Simple SummaryExploring the possibility of using well-known marketed drugs in new therapeutic indications, commonly known as drug repurposing, offers certain advantages over discovering new substances for medicinal use; it saves time and costs and reduces risks as the safety profile is, in many cases, well-established. This approach has grasped the interest of scientists for one of the most lethal conditions worldwide—cancer. Several preclinical and observational studies showed that various drugs may benefit oncological patients. Placebo- or no intervention-controlled clinical trials can offer evidence regarding the efficacy of a drug in a particular therapeutic indication. This systematic review summarizes randomized controlled clinical trials that evaluate drug repurposing possibilities in cancer for drugs that are currently authorized for non-oncological indications.AbstractQuality pharmacological treatment can improve survival in many types of cancer. Drug repurposing offers advantages in comparison with traditional drug development procedures, reducing time and risk. This systematic review identified the most recent randomized controlled clinical trials that focus on drug repurposing in oncology. We found that only a few clinical trials were placebo-controlled or standard-of-care-alone-controlled. Metformin has been studied for potential use in various types of cancer, including prostate, lung, and pancreatic cancer. Other studies assessed the possible use of the antiparasitic agent mebendazole in colorectal cancer and of propranolol in multiple myeloma or, when combined with etodolac, in breast cancer. We were able to identify trials that study the potential use of known antineoplastics in other non-oncological conditions, such as imatinib for severe coronavirus disease in 2019 or a study protocol aiming to assess the possible repurposing of leuprolide for Alzheimer’s disease. Major limitations of these clinical trials were the small sample size, the high clinical heterogeneity of the participants regarding the stage of the neoplastic disease, and the lack of accounting for multimorbidity and other baseline clinical characteristics. Drug repurposing possibilities in oncology must be carefully examined with well-designed trials, considering factors that could influence prognosis.