<jats:p> TPS635 </jats:p><jats:p> Background: Over 70% of patients with pancreatic ductal adenocarcinoma (PDAC) present with metastatic disease where the mainstay of treatment is combination chemotherapy. Two pivotal phase III trials showed survival benefit of mFOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel (GnP), respectively, compared to gemcitabine alone. Both are considered standard 1st line treatment options but have not been compared prospectively. Other than the BRCA phenotype there are no predictive molecular markers to identify which patients will benefit from mFFX versus GnP. Growing data suggests that RNA signatures and GATA6 expression may predict response to chemotherapy. Genomic platforms do identify small subsets of patients who may benefit from a targeted approach however, impact has been small. Patient-derived organoids (PDOs) are now feasible to passage for drug pharmacotyping that could inform drug therapy approaches. Combining all molecular strategies in real time including genomics, RNA signatures and adding PDO drug sensitivities could enable better precision choices for more patients with metastatic PDAC. Methods: PASS-01 is a multi-institutional randomized phase II trial evaluating the benefit of 1st line mFFX vs GnP in de novo metastatic PDAC patients with good PS who have undergone baseline tumor biopsies with tissue prepared for whole genome (WGS) and RNA sequencing and PDO generation/pharmacotyping using standard and novel drugs. The 1<jats:sup>0</jats:sup> objective is to determine the PFS benefit of mFFX compared to GnP as 1st line treatment with 80% power to detect a median PFS of 7 vs 5 months, favoring mFFX. 27 of a planned 150 patients have been accrued to date. Secondary endpoints include ORR (RECIST), DOR, OS by chemotherapy and biomarkers of therapy response including GATA-6 as a surrogate biomarker for the Moffit RNA classifier. Exploratory objectives include: to evaluate if each PDO DNA/RNA signature matches the patient and if the PDO chemotherapy sensitivities correlate to the patient’s 1st line response; to evaluate the benefit in switching patients to 2nd line treatment based on PDO drug sensitivity; to evaluate novel agents derived from PDO pharmacotyping and potential findings from profiling in 2nd/3rd line treatment; to explore retrospectively whether serial cell-free circulating tumor DNA analysis, circulating tumor cells and CA19.9 could reflect potential early predictors of emerging or de novo resistance and explore biomarkers of immune-oncologic sensitivity with multiplex immunohistochemistry. Each patient’s WGS and PDO data is discussed at a combined tumor board with study investigators immediately following their 1st 8-week CT and ongoing as data develops with the goal of recommending precision treatment choices back to their treating investigator. References: Conroy T et al. NEJM, 2011.; Von Hoff DD et al. NEJM,2013; Aung KL et al. CCR 2017; O’Kane G et al. CCR 2019; Tiriac H et al. Can Discov, 2018. Clinical trial information: NCT04469556. </jats:p>