Recent advances in discriminating prostate cancer from benign prostatic diseases in the pre-biopsy population.

Prostate cancer (PCa) remains one of the most prevalent malignancies and a major cause of cancer-related deaths among men worldwide. Current pre-biopsy evaluation relies primarily on serum prostate-specific antigen (PSA) testing and multiparametric MRI (mpMRI), but both approaches have limited specificity, particularly in the diagnostic gray zone (PSA 4-10 ng/mL and/or equivocal MRI findings such as Prostate Imaging Reporting and Data System (PI-RADS) category 3 lesions). In this setting, overlap between PCa and benign prostatic diseases frequently leads to unnecessary biopsies. This unmet clinical need has driven the development of novel diagnostic strategies designed to better discriminate PCa from benign prostatic diseases before biopsy. In this review, we provide a comprehensive overview of recent advances in non-invasive diagnostic strategies, including liquid-based molecular biomarkers, advanced imaging modalities, and multimodal integrative frameworks. These advances may improve diagnostic accuracy, reduce unnecessary biopsies, and support personalized risk stratification and biopsy decision-making. Moreover, we highlight the paradigm shift from single-parameter screening to multimodal integration, including artificial intelligence-based approaches in early PCa screening. Overall, these non-invasive strategies may help reduce diagnostic uncertainty in the gray zone and support more precise and personalized biopsy decision-making.