Clinical trial designs in the era of biomarker-guided therapies

As molecular profiling improves, treatment responses are increasingly observed in smaller, biomarker-defined subgroups, highlighting the need for novel clinical trial designs and endpoints. We review principles for the selection and assessment of biomarkers, a crucial component of biomarker-enriched protocols, and illustrate common pitfalls in biomarker ascertainment through recent examples. We summarize current response assessment criteria and their integration into single-arm trials with surrogate endpoints based on response rate, which have supported recent accelerated regulatory approvals in biomarker-selected populations. We describe how window-of-opportunity trials can help validate CNS penetration and target engagement early, and define master protocol designs: basket, umbrella, and adaptive platform trials. Finally, we evaluate external control arms and their current role in neuro-oncology research. Throughout, we provide guidance on the use of novel designs and endpoints while preserving scientific rigor.