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PSMA and Beyond 2025: PRIMARY Score and Where it Plays a Role

(UroToday.com) The 2025 PSMA and Beyond annual meeting featured a PSMA session and a presentation by Dr. Michael Hofman discussing the PRIMARY score and where it plays a role. In Australia, it has been a transformational decade for PSMA PET/CT with regards to utilization in 2014 compared to 2024:

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Dr. Hofman notes that it can be very difficult to image tumors on a multiparametric MRI, whereas a PSMA PET in this setting makes tumor identification much easier: 

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In 2021, Dr. Hofman and his colleauges published PRIMARY,1 a prospective multicenter study assessing the additive diagnostic value of PSMA PET/CT to multiparametric MRI in the diagnosis of prostate cancer (which was awarded the EAU scientific paper of the year in 2021). There were 296 men enrolled with suspected prostate cancer, with no prior biopsy or MRI, recent MRI (6 months), and planned transperineal biopsy based on clinical risk and MRI. Among 291 patients, combined PSMA PET + MRI improved NPV compared with MRI alone (91% versus 72%, test ratio 1.27 [1.11-1.39], p < 0.001). Sensitivity also improved (97% versus 83%, p < 0.001), however specificity was reduced (40% versus 53%, p = 0.011). Of all men, 19% were PSMA PET + MRI negative (38% of PI-RADS 2/3) and could potentially have avoided biopsy, risking delayed clinically significant prostate cancer detection in 3.1% men with clinically significant prostate cancer (5/162) or 1.7% (5/291) overall:

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Additionally, this trial showed an association between SUVmax/PSMA intensity and tumor aggressiveness:

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Although it is too early to say that PSMA PET can replace prostate biopsy, Dr. Hofman notes that if an MRI is positive (PIRADS 4 or 5) and a PSMA PET is positive (SUVmax >9), in this trial, 100% of patients had prostate cancer. Additionally, if there was any PIRADS lesions (PIRADS 2-5) and the PSMA PET was positive (SUVmax >12), 100% of these patients had prostate cancer. Of note, lower SUVs are less specific, given that this is an equivocal zone for prostate cancer, and SUV alone has insufficient accuracy, thus pattern is important in these instances:2

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Dr. Hofman also notes that focal transition and peripheral zones are always suspicious:

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Mazzone et al.3 just published a systematic review and meta-analysis assessing the role of PSMA PET for prostate cancer diagnosis and primary staging before definitive therapy, reporting a pooled sensitivity of PSMA PET for the detection of clinically significant prostate cancer of 82% (95% CI 76–90%) and pooled specificity of 67% (95% CI 46–85%). Moreover, in analyses testing for the predictive value, pooled meta-analyses using random-effect models demonstrated a PPV of 77% (95% CI 63–88%) and an NPV of 73% (95% CI 56–87%). A summary of pooled meta-analyses testing the sensitivity, specificity, and positive and negative predictive values of PSMA PET and the combination of PSMA PET + MRI for the detection of clinically significant prostate cancer is highlighted in the following figure:

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Dr. Hofman cautions that we have to be aware of PSMA-negative tumors, such as the following example that is PSMA negative, with an MRI PIRADS 5, Gleason 5+5 = 10 prostate cancer. However, this entity is quite rare, with an estimated 3.3% of patients having prostate cancer and low intraprostatic uptake:

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Next, Dr. Hofman discussed the phase III trial protocol of PRIMARY2, assessing the additive value of PSMA PET in men with negative or equivocal MRI to diagnose clinically significant prostate cancer. The impetus for this trial is that among men with an elevated PSA and/or abnormal digital rectal examination, 2 in 5 men have no clinically significant prostate cancer on biopsy. Thus, there is added discomfort and potential complications associated with biopsy in these patients, increased patient worry and anxiety, as well as increased healthcare costs. MRI has improved the diagnosis of prostate cancer, however, it still leads to unnecessary prostate biopsies and overdiagnosis. In PRIMARY2, 660 patients with a normal or equivocal MRI (PIRADS 2 and at risk or PIRADS 3) will be randomized to standard of care template prostate biopsy versus PSMA PET. If the PSMA PET is normal, there will be no prostate biopsy, and if the scan is positive then the patient will undergo a targeted prostate biopsy. Follow-up will be over 2 years. The objectives of the trial are to demonstrate non-inferiority with standard of care with MRI and the addition of PSMA PET:

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Additional objectives are to reduce complications by limiting the number of targeted biopsies, and to measure the impact on health economics and patient reported outcomes.

Dr. Hofman concluded his presentation by discussing the PRIMARY score and where it plays a role with the following take home points specific to PSMA PET for diagnosis:

  • We can see the invisible tumors that MRI misses with PSMA PET
  • Imaging histopathology with PSMA PET: is there a group of patients who can skip biopsy?
  • If intensity is lower, the pattern matters: we can use the PRIMARY score to standardize the reports
  • PSMA PET/CT is complementary to MRI, and we await results from PRIMARY2 and other trials 

Presented by: Michael Hofman, MBBS, Peter MacCallum Cancer Centre, Melbourne, Australia

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 PSMA and Beyond Annual Meeting, Los Angeles, CA, Fri, Mar 28 – Sat, Mar 29, 2025. 

References:

  1. Emmett L, Butaeu J, Papa N, et al. The Additive Diagnostic Value of Prostate-specific Membrane Antigen Positron Emission Tomography Computed Tomography to Multiparametric Magnetic Resonance Imaging Triage in the Diagnosis of Prostate Cancer (PRIMARY): A Prospective Multicentre Study. Eur Urol. 2021 Dec;80(6):682-689.
  2. Emmett L, Papa N, Buteau J, et al. The PRIMARY Score: Using Intraprostatic 68Ga-PSMA PET/CT Patterns to Optimize Prostate Cancer Diagnosis. J Nucl Med. 2022 Nov;63(11):1644-1650.
  3. Mazzone E, Cannoletta D, Quarta L, et al. A comprehensive systematic review and meta-analysis of the role of prostate-specific membrane antigen positron emission tomography for prostate cancer diagnosis and primary staging before definitive treatment. Eur Urol. 2025 Mar 27 [Epub ahead of print].