Rethinking the role of synergy calculations in the next century of drug combination discovery

Therapeutic strategies increasingly leverage drug combinations, yet preclinical drug synergy frameworks often hinder, rather than accelerate, the clinical translation of medicinal combinations. To modernize the field of drug combination discovery, a multidisciplinary group of practitioners collaborated to distill three key observations underlying successful and failed drug combinations in oncology. These observations are that (1) activity, not synergy, is the primary determinant of a combination's clinical success; (2) synergistic combinations, without disease specificity, commonly fail due to toxicity; and (3) antagonistic combinations are an important and understudied means of improving clinical outcomes. We support the validity of these observations with a mixture of theory, reanalysis of public databases, and review of the literature. Together, these observations argue for a paradigm shift in how preclinical drug combination studies are designed and interpreted to better align with the clinical goals of discovering safe and effective combination therapies.