Defining a Safe Biopsy Deferral Strategy in Patients With Low‐Risk or Equivocal MRI Findings Using Prostate‐Specific Antigen‐Based Metrics

ABSTRACT Background Management of men with equivocal MRI findings remains uncertain, while low‐risk MRI may still harbor clinically significant prostate cancer (csPCa). We examined whether prostate‐specific antigen (PSA)‐based measures could identify a low‐risk subgroup suitable for biopsy deferral in patients with Prostate Imaging–Reporting and Data System (PI‐RADS) 1–3 lesions, and which clinical & imaging factors further refined risk stratification. Methods This prospective single‐center study included 473 consecutive patients with index PI‐RADS 1–3 findings on prostate MRI who underwent systematic and/or MRI/US fusion‐guided biopsy between May 2019 and December 2025. Patient‐level csPCa (grade group ≥ 2) detection rates (CDR) were calculated across PI‐RADS groups. csPCa detection, biopsy avoidance, and missed csPCa were assessed using biopsy‐deferral thresholds based on PSA (< 3 ng/mL), age‐adjusted PSA, and PSA density (PSAD) (< 0.10 and < 0.15 ng/mL 2 ). Logistic regression analyses identified independent predictors of PCa and csPCa. Results The cohort comprised 172 patients with PI‐RADS 1, 126 with PI‐RADS 2, and 175 with PI‐RADS 3 index lesions. In PI‐RADS 1–2, csPCa was detected in 2.2% (1/46) of patients with PSA < 3, whereas for PSAD < 0.10, the CDR was 5.3% (10/190). Avoided biopsy rates were 15.4% (46/298) and 63.8% (190/298), and missed csPCa rates were 3.3% (1/30) for PSA < 3% and 33.3% (10/30) for PSAD < 0.10, respectively. In PI‐RADS 1–3, csPCa was detected in 5.6% (4/76) of patients with PSA < 3 ng/mL, while for PSAD < 0.10, CDR was 8.8% (26/295). Biopsy avoidance was 16.1% (76/473) for PSA < 3 ng/mL and 62.4% (295/473) for PSAD < 0.10, with missed csPCa rates of 5.6% (4/71) and 36.6% (26/71), respectively. On multivariable analysis, higher log 2 (PSAD) was independently associated with csPCa in both PI‐RADS 1–2 (OR, 2.171; 95% CI, 1.255–3.757; p = 0.006) and PI‐RADS 1–3 (OR, 2.727; 95% CI, 1.844–4.033; p < 0.001) cohorts. In patients with index PI‐RADS 1–3 findings, prior negative biopsy was independently associated with lower odds of csPCa (OR = 0.425; 95% CI, 0.182–0.991; p = 0.048). Non‐diagnostic MRI quality was independently associated with PCa detection in the PI‐RADS 1–2 cohort (OR, 2.367; 95% CI, 1.276–4.388; p = 0.006). Conclusions In men with index PI‐RADS 1–3 lesions, PSA < 3 ng/mL identified a very low‐risk subgroup with low csPCa detection, and few missed csPCa. Conventional PSAD cutoffs performed worse for biopsy deferral, with a higher rate of missed csPCa. Biopsy decisions for PI‐RADS 1–3 lesions are best guided by a composite assessment that incorporates PSA, PSAD, PI‐RADS category, prior biopsy status, MRI quality, and lesion burden.