PURPOSE: Neoadjuvant chemotherapy is standard of care in human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC), irrespective of the hormone receptor status. Trastuzumab-emtansine (T-DM1), antibody-drug conjugate, is highly effective in HER2+ EBC; however, no survival data are available for de-escalated antibody-drug conjugate-based neoadjuvant therapy without conventional chemotherapy. PATIENTS AND METHODS: In the WSG-ADAPT-TP (ClinicalTrials.gov identifier: NCT01779206) phase II trial, 375 centrally reviewed patients with hormone receptor-positive (HR+)/HER2+ EBC (clinical stage I-III) were randomly assigned to 12 weeks of T-DM1 with or without endocrine therapy (ET) or trastuzumab + ET once every 3 weeks (ratio 1:1:1). Adjuvant chemotherapy (ACT) omission was allowed in patients with pathologic complete response (pCR). In this study, we report the secondary survival end points and biomarker analysis. Patients who received at least one dose of study treatment were analyzed. Survival was analyzed using the Kaplan-Meier method, two-sided log-rank statistics, and Cox regression models stratified for nodal and menopausal status. P values < .05 were considered statistically significant. RESULTS: T-DM1, T-DM1 + ET, and trastuzumab + ET induced similar 5-year invasive disease-free survival (iDFS; 88.9%, 85.3%, 84.6%; Plog-rank = .608) and overall survival rates (97.2%, 96.4%, 96.3%; Plog-rank = .534). Patients with pCR versus non-pCR had improved 5-year iDFS rates (92.7% v 82.7%; hazard ratio, 0.40 [95% CI, 0.18 to 0.85]). Among the 117 patients with pCR, 41 did not receive ACT; 5-year iDFS rates were similar in those with (93.0% [95% CI, 84.0 to 97.0]) and without ACT (92.1% [95% CI, 77.5 to 97.4]; Plog-rank = .848). Translational research revealed that tumors with PIK3CA wild type, high immune marker expression, and luminal-A tumors (by PAM50) had an excellent prognosis with de-escalated anti-HER2 therapy. CONCLUSION: The WSG-ADAPT-TP trial demonstrated that pCR after 12 weeks of chemotherapy-free de-escalated neoadjuvant therapy was associated with excellent survival in HR+/HER2+ EBC without further ACT. Despite higher pCR rates for T-DM1 ± ET versus trastuzumab + ET, all trial arms had similar outcomes because of mandatory standard chemotherapy after non-pCR. WSG-ADAPT-TP demonstrated that such de-escalation trials in HER2+ EBC are feasible and safe for patients. Patient selection on the basis of biomarkers or molecular subtypes may increase the efficacy of systemic chemotherapy-free HER2-targeted approaches.