Approximately 1 million prostate biopsies are performed yearly in the United States, with only ~25% resulting in prostate cancer diagnosis. However, ~40% of men receive multiple biopsies for fear of cancer being missed. DNA hypermethylation is ideally suited for early disease detection and could be used to prevent unnecessary biopsies. Men with low-risk epigenetic signatures may forego subsequent biopsy and potential complications. A meta-analysis of two validation studies was conducted to gain additional insight into the benefits for patient risk stratification. In the Methylation Analysis to Locate Occult Cancer (MATLOC) study a negative predictive value of 90% was obtained, which represents a significant improvement over standard of care. This was confirmed in the Detection of Cancer Using Methylated Events in Negative Tissue (DOCUMENT) study (88% negative predictive value), which was designed to validate the performance in an independent cohort. The epigenetic assay, in combination with other known risk factors, may help reduce unnecessary repeat prostate biopsies and identify men at highest risk of harboring occult high-grade prostate cancer.