The Futility of Futility Analyses in Adjuvant Trials in Hormone Receptor-Positive Breast Cancer

An interim analysis is commonly used in phase III superiority trials to compare treatment arms, with the goal of terminating exposure of patients to ineffective or unsafe drugs or to identify highly effective therapies for earlier public disclosure. Traditionally, interim analyses have been designed to identify early evidence of extremely large benefit of the experimental approach, potentially leading to early dissemination of effective treatments. Increasingly, interim analysis has also involved analysis of futility, which may lead to early termination of a trial that will not yield additional useful information. This presents an important challenge in early stage hormone receptor-positive breast cancer, where recurrence often occurs late, with a steady annual event rate up to 20 years. Early analysis of events may miss late treatment effects that can be observed only with longer follow-up. We discuss approaches to futility analysis in adjuvant clinical trials in hormone receptor-positive breast cancer, the role of the Data Safety Monitoring Committee in such analyses, considerations of the potential harms vs benefits of treatment, and the risks of continuing vs early termination of a trial.