Trastuzumab deruxtecan in hormone receptor-positive, HER2-low/-ultralow metastatic breast cancer (DESTINY-Breast06): outcome analyses by time to progression on prior first-line endocrine therapy with CDK4/6 inhibitor and baseline burden of disease

BACKGROUND: In DESTINY-Breast06, trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) versus physician's choice of chemotherapy (TPC) for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-low/-ultralow metastatic breast cancer (mBC), without new safety signals. We report additional analyses exploring outcomes for patients with characteristics that affect prognosis. PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd (5.4 mg/kg) once every 3 weeks or TPC. Subgroups were specified post hoc from the intent-to-treat population (N = 866). Outcomes were PFS, objective response rate (ORR), and duration of response (DOR) by blinded independent central review via RECIST 1.1. Time from randomization until second progression or death (PFS2) by investigator and safety were also assessed. RESULTS: Within subgroups, baseline disease characteristics and prior therapies were balanced across treatments. Median PFS (95% confidence interval) favored T-DXd versus TPC regardless of time to progression (TTP) on prior first-line endocrine therapy (ET) + cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i): <6 months: 14.0 (11.2-15.9) versus 6.5 (4.2-8.4) months for T-DXd versus TPC; 6-12 months: 13.2 (8.6-16.4) versus 6.9 (4.3-10.4) months; >12 months: 12.9 (9.8-17.1) versus 8.2 (6.9-10.9) months. A consistent PFS benefit with T-DXd over TPC was observed for patients with primary or secondary endocrine resistance, and across indicators of high or low disease burden (defined as visceral/non-visceral disease, presence/absence of liver metastases, three or more/less than three disease sites, and >median/≤median baseline tumor size). In all subgroups, confirmed ORR favored T-DXd (36.7% to 67.7%) versus TPC (16.7% to 37.5%), and median DOR (confirmed response) was longer with T-DXd. T-DXd also prolonged PFS2 versus TPC across subgroups. Safety profiles of T-DXd and TPC in subgroups were consistent with the overall safety population. CONCLUSIONS: These data support T-DXd as a broadly efficacious treatment for patients with HR-positive, HER2-low/-ultralow mBC after one or more ETs, regardless of TTP on prior first-line ET + CDK4/6i, endocrine resistance, or disease burden.