We discuss clinically relevant endpoints (complete response, invasive recurrence, bladder-intact survival, and salvage RC), patient selection (carcinoma in situ, hydronephrosis, debulking feasibility, and histology), and DNA damage response (DDR) biology-highlighting <i>ERCC2</i> and related pathways as determinants of chemo-radiation sensitivity. The gene discussed is ERCC2; the disease is hydronephrosis.