MRI is now central to the diagnostic pathway for men with suspected prostate cancer. However, some men have a non-suspicious or equivocal MRI result while still having clinical risk factors that raise concern for clinically significant prostate cancer. In this setting, prostate biopsy is often recommended, although many biopsies detect no cancer or clinically insignificant disease.
A phase 3 trial evaluated whether [68Ga]Ga-PSMA-11 PET-CT could help guide biopsy decisions in biopsy-naive men with suspected prostate cancer and either PI-RADS 3 MRI findings or PI-RADS 2 MRI findings with additional high-risk clinical features.
The original article, titled “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,” was published in The Lancet Oncology on June 10, 2026.
Authors: James P. Buteau, Daniel Moon, Michael T. Fahey, Matthew J. Roberts, Narjess Ayati, Nathan Papa, Declan G. Murphy, Veeru Kasivisvanathan, Haryana M. Dhillon, Yang T. Du, Philip Dundee, Jessica Foudoulis, David Hennes, Anthony C. Hutton, Jordan Idiare, Greg Jack, Sheshang Kamath, Sophie N. Lee, Su-Faye Lee, Sze Ting Lee, Scott Leslie, Sidney M. Levy, Emma Link, Catherine Mitchell, Joshua J. Morigi, Andrew Nguyen, Joanna Olphert, Manish I. Patel, David A. Pattison, Adam Pearce, Marlon Perera, Ruban Thanigasalam, Alice Thomson, John Yaxley, James Thompson, Michael S. Hofman, Louise Emmett, and the PRIMARY2 Trial Investigators.
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About the Trial
PRIMARY2 was an investigator-initiated, multicentre, non-inferiority, phase 3 randomised controlled trial conducted at seven hospitals in Australia. Eligible participants were biopsy-naive men with clinical suspicion of significant prostate cancer, PSA of 20 ng/mL or less, clinical T2 disease or less, and either equivocal PI-RADS 3 MRI or non-suspicious PI-RADS 2 MRI with at least one high-risk feature, such as PSA density greater than 0.1 ng/mL/mL, abnormal digital rectal examination, strong family history, BRCA mutation, PSA greater than 10 ng/mL, PSA doubling time shorter than 36 months, or PSA velocity greater than 0.75 ng/mL per year.
Participants were randomly assigned to either systematic transperineal prostate biopsy or [68Ga]Ga-PSMA-11 PET-CT. In the PSMA PET-CT group, participants with a positive scan, defined as PRIMARY score 3–5, underwent targeted transperineal prostate biopsy. Participants with a negative scan, defined as PRIMARY score 1–2, avoided biopsy and continued PSA surveillance.
The co-primary endpoints were the proportion of participants with clinically significant prostate cancer, defined as Gleason score 3+4 (≥10% pattern 4) or higher, and the proportion of participants in the PSMA PET-CT group who avoided biopsy within 6 months.
Key Results
A total of 660 participants were enrolled between March 2022 and August 2025. The median age was 61 years, median PSA was 5.2 ng/mL, and median PSA density was 0.13 ng/mL/mL. Overall, 51% of participants had PI-RADS 2 MRI findings and 49% had PI-RADS 3 findings. Clinically significant prostate cancer was detected in 39 of 331 participants in the PSMA PET-CT group, compared with 51 of 329 participants in the systematic biopsy group.
Clinically significant prostate cancer was detected in 12% of participants in the PSMA PET-CT group and 16% in the systematic biopsy group. This met the trial’s prespecified non-inferiority criteria, supporting the use of PSMA PET-CT as a biopsy-triage strategy in this selected population. At the same time, [68Ga]Ga-PSMA-11 PET-CT allowed 163 of 331 participants, or 49%, to avoid prostate biopsy within 6 months.
The PSMA PET-CT pathway also reduced the diagnosis of clinically insignificant prostate cancer. Clinically insignificant disease was detected in 14% of participants in the PSMA PET-CT group versus 32% in the systematic biopsy group. Among participants who underwent biopsy, the mean number of biopsy cores was lower in the PSMA PET-CT group than in the systematic biopsy group: 19.6 versus 24.8 cores.
Safety and Patient-Reported Symptoms
Biopsy-related symptoms were broadly similar between groups among participants who underwent prostate biopsy. Pain was reported by 21% of participants in both groups. Haematuria was reported by 38% in the PSMA PET-CT group and 43% in the control group. Haematospermia was reported by 48% and 45%, respectively. Erectile dysfunction, assessed using the SHIM questionnaire, was similar at baseline and did not increase after biopsy.
Interpretation
PRIMARY2 suggests that [68Ga]Ga-PSMA-11 PET-CT may improve the diagnostic pathway for selected men with suspected prostate cancer who have equivocal or non-suspicious MRI findings but remain at high clinical risk.
In this trial, the PSMA PET-CT strategy avoided biopsy in nearly half of participants, reduced detection of clinically insignificant prostate cancer, and maintained non-inferior detection of clinically significant prostate cancer compared with systematic transperineal biopsy. The findings are particularly relevant for men in whom MRI does not clearly identify suspicious disease but clinical features still raise concern.
Limitations
Follow-up is ongoing, and longer-term outcomes are still needed, especially for participants with negative PSMA PET-CT who avoided biopsy. Biopsy data were missing in some participants, with a higher proportion in the control group than in the PSMA PET-CT group, and the per-protocol sensitivity analysis had limited interpretability because a substantial proportion of participants were excluded.
The study used [68Ga]Ga-PSMA-11 PET-CT, so the findings cannot automatically be extrapolated to other PSMA radiopharmaceuticals. Health-economic analyses are also needed to better understand whether the cost of PSMA PET-CT could be offset by fewer biopsies.
The trial focused on men with PI-RADS 2 or PI-RADS 3 MRI findings, so these results do not answer whether PSMA PET-CT can reduce biopsy in men with PI-RADS 4 or PI-RADS 5 findings.
Takeaway
PRIMARY2 provides phase 3 randomised evidence that [68Ga]Ga-PSMA-11 PET-CT can help triage biopsy decisions in selected biopsy-naive men with suspected prostate cancer who have PI-RADS 3 MRI findings or PI-RADS 2 MRI findings with high-risk clinical features. The strategy avoided biopsy in about half of participants and reduced detection of clinically insignificant disease, while preserving detection of clinically significant prostate cancer in the reported analysis.