Late-phase oncology randomized controlled trials (RCT) form the primary basis for approval of new cancer therapies by regulatory agencies. Therefore, it is essential to comprehensively understand the design of these trials, recognize potential biases that may arise during the study, and address subsequent challenges in interpreting the findings. This knowledge is invaluable for both trialists and clinicians in order to enable informed decision-making and empower patients to actively participate in treatment recommendations. Furthermore, given the substantial costs and time investment involved in the development of novel therapies,1 it is imperative to optimize all available resources for the benefit of patient care. In this article, we present an overview of key topics in late-phase clinical trial design and execution (Table). Topics covered include the selection of primary endpoints, identification of potential sources of bias, considerations for superiority and noninferiority trials, exploration of alternative survival endpoints, and the role of Bayesian statistical inference in cancer trials. Lastly, we discuss controversies on the appropriate utilization of late-phase trial data to inform regulatory decisions.