The Absolute Effect / Evidence / Breast Cancer
DESTINY-Breast04
Clinical question: In previously treated HER2-low metastatic breast cancer, does trastuzumab deruxtecan improve PFS and OS compared with physician's-choice chemotherapy?
Registry: NCT03734029 · One underlying study; aliases and follow-up publications consolidated.
Design, population and eligibility
International, open-label, randomized phase III trial; 2:1 allocation to trastuzumab deruxtecan or physician's-choice chemotherapy.
557 patients randomized: 373 trastuzumab deruxtecan and 184 physician's-choice chemotherapy. 494 had HR-positive and 63 HR-negative disease.
Unresectable/metastatic HER2-low breast cancer (IHC 1+ or IHC 2+/ISH-negative) previously treated with one or two lines of chemotherapy in the metastatic setting; prior chemotherapy in the neoadjuvant/adjuvant setting was also relevant to eligibility.
Primary analysis followed by extended survival analysis at median 32.0 months.
Treatment and comparator
Trastuzumab deruxtecan 5.4 mg/kg IV every 3 weeks versus physician's-choice chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) until progression or unacceptable toxicity.
Primary and secondary endpoints
Primary endpoints: PFS by blinded independent central review and OS in the HR-positive cohort; key secondary endpoints included PFS and OS in the overall population, response and safety.
Key efficacy results
In the HR-positive cohort, median PFS was 10.1 versus 5.4 months (HR 0.51; 95% CI 0.40–0.64) and primary-analysis median OS 23.9 versus 17.5 months (HR 0.64; 95% CI 0.48–0.86; p=0.003). In the overall population, median PFS was 9.9 versus 5.1 months (HR 0.50; 95% CI 0.40–0.63) and OS 23.4 versus 16.8 months (HR 0.64; 95% CI 0.49–0.84).
At extended follow-up of 32 months, overall median OS was 22.9 versus 16.8 months (HR 0.69; 95% CI 0.55–0.86); in HR-positive disease, 23.9 versus 17.6 months (HR 0.69; 95% CI 0.55–0.87).
Source-reported outcome visualization
Median PFS and OS in HR-positive cohort / overall cohort; scaled within each pair.
Bars compare reported medians, not fixed-time event-free probabilities. No NNT is calculated from median survival.
Absolute effect
Median PFS and OS differences are clinically meaningful but cannot be converted into NNT. No fixed-time absolute survival NNT is assigned here because the selected published landmark rates are not consistently reported for the same prespecified population and analysis cut-off.
Trial-specific toxicity and treatment burden
Grade ≥3 adverse events occurred in 52.6% with trastuzumab deruxtecan versus 67.4% with chemotherapy in the primary analysis. Drug-related interstitial lung disease/pneumonitis occurred in 12.1%, including fatal events (0.8%). Nausea, fatigue, alopecia, anaemia and neutropenia were common. Treatment discontinuation for adverse events was more frequent with trastuzumab deruxtecan; ILD surveillance and early corticosteroid management are essential.
Quality of life and patient-reported outcomes
Time to deterioration in global health status/QoL favoured trastuzumab deruxtecan over chemotherapy in the primary report. This benefit must be weighed against the distinct ILD risk and need for ongoing monitoring.
Subgroups and applicability
Benefit was observed in HR-positive and HR-negative cohorts, although the HR-negative subgroup was small (n=63) and estimates are less precise. Efficacy was consistent across HER2 IHC 1+ and IHC 2+/ISH-negative groups and exploratory prior CDK4/6 inhibitor subgroups.
Current-practice context · reviewed 2 November 2026
Trastuzumab deruxtecan is an established option after prior chemotherapy for HER2-low metastatic breast cancer. The 2025 extended survival analysis confirms durable OS benefit. Earlier-line endocrine-resistant HER2-low/ultralow sequencing has also evolved (e.g. DESTINY-Breast06), so the exact place in sequence depends on prior therapy, HER2 expression, HR status and current local approvals.
Limitations and critical interpretation
HER2-low is an immunohistochemistry-defined category with interobserver variability, especially around IHC 0 versus 1+. HR-negative numbers were small. ILD/pneumonitis can be fatal. The trial does not establish benefit in all HER2 IHC 0 tumours.
Bottom line: DESTINY-Breast04 established trastuzumab deruxtecan as a practice-changing ADC for HER2-low metastatic breast cancer after chemotherapy, improving PFS and OS; the major treatment-specific hazard is potentially fatal ILD.
Primary sources and follow-up publications
- DESTINY-Breast04 primary report, NEJM 2022
- Long-term OS analysis, Nature Medicine 2025
- DESTINY-Breast04 registry
All outcome values above are transcribed from the linked trial reports or their prespecified follow-up publications. Unreported values are not imputed. No NNT is derived from median survival.