Prostate
PSMA-PET tested as a biopsy triage tool in biopsy-naive men, the first RCT after the non-randomised PRIMARY study.
PRIMARY2 NCT05154162
ForBiopsy-naive suspected PCa, PI-RADS 2 + red flag or PI-RADS 3, PSA โค20, โคcT2
12% vs 16%
โ3.7% (95% CI โ8.9 to 1.5), p=0.0093; non-inferior at 10% margin
TL;DRBiopsy avoided in 49%; csPCa 12% vs 16% with PSMA-PET vs systematic biopsy, non-inferior in ITT, in biopsy-naive men with equivocal or high-risk non-suspicious MRI.
The csPCa shortfall sits in GS 3+4 disease: GS โฅ4+3=7 was found in 14 (4%) PSMA-PET vs 16 (5%) biopsy pts, while clinically insignificant diagnoses fell from 105 (32%) to 46 (14%). Men reaching definitive-treatment consults through this pathway are filtered away from low-grade disease, not from GS โฅ4+3; only 7 (1%) have had RT so far.
In a biopsy-naive man with PI-RADS 3, or PI-RADS 2 plus a red flag, and PSA โค20 ng/mL, this informs replacing systematic biopsy with PSMA-PET triage and PSA surveillance if PET-negative; it does not extend to PI-RADS 4โ5 MRI. The longer read
Half the PSMA-PET arm (163/331) avoided biopsy, and biopsied pts needed fewer cores (mean 19.6 vs 24.8). The catch for the proceduralist: 35 control pts never got their biopsy vs 7 PSMA-PET, and non-inferiority fails in the worst case once 4 of those 35 are assumed csPCa.
8 details
Investigator-initiated phase 3 non-inferiority RCT at seven Australian hospitals; 1:1 web-based randomisation stratified by site, no masking. N=660 (329 systematic biopsy, 331 PSMA-PET); median follow-up 6.0 mo (IQR 5.1โ7.0).
Biopsy-naive men with suspected csPCa and PI-RADS 3, or PI-RADS 2 plus โฅ1 red flag (PSA density >0.1 ng/mL/mL, abnormal DRE, strong family history, BRCA mutation, PSA >10 ng/mL, PSA doubling time <36 mo, PSA velocity >0.75 ng/mL/yr); PSA โค20 ng/mL, โคcT2. Median age 61, median PSA 5.2 ng/mL, PI-RADS 2 in 335 (51%).
Experimental: pelvic-only [68Ga]Ga-PSMA-11 PET-CT (1.8โ2.2 MBq/kg) read on the PRIMARY score; score 3โ5 โ PSMA-targeted TP biopsy, score 1โ2 โ no biopsy and PSA review at 6, 12, 18, 24 mo. Control: systematic TP biopsy, โฅ12 cores, MRI-targeted cores permitted for PI-RADS 3.
Co-primary: csPCa (GS 3+4 with โฅ10% pattern 4, or higher) on biopsy within 3 mo, NI margin 10%; and biopsy avoidance within 6 mo in the PSMA-PET arm vs a 20% threshold. Secondary: clinically insignificant PCa, alternate csPCa definitions, core number, inter-reader agreement, complications and PROs.
Both co-primaries met in ITT: csPCa detection non-inferior (p=0.0093) and biopsy avoided in 163 (49%) of 331. 166 (50%) of 329 scanned were PRIMARY-negative; central vs local agreement ฮบ=0.81 (95% CI 0.75โ0.87).
| Endpoint | PSMA-PET | Systematic biopsy | Difference |
|---|---|---|---|
| csPCa (GS 3+4 with โฅ10% pattern 4, or higher) | 39 (12%) | 51 (16%) | โ3.7% (95% CI โ8.9 to 1.5), p=0.0093, NI |
| Clinically insignificant PCa | 46 (14%) | 105 (32%) | โ18% (97.5% CI โ25 to โ11), p<0.0001 |
| No cancer on biopsy | 73 (22%) | 138 (42%) | not reported |
| GS โฅ3+4=7 (any pattern 4 fraction) | 56 (17%) | 79 (24%) | โ7.1% (95% CI โ13.2 to โ1.0) |
| GS โฅ4+3=7 | 14 (4%) | 16 (5%) | โ0.6% (โ3.8 to 2.5) |
| Mean cores per biopsied pt | 19.6 (SD 12.1) | 24.8 (SD 9.0) | not reported |
| MRI | PSMA-PET | Systematic biopsy |
|---|---|---|
| PI-RADS 2 | 15/155 (10%) | 22/180 (12%) |
| PI-RADS 3 | 24/176 (14%) | 29/149 (19%) |
| Analysis | PSMA-PET | Systematic biopsy | Difference (95% CI) |
|---|---|---|---|
| Covariate-adjusted (prespecified) | 8% | 13% | โ4.8% (โ9.5 to โ0.1) |
| Per-protocol (prespecified) | 27/236 (11%) | 47/255 (18%) | โ7.0% (โ13.3 to โ0.7) |
| Biopsy per protocol (post-hoc) | 39/324 (12%) | 51/294 (17%) | โ5.3% (โ11.0 to 0.3) |
| Best case (prespecified) | 14% | 16% | โ1.6% (โ7.3 to 4.1) |
Among biopsied pts, pain 33 (21%) PSMA-PET vs 62 (21%) control, haematuria 60 (38%) vs 126 (43%), haematospermia 77 (48%) vs 133 (45%). SHIM-assessed erectile dysfunction did not rise after biopsy: 50 (31%) of 160 vs 91 (31%) of 294.
The MRI-first pathway (PROMIS, PRECISION) defines who with a suspicious scan is biopsied; PRIMARY2 targets the equivocal or non-suspicious MRI group it leaves behind. The prior evidence was the non-randomised PRIMARY study, which showed improved NPV for csPCa in an MRI-triaged population, and the authors found no prior RCT of PSMA-PET in the diagnostic setting.
Per-protocol analysis excluded 169 (26%) of 660 for out-of-window imaging or biopsy, or off-protocol biopsy type. Baseline MRI mix was imbalanced (PI-RADS 2 in 55% control vs 47% PSMA-PET), and the csPCa gap was wider in PI-RADS 3 (14% vs 19%). Single-country, accredited-camera Ga-68 protocol; ethnicity not collected.
The biopsy-avoidance benefit is clear; the detection claim rests on the ITT and covariate-adjusted analyses, since per-protocol and post-hoc bounds fall past the margin. The shortfall concentrates below GS 4+3 (GS โฅ4+3=7: โ0.6%), so the open question is whether PSA surveillance recaptures missed GS 3+4 disease in the 159 unbiopsied PET-negative men.
CONSORT flow
ITT met the 10% NI margin, but per-protocol (lower CI โ13.3) and post-hoc (โ11.0) bounds cross it; 35 vs 7 unbiopsied pts, worst case fails at 4.
- Missed csPCa in PET-negative men on PSA surveillance beyond 6 months
- Transferability to other PSMA radiopharmaceuticals and centres
- Cost-effectiveness of PSMA-PET triage vs systematic biopsy