Enrolling adequate numbers of patients into the control arm of randomized controlled trials (RCTs) often presents barriers. There is interest in leveraging real-world data (RWD) from electronic health records (EHRs) to construct external control (EC) arms to supplement RCT control arms and form hybrid control (HC) arms. This investigation showed the use of an HC arm in second-line metastatic pancreatic ductal adenocarcinoma (PDAC). The RCT experimental arm (atezolizumab + PEGylated recombinant human hyaluronidase (Atezo + PEGPH20)) was compared with an HC arm consisting of patients treated with modified FOLFOX6 or gemcitabine/nab-paclitaxel from the MORPHEUS PDAC internal control arm supplemented with data from a nationwide EHR-derived de-identified database as the EC arm. The EC arm was constructed by applying key inclusion/exclusion criteria from the MORPHEUS PDAC trial to patients from the real-world cohort. Baseline variables were balanced using propensity score matching and covariate adjustment. Three analysis approaches-Cox model with pooled-control data, Cox model with control arm-specific frailty, and Bayesian analysis using a commensurate prior-were assessed. Overall survival was similar between the treatment arms. The direction and magnitude of hazard ratios (HRs) from the multiple HC analyses (HRs ranged from 1.02 to 1.06) were comparable with the reported trial HR (HR 0.91
95% CI: 0.56, 1.49). This analysis demonstrates the feasibility and applicability of leveraging RWD in clinical trial design to supplement clinical trial control arms.