Polypharmacy, polypharmacology, and polypharmacotherapy: clarifying definitions and complementary roles in cancer treatment – a narrative review

INTRODUCTION: Cancer treatment is predominantly guided by the Somatic Mutation Theory (SMT), which focuses on highly selective drugs targeting driver mutations. This approach has transformed outcomes in specific cancers, including chronic myeloid leukemia, advanced melanoma, renal cell carcinoma, and HER2-positive breast cancer. However, its overall impact remains limited: cancer drug development has an approximate 5.2% success rate, with a median overall survival benefit of only 2.8 months across 124 FDA-approved drugs (374 indications) from 2003 to 2021. These limitations underscore the need for complementary strategies. AREAS COVERED: This narrative review examines three interrelated concepts in cancer care. POLYPHARMACY: concurrent use of multiple drugs for different conditions in one patient. Polypharmacology: design of single drugs that engage multiple molecular targets within one disease, often via multi-target-directed ligands (MTDLs) to disrupt redundant pathways and delay resistance. Polypharmacotherapy: simultaneous use of multiple (often repurposed non-oncology) drugs to target diverse pathways in a cancer patient. EXPERT OPINION: Polypharmacy requires optimization to minimize risks. Polypharmacology should advance through computational design of balanced MTDLs. Polypharmacotherapy provides a pragmatic, equitable complement to SMT-based precision oncology. Urgent clinical trials are needed to validate this approach, overcome commercial and structural barriers, and improve treatment efficacy, accessibility, and equity worldwide.