Background: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload, is approved for pts with unresectable or metastatic HER2+ BC with ≥2 prior anti-HER2–based therapies. T-DXd showed improved progression-free survival vs trastuzumab emtansine (T-DM1) as an earlier-line treatment (tx) for pts with HER2+ metastatic BC in the phase 3 DESTINY-Breast03 trial (Cortes J, et al. Ann Oncol. 2021;32:S1283-S1346. Abstract LBA1). Preliminary antitumor activity of T-DXd was shown in heavily pretreated pts with HER2-low advanced/metastatic BC in the phase 1 DS8201-A-J101 trial (Modi S, et al. J Clin Oncol. 2020;38:1887-1896). We report preliminary results from the dose-finding phase of 2 trials investigating T-DXd combination tx in HER2+ or HER2-low metastatic BC. Methods: DB-07 (phase 1b/2; NCT04538742) and DB-08 (phase 1b; NCT04556773) are 2-part, modular, open-label, multicenter trials of T-DXd combined with other anticancer tx in pts with advanced/metastatic BC that is HER2+ (DB-07) or HER2 low (DB-08). Part 1 of each study is an ongoing dose-finding phase; pts must have ≥1 prior tx for metastatic BC. Part 2 of each study is a dose-expansion phase; pts must have no (DB-07) or ≤1 (DB-08) prior tx for metastatic BC. We report preliminary results from the T-DXd + pertuzumab module of DB-07 part 1 (data cutoff: Oct 15, 2021) and T-DXd + anastrozole and T-DXd + fulvestrant modules of DB-08 part 1 (data cutoff: Sep 27, 2021); pts in the DB-08 modules must be hormone receptor positive. The part 1 primary objective was to assess safety and tolerability and determine the recommended phase 2 dose (RP2D) according to the modified toxicity probability interval-2 algorithm. Pts were followed up beyond the 21-day dose-limiting toxicity (DLT) period (28 days for T-DXd + fulvestrant) for safety events. Results: In DB-07, 7 pts were enrolled and received T-DXd 5.4 mg/kg + pertuzumab 420 mg (loading dose: 840 mg) every 3 wk (q3w; not evaluable for DLTs, n = 1). In DB-08, 6 pts were enrolled and received T-DXd 5.4 mg/kg q3w + anastrozole 1 mg daily (not evaluable for DLTs, n = 1); another 6 pts were enrolled and received T-DXd 5.4 mg/kg q3w + fulvestrant 500 mg every 4 wk (loading dose: 500 mg cycle 1 days 1 and 15). For all 3 modules, no DLTs were reported in any DLT-evaluable pts; the dose levels used in part 1 were approved to be the RP2Ds for use in the dose-expansion part of each corresponding module. No deaths on study or cases of interstitial lung disease/pneumonitis were reported to date. Conclusions: The RP2Ds for the T-DXd combinations were the standard doses for BC of each individual drug. These studies are ongoing, with additional T-DXd combinations being evaluated and further follow-up underway. Clinical trial information: NCT04538742; NCT04556773.