The PRIMARY2 Phase 3 Trial: PSMA PET/CT Halves Prostate Biopsies in Equivocal MRI Findings

KEY FINDINGS

• Trial: PRIMARY2 is the first phase 3 randomized controlled trial to evaluate PSMA PET/CT for diagnostic purposes; 660 biopsy-naive men were randomized at seven Australian centres.
• Avoidance of biopsy: 49% (163/331) of patients in the PSMA PET/CT arm were able to avoid biopsy (95% CI 44-55; p<0.0001).
• Detection of significant cancer: The detection rate of ISUP ≥2 cancer was 12% (39/331) in the PSMA PET/CT arm and 16% (51/329) in the systematic biopsy arm; a difference of -3.7% (p=0.0093) - non-inferiority was met.
• Overdiagnosis fell: The diagnosis of clinically insignificant cancer (ISUP 1) was 32% in the biopsy arm versus 14% in the PSMA PET/CT arm (a difference of -18%; p<0.0001).
• High-grade disease was not missed: The rate of Gleason 4+3 and higher disease was similar in the two arms (4.2% - 4.8%).
• Reproducibility: Inter-reader agreement for the PRIMARY score was κ=0.81.

Background: The Clinical Dilemma of an Equivocal MRI Finding

Multiparametric prostate MRI (mpMRI) has transformed the prostate cancer diagnostic pathway; with PRECISION and similar trials, MRI-led targeted biopsy has become the standard approach. Nevertheless, an important grey area persists in daily practice: patients with PI-RADS 2 (non-suspicious) findings but high clinical risk, and PI-RADS 3 (equivocal) lesions.

In this patient group the decision is squeezed between three options: skipping biopsy entirely and accepting the risk of missing a significant cancer; performing a systematic biopsy and accepting both procedure-related morbidity and the overdiagnosis of clinically insignificant cancers; or deferring the decision with surveillance and repeat PSA. Although infection risk has fallen with transperineal biopsy, the need for anaesthesia and the risks of haematuria, haematospermia, pain and acute retention persist. More importantly, a significant proportion of the ISUP 1 cancers detected will remain clinically silent throughout the patient's lifetime while bringing the label of "cancer" and its accompanying psychological burden.

What is the PRIMARY score? It is a structured 1-5 reporting system developed to allow PSMA PET/CT to be used in the diagnosis of the primary tumour rather than only for metastatic staging. The pattern of PSMA uptake within the prostate (focal/diffuse, transition/peripheral zone), its intensity (SUVmax) and its anatomical distribution are assessed together. Scores 1-2 are considered negative and 4-5 positive; score 3 is classified according to an SUVmax threshold.

Study Design

PRIMARY2 is an investigator-initiated, multicentre, non-inferiority phase 3 randomized controlled trial. The results were first presented at the 2026 EAU Annual Congress (Abstract GC26-006) and subsequently published in The Lancet Oncology.

Key Results

The most noteworthy aspect of this table is that two results were achieved at the same time: biopsy numbers were halved while the detection rate of clinically significant cancer was preserved, and the burden of unnecessary diagnosis fell markedly. Whereas a trade-off between sensitivity and specificity is usually expected in diagnostic pathways, the markedly increased uptake of PSMA PET/CT in aggressive tumours has largely eliminated that trade-off.

Implications for Clinical Practice

1. A new step in the diagnostic pathway: post-MRI triage

PRIMARY2 extends the role of PSMA PET/CT beyond staging in advanced disease and theranostic patient selection. The findings show that in patients in whom MRI remains equivocal, PSMA PET/CT can be positioned as a second filter guiding the biopsy decision.

2. Directly addressing the problem of overdiagnosis

The most deep-rooted criticism of prostate cancer screening is overdiagnosis. The fall in the diagnosis of insignificant cancer from 32% to 14% is a technological answer to that criticism: roughly 18 in every 100 patients are protected from a "cancer" diagnosis that would bring them no clinical benefit, along with the accompanying active surveillance protocols, repeat biopsies and psychological burden.

3. Patient experience and psychological burden

The anticipation of biopsy, the procedure itself and the period of waiting for the result are the stages at which anxiety is most intense. Being able to offer roughly half of patients an imaging-based, non-invasive reassurance is not merely a reduction in the number of procedures but a qualitative improvement in the patient experience.

4. Feasibility: resources, cost and access

The main obstacle to disseminating these results is not clinical but infrastructural. PSMA PET/CT is a method requiring nuclear medicine infrastructure, a radiopharmaceutical supply chain and experienced reporting. However, a cost analysis performed per scan alone would be misleading: the biopsies avoided, the complications prevented and the cost of years of active surveillance in unnecessarily diagnosed patients must be included in the equation.

5. Limitations

The population is narrowly defined: biopsy-naive patients with PSA <20 ng/mL and PI-RADS 2-3. Lesions with high PI-RADS scores, candidates for repeat biopsy and patients on active surveillance fall outside these data. The trial was conducted in a single country at highly experienced centres. In addition, confirming long-term oncological safety with follow-up data in patients who avoided biopsy is critically important.

From the uro-oncological surgeon's perspective: Diagnosing clinically insignificant disease less often means that indications for radical treatment are directed to a more appropriate population - that is, robotic radical prostatectomy performed in patients who will genuinely benefit. Conversely, in patients selected by a positive PSMA PET/CT, the surgical population can be expected to shift towards a higher-risk profile; this will increase the importance of nerve-sparing techniques, extended lymph node dissection and multidisciplinary planning.

Conclusion

PRIMARY2 is an important trial generating level 1 evidence in the prostate cancer diagnostic pathway. In biopsy-naive men with equivocal MRI findings, adding 68Ga-PSMA-11 PET/CT halved the need for biopsy, preserved the detection rate of clinically significant cancer and markedly reduced overdiagnosis.

These findings support considering the inclusion of PSMA PET/CT in the diagnostic workflow in appropriately selected patients. Its entry into routine practice, however, depends on resolving accessibility, cost-effectiveness and standardisation of reporting. Until a guideline-level recommendation emerges, this approach should be handled at experienced centres and within a framework of multidisciplinary assessment.

References

• Emmett L, Buteau J, Papa N, et al. Effect of [68Ga]Ga-PSMA-11 PET-CT in the diagnosis of prostate cancer in men with equivocal or clinically high-risk non-suspicious findings on multiparametric MRI (PRIMARY2): a multicentre, non-inferiority, phase 3, randomised controlled trial. The Lancet Oncology, 10 June 2026.
• The ASCO Post. PSMA PET/CT Scan Reduces Need for Prostate Cancer Biopsies by 50%. 18 March 2026.
• Urology Times. PRIMARY2: PSMA-PET/CT can safely reduce prostate biopsies in men with equivocal MRI.
• UroToday. EAU 2026: PRIMARY2 - Impact of 68Ga-PSMA-11 PET/CT in the Diagnosis of Prostate Cancer in Men with Equivocal or Non-Suspicious Findings on mpMRI.
• Renal & Urology News. PSMA PET After MRI Reduces Biopsies, Maintains Clinically Significant PCa Detection.
• European Urology Open Science. Clinical Trial Protocol for PRIMARY2.