PRIMARY2: PSMA-PET/CT can safely reduce prostate biopsies in men with equivocal MRI

Use of prostate-specific membrane antigen (PSMA)-PET/CT in men with clinical risk factors but non-suspicious or equivocal MRI findings reduced the need for prostate biopsy by nearly half without significantly compromising the detection of clinically significant prostate cancer, according to results from the phase 3 PRIMARY2 trial (NCT05154162) presented at the 41st Annual Congress of the European Association of Urology in London, UK.¹

James Buteau, MD, FRACP, FRCPC, who presented the results on behalf of all the investigators, explained that multiparametric MRI has become a central component of prostate cancer diagnosis and is recommended by major guidelines for risk stratification before biopsy.² However, patients with equivocal or non-suspicious MRI findings may still undergo biopsy when clinical risk factors persist, often leading to detection of indolent disease or negative biopsy results.

PSMA-PET imaging has gained widespread attention for its ability to detect prostate cancer lesions through radiotracers that bind to PSMA, a cell-surface protein highly expressed in most prostate cancer cells. Prior work on PSMA-PET has shown that the modality can differentiate between pattern 4 and pattern 3, “making this potentially ideal to detect clinically significant prostate cancer,” Buteau explained.

PRIMARY2 is among the first randomized trials to evaluate PSMA PET for the intraprostatic diagnosis of prostate cancer before biopsy.

“PSMA PET/CT scanning makes prostate cancer cells light up in a remarkable way, particularly in more aggressive cancers,” explained Buteau, who is a nuclear medicine physician at the Peter MacCallum Cancer Centre in Australia.³ “It’s rare to see such strong imaging that could be so powerful in the clinic. Incorporating this testing into clinical care could help to address the major challenge of prostate cancer overdiagnosis, which leads to at best unnecessary and at worst harmful treatment for cancers that would never cause any harm.”

The investigator-initiated, randomized phase 3 PRIMARY2 trial was conducted across 7 centers in Australia. The study enrolled 660 biopsy-naïve men with suspected prostate cancer who had non-suspicious or equivocal multiparametric MRI findings (PI-RADS 2 or 3) but additional clinical risk factors such as elevated prostate-specific antigen (PSA) density (>0.1) or strong family history.

Participants were randomly assigned in a 1:1 ratio to undergo standard-of-care transperineal systematic biopsy (n = 329) or an imaging-based strategy using pelvic [⁶⁸Ga] Ga-PSMA-11 PET/CT (n = 331).

In the experimental arm, patients with positive PSMA-PET findings (n = 163)—defined by a PRIMARY score of 3 to 5—underwent targeted biopsy guided by PSMA-PET and MRI findings. Those with negative scans (PRIMARY scores 1 or 2; n = 166) avoided biopsy and entered surveillance.

The study included 2 co-primary end points analyzed in the intention-to-treat population: detection of clinically significant prostate cancer, defined as Gleason score 3+4 with at least 10% pattern 4; and the proportion of patients who avoided biopsy within 6 months. The trial’s key secondary end point was the proportion of patients with clinically insignificant prostate cancer.

Baseline characteristics were similar between both arms.

Biopsy avoidance occurred in 49% of patients (95% CI, 44 to 55) assigned to the PSMA-PET arm (163 of 331), meeting the prespecified threshold for clinical significance (P < .0001). Meanwhile, detection of clinically significant prostate cancer occurred in 12% of patients in the PSMA-PET arm compared with 16% in the systematic biopsy arm, representing a difference of -3.7% (95% CI, -8.9 to 1.5) that fell within the prespecified noninferiority margin (P = .0093). When defining clinically significant prostate cancer as a Gleason score of 4 + 3 = 7 or higher, the detection of clinically significant prostate cancer occurred in 4.2% of patients in the experimental arm vs 4.8% of patients in the control arm (difference, -0.63; 95% CI, -3.8 to 2.5).

The PSMA-PET strategy also significantly reduced diagnoses of clinically insignificant prostate cancer. Low-risk disease was identified in 14% of patients in the experimental group compared with 32% in the control group, a difference of -18% (P < .0001).

Interpretation of PSMA-PET scans demonstrated strong inter-reader agreement between local and central reviewers (κ = 0.81), suggesting reproducibility of the imaging scoring system used in the study.

Commenting on the findings, co-lead investigator Louise Emmett, director of theranostics and nuclear medicine at St Vincent's Hospital, Sydney, added, “Getting told you have a risk of prostate cancer is a huge cause of anxiety and concern. Our findings show that PSMA PET/CT after MRI offers a 'belt and braces' approach that can determine which people have a clinically significant cancer, and which people are at low risk and don’t need a biopsy or further testing. PRIMARY2 is the largest of a series of studies undertaken by this group, exploring whether PSMA PET/CT scanning could improve prostate cancer diagnosis and reduce unnecessary biopsies for patients.”

During the presentation, Buteau noted several limitations of the current study, including the contentious definition of clinically significant prostate cancer and the fact that MRI was not centrally reviewed. He emphasized that longer-term follow-up will better inform on the outcomes of these patients, as well as the impact of this workflow on cost and patient anxiety and worry.

“In summary, the addition of PSMA-PET to high clinical risk PI-RADS 2 or 3 MRI halved the number of men requiring biopsy, and this led to a reduction of the diagnosis of insignificant malignancy without compromising the diagnosis of clinically significant prostate cancer,” Buteau concluded during the presentation.¹ “I would like to first and foremost thank all the participants who enrolled in the trial, as well as all the urologists who recruited these patients and followed them very closely.”

REFERENCES

1. Buteau JP, Moon D, Fahey MT, et al. Impact of [68Ga]Ga-PSMA-11 PET/CT in the diagnosis of prostate cancer in men with equivocal or non-suspicious findings on multi-parametric MRI (PRIMARY2): a multi-centre, phase III, randomised trial. Presented at: 41st Annual Congress of the European Association of Urology. London, UK. March 13-16, 2026

2. European Association of Urology. EAU Guidelines on Prostate Cancer. Updated 2024.
https://uroweb.org/guidelines/prostate-cancer

3. Scan that makes prostate cancer cells glow could cut need for biopsies. News release. European Association of Urology. March 13, 2026. Accessed March 13, 2026. https://uroweb.org/news/scan-that-makes-prostate-cancer-cells-glow-could-cut-need-for-biopsies-2