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4152 Background: Despite huge efforts patients (pts) with advanced PDAC, still have a dismal long-term prognosis. The lack of available good-quality tissue samples for next generation sequencing (NGS) prevents from finding actionable alterations that could guide personalized treatments. Circulating tumor DNA (ctDNA) provides a non-invasive method for obtaining molecular information with therapeutic potential. Here, we present prospective data of ctDNA sequencing in pts with PDAC. Methods: We collected a single blood sample from advanced PDAC pts at any line of treatment (Tx) and at least 10 days apart from their last therapy. The samples were analyzed by Guardant360 plasma-based NGS, a standardized assay which covers microsatellite instability [MSI] evaluation and analysis of all four types of somatic alterations in 74 genes. Alterations were reported either as pathogenic or non-pathogenic. We classified each gene alteration according to the different OncoKB therapeutic levels of evidence [LE]. Additionally, we gathered the dates of both blood collection and molecular report. In case the molecular report showed no tumor-related alterations, it was interpreted as either absence of detectable mutations or low ctDNA levels, which would translate low disease burden or pts responding to therapy. Demographic and clinical data have been accessed from the medical records. Results: From 08/2019 to 09/2021 we collected blood samples from 94 PDAC pts. 56% of them were male and 53% were >65 years old. At the time of sample collection, nearly all pts were metastatic (98%). Regarding previous lines of Tx, 57% pts were Tx naïve; 10% were receiving active systemic Tx and 33% had experienced disease progression. Molecular reports were available in an average of 9.1 days. A total of 243 gene alterations were detected, having 94% of pts at least 1 genomic alteration, which was pathogenic in 69% of the cases (see Table). There were no pathogenic alterations ranked as OncoKB LE 1-2 ( MSI or NTRK). Seventy alterations (30%) were ranked as OncoKB LE 3A and 4 ( ARID1A, BRAC2, CDKN2A, KRAS). Three of these pts were treated with PARP inhibitors due to the presence of BRCA2 mutations. No ctDNA was detected in 15 pts (16%), despite being the sample collected >10 days from receiving their last Tx. Of these, 11 had low tumor burden (only peritoneal or lung metastases) and 4 had documented response to the Tx by the time the samples were collected. Conclusions: Real-time and prospective genomic profiling of pts with advanced PDAC using ctDNA is feasible and conveniently fast, which would allow its role in identifying and developing therapeutic targets for approved Tx or clinical trial treatments. [Table: see text]