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Introduction: Bladder cancer (BC) is the most frequent urinary system cancer in the US. Neoadjuvant chemotherapy before cystectomy for muscle-invasive BC is standard management, though the absolute survival benefit is small, with many patients progressing during chemotherapy. Identifying therapies with a high probability of specific activity against each patient’s tumor remains a critical need. Methods: Following informed consent, from patients undergoing a transurethral resection of bladder tumor or cystectomy, 1+ gram of tumor was procured and divided between DNA/RNA sequencing, organoid drug-screening, and single-cell sequencing of cells surviving chemotherapy. Tissue was dissociated, filtered, and resuspended in organoid media for minimal passaging and drug screening. Drugs were tested at the maximum plasma concentration (Cmax) in human trials, so to provide physiologic relevance. When material was sufficient, cells were additionally tested using dose response. Cmax screening results were normalized to control such that a value of “100” indicated no difference in organoid viability compared to control, and a value of 0 indicated complete response. The number of drugs screened was dependent upon tissue available, with up to 34 drugs screened at Cmax and 9 drugs screened in dose response format. Results: Thus far, >100 patient-derived organoids have undergone collection and development with ~ 2/3 samples collected resulting in organoid development and drug screening. RNA sequencing and GSEA enriched pathways across organoids was compared to other published datasets, noting high levels of correlation between our organoid models and in particular, the Cancer Cell Line Encyclopedia urethral lines. Moreover, analysis of subtype and mutation/copy number data further indicate that our organoid dataset is representative of the full spectrum of disease. RNA sequencing and subtyping of cultured organoids compared to patient tissue indicate that organoid models are representative of patient tissue and do not undergo subtype shifts in our short-term 3D cultures. Our drug screening results highlight the large spectrum of response to chemotherapies that in fact, clinically benefit only a small proportion of patients in the neoadjuvant setting. Crucially, we identify promising targeted therapies to consider for patients who progress following resection and adjuvant chemotherapy. Conclusions: Rapid organoid development, characterization, and drug screening allows for the prediction of therapeutic response in ~10 days following sample collection. Use of this technique on tissue provided during disease work-up may further guide selection of effective therapeutic agents in patients with bladder cancer. This would overall minimize the morbidity of standard of care therapies and could be used to identify alternative therapeutics for patients who progress on standard therapies. Citation Format: Nathan M. Merrill, Liwei Bao, Xu Cheng, Nathalie Vandecan, Zhaoping Qin, Albert Liu, Athena Apfel, Laura Goo, Lila Tudrick, Armand Bankhead III, Phil Palmbos, Samuel Kaffenberger, Khaled Hafez, Jeffrey Montgomery, Todd Morgan, Ajjai Alva, Aaron Udager, Matthew Soellner, Sofia Merajver. Functional assays of drug sensitivity in real-time from patient material for precision oncology in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3072.