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Investigator-initiated, multicentre, non-inferiority phase 3 RCT at seven Australian hospitals, randomised 1:1 (block sizes 2 or 4, stratified by site) via a central web system. No masking of participants or investigators. Enrolment March 2, 2022 to Aug 24, 2025; data cutoff Dec 5, 2025; median follow-up 6.0 months (IQR 5.1-7.0).

Biopsy-naive men with clinical suspicion of significant prostate cancer and PI-RADS 2 or 3 mpMRI plus at least one red flag (PSA density >0.1 ng/mL/mL, abnormal DRE, strong family history, BRCA mutation, PSA >10, PSA doubling time <36 months, or PSA velocity >0.75 ng/mL per year), PSA ≤20 ng/mL, clinical T2 or less. Median age 61 (IQR 56-66), median PSA 5.2 ng/mL, median PSA density 0.13; PI-RADS 2 in 335 (51%) and PI-RADS 3 in 325 (49%).

Experimental: pelvic-only [68Ga]Ga-PSMA-11 PET-CT within 28 days of randomisation, 1.8-2.2 MBq/kg, furosemide 20 mg recommended, acquisition 60-70 min post-injection, low-dose CT without contrast. PRIMARY score 3-5 → PSMA-targeted (plus MRI-targeted) transperineal biopsy; score 1-2 → no biopsy, PSA surveillance at 6, 12, 18 and 24 months. Control: systematic transperineal biopsy, minimum 12 cores.

Co-primary: proportion with clinically significant cancer (Gleason 3+4 with ≥10% pattern 4 or higher) on biopsy within 3 months, non-inferiority margin 10%; and proportion in the PET arm avoiding biopsy within 6 months, threshold 20%. Secondary: clinically insignificant cancer, alternate csPCa definitions, core number, interobserver variability, and patient-reported outcomes.

Both co-primaries met. Covariate-adjusted sensitivity analysis gave 8% vs 13%, difference -4.8% (95% CI -9.5 to -0.1); per-protocol gave 27 (11%) of 236 vs 47 (18%) of 255, difference -7.0% (-13.3 to -0.7). In the PET arm 166 (50%) of 329 scanned were PRIMARY-negative and 163 (50%) positive.

Post-biopsy symptoms were similar between arms: pain 33 (21%) experimental vs 62 (21%) control, haematuria 60 (38%) vs 126 (43%), haematospermia 77 (48%) vs 133 (45%). SHIM-assessed erectile dysfunction did not increase after biopsy (50 [31%] of 160 vs 91 [31%] of 294). The real safety argument is exposure avoided rather than toxicity reduced: 159 men had no biopsy at all.

The only prior evidence was the non-randomised PRIMARY cohort (2021), which reported improved NPV for csPCa in an MRI-triaged population going to systematic biopsy. A literature search to Dec 11, 2025 found no randomised trials of PSMA-PET in the diagnostic setting, so this is the first randomised test of the question rather than a confirmation of one.

Missing protocol biopsies were differential (35 [11%] control vs 7 [2%] experimental), and the prespecified worst-case scenario crosses the 10% margin once four of the 35 unbiopsied controls truly had csPCa, so the non-inferiority claim rests on how those men are counted. The 159 men who avoided biopsy carry no confirmatory histology at a median 6.0 months, and the trial reports 51 (8%) prostatectomies and 7 (1%) radiotherapy with definitive management deferred to the final analysis.

The trial answers a triage question, not a detection-accuracy question: it shows a PSMA-negative result can stand in for a negative biopsy over 6 months in a low-yield population, and that the biopsies still done return less indolent disease. What it does not settle is whether the avoided biopsies were truly negative, or whether the same result holds with an 18F-labelled tracer, at a non-accredited site, or in a health system where a PET costs more than the biopsy it replaces.

Randomised phase 3, prespecified co-primaries both met, so a triage step that halves biopsies is now tested evidence against a biopsy-everyone pathway. Short follow-up limits durability, not internal validity.