Objectives: To compare the effect of different PSA density (PSAD) thresholds on the accuracy for clinically significant prostate cancer (csPCa) of the Prostate Imaging Reporting And Data System v.2.1 (PI-RADSv2.1). Methods: We retrospectively included 123 biopsy-naive men who underwent multiparametric magnetic resonance imaging (mpMRI) and transperineal mpMRI-targeted and systematic prostate biopsy between April 2019 and October 2020. mpMRI, obtained on a 3.0T magnet with a PI-RADSv2.1- compliant protocol, was read by two radiologists (>1500/>500 mpMRI examinations). csPCa was defined as International Society of Urogenital Pathology grading group ≥2. Receiver operating characteristic analysis was used to calculate per-index lesion sensitivity, specificity, and area under the curve (AUC) of PI-RADSv. 2.1 categories after adjusting for PSAD ≥0.10,≥0.15, and ≥0.20 ng/mL ml-1. Per-adjusted category cancer detection rate (CDR) was calculated, and decision analysis performed to compare PSAD-adjusted PI-RADSv. 2.1 categories as a biopsy trigger. Results: CsPCa prevalence was 43.9%. PSAD-adjustment increased the CDR of PI-RADSv2.1 category 4. Sensitivity/ specificity/AUC were 92.6%/53.6%/0.82 for unadjusted PI-RADS, and 85.2%/72.4%/0.84, 62.9%/85.5%/0.83, and 92.4%/53.6%/0.82 when adjusting PI-RADS categories for a 0.10, 0.15, and 0.20 ng/ml ml-1 PSAD threshold, respectively. Triggering biopsy for PI-RADS four lesions and PSAD ≥0.10 ng/mL ml-1 was the strategy with greatest net benefit at 30 and 40% risk probability (0.307 and 0.271, respectively). Conclusions: PI-RADSv2.1 category four with PSAD ≥0.10 ng/mL ml-1 was the biopsy-triggering cut-off with the highest net benefit in the range of expected prevalence for csPCa.
