# DESTINY-Breast04

Source: https://onco.cc/trials/destiny-breast04/  
OnCo record `destiny-breast04` (Trial). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Created a new category of breast cancer, HER2-low, by showing Enhertu works in tumours previously called HER2-negative.

## Summary

DESTINY-Breast04, trial NCT03734029 sponsored by Daiichi Sankyo and AstraZeneca and published in the New England Journal of Medicine in 2022, created a new category of breast cancer, HER2-low, by showing that trastuzumab deruxtecan works in tumours previously called HER2-negative after chemotherapy. It randomised 557 patients to trastuzumab deruxtecan or chemotherapy, met its primary progression-free survival endpoint in the HR-positive cohort and showed an overall survival benefit in all patients, with an exploratory HR-negative cohort pointing the same way, and it drew a standing ovation at ASCO 2022 as roughly half of all breast cancers became eligible for a HER2-directed drug. Whether pathologists can score HER2-low reproducibly is the open question.

## Fields

- Kind: Trial
- Status: positive
- Last checked: 2026-09-04
- Registry id: NCT03734029
- Phase: 3
- Setting: HER2-low metastatic breast cancer after chemotherapy: T-DXd vs chemotherapy
- Sponsor: Daiichi Sankyo / AstraZeneca
- Enrolled: 557
- Result: OS HR 0.64.
- Outcomes: Progression-free survival, HR+ cohort (BICR): Trastuzumab deruxtecan 10.1 months vs Chemotherapy (TPC) 5.4 months, HR 0.51; Overall survival, all patients: Trastuzumab deruxtecan 23.4 months vs Chemotherapy (TPC) 16.8 months, HR 0.64; Progression-free survival, HR-negative (TNBC) cohort: Trastuzumab deruxtecan 8.5 months vs Chemotherapy (TPC) 2.9 months, HR 0.46
- Replication: Confirmed and extended by DESTINY-Breast06 (HER2-low and ultralow, chemotherapy-naive) with a near-identical PFS hazard ratio.

## Notes

- Triple-negative cohort: 63 of 557 patients (11.3 percent) were hormone-receptor-negative; median progression-free survival in that exploratory cohort 8.5 versus 2.9 months (hazard ratio 0.46) and overall survival favoured trastuzumab deruxtecan at the 32-month follow-up (Nature Medicine 2025: overall cohort 22.9 versus 16.8 months, hazard ratio 0.69). Interstitial lung disease 12.1 percent, 0.8 percent fatal. UK sites (registry, 7): Royal Cornwall Truro, Queen Mary University of London, University College London Hospitals, Royal Free, Western General Edinburgh, Nottingham City, Royal Surrey Guildford. England: NICE TA992 (29 July 2024) does not recommend the drug for HER2-low disease; rapid review GID-TA12551 in development.

## Sources

- ClinicalTrials.gov NCT03734029: https://clinicaltrials.gov/study/NCT03734029
- DESTINY-Breast04 long-term survival (Nature Medicine 2025): https://doi.org/10.1038/s41591-025-03981-4
- NICE TA992 (29 July 2024): not recommended: https://www.nice.org.uk/guidance/ta992

## Connected records

- cancers: [HER2-low and HER2-ultralow metastatic breast cancer](https://onco.cc/cancers/her2-low-metastatic-breast-cancer/), [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Metastatic triple-negative breast cancer](https://onco.cc/cancers/tnbc-metastatic/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Topoisomerase-I inhibitors (and ADC payloads)](https://onco.cc/technologies/topoisomerase-inhibitors/)
- drugs: [Eribulin](https://onco.cc/drugs/eribulin/), [HER2 IHC and ISH companion assays (HercepTest, PATHWAY 4B5, HER2 Dual ISH)](https://onco.cc/drugs/her2-testing-assays/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/)
- companies: [AstraZeneca](https://onco.cc/companies/astrazeneca/), [Daiichi Sankyo](https://onco.cc/companies/daiichi-sankyo/)
- terms: [Control arm and comparator (investigator's choice)](https://onco.cc/terms/control-arm/), [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/), [HER2-low eligibility for trastuzumab deruxtecan, and TROP2 ADCs without a test (triple-negative disease)](https://onco.cc/terms/her2-low-and-trop2-adc-eligibility-tnbc/), [Palliation in advanced triple-negative breast cancer: brain, bone, pleura, skin and end of life](https://onco.cc/terms/tnbc-symptom-control-palliation/)
- people: [Shanu Modi](https://onco.cc/people/shanu-modi/)
- key papers: [Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer](https://onco.cc/key-papers/paper-schettini-her2-low-features-npj-breast-cancer-2021/), [DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group](https://onco.cc/key-papers/paper-destiny-breast04-nejm-2022/), [Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial](https://onco.cc/key-papers/paper-destiny-breast04-nat-med-2025-update/)
- roadmaps: [ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs](https://onco.cc/roadmaps/adc-generations/), [TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line](https://onco.cc/roadmaps/tnbc-history/), [Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem](https://onco.cc/roadmaps/tnbc-roadmap/)
- ideas: [A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer](https://onco.cc/ideas/idea-tnbc-adc-sequencing-trial/), [AI quantification of HER2-low and HER2-ultralow](https://onco.cc/ideas/idea-ai-her2-low-scoring/), [Calibrated reference slides so every lab scores HER2-low the same way](https://onco.cc/ideas/idea-tr2-her2-low-reference-materials/), [Reflex re-scoring of HER2 0 versus 1+ with digital assistance so every eligible triple-negative patient reaches trastuzumab deruxtecan](https://onco.cc/ideas/idea-tnbc-her2-ultralow-testing-uptake/)
- pairings: [HER2-low scoring → T-DXd](https://onco.cc/pairings/her2-low-to-tdxd/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/)

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