A better understanding of cancer biology has led to the development of targeted therapies specifically designed to modulate an altered molecular pathway in the cancer cells or their microenvironment. Despite the identification of molecular targets across cancer types, most of targeted therapies were developed per cancer type. In this ancestral paradigm, randomization was the gold-standard approach for market access. Randomization of large patient populations was feasible for drugs developed in common cancer types but more challenging in rare cancer types. The traditional paradigm of drug development in oncology was further challenged by the ever-expanding molecular segmentation of cancer with ever-smaller subgroups of patients who might benefit from specific targeted therapies or immunotherapies and the identification of molecular alterations against which drugs may be effective across cancer types. In this novel drug development paradigm, novel ways of evaluating the efficacy of drugs are highly needed in these small patient populations. One approach is to use each patient as his/her own control by comparing the efficacy of a drug to the efficacy of prior treatments received. This approach allows to overcome patient heterogeneity, especially in a tissue-agnostic drug development paradigm.