This study aimed to evaluate the diagnostic potential of soluble Programmed Death Ligand 1 (sPD-L1) and Programmed Death 1 (sPD-1) molecules in plasma, along with urinary mRNA biomarkers—Prostate-Specific Membrane Antigen (PSMA), Prostate Cancer Antigen 3 (PCA3), and androgen receptor (AR) genes—for identifying clinically significant prostate cancer (PCa), defined as pathological stage 3. Here, SPDL1 is linked to Familial prostate cancer.