PSMA PET: the answer to MRI-occult prostate cancer… or another mirage?

Multiparametric MRI (mpMRI) has transformed the diagnostic pathway for suspected prostate cancer by improving the detection of clinically significant prostate cancer (csPCa) and reducing unnecessary biopsies. However, its negative predictive value declines in higher-risk populations, and up to 30% of men with negative or indeterminate mpMRI (PI-RADS 1-3) may still harbour csPCa, particularly those with adverse clinical features. Variability in MRI quality, reader expertise, and reference standards further limits reproducibility outside expert centres. Prostate-specific membrane antigen (PSMA) PET-CT has emerged as a promising complementary modality. Beyond its role in staging and recurrence, prospective studies support its value in the pre-biopsy setting. Trials such as PRIMARY, PEDAL, and others demonstrate that PSMA PET/CT can detect a substantial proportion of csPCa missed by mpMRI, with high sensitivity and negative predictive value. The development of structured reporting systems, notably the PRIMARY score, represents an important step towards standardisation and improved comparability across studies. Despite encouraging diagnostic performance, critical uncertainties remain. The biological significance of PSMA-positive, MRI-negative lesions is unclear, and higher detection rates may partly reflect intensified sampling rather than clinically meaningful disease. Cost-effectiveness, optimal patient selection, and the positive predictive value of PSMA-avid lesions in MRI-negative prostates require further prospective validation. This opinion piece reviews high-quality prospective evidence and argues that PSMA PET/CT has the potential to refine risk stratification and reduce unnecessary biopsies in selected men with persistent suspicion of prostate cancer. Integration into diagnostic pathways should be guided by imaging performance and biological relevance, ensuring that the detected disease is clinically meaningful. KEY POINTS: Question Can PSMA PET/CT improve risk stratification and reduce missed clinically significant prostate cancer in men with negative or indeterminate mpMRI? Findings Prospective studies show PSMA PET/CT complements mpMRI, achieving high sensitivity and negative predictive value while detecting a substantial proportion of significant cancers missed by MRI. Clinical relevance PSMA PET/CT may help safely avoid unnecessary biopsies and identify clinically significant disease in selected men after negative or equivocal MRI, but adoption requires standardised reporting, biological validation of PSMA-positive/MRI-negative lesions, and careful evaluation of cost-effectiveness within routine clinical pathways.