A commentary notes that whether neratinib is a clinically meaningful treatment strategy and its place in the treatment landscape for early-stage HER2-positive breast cancer will depend on the results of both the adjuvant APHINITY trial and effective toxicity management, and on a better understanding of risk stratification. It adds that as the prognosis for HER2-positive disease improves, predictive biomarkers should be identified and validated to enable efforts to be focused on high-risk patients and avoid unnecessary toxicity, cost, and time on treatment.