Blood-, urine-, or tissue-based biomarkers may provide additional information for risk stratification in patients with a prior negative biopsy and with ongoing suspicion for GG2+ prostate cancer. Several blood-, urine-, and tissue-based biomarkers have been developed and reported in several studies with varying performance characteristics. These tests generally present percentage risk of biopsy-detectable disease (and/or GG2+), and it is up to the clinician and patient to decide on the threshold for proceeding with a biopsy with consideration given to the performance metrics of the test. For example, the proportion of GG2+ prostate cancer missed by 4Kscore at ³ 10%, 15%, and 20% threshold were 5%, 16%, and 16%, respectively, which might impact a patient’s decision to pursue a repeat prostate biopsy.199 In another example, a validation study showed that using a threshold of 40 for MPS would result in 95% NPV and avoid 67% of biopsies among those considering repeat prostate biopsy.253 The MPS2 urine-based biomarker may help avoid half of biopsies while maintaining 95% sensitivity for GG2 cancer detection.182 Additionally, there is significant heterogeneity in the outcomes reported for these biomarkers. For example, ConfirmMDx, the only tissue-based biomarker assessing epigenetic changes in GSTP1, APC, RASSF1 in negative biopsy tissue was developed in the MATLOC study254 and validated in the DOCUMENT255 study to detect any prostate cancer and not specifically for GG2+ disease. Moreover, how to integrate the use of these tests with mpMRI in prostate cancer early detection paradigms is yet to be studied comprehensively.211, 212, 256 In a study, combining mpMRI with PHI improved the NPV of mpMRI from 78% to 95% and AUC from 0.64 to 0.75 for detecting GG2+ cancer.211 In a recent study, MPS was shown to be significantly associated with GG2+ cancer across all PI-RADS scores inclusive of PI-RADS 3 lesions.256 Pending future prospective validation studies, biomarkers may augment mpMRI for identifying patients for prostate biopsy especially in patients with negative or equivocal mpMRI findings but with ongoing suspicion for GG2+ cancer. It is imperative clinicians are familiar with biomarkers, understand what information or data each test provides, and consider whether additional information will impact management decisions before ordering a test. As in the PSA screening setting, the use of SDM is highly recommended given the uncertainty involved.