In patients with a suspicion for GG2+ prostate cancer who are undergoing biopsy, the CDRs associated with transrectal versus transperineal biopsy route are not significantly different.168, 310 Prior data from case series suggested that transperineal biopsy may detect anterior and apical cancers at a higher rate or yield longer cancer core length and percentage of core involvement.311-313 However, 2 subsequent meta-analyses, 1 of 11 retrospective series311  and another of 3 randomized controlled studies314 do not suggest a difference in the overall detection rates of clinically significant prostate cancer between the transperineal or transrectal biopsy approaches. Data from the pre- and post-MRI guided biopsy era suggest that similarity in cancer detection rates is consistent regardless of the use of MRI imaging.315 In the PERFECT trial, Ploussard et al. found that transrectal biopsies may have a higher rate of detection for peripheral zone cancers, while transperineal biopsies may be better at detecting anterior zone cancers.316 The most recently reported randomized trial on this topic, the TRANSLATE study, fell outside the search range for the updated search conducted in 2024.317 Data from the TRANSLATE suggest that the study was powered to demonstrate a difference of 10% in detection rate of Gleason GG2+ prostate cancer between those undergoing local anesthetic transperineal prostate biopsy (LATP) versus transrectal ultrasound (TRUS) guided biopsies. The actual difference detected was 6%. Almost all the differences between the groups favoring LATP biopsy was from a higher level of detection of GG2 cancer (52.8% versus 45.7%) with no differences between groups for detection of GG3+ prostate cancer. There was no difference in overall complication rates between the groups including infection requiring hospital admission. Local pain was higher among those undergoing LATP. All patients undergoing TRUS biopsy received antibiotic prophylaxis compared to only 11% in the LATP group. Per prespecified subgroup analysis, lesion site did not seem to affect detection rates, and the only significant variable was prostate volume with detection rate by LATP being higher in those with prostate volume < 50 cc. Prior meta-analyses and retrospective reviews of single center data suggest a lower risk of infections with the transperineal approach; however, these data are not entirely substantiated by recently reported RCTs (0.8% to 2.6% versus 0% to 2.7%; transperineal versus TRUS biopsies, respectively) including the recently reported TRANSLATE study (<1% versus 2%; transperineal versus TRUS biopsies, respectively).316-320 One has to acknowledge, however, that the usage of antibiotic prophylaxis is significantly lower to none in those undergoing transperineal biopsies. The three RCTs comparing transperineal and transrectal prostate biopsy had different primary endpoints and trial designs. The PREVENT trial320 and the PROBE-PC trial318, 319 were superiority trials aiming to demonstrate a difference in infectious complication rates of 0.4% versus 5% or 0.8% versus 4%, respectively, in the two trials, between the transperineal and the transrectal biopsy arms.318, 320 The PERFECT trial was a non-inferiority trial aimed at demonstrating equivalence in detection of clinically significant prostate cancer between transperineal and transrectal biopsy arms.316 It is noted that two of the three (PREVENT and PERFECT trials) and many of the recent studies on this subject have used patients exclusively undergoing MRI-guided prostate biopsies.314 Antibiotic regimen also varied between the two trials aimed at demonstrating differences in infection rates (PREVENT and PROBE-PC trials).314 In the PREVENT trial, patients undergoing transperineal biopsy did not receive any antibiotics, whereas those undergoing transrectal biopsy received prophylactic antibiotics based on prebiopsy rectal swab culture. In the PROBE-PC study, those undergoing transperineal biopsy received prophylactic antibiotics based on surgeon assessment of high risk (4/367 patients) while all patients undergoing transrectal biopsy received either 1 day of oral antibiotics or a combination of oral antibiotics and intramuscular antibiotics. The incidence of infection was not statistically significantly different between the two arms in any of the three randomized trials. It is also unclear if the administration of routine prophylactic antibiotics versus rectal swab directed antibiotics significantly impacts the occurrence of infectious complications.321, 322 There was one episode of sepsis in the PERFECT trial in the transrectal biopsy arm. The overall incidence of infectious complications of any kind was approximately 2% in either the transperineal or transrectal biopsy group.314 Some cohort studies do indicate a higher rate of urinary tract infections even with antibiotic prophylaxis in the transrectal biopsy patients.323 It is to be noted that the other potential complication of urinary retention was not statistically different between the transrectal or transperineal biopsy groups; rectal bleeding was more common among those undergoing transrectal biopsies, as was the incidence of prolonged hematospermia. Pain, particularly persistent pain, was more common among those undergoing transperineal biopsy versus transrectal biopsy.320, 324, 325 Use of transperineal biopsies may have specific value in patients who have experienced infectious complications with a prior biopsy, are at higher risk for biopsy-related infection, or have anterior lesions that may not be as easily accessible transrectally. There are multiple RCTs listed in clinicaltrials.gov that address these and other questions (<a href="https://clinicaltrials.gov/ct2/show/NCT04815876">https://clinicaltrials.gov/ct2/show/NCT04815876</a>, <a href="https://clinicaltrials.gov/ct2/show/NCT05179694">https://clinicaltrials.gov/ct2/show/NCT05179694</a>, <a href="https://clinicaltrials.gov/study/NCT05763355">https://clinicaltrials.gov/study/NCT05763355</a>) and the results are pending. Given the concern surrounding the rising rate of sepsis and antibiotic resistance, using transperineal biopsy to mitigate these concerns is a reasonable approach and is gaining traction. The lack of definitive results supporting the superiority of the transperineal biopsy approach either for clinically significant cancer detection or for reduction of infection rates render it difficult to exclusively emphasize the transperineal approach over the transrectal approach at this time. The transperineal approach requires specific equipment such as a biplanar linear side firing probe, precise delivery of local anesthetic, training in localization and other accessories which can facilitate the procedure. On the other hand, use of transrectal approach may be appropriate in certain situations (e.g., patient preference/comfort, patient cannot be placed into the lithotomy position, clinician training/experience or lack of appropriate equipment for the transperineal approach). Moreover, use of adjunctive measures (e.g., rectal swab cultures, augmented antibiotic approaches) to reduce sepsis for a transrectal biopsy approach have also been shown to reduce sepsis and have been effective in the randomized trials as well as in several retrospective studies, with lower than expected cases of infection complications including sepsis.326