The optimization of dosing strategies is critical for maximizing efficacy and minimizing toxicity in drug development, particularly for drugs with narrow therapeutic windows such as antibody-drug conjugates (ADCs). This study demonstrates the utility of Nectin-4-targeted positron emission tomography (PET) imaging using [ 68 Ga]AJ647 as a non-invasive tool for real-time assessment of target engagement in enfortumab vedotin (EV) therapy for urothelial carcinoma (UC). By leveraging the specificity of [ 68 Ga]AJ647 for Nectin-4, we quantified dynamic changes in target engagement across preclinical models and established its correlation with therapeutic outcomes. PET imaging revealed dose-dependent variations in Nectin-4 engagement, with suboptimal EV doses resulting in incomplete Nectin-4 engagement and reduced tumor growth. Importantly, target engagement measured by PET emerged as a more reliable predictor of therapeutic efficacy than dose or baseline Nectin-4 expression alone. Receiver operating characteristic (ROC) analysis identified a target engagement threshold that is determinant of response, providing a quantitative benchmark for dose optimization. Furthermore, PET imaging measures provide a promising framework to account for key challenges in ADC development, including tumor heterogeneity, declining drug-to-antibody ratios over time, and limitations of systemic pharmacokinetic measurements to account for tumor-drug interactions. These findings underscore the transformative potential of integrating PET pharmacodynamic measures as early biomarkers to refine dosing strategies, improve patient outcomes, and accelerate the clinical translation of next-generation targeted therapeutics.