PROJECT SUMMARY/ABSTRACT Prostate cancer (PCa) is the most commonly diagnosed type of cancer and the second leading cause of cancer related death among US men. The best current estimate of PCa aggressiveness is the Gleason score obtained from core biopsy. The most common biopsy method is freehand transrectal ultrasound (TRUS) guided. Since ultrasound only rarely identifies PCa visually, systematic biopsy (SB) intends to sample the prostate evenly. But freehand SB is highly inconsistent, subjective, and results in uneven sampling, leaving large regions of the prostate unsampled, which can lead to under-sampling of clinically significant cancer and under-staging of PCa diagnosis at biopsy. The current trend in prostate biopsy is directed towards a targeted biopsy (TB) approach guided by multiparametric Magnetic Resonance Imaging (mpMRI). Several advanced biopsy devices are available and register (fuse) the mpMRI to interventional ultrasound. TB yield a higher significant PCa detection rate than SB. But SB on patients with no mpMRI findings found many men to harbor PCa, so SB is currently performed in addition to TB. However, SB use the same 12-core extended sextant plan for all patients regardless of their gland shape. Moreover, significant variability exists among urologists at freehand biopsy, even with the fusion devices. Our team has developed and tested the feasibility of a novel robotic device that takes SB from a one- size-fits-all to a patient-optimized plan, and from a freehand to a hands-free skill-independent robot- assisted procedure. No similar devices currently exist. This technology consists of a robotic ultrasound probe manipulator and software for ultrasound processing, robot control, fusion TB, and optimized SB planning. Our novel SB planning software optimizes the biopsy core locations for each patient to maximize the likelihood of detecting clinically significant PCa and taking into account mpMRI visible lesions, if available. The robotic device was cleared for clinical trials by the Food and Drug Administration and our Institutional Review Board approved the study. A Phase 0, Safety and Feasibility clinical trial was successfully completed. We propose a Phase I clinical trial to gain early evidence on the effectiveness of personalized biopsy planning and precision biopsy to improve the detection rate of clinically significant PCa in a randomized clinical trial versus one of the most common fusion biopsy devices on the market. The specific aims of the 5-year project are: A1) Perform randomized clinical trial of robot vs. the fusion device. Include patients with mpMRI exams. On each arm, perform SB on PI-RADS≤2 and TB+SB on PI-RADS≥3 patients; A2) Record pathology from subset of patients of A1 who proceed to radical prostatectomy, and compare biopsy to prostatectomy results on both arms; A3) Offline, simulate SB alone plans for patients who undergo SB+TB and determine if SB cores could overlap TB locations;