Supplementary materials: Population-adjusted network meta-analyses provide new insights into the efficacy of treatment alternatives for metastatic castration-sensitive prostate cancer

These are peer-reviewed supplementary materials for the article 'Population-adjusted network meta-analyses provide new insights into the efficacy of treatment alternatives for metastatic castration-sensitive prostate cancer' published in the Journal of Comparative Effectiveness Research.Supplementary methodsSystematic literature reviewTargeted literature reviews on effect modifiers in mCSPCDetailed methodsSupplementary resultsSystematic literature reviewTargeted literature reviews on effect modifiers in mCSPCReported subgroups for NMITable of assumptionsAdditional assumptions required for NMIModel fit results – NMIReferencesAim: Recent network meta-analyses (NMAs) in metastatic castration-sensitive prostate cancer have not adequately addressed potential treatment effect modifiers and population imbalances, which introduces bias. Although, individual-patient data (IPD) are seldom available across all trials, recent methodological advances allow adjustments using a combination of IPD and aggregate data. Materials & methods: IPD from the ARASENS trial (darolutamide + docetaxel + androgen-deprivation-therapy [ADT]) and aggregate data from a systematic review were analyzed. Two methods were used to adjust for population imbalances: multilevel network meta-regression (ML-NMR) using baseline characteristics, and network meta-interpolation (NMI) using subgroup data. Relative effects were estimated for an ARASENS-like population, with sensitivity analysis in an average trial population. Results: Twelve studies, including ARASENS, were included. All studies reported baseline characteristics for ML-NMR. Sufficient subgroup data for NMI were available in 8/12 studies for overall survival (OS) and 5/12 studies for progression-free survival (PFS). Darolutamide + docetaxel + ADT showed significant benefit over docetaxel + ADT, ADT and standard-nonsteroidal-antiandrogen + ADT in all analyses. ML-NMR showed improved OS for darolutamide + docetaxel + ADT compared with abiraterone + docetaxel + ADT, apalutamide + ADT, enzalutamide + ADT and abiraterone + ADT. ML-NMR also showed improved PFS for darolutamide + docetaxel + ADT compared with apalutamide + ADT and enzalutamide + ADT. Using NMI, darolutamide + docetaxel + ADT demonstrated OS benefit over abiraterone + ADT and PFS benefit relative to abiraterone + ADT and apalutamide + ADT. Findings were consistent in an average population, although ML-NMR did not show significant OS benefit of darolutamide + docetaxel + ADT over apalutamide+ADT. Conclusion: Improved outcomes were observedwith darolutamide+docetaxel+ADT compared with other therapies. By incorporating effect modifiers and addressing population imbalances, we provide clinicians with a more accurate understanding of treatment efficacy for better-informed decision-making.