Influence of Prostate Volume on Targeted Biopsy Outcomes and PI-RADS Predictive Value for Significant Prostate Cancer

<b>Background/Objectives</b>: Multiparametric MRI (mpMRI) and targeted biopsies have revolutionized prostate cancer (PC) detection through the Prostate Imaging Reporting and Data System (PIRADS). However, the effect of prostate volume on cancer detection and the predictive accuracy of PIRADS in the mpMRI-guided biopsy era remains unclear. The aim was to assess whether prostate volume affects detection rates of clinically significant prostate cancer (CSPC) and high-risk prostate cancer (HRPC) and modifies the predictive performance of the PIRADS score. <b>Methods</b>: We retrospectively analyzed 361 biopsy-naïve men who underwent mpMRI-fusion transperineal biopsies between 2016 and 2023. Lesions graded PIRADS ≥ 3 were targeted alongside systematic sampling. A receiver-operating characteristic (ROC) curve (AUC = 0.74) defined a 44 mL cutoff separating small (<44 mL; n = 160) and large (≥44 mL; n = 193) prostates. Logistic regression and cubic-spline analyses evaluated associations between prostate volume, PIRADS, and cancer outcomes. <b>Results</b>: Any cancer was detected in 74.3% of small versus 35.5% of large prostates (<i>p</i> < 0.001); CSPC in 42.5% vs. 19.6% (<i>p</i> < 0.001); HRPC in 14.3% vs. 5.5% (<i>p</i> < 0.001). Small prostate volume independently predicted any cancer (OR 7.31; 95% CI 4.22-12.7), CSPC (OR 5.08; 95% CI 2.87-8.99), and HRPC (OR 4.50; 95% CI 1.80-11.3). Between 40 and 70 mL, each 10 mL increase in volume reduced CSPC risk by 61% (<i>p</i> = 0.008). Prostate volume significantly modified PIRADS accuracy: in large glands, PIRADS 3 lesions carried only 2% risk for CSPC and 0% for HRPC, while in small prostates, PIRADS 3 conferred a 16.9-fold increased CSPC risk. <b>Conclusions</b>: Prostate volume inversely correlates with cancer detection and aggressiveness. PIRADS performance is volume-dependent; PIRADS 3 lesions in large prostates rarely represent significant cancer and may not warrant biopsy.