A noninvasive assay capable of quantifying prostate cancer biomarkers in untreated urine is an elusive diagnostic technique with various obstacles. Difficulties arise because untreated urine contains varying salt concentrations and pH levels even though they are from the same patient. Untreated urine also possesses a fewer number of cancer biomarkers than can be found in serum and a greater number of other biomolecules, which reduces the signal-to-noise ratio. Consequently, urine preconditioning processes and digital rectal examination (DRE) to increase cancer biomarker concentration is of utmost importance in current urine assays. To address these issues, an ion-responsive urine sensor (IRUS) measuring differential electrical signals is presented as a self-normalized detection method. FET biosensor with a disposable sensing gate forms the basis of the proposed IRUS and has the capability to detect prostate cancer biomarkers in untreated urine.