Prostate-specific membrane antigen (PSMA)-based imaging in localized and advanced prostate cancer: a narrative review

Combined molecular and morphologic imaging modalities have emerged in recent years as an alternative to conventional imaging in prostate cancer (PC). In particular, novel prostate-specific membrane antigen (PSMA) radiotracers have demonstrated increased sensitivity and specificity for the initial staging of men with clinically localized PC, as well as for PC detection in the setting of biochemical recurrence (BCR). Molecular imaging is increasingly used to guide treatment decisions in these patients—though its impact on survival has yet to be established. Improved PC detection in men with BCR has also helped to identify a subset of patients with oligometastatic disease. The optimal management of oligometastatic PC and the role of metastasis-directed therapies (MDT) are the subjects of ongoing studies. In comparison to clinically localized or biochemically recurrent PC, the role of molecular imaging in men with advanced disease is less established. In metastatic castration-resistant PC (mCRPC), PSMA-based imaging has primarily been investigated as a companion diagnostic tool to predict and monitor response to PSMA-targeted radioligand therapy (RLT). More recent efforts have focused on using molecular imaging to monitor treatment response to conventional chemohormonal therapies. However, despite promising early results, several barriers remain to the widespread use of PSMA-based imaging in metastatic PC: temporary flares in PSMA uptake have been described in a subset of patients after initiation of therapy, and the underlying mechanism and clinical implications of this phenomenon are still poorly understood. Furthermore, whereas PSMA is invariably expressed in hormone-sensitive PC, loss of PSMA expression is increasingly recognized in a subset of mCRPC patients with aggressive disease. Although this may limit the use of PSMA-based imaging as a standalone modality in advanced PC, loss of PSMA uptake may also provide non-invasive and clinically relevant molecular insight on patients’ underlying tumor biology.