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Introduction: The third-generation antibody-drug conjugates (ADC), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), recently obtained approval for metastatic breast cancer treatment across various subtypes and therapeutic contexts., Materials and Methods: This retrospective, multicentric study evaluated real-world tolerability, feasibility and efficacy in a pre-treated, real-world cohort at three major German breast cancer centers., Results: 125 patients treated with T-DXd or SG from November 2020 to June 2023 were included (T-DXd: 77 patients; SG: 48 patients). The median treatment duration was 6.0 months for T-DXd and 3.5 months for SG therapy, with a median follow-up duration of 10.4 months for T-DXd (95% CI: 8.4-11.6) and 11.8 months for SG (95% CI: 8.0-14.4). Severe neutropenia (CTC ≥ III°) occurred in 33.3% during SG therapy, with a numerical reduction observed following primary, prophylactic use of G-CSF. T-DXd-associated pneumonitis occurred in 8 out of 77 patients (10.4 %). Median progression-free survival (mPFS) was 8.6 months (95% CI: 5.8-12.4) with T-DXd (HER2+: 10.8; HER2-low: 4.7) and 4.9 months (95% CI: 2.8-6.3) with SG (TNBC 4.9; HR+/HER2-: not reached). Median overall survival (OS) was 23.8 months (95% CI: 16.1-not estimable) with T-DXd (HER2+: 27.1; HER2-low: not reached), and 12.4 months (95% CI: 8.7-not estimable) with SG therapy (TNBC: 12.4, HR+/HER2-: not reached). 95.7% of the protocol-specified, therapeutic dose was administered for T-DXd and 89.6% for SG., Conclusion: Overall, this indicates good feasibility, tolerability, and effectiveness of ADC therapies in the real-world setting., Competing Interests: Conflict of Interest H. Schäffler: Travel Support by Daiichi Sankyo and Gilead, Honoraria by Novartis; D. Jakob: none; S. Huesmann: none; K. Pfister: Honoraria by Pfizer Novartis and Gilead; K. Veselinovic: Honoraria by Roche, Pfizer, AstraZeneca; F. Schochter: Travel Support, Honoraria and Consulting Fees by AstraZeneca, Roche, Karyopharm, Merck, GlaxoSmithKline, Eisai, Clovis; E. Leinert: none; V. Fink: none; B. Rack: Honoraria and research funding by AstraZeneca and Novartis; A. Englisch: none; L. Volmer: none; T. Engler: Travel Support, Honoraria and Consulting Fees by AstraZeneca, GSK, Gilead, Novartis, Lilly, Pfizer, MSD, Pierre Fabre, Stemline, Roche, Daiichi Sankyo; ML. Frevert: Honoraria by Novartis; I. Juhasz-Böss: none; S. Brucker: Travel Support and Consulting Fees by Hologic, Sanofi, AstraZeneca, Lilly, MSD, Medtronic, Pfizer; S. Heublein: research funding and honoraria from Clovis Oncology, Inc., GlaxoSmithKline, Novartis, Roche, AstraZeneca and Pfizer. Participation in advisory boards for Novartis, GlaxoSmithKline, and Merck Sharp & Dohme Corporation; W. Janni: Travel Support, Honoraria and Consulting Fees by Daiichi Sankyo, AstraZeneca, Gilead; FA. Taran: Travel Support by Gilead, Consulting Fees by AstraZeneca, Gilead, MSD, ImmunoGen, Onkowissen, Roche, GSK; A. Hartkopf: Travel Support by Daiichi Sankyo, Gilead, Roche, AstraZeneca, Pfizer, Honoraria by Daiichi Sankyo, Gilead, Seagen, Roche, AstraZeneca, Pfizer, Lilly, MSD, Novartis; D. Dannehl: Travel Support by Gilead and Daiichi Sankyo, Honoraria by Gilead., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)