In a systematic review of 42 studies, the NPV of a “negative” MRI (defined as PI-RADS 1 to 2) to detect GG2+ prostate cancer among biopsy-naïve patients was 91%.165 Thus, approximately 1 in 10 patients who have a negative prostate MRI may have GG2+ cancer on biopsy, although rates widely vary by study and the risk factors of the individual person. If the definition of a “negative” MRI was expanded to include PI-RADS 3, then NPV decreased to 87%.165 Multiple factors contribute to risk calculation, including race, age, total PSA, PSA density, percent free PSA, and family history of prostate cancer, as used in available risk calculators. Therefore, patients with elevated risk for GG2+ prostate cancer and absence of findings on MRI should proceed with a systematic biopsy. Among the factors to predict clinically significant prostate cancer in patients with negative (PI-RADS 1 to 2) or equivocal (PI-RADS 3) results, PSA density (i.e., serum PSA divided by gland volume) has been the most extensively investigated. Haj-Mirzaian et al. conducted a systematic review and meta-analysis of 72 studies including 36,366 patients to determine the optimal prostate biopsy decision-making strategy for avoiding unnecessary biopsies and minimizing the risk of missing clinically significant cancers by combining MRI PI-RADS scores and clinical data. In patients with negative MRI (PI-RADS 1 to 2), adding PSA density significantly improved the ability to exclude clinically significant prostate cancer. Using a PSA density threshold of 0.15 ng/mL/cc, biopsy could be avoided in up to 67% of patients with GG2+ prostate cancer while maintaining a 94% NPV. Similarly, in those with equivocal MRI (PI-RADS 3), using a PSA density threshold of 0.10 ng/mL/cc, biopsy could be avoided in up to 43% of patients while maintaining a 93% NPV. The strategy to forego biopsy in those with PI-RADS 3 or less and PSA density less than 0.10 ng/mL2 or less than 0.15 ng/mL2 would avoid 30% or 48% of unnecessary biopsies, respectively, while maintaining sensitivity of 97% or 95%, respectively. Across analyses, PSA density was consistently the strongest predictor of clinically significant disease in MRI-negative or equivocal cases, outperforming total PSA and other clinical factors. These findings suggest that incorporating PSA density could guide biopsy decisions in patients with negative or equivocal MRI findings, reducing unnecessary procedures.166 A systematic biopsy should include a minimum of 12 cores, distributed throughout the prostate, with thorough sampling of the peripheral zone. Various templates employing these principles exist for transrectal and transperineal approaches.167-170 If a decision is made after SDM to omit a systematic biopsy, patients should be informed of their risk for underdiagnosing clinically significant prostate cancer.