1632P Organoids as tools for functional precision oncology in advanced pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has a steadily increasing incidence and a poor prognosis. Patient (pts) tumors’ derived organoids (PDO) are promising models for functional precision oncology (FPO). This study aims to evaluate whether PDO can be implemented in clinical practice for the management of PDAC pts. During 2021-2022, pts were prospectively enrolled in an IRB-approved protocol (NCT04932525). Main inclusion criteria were histologically confirmed PDAC, at least one tumor accessible site (biopsy, surgery or effusions) and ECOG performance status 0-1. The efficacy of 25 antitumor therapies was tested (=chemogram) (ATP luminescence test). A scoring system was developed to rank drugs and to find hits. Overall, 81 patients were included (median age 61 years; median previous treatment lines 2 [range: 0-5]). 91% pts had previously received FOLFIRINOX, 61% gemcitabine and 49% (nab)-paclitaxel. PDO take-on rate was 62% (n=50/81) (notably, liver biopsy: 64%, ascites: 93%). Mean turnaround-time to chemogram was 6.7 weeks. Main PDO molecular alterations were KRAS (98%), TP53 (72%), CDKN2A/B (17%) and SMAD4 (17%) with good concordance rate (88%) with initial tumor. Median patients’ overall survival from PDO sampling was shorter when PDO were established (p<0.01). Median number of hits was 3 (range 0-12). In 89% of cases, at least 1 hit was identified, and in 84% of cases, at least one of the hits was not a Standard-of-Care (SOC, i.e., 5-FU, irinotecan, oxaliplatin, gemcitabine, or paclitaxel). Main identified hits were gemcitabine (n=17/50), docetaxel (n=16/50), olaparib (n=15/50), and vinorelbine (n=15/50). Evaluable pts that received a treatment that was a hit after PDO biopsy had a longer growth modulator index (GMI) (p= 0.0007) disease control rate (p=0.001) and progression-free survival (p=0.07, NS) than others. Sensitivity and specificity of PDO to predict pts response were 80% and 95.7% respectively. We report a large prospective study that aims to implement PDO-based FPO for PDAC. In a clinically relevant turnaround time, at least one putative hit was identified in 89% of cases with good sensitivity and specificity. The benefit of PDO-based FPO warrant to be confirmed in a prospective randomized trial.