MRI is recommended for men with clinical suspicion of significant prostate cancer. Those with high clinical risk but non-suspicious or equivocal MRI often undergo prostate biopsy, but have a low likelihood of clinically significant prostate cancer, and a high incidence of clinically insignificant prostate cancer. We aimed to investigate whether gallium-68 ([68Ga]Ga)-prostate-specific membrane antigen (PSMA)-11 PET-CT could reduce the number of people requiring prostate biopsy and limit biopsy to targeted cores, without compromising clinically significant prostate cancer diagnosis.
In this multicentre, non-inferiority, phase 3, randomised controlled trial, done at at seven Australian hospitals, we recruited biopsy-naive participants with clinical suspicion of significant prostate cancer, equivocal (Prostate Imaging-Reporting and Data System [PI-RADS] 3) or non-suspicious (PI-RADS 2) MRI but high clinical risk (eg, prostate-specific antigen [PSA] density of >0·1 ng/mL/mL, strong family history of prostate cancer, abnormal digital rectal examination, BRCA mutation, PSA >10 ng/mL, PSA doubling time <36 months, or PSA velocity >0·75 ng/mL per year), PSA of 20 ng/mL or less, and clinical T2 disease or less. Participants were randomly assigned (1:1) using a centralised web-based system to undergo [68Ga]Ga-PSMA-11 PET-CT (experimental group) or systematic transperineal prostate biopsy (control group), using block sizes of two or four and stratification by study site. There was no masking for participants or investigators. Participants with positive [68Ga]Ga-PSMA-11 PET-CT (PRIMARY score 3-5) underwent PSMA-PET-targeted transperineal prostate biopsies, whereas those with a negative result (PRIMARY score 1-2) avoided biopsy. The co-primary outcomes were the proportion of participants with clinically significant prostate cancer, defined as a Gleason score of 3 + 4 (≥10% pattern 4) or higher, and the proportion of participants in the [68Ga]Ga-PSMA-11 PET-CT group who avoided biopsy within 6 months of random assignment. A two-sided 95% Wald CI based on a binomial model was used to estimate the risk difference in the proportion of participants with clinically significant prostate cancer (non-inferiority margin 10%) and to estimate the proportion of participants in the experimental group who had avoided biopsy 6 months after random assignment (20% threshold), analysed based on intention to treat. This trial is registered with ClinicalTrials.gov, NCT05154162, and participant follow-up is ongoing.
Between March 2, 2022, and Aug 24, 2025, 660 eligible male participants were enrolled and had a median age of 61 years (IQR 56-66), a median PSA of 5·2 ng/mL (4·0-7·0), and a median PSA density of 0·13 ng/mL/mL (0·09-0·17). There were PI-RADS 2 in 335 (51%) participants and PI-RADS 3 in 325 (49%) participants. Ethnicity data were not collected. 329 (50%) were assigned to the control group with systematic transperineal prostate biopsy, and 331 (50%) were assigned to the experimental group with [68Ga]Ga-PSMA-11 PET-CT. The proportion of participants with clinically significant prostate cancer in the experimental group (39 [12%] of 331) was non-inferior to the control (51 [16%] of 329; difference -3·7% [95% CI -8·9 to 1·5%]; p=0·0093). Use of [68Ga]Ga-PSMA-11 PET-CT avoided biopsy in 163 (49%) of 331 participants (95% CI 44 to 55%; p <0·0001). After prostate biopsy, participants reported similar proportions of pain (33 [21%] in the experimental group vs 62 [21%] in the control group), haematuria (60 [38%] vs 126 [43%]), and haematospermia (77 [48%] vs 133 [45%]).
[68Ga]Ga-PSMA-11 PET-CT could have the potential to improve the diagnostic pathway of patients with a high clinical risk but non-suspicious or equivocal prostate MRI. Further research, including health-economic analyses and validation with other PSMA radiopharmaceuticals, are needed to confirm the clinical implementation and generalisability of this approach.
Prostate Cancer Foundation, National Health and Medical Research Council, St Vincent's Curran Foundation, and Peter MacCallum Cancer Foundation.
The Lancet. Oncology. 2026 Jun 10 [Epub ahead of print]
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, PRIMARY2 Trial Investigators
Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia., Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; University of Melbourne, Royal Melbourne Clinical School, Melbourne, VIC, Australia., Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Faculty of Health, Medicine and Behavioural Sciences, University of Queensland, Brisbane, QLD, Australia., Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia., Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia., Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Division of Surgery and Interventional Science, University College London, London, UK; Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Psycho-Oncology Cooperative Research Group, School of Psychology, Faculty of Science, The University of Sydney, Sydney, NSW, Australia., Department of Nuclear Medicine, PET and Bone Densitometry, Royal Adelaide Hospital, Adelaide, SA, Australia., University of Melbourne, Royal Melbourne Clinical School, Melbourne, VIC, Australia., Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., St George Clinical School, University of New South Wales, Sydney, NSW, Australia., Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia., Department of Surgery, Austin Health, Melbourne, VIC, Australia., Department of Urology, Royal Darwin Hospital, Darwin, NT, Australia., Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia., Department of Urology, Chris O'Brien Lifehouse, Sydney, NSW, Australia; Faculty of Medicine, University of Sydney, Sydney, NSW, Australia., Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Molecular Imaging Unit, Royal Darwin Hospital, Darwin, NT, Australia., Department of Urology, Westmead Hospital, University of Sydney, Sydney, NSW, Australia., Department of Nuclear Medicine and PET Services, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Brisbane, QLD, Australia., Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia., Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Department of Surgery, Austin Health, Melbourne, VIC, Australia., Department of Urology, Chris O'Brien Lifehouse, Sydney, NSW, Australia; Concord Clinical School, University of Sydney, Sydney, NSW, Australia., Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Electronic address: ., Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia.