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Project Optimus has been reforming the dose selection and optimization paradigm in oncology. In this context, model-informed drug development (MIDD) approaches were utilized to validate the optimal dose selection of 6 mg/kg every 3 weeks (Q3W) for datopotamab deruxtecan (Dato-DXd) in patients with HR-positive/HER2-negative breast cancer (HR+/HER2- BC). A Tumor Growth Inhibition (TGI)-Progression-Free Survival (PFS) modeling framework was developed to assess the relationship between Dato-DXd PK exposure, tumor dynamics, and PFS, and support virtual trial simulations at different Dato-DXd dose levels. Simulations suggested that Dato-DXd at 6 mg/kg Q3W provide superior tumor control and improved PFS compared to a lower dose in patients with HR+/HER2- BC. This work underscores the importance of integrating advanced modeling techniques into the dose optimization paradigm.