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Background and Aims: Pancreatic ductal adenocarcinoma (PDAC) has the worst survival rate among tumors. At the time of diagnosis, more than 80% of PDACs are considered to be surgically unresectable, and there is an unmet need for treatment options in these inoperable PDACs. This study aimed to establish a patient-derived organoid (PDO) platform from EUS-guided fine-needle biopsy (EUS-FNB) collected at diagnosis and to determine its clinical applicability for the timely treatment of unresectable PDAC., Methods: Patients with suspected PDAC were prospectively enrolled at the Samsung Medical Center from 2015 to 2019. PDAC tissues were acquired by means of EUS-FNB to establish PDAC PDOs, which were comprehensively analyzed for histology, genomic sequencing, and high-throughput screening (HTS) drug sensitivity test., Results: PDAC PDOs were established with a success rate of 83.2% (94/113). It took approximately 3 weeks from acquiring minimal EUS-FNB specimens to generating sufficient PDAC PDOs for the simultaneous HTS drug sensitivity test and genomic sequencing. The high concordance between PDAC tissues and matched PDOs was confirmed, and whole-exome sequencing revealed the increased detection of genetic alterations in PDOs compared with EUS-FNB tissues. The HTS drug sensitivity test showed clinical correlation between the ex vivo PDO response and the actual chemotherapeutic response of the study patients in the real world (13 out of 15 cases). In addition, whole-transcriptome sequencing identified candidate genes associated with nab-paclitaxel resistance, such as ITGB7, ANPEP, and ST3GAL1., Conclusions: This PDAC PDO platform allows several therapeutic drugs to be tested within a short time window and opens the possibility for timely personalized medicine as a "patient avatar model" in clinical practice., Competing Interests: Disclosure All authors disclosed no financial relationships. This work was supported by the National Research Foundation (NRF) of Korea funded by the Ministry of Science and Information and Communication Technology (MSIT) (grant nos. NRF-2017R1A2B2007130, NRF-2019R1C1C1008646, NRF-2020R1F1A1072692, NRF-2020R1A2C2102023, NRF-2020R1A2C3006535, and NRF-2021R1A2C1094009) and a grant from the Korean Gastroenterology Fund for Future Development. This research was also supported by the Collaborative Genome Program for Fostering New Post-genome Industry through the NRF, funded by the MSIT (grant nos. NRF-2017M3C9A5031002 and NRF-2017M3C9A5031004), the Basic Science Research Program through the NRF funded by the Ministry of Education (grant no. NRF-2018R1A6A1A03025810), and the Bio and Medical Technology Development Program of the NRF funded by the MSIT (grant no. NRF-2016M3A9B4918405). This study was also supported by the Future Medicine 20∗30 project of the Samsung Medical Center (SMC) (gant nos. SMX1230041 and SMO1230021) and an SMC research and development grant (grant no. SMO1230661)., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)