Pharmacogenomic Stratification for Oncology Drug Repurposing: An Exposure Target Context Eligibility Framework

In spite of plausible biology, the majority of oncology trials involving drug repurposing have failed to demonstrate any efficacy. Numerous factors can potentially cause failure, including issues with dosing, drug strength, the trial design itself, and patient diversity. A major, potentially correctable contributor is the absence of pharmacogenomic eligibility criteria. Here, we propose the Pharmacogenomic Stratification Framework for Drug Repurposing (PSDR), a novel framework for drug response that encompasses the triad of Exposure (E, pharmacokinetic adequacy), Target engagement (T, somatic tumor genomics), and Context competence (C, tumor microenvironment). These domains are represented as R = E × T × C, an eligibility model capturing the necessary, though not sufficient, conditions for anticancer drug activity. The model is not presented as an empirically validated quantitative law but as a conceptual framework to guide biomarker-stratified trial design. We derive five testable pharmacogenomic hypotheses for metformin, statins, beta-blockers, NSAIDs, and SSRIs, and propose a three-point PSDR eligibility scoring system. Prospective validation of each hypothesis in appropriately stratified cohorts is required before clinical implementation. The PSDR framework complements rather than replaces existing precision oncology resources (OncoKB, CIViC, PharmGKB, CPIC, DepMap, GDSC) by integrating germline pharmacokinetics, somatic genomics, and microenvironmental profiling for repurposed agents. If validated, PSDR-guided enrichment designs could substantially improve the efficiency and interpretability of repurposing trials. The PSDR framework should be considered a conceptual and hypothesis-generating model that requires prospective validation before clinical implementation.