PROJECT SUMMARY/ABSTRACT Prostate cancer is the most commonly diagnosed malignancy in U.S. men. There are approximately 1 million prostate biopsy (Bx) performed annually in the U.S. Almost all Bx are performed as an office based procedure in under 15 minutes. The precision of Bx has improved over the last decade with the introduction of MRI guidance/targeting of suspicious lesions within the prostate. However, significant limitations remain with this approach, including a significantly increasing risk of post-Bx infection. This arises because more than 97% of all prostate Bx are performed via a transrectal (TR) approach that introduces rectal bacteria with each pass of the Bx needle into the sterile urinary tract. The current risk of post-TR Bx infection, even with antimicrobial prophylaxis, is high at approximately 7% overall with 3% (30,000 men) requiring hospitalization annually. Transperineal (TP) Bx is an alternate approach that eliminates the direct introduction of bacteria from the rectum to the prostate. This approach, which is perfomed without antimicrobial prophylaxis, instead passes the Bx needle through the perineal skin and pelvic floor. TP Bx has not been widely adopted for several reasons. Historically, it has been considered too painful for patients in the clinic and thus was traditionally performed under general anesthesia. The added time, inconvenience and cost has limited its national adoptance. Second when TR Bx was initially adopted over 40 years ago, antibiotic resistance of rectal flora was not a challenge. Beyond the potential for in-office TP Bx to significantly reduce or eliminate Bx infections, TP Bx may also improve cancer detection as studies of TP Bx (performed under general anesthesia) demonstrate higher detection rates for prostate cancer, particularly for anterior zone tumors, compared to TR Bx. This is notable as anterior tumors are difficult to sample with TR Bx. Anterior tumors are also twice as likely to occur in African American men. In fact, our research demonstrates that some of the outcomes disparities in African American men may stem from an underdiagnosis of anterior prostate cancers. Although TR Bx is used widely, it is associated with a significant and increasing risk of Bx infections due to growing antibiotic resistance, highlighting the urgent need for a safer alternative approach to prostate Bx. We have refined a TP Bx approach under local anesthesia with MRI-targeting/guidance without the need for antibiotic prophylaxis. We hypothesize that TP MRI targeted Bx will: (1) largely eliminate post-Bx infections and costly hospitalizations for urosepsis; (2) be performed in the office with similar discomfort and non-infectious complications compared to TR MRI targeted Bx; and (3) have significantly better detection of prostate cancer. A multi-center randomized controlled trial will be conducted to evaluate in-office TP MRI targeted vs. TR MRI targeted Bx, the current gold standard. This has transformati...