Background: In this large phase III trial, median progression-free survival (PFS) improved by 5.1 mo with E+O compared to P+O in patients (pts) with NET associated with carcinoid syndrome. Baseline imbalances including WHO performance status (PS) and primary site favoring P+O confounded primary analysis. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are important biomarkers in NET. Analyses were performed to identify prognostic factors and adjust for baseline imbalances. Methods: Pts were randomized to E+O (n=216) or P+O (n=213). Potential prognostic factors including baseline CgA (≤2×ULN vs >2×ULN), baseline 5-HIAA (≤median vs >median at baseline), age (<65 vs ≥65), gender, race, WHO PS (0 vs 1, 2), primary site (lung vs other), prior somatostatin analog use (yes vs no), duration from diagnosis (<6 mo, 6-24 mo, 2-5 yr, >5 yr), and organs involved (liver, bone) were assessed in univariate analysis using the log rank test and stepwise regression using Cox proportional hazards model. Results: Median PFS (mo) was significantly longer for pts with nonelevated CgA (27 vs 11; p<.001) and nonelevated 5-HIAA (17 vs 11; p<.001). Analyses also indicated age (14 vs 12; p=.01), WHO PS (17 vs 11; p=.004), liver involvement (14 vs not reached; p=.02), bone metastases (8 vs 15; p<.001), and lung as primary site (11 vs 14; p=.06) as potentially prognostic. Multivariate analysis indicated that significant prognostic factors for PFS included baseline CgA (HR, 0.47; CI, 0.34-0.65; p<.001), WHO PS (HR, 0.69; CI, 0.52-0.90; p=.006), bone involvement (HR, 1.52; CI, 1.06-2.18; p=.02), and lung as primary site (HR, 1.55; CI, 1.01-2.36; p=.04). Adjusted for covariates, a 38% reduction in risk of progression was observed for E+O (HR, 0.62; 95% CI, 0.51-0.87; p=.003). Conclusions: In the phase III RADIANT-2 trial, baseline CgA levels, WHO PS, lung as primary site, and bone involvement were important prognostic factors. Exploratory analysis adjusted for these prognostic factors indicated significant benefit of everolimus therapy.