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
28 affiliations
- 1Prostate 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
- 2Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; University of Melbourne, Royal Melbourne Clinical School, Melbourne, VIC, Australia
- 3Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- 4Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Faculty of Health, Medicine and Behavioural Sciences, University of Queensland, Brisbane, QLD, Australia
- 5Department 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
- 6Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia
- 7Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- 8Division 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
- 9Psycho-Oncology Cooperative Research Group, School of Psychology, Faculty of Science, The University of Sydney, Sydney, NSW, Australia
- 10Department of Nuclear Medicine, PET and Bone Densitometry, Royal Adelaide Hospital, Adelaide, SA, Australia
- 11University of Melbourne, Royal Melbourne Clinical School, Melbourne, VIC, Australia
- 12Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- 13St George Clinical School, University of New South Wales, Sydney, NSW, Australia
- 14Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia
- 15Department of Surgery, Austin Health, Melbourne, VIC, Australia
- 16Department of Urology, Royal Darwin Hospital, Darwin, NT, Australia
- 17Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia
- 18Department of Urology, Chris O'Brien Lifehouse, Sydney, NSW, Australia; Faculty of Medicine, University of Sydney, Sydney, NSW, Australia
- 19Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- 20Molecular Imaging Unit, Royal Darwin Hospital, Darwin, NT, Australia
- 21Department of Urology, Westmead Hospital, University of Sydney, Sydney, NSW, Australia
- 22Department of Nuclear Medicine and PET Services, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Brisbane, QLD, Australia
- 23Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
- 24Sir 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
- 25Department of Urology, Chris O'Brien Lifehouse, Sydney, NSW, Australia; Concord Clinical School, University of Sydney, Sydney, NSW, Australia
- 26Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- 27Prostate 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: [email protected]
- 28Department 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
Abstract
Background 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 ([ 68 Ga]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. Methods 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 [ 68 Ga]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 [ 68 Ga]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 [ 68 Ga]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. Findings 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 [ 68 Ga]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 [ 68 Ga]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%]). Interpretation [ 68 Ga]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. Funding Prostate Cancer Foundation, National Health and Medical Research Council, St Vincent's Curran Foundation, and Peter MacCallum Cancer Foundation.
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BibTeX
@article{buteau2026effect,
title = {{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}},
author = {James Patrick Buteau and Daniel Moon and Michael T. Fahey and Matthew J. Roberts and Narjess Ayati and Nathan P. Papa and Declan G. Murphy and Veeru Kasivisvanathan and Haryana Mary Dhillon and Yang Du and Philip Dundee and Jessica Foudoulis and David M. Z. B. Hennes and Anthony C. Hutton and Jordan Idiare and Gregory S. Jack and Sheshang Kamath and Sophie Nancy May Lee and Su-Faye Lee and Sze Ting Lee and Scott Leslie and Sidney M. Levy and Emma Link and Catherine Mitchell and Joshua James Morigi and Andrew Nguyen and Joanna Olphert and Manish I Patel and David A. Pattison and Adam Kieran Pearce and Marlon Perera and Ruban Thanigasalam and Alice Thomson and John William Yaxley and James Edward Thompson and Michael S. Hofman and Louise Emmett and Laura Adams and Tim J Akhurst and Omar Alghazo and Ramin Alipour and Narjess Ayati and Aries Balino and Ashley Baring and Salvatore Berlangieri and Madison Bills and Emma Boehm and Raef Boktor and Neeraja Bollampally and Caitlin Burt and James Patrick Buteau and Emma Callegari and Anthony Cardin and Yee Chan and David C Chen and Tina Chen and Karla Cullen and Richard De Abreu Lourenco and Katrina Devitt and Nattakorn Dhiantravan},
journal = {The Lancet Oncology},
year = {2026},
month = jun,
doi = {10.1016/s1470-2045(26)00120-8},
url = {https://doi.org/10.1016/s1470-2045(26)00120-8},
note = {CC BY},
}
RIS
TY - JOUR
TI - 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
AU - James Patrick Buteau
AU - Daniel Moon
AU - Michael T. Fahey
AU - Matthew J. Roberts
AU - Narjess Ayati
AU - Nathan P. Papa
AU - Declan G. Murphy
AU - Veeru Kasivisvanathan
AU - Haryana Mary Dhillon
AU - Yang Du
AU - Philip Dundee
AU - Jessica Foudoulis
AU - David M. Z. B. Hennes
AU - Anthony C. Hutton
AU - Jordan Idiare
AU - Gregory S. Jack
AU - Sheshang Kamath
AU - Sophie Nancy May Lee
AU - Su-Faye Lee
AU - Sze Ting Lee
AU - Scott Leslie
AU - Sidney M. Levy
AU - Emma Link
AU - Catherine Mitchell
AU - Joshua James Morigi
AU - Andrew Nguyen
AU - Joanna Olphert
AU - Manish I Patel
AU - David A. Pattison
AU - Adam Kieran Pearce
AU - Marlon Perera
AU - Ruban Thanigasalam
AU - Alice Thomson
AU - John William Yaxley
AU - James Edward Thompson
AU - Michael S. Hofman
AU - Louise Emmett
AU - Laura Adams
AU - Tim J Akhurst
AU - Omar Alghazo
AU - Ramin Alipour
AU - Narjess Ayati
AU - Aries Balino
AU - Ashley Baring
AU - Salvatore Berlangieri
AU - Madison Bills
AU - Emma Boehm
AU - Raef Boktor
AU - Neeraja Bollampally
AU - Caitlin Burt
AU - James Patrick Buteau
AU - Emma Callegari
AU - Anthony Cardin
AU - Yee Chan
AU - David C Chen
AU - Tina Chen
AU - Karla Cullen
AU - Richard De Abreu Lourenco
AU - Katrina Devitt
AU - Nattakorn Dhiantravan
PY - 2026
DA - 2026/06/10
JO - The Lancet Oncology
DO - 10.1016/s1470-2045(26)00120-8
UR - https://doi.org/10.1016/s1470-2045(26)00120-8
AB - Background 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 ([ 68 Ga]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. Methods 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 [ 68 Ga]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 [ 68 Ga]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 [ 68 Ga]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. Findings 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 [ 68 Ga]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 [ 68 Ga]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%]). Interpretation [ 68 Ga]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. Funding Prostate Cancer Foundation, National Health and Medical Research Council, St Vincent's Curran Foundation, and Peter MacCallum Cancer Foundation.
SN - 1470-2045
SN - 1474-5488
ER -