Abstract The third-generation antibody-drug conjugates, Trastuzumab-Deruxtecan (T-DXd) and Sacituzumab Govitecan (SG), have been approved for the treatment of metastatic breast carcinoma in various subtypes and therapeutic settings based on compelling Phase III study data. (DESTINY-Breast03 (T-DXd; HER2-positive), DESTINY-Breast04 (T-DXd; HER2-low), ASCENT (SG; triple-negative), and TROPiCS-02 (SG; HR+/HER2-negative). The aim of this retrospective study conducted at two major German Breast centers was to evaluate the tolerability, adherence, and efficacy of both substances in the real-world setting. All patients treated outside of clinical trials with T-DXd or SG at the Department of Gynecology and Obstetrics, Ulm University Hospital and the Department of Women’s Health, Tuebingen University Hospital between November 2020 and May 2023 were included in this retrospective analysis. Seventy-five patients were included [T-DXd: 46; SG: 29]. The mean duration of therapy was 5.4 months [T-DXd: 6.2; SG: 4.2]. The real-world cohort was more heavily pretreated than the corresponding study cohorts, with a mean of 4.2 systemic therapies in the metastatic setting prior to T-DXd therapy and 3.6 systemic therapies prior to SG therapy. The administered cumulative dose on average was 87.9% [T-DXd: 94%; SG: 79%] of the theoretical full dose or 95.3% [T-DXd: 98%; SG: 92%] when considering dose reductions that occurred. Hematotoxicities of CTC ≥ 3° occurred in 11% of patients treated with T-DXd and in 41% of patients treated with SG. Neutropenia was the predominant severe hematotoxicity (CTC≥III°) observed during SG therapy, occurring in 38% of patients. The occurrence of neutropenia during SG therapy was reduced with primary prophylactic administration of Granulocyte-Colony Stimulating Factor (GCSF), with a rate of 29% (21/29) of patients experiencing neutropenia ≥CTC-III°, compared to 63% (8/29) without primary prophylactic GCSF. Therapy-associated pneumonitis under T-DXd occurred in 5 out of the 46 included patients and was successfully treated with corticosteroids in all cases (CTC II° in 4 cases, CTC III° in 1 case). The median progression-free survival (PFS) from initial administration was 7.7 months under T-DXd [HER2-positive: 9.0; HER2-low: 6.1], and 4.8 months under SG [TNBC 4.8; HR+/HER2-negative: 2.8]. The median overall survival from initial administration was 27.1 months under T-DXd [HER2-positive: 27.1; HER2-low: not reached], and 11.9 months under SG therapy [TNBC: 11.0, HR+/HER2-negative: not reached]. This analysis provides evidence of the efficacy and tolerability of T-DXd and SG in a heterogeneous and heavily pretreated cohort in a real-world setting. However, a conclusive assessment of progression-free survival (PFS) and overall survival (OS) is not feasible yet, as a substantial number of patients are still under treatment. Updated PFS and OS data, with a specific focus on the therapy indication, will be presented at the meeting. Citation Format: Henning Schäffler, Dominik Dannehl, Kristina Veselinovic, Franziska Mergel, Kerstin Pfister, Brigitte Rack, Visnja Fink, Elena Leinert, Lea Volmer, Tobias Engler, Sara Brucker, Wolfgang Janni, Andreas Hartkopf. Novel antibody-drug-conjugates in clinical routine: adherence, efficacy and tolerability - real-world data from German breast centers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-11.