PROJECT SUMMARY There are clear limitations to the current approach to prostate cancer (PCa) diagnosis. Approximately half of the men who undergo a transrectal prostate biopsy—an extremely uncomfortable, invasive procedure with significant risk including sepsis—are not found to have PCa. For those who have PCa, many have indolent cancers that are best managed with active surveillance (AS), which requires annual repeat biopsies due to a lack of accurate noninvasive tools. Biomarkers and prostate magnetic resonance imaging (MRI) have been increasingly used to attempt to address this problem. However, the currently available tools are not accurate enough alone or in combination to forgo biopsy. We have developed a new MRI sequence (diffusion basis spectrum imaging) and a method of analyzing these imaging metrics—diffusion histology imaging (DHI)—that may overcome the limitations of conventional MRI interpretation. Preliminary data demonstrates high accuracy of DHI to predict prostate biopsy results (presence of cancer and grade of cancer when present). We aim to apply DHI to patients in two distinct clinical settings: Aim 1, initial biopsy for PSA screening, and Aim 2, repeat biopsy for known indolent PCa managed with AS. We also plan for Aim 3 to update our DHI model based on the data obtained in these aims, then recruit and test the updated DHI model in an independent group of patients undergoing PSA screening. We hypothesize that DHI will allow for accurate and non-invasive diagnosis of PCa, and thus reduce unnecessary biopsies. In our proposed studies, the men will have had biomarker testing, then receive a clinical prostate MRI (conventional sequences) with the DBSI imaging protocol added onto it prior to biopsy. The DBSI imaging will be analyzed post-acquisition by our DHI model. Note that the DBSI protocol will add just a few minutes to the total duration of the clinical MRI and will not significantly impact the patient or the clinical imaging workflow. In parallel to conventional MRI interpretation and biopsy per clinical care, our team will perform DHI analysis on the MRI images. By comparing DHI to biomarkers and conventional MRI against the histopathologic gold standard (biopsy) in a prospective manner, we will determine if DHI can be used to noninvasively diagnose and monitor PCa; therefore, supporting the clinical translation of DHI to be used as an alternative to invasive biopsies.