This systematic review and meta-analysis aimed to determine the optimal strategy for combining MRI Prostate Imaging Reporting and Data System (PI-RADS) and clinical data to decide whether to perform a prostate biopsy in men with suspected clinically significant prostate cancer (csPCa). The study included 72 studies with 36,366 patients, evaluating the association between PI-RADS scores and clinical parameters with csPCa. Univariable meta-regression showed that PI-RADS 4 and 5 lesions were significantly associated with a higher risk of csPCa, while PI-RADS 3 lesions were not. Multivariable meta-regression identified prostate-specific antigen density (PSAD) as the only independent clinical factor associated with csPCa, alongside PI-RADS 5. The strategy of avoiding biopsy in patients with PI-RADS 3 or less and PSAD <0.10 ng/mL reduced unnecessary biopsies by 30%, maintaining a sensitivity of 97%. Similarly, avoiding biopsy in patients with PI-RADS 3 or less and PSAD <0.15 ng/mL reduced unnecessary biopsies by 48%, with a sensitivity of 95%. These findings suggest that combining PI-RADS with PSAD can help avoid unnecessary biopsies while maintaining high sensitivity.This systematic review and meta-analysis aimed to determine the optimal strategy for combining MRI Prostate Imaging Reporting and Data System (PI-RADS) and clinical data to decide whether to perform a prostate biopsy in men with suspected clinically significant prostate cancer (csPCa). The study included 72 studies with 36,366 patients, evaluating the association between PI-RADS scores and clinical parameters with csPCa. Univariable meta-regression showed that PI-RADS 4 and 5 lesions were significantly associated with a higher risk of csPCa, while PI-RADS 3 lesions were not. Multivariable meta-regression identified prostate-specific antigen density (PSAD) as the only independent clinical factor associated with csPCa, alongside PI-RADS 5. The strategy of avoiding biopsy in patients with PI-RADS 3 or less and PSAD <0.10 ng/mL reduced unnecessary biopsies by 30%, maintaining a sensitivity of 97%. Similarly, avoiding biopsy in patients with PI-RADS 3 or less and PSAD <0.15 ng/mL reduced unnecessary biopsies by 48%, with a sensitivity of 95%. These findings suggest that combining PI-RADS with PSAD can help avoid unnecessary biopsies while maintaining high sensitivity.