A 64-year-old man with metachronous metastatic urothelial carcinoma originating from the right renal pelvis underwent nectin-4-targeted [ 68 Ga]Ga-NECT-224 PET/CT prior to initiation of nectin-4-targeted antibody-drug conjugate (ADC) therapy with enfortumab-vedotin (PADCEV), in combination with pembrolizumab. A CT follow-up after 3 months of ADC therapy showed a progressive adrenal metastasis. Subsequent [ 68 Ga]Ga-NECT-224 PET/CT restaging revealed multiple new lesions with intense nectin-4 expression. This case illustrates the potential of [ 68 Ga]Ga-NECT-224 PET/CT to visualize heterogeneous nectin-4 expression, its potential in therapy guidance, and highlights the need for theranostic strategies in patients retaining target expression despite cytotoxic therapy resistance.