Background: There is increasing evidence suggesting benefit from a neoadjuvant approach to PC. However, the optimal regimen is unclear and will likely require a precision medicine approach. Platinum-containing regimens have shown survival benefit for PC, with occasional exceptional responders, but biomarkers (BM) of response are not well defined and treatment decisions are often based on patient performance status (PS) and co-morbidity. Tumors may show defective DNA damage response (DDR), conferring potential selective sensitivity to DNA-damaging agents (e.g. platinum) and newer targeted agents. We have shown that DDR deficiency (DDRd) is present in up to 20% of PC. This study aimed to exploit DDRd as a therapeutic vulnerability, with integrated analysis to define candidate BM for FA and AG response. Methods: Patients with resectable and borderline resectable PDAC patients who were deemed fit for potential surgery were recruited into the trial between April 2019 and July 2021. All had been molecularly profiled using the Precision-Panc Clinical Cancer Genome including a novel DDRd assay, and the transcriptome with longitudinal sampling (pre-, during, and post-treatment). Patients received either FA (nab-paclitaxel 150mg/m2 IV, oxaliplatin 85mg/m2, folinic acid 350mg flat dose, fluorouracil infusion 2400mg/m2 continuous IV infusion), or AG (nab-paclitaxel 125mg/m2, gemcitabine 1000 mg/m2) for 3 months, based on patient age and PS. The primary endpoint was disease progression (DP) during neoadjuvant therapy. Results: 31 patients in total were recruited into the trial unfortunately the trial was terminated early due to funding issues. The median age was 62 years old (31-73) 21 patients were male and 10 female. 7 resectable cases and 24 borderline resectable at diagnosis were included in the study. 26 patients were recruited to the FOLFOX-A arm and 5 to the AG arm. Following chemotherapy 6 patients had partial response, 17 stable disease and 6 progressive disease. 23 patients proceeded to surgery of which 6 the radical surgery was abandoned due to extent of malignancy The overall median survival time was 20.6 months with a 90% confidence interval of (12.9 months to 24.9 months). The median survival time was 23.7 months with 90% confidence interval of (12.9 months to 24.9 months) for FOLXFOX-A, and 20.5 months with a 90% confidence interval of (8.9 months to NA) for the AG arm Conclusions: We have demonstrated that these 2 regimes can be utilised in the neoadjuvant setting with surgery being undertaken safely following therapy (there was no surgical mortality and morbidity is in line of other international series). Further work is ongoing to identify potential biomarkers which may lead to better patient selection for a neoadjuvant approach. Clinical trial information: ISRCTN34129115.