Transition from Transrectal Systematic to Transperineal Lesion-Focused Prostate Biopsy: A Real-World Comparative Analysis

<b>Background/Objectives:</b> The transperineal (TP) approach has progressively replaced the transrectal (TR) approach for prostate biopsy because of its improved safety profile. However, its impact on the detection of clinically significant prostate cancer (csPCa), particularly within modern lesion-focused biopsy strategies that combine targeted and perilesional sampling, remains uncertain. We aimed to evaluate the real-world diagnostic impact of transitioning from a TR systematic-based biopsy strategy to a TP lesion-focused approach. <b>Methods:</b> We conducted a retrospective single-centre study including consecutive men who underwent image-guided prostate biopsy between 2018 and 2025. Only patients with a single MRI-visible lesion (PI-RADS ≥ 3) were included. Two biopsy strategies were compared: TR systematic biopsy (TR-SBx), combining targeted and systematic cores, and TP lesion-focused biopsy (TP-LFx), combining targeted and perilesional cores. The primary outcome was the detection of csPCa (Gleason Grade Group ≥ 2). Secondary outcomes included detection of Gleason Grade Group 1 cancer and negative biopsies. Inverse probability of treatment weighting (IPTW) based on a propensity score was applied to adjust for baseline differences. Doubly robust weighted logistic regression models were used, with predefined subgroup and sensitivity analyses. <b>Results:</b> Among 1032 included patients, 931 underwent TR-SBx and 101 TP-LFx. After restriction to the region of common support, 528 patients were retained for IPTW analyses. In the IPTW-adjusted analysis, TP-LFx was associated with higher csPCa detection compared with TR-SBx (adjusted odds ratio [OR] 2.52, 95% confidence interval [CI] 1.40-4.52; <i>p</i> = 0.002) and with lower detection of Gleason Grade Group 1 cancer (OR 0.50, 95% CI 0.27-0.92; <i>p</i> = 0.03). Subgroup analyses suggested a stronger association in patients with prior negative biopsy and in anterior or apical lesions. <b>Conclusions:</b> In routine clinical practice, transitioning from a transrectal systematic-based biopsy strategy to a transperineal lesion-focused approach was associated with improved detection of csPCa and reduced overdiagnosis. These findings support the consideration of transperineal, lesion-focused MRI-guided biopsy strategies in contemporary prostate cancer diagnostics.