Metastatic pancreatic cancer (mPC) has a dismal prognosis, with first line systemic therapy relying primarily on FOLFIRINOX (5FU/irinotecan/oxaliplatin) or AG (Gemcitabine/Nab-Paclitaxel). Therapeutic options for mPC refractory to these regimens remain poorly-defined, and data on later lines options are scare. This prospective, single-arm study (NCT05481463) evaluated the safety and preliminary efficacy of combining the anti-angiogenic agent surufatinib with the cytotoxic drug TAS-102 (Trifluridine/Tipiracil) in mPC patients who had progressed on ≥ 2 prior lines of therapy. Primary and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Among 20 patients analyzed for efficacy, median PFS was 2.35 months (95% CI: 1.91-3.94) and median OS was 6.34 months (95% CI: 3.81-10.09). The ORR and DCR were 20% (4/20; all partial response) and 30% (6/20), respectively. All patients experienced treatment emergent adverse events (TEAEs), with anemia (59.1%), neutropenia (54.6%), leukopenia (50.0%), and lymphopenia (45.5%) as the most common any-grade events. Grade ≥3 TEAEs including neutropenia (31.8%), lymphopenia (13.6%), and anemia (9.1%), were observed in 50.0% (11/22) of patients. Subgroup analysis identified metastases involving > 2 organs or hepatic sites as potential predicative biomarkers for inferior efficacy. Proteomic screening revealed that overexpressed OCIAD2 correlated with poor prognosis, a finding validated in two publicly available external cohorts (CPTAC database and RuiJin cohort). In conclusion, combination of TAS-102 and surufatinib demonstrates clinically meaningful efficacy and manageable toxicity as a later line therapeutic option for refractory mPC. The biomarkers identified in this study may hold the potential to guide patient stratification and warrant further investigation to optimize precision application of this regimen.