Background: Real-world data (RWD) can contextualize clinical trial data. We present real-world evidence that supplemented the single-arm DESTINY-Breast01 trial, which assessed the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2-positive (HER2þ) metastatic breast cancer (mBC) previously treated with trastuzumab emtansine (T-DM1). Patients and methods: Patients from the French Epidemiology Strategy and Medical Economics (ESME) mBC database who initiated treatment for HER2þ mBC between 1 January 2008 and 31 December 2016, and received one or more treatment lines following T-DM1 were propensity score matched 1 : 1 to patients from DESTINY-Breast01 to create an ESME DB-01 matched cohort. Treatment patterns, real-world best overall response, real-world objective response rate (rwORR), real-world disease control rate (rwDCR), real-world progression-free survival (rwPFS), and overall survival (OS) were estimated, including by prior pertuzumab exposure and de novo/relapsed mBC status. Results: A total of 137 patients from the ESME mBC database (78 received prior pertuzumab, 59 did not) were matched to 137 patients from DESTINY-Breast01. In the ESME DB-01 matched cohort, 73.7% received an anti-HER2 drug after T-DM1 treatment. The rwORR was 12.2% (95% confidence interval [CI] 6.2% to 18.2%; only partial responses) and rwDCR was 73.9% (95% CI 65.9% to 81.9%). The median rwPFS was 4.7 months (95% CI 3.8-6.0 months) and similar regardless of prior pertuzumab exposure or de novo/relapsed mBC status. The median OS was 24.1 months (95% CI 18.5-26.4 months) and longer in patients naive to versus exposed to pertuzumab and in patients with de novo versus relapsed mBC. Conclusion: These RWD contextualized results of DESTINY-Breast01 and demonstrated an unmet medical need in patients with HER2þ mBC after T-DM1 treatment