In the absence of predictive biomarkers and representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a fatal and heterogeneous malignancy, researchers established patient-derived (PD) tumoroids from biobanked tissue samples. This model facilitated rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. PD tumoroids accurately mirrored biological features of high-grade GEP-NEN and replicated clinical responses to cisplatin and temozolomide. Investigation of treatment-induced adaptive stress responses identified synergistic effects of Lysine demethylase 5 A and interferon-beta with cisplatin. Notably, ex vivo drug response correlated with patients’ clinical responses, suggesting potential for personalized therapeutic options for advanced high-grade GEP-NEN.