PSMA PET and RLT 2024: Evaluation of the Primary Tumor with PSMA PET: Time Impact of the PRIMARY Trial

( The 2024 PSMA conference featured a presentation by Dr. Louise Emmett discussing evaluation of the primary tumor with PSMA PET and the time impact of the PRIMARY trial. Dr. Emmett started by emphasizing that based on the PRECISION1 and PROMIS2 trials we know that MRI guided biopsy improves the diagnostic accuracy and reduces the number of required biopsies for prostate cancer diagnosis.

However, questions remain regarding the safety of not biopsying clinically high risk PI-RADS 2 MRI findings (with 25% ISUP 2 in the PROMIS trial). Furthermore, in PRECISION, many biopsies using MRI triaging remain negative (32%). So, is there a way we can further safely reduce biopsies so that we only biopsy those men who have a significant malignancy?

The PSMA protein is a type II transmembrane glycoprotein expressed in normal human prostate epithelium, which also has an oncogenic signaling role that actively promotes cell proliferation. Dr. Emmett then discussed the PRIMARY study, which assessed the additive diagnostic value of PSMA PET/CT to MRI triage in the diagnosis of prostate cancer.3 This trial was a multicenter, phase II imaging trial that evaluated if a limited (i.e. pelvic-only) 68Ga-PSMA-11 PET/CT in combination with mpMRI can reliably discriminate men with clinically significant prostate cancer (i.e. ≥grade group 2) from those without clinically significant disease. The trial included 291 men with suspected prostate cancer (PSA <20 ng/mL), no previous biopsy, recent MRI within 6 months, and planned transperineal biopsy based on clinical risk and MRI. For analysis, the combination of PSMA and MRI was considered negative for PSMA negative PI-RADS 2/3 or positive for either PSMA positive PI-RADS 2/3 or PI-RADS 4/5. Of these 291 men, 162 (56%) had clinically significant prostate cancer. MRI, PSMA, and PSMA + MRI was positive in 67%, 73%, and 81% of patients, respectively. Combination PSMA and MRI, compared to MRI alone, improved the sensitivity (97% versus 83%, p<0.001) and NPV (91% versus 72%, p<0.001). However, this was at the cost of reduced specificity (40% versus 53%, p = 0.001). Among all patients, 56 (19%) were both PSMA and MRI negative and could have potentially avoided a biopsy at a risk of delayed clinically significant prostate cancer detection of 3.1%:
Dr. Emmett notes that for PSMA peptides, there is significant SUVmax variability. This is likely secondary to variable binding affinity, variable half lives, variable injection quantity, and variable time between injection and imaging. Indeed, this pattern was evident in the PRIMARY trial:

By way of a post hoc analysis of the PRIMARY study, Dr. Emmett and colleagues evaluated the clinical significance of patterns of intraprostatic PSMA activity, proposing a 5-point PRIMARY score to optimize the accuracy of 68Ga-PSMA PET/CT for clinically significant prostate cancer in a low-prevalence population.4 The following is an anatomic representation of the central zone, transition zone, and peripheral zone and patterns of intraprostatic PSMA activity (diffuse transition zone (A), symmetric central zone (B), focal transition zone (C), and focal peripheral zone (D)):PSMA activity (diffuse transition zone (A), symmetric central zone (B), focal transition zone (C), and focal peripheral zone (D) 
The PRIMARY Score is delineated as follows:

Score 1: No dominant intra-prostatic pattern on PSMA. Low grade activity (8.5% clinically significant prostate cancer)

Score 2: Diffuse transition zone activity or symmetrical central zone activity that does not extend to the prostate margin on CT (27% clinically significant prostate cancer)

Score 3: Focal transition zone activity visually twice above background transition zone activity (38% clinically significant prostate cancer)

Score 4: Focal peripheral zone activity (no minimum intensity) (76% clinically significant prostate cancer)

Score 5: PSMA SUVmax > 12 (100% clinically significant prostate cancer)

The following highlights 68Ga-PSMA PET/CT examples of the PRIMARY scores:PRIMARY trial SCORES
The PRIMARY score also correlated well with ISUP Grade Group:PRIMARY score  correlated with ISUP Grade Group
Dr. Emmett’s group also published earlier this month on the reproducibility and accuracy of the PRIMARY score on PSMA PET and PI-RADS using a real-world database.5 This was a retrospective study of 227 men with mpMRI and 68Ga-PSMA PET/CT prior to transperineal biopsy. Each scan was double read with a third reader for discordance (six readers for PSMA PET and MRI); readers were trained based on a single 1-hour education session on the PRIMARY score. Overall, interrater reliability was higher for the PRIMARY score (κ = 0.70) than for PI-RADS (κ = 0.58) when assessed as a binary category (benign vs. malignant), which was similar for all 5 categories (κ = 0.65 vs. 0.48):2 category score 5 category score
Furthermore, the diagnostic performance to detect clinically significant prostate cancer was comparable between PSMA PET and mpMRI:

  • Sensitivity, 86% vs. 89%
  • Specificity, 76% vs. 74%
  • Positive predictive value, 88% vs. 88%
  • Negative predictive value, 72% vs. 76%

Using combined imaging, the sensitivity was 94%, specificity was 68%, positive predictive value was 86%, and negative predictive value was 85%. In work from her group that is currently under submission, Dr. Emmett notes that a composite PRIMARY/PI-RADS score of 5 has a Gleason Group 3-5 incidence of 93%.

 Finally, Dr. Emmett discussed the ongoing PRIMARY 2 trial, which is a phase III, multi-center, randomized controlled trial investigating the additive diagnostic value of 68Ga-PSMA-11 PET/CT in men with negative/equivocal MRI in the diagnosis of clinically significant prostate cancer (n = 660). The co-primary endpoints are the difference between arms in clinically significant prostate cancer detection, and percentage of patients who avoid a transperineal biopsy. This study will measure the impact of PSMA PET/CT on health economics and patient reported outcomes, with the goal of reducing overdiagnosis and complications from biopsy.

Dr. Emmett concluded her presentation discussing evaluation of the primary tumor with PSMA PET and the time impact of the PRIMARY trial with the following take-home points:

  • The combination of PSMA PET/MRI is more accurate than either modality in isolation (in high risk populations)
  • There is a need to prove the addition of PSMA to MRI is cost effective and impactful for patient outcomes, which will be addressed in PRIMARY 2
  • Perhaps there is a potential role for biopsy avoidance and/or minimization
  • It remains to be established if there is value for PSMA PET in focal therapy and active surveillance

Presented by: Louise Emmett, MD, MBChB, FRACP, St. Vincent's Hospital, Sydney, 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 2024 PSMA Conference, San Francisco, CA, Thurs, Jan 18 – Fri, Jan 19, 2024.

Related content: PSMA PET & The Impact of the PRIMARY Trial "Presentation" - Louise Emmett


  1. Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or standard biopsy for prostate cancer diagnosis. N Engl J Med 2018;378(19):1767-1777.
  2. Ahmed HU, El-Shater Bosaily A, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): A paired validating confirmatory study. Lancet 2017;389(10071):815-822.
  3. 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.
  4. 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.
  5. Emmett L, Papa N, Counter W, et al. Reproducibility and Accuracy of the PRIMARY Score on PSMA PET and of PI-RADS on Multiparametric MRI for Prostate Cancer Diagnosis within a Real-World Database. J Nucl Med. 2024 Jan 2;65(1):94-99.