low indication is forecast to add $1.5-2.0 billion in annual sales; a US rejection would block much of that potential.
The regulatory split also raises a broader question: how should new ADC indications be evaluated against Phase 3 endpoints? Over the past two years the FDA has applied a tighter standard to ADC approvals showing 'improved but non-dramatic' survival benefit, a pattern also visible in the sacituzumab tirumotecan decision for occipital-lobe cancer. SVB Securities sector analyst Andrew Berens said: 'The Phase 3 bar for the ADC class is rising — Europe takes a more flexible read; the US is tighter.'
For patients, the practical question is what changes now. Datroway is currently available in the United States under accelerated approval for HER2-positive disease and for hormone-negative HER2-low disease; this week's discussion concerned the expanded indication. Hormone-positive HER2-low patients in the United States will continue with the current standard of care, T-DXd (Enhertu); in Europe, Datroway will become an alternative.
Breast cancer specialists will watch the FDA's formal 14 July decision. ODAC recommendations are not binding; the FDA approved drugs over negative ODAC votes on three occasions in early 2025. But given the data sit right at the statistical boundary, sector consensus expects the FDA to follow ODAC. Either way, this case is a meaningful test for how Phase 3 evidence is harmonised across regulators for third-generation ADCs.
*This article is not medical advice. Always discuss treatment options with your oncology specialist.*