Pragmatic Study on the Use of 68Ga-PSMA-617 PET/CT Imaging as a Standard of Care to Influence Clinical Management of Tumors Overexpressing PSMA.

In developed countries such as Canada, prostate cancers are the most frequently diagnosed and the third deadliest cancer among men. Early detection and management of low-stage prostate cancer leads to a 5-year survival rate nearing 100%. However, advanced and metastatic prostate cancers remain a clinical challenge to both assess and treat, despite significant advances in the field in the last years.

Among the best existing diagnostic tools for advanced cancers overall, FDG-PET suffers from a very low sensitivity for prostate cancers. Indeed, not only those lesions are most of the time hypometabolic and indolent, but also loco regional assessment is heavily impaired by the proximity of the background-generating, radio metabolite-rich bladder. Other imaging modalities such as Computed Tomography (CT) and Magnetic Resonance imaging (MRI) do not perform better, and are also plagued with relatively low sensitivity and specificity. As such, alternative, PET tracers were developed in order to better assess metastatic prostate cancers. One of the earliest attempts was with choline-derived tracers (either labeled with 11C or 18F) which showed superior diagnostic properties than FDG, but still harbors a range of sensitivity from poor to excellent depending of the site of the lesions. Recently, the amino acid analog 18F-fluciclovine (Axumin) showed great promises thanks to a low renal excretion and high prostate tumor uptake which resulted in much improved sensitivity. However, while both choline and fluciclovine offer precise prostate cancer diagnostic, they do not provide much information about the prognostic of the disease or the efficacy of targeted therapies.

The Prostate Specific Membrane Antigen (PSMA) is a transmembrane glycoprotein with folate hydroxylase and glutamate carboxypeptidase enzymatic activities. PSMA was first reported to be strongly expressed in more than 90% of prostate cancers. Moreover, PSMA expression on prostate tumors is proportional to the plasmatic concentration of the routinely-assessed Prostate Specific Antigen (PSA), which is currently the main screening and treatment follow-up tool for prostate cancer. PSMA overexpression occurs most frequently in high-grade and metastatic diseases, as well as for castration-resistant cancers. As such, PSMA constitutes a target of choice for an imaging modality aiming for prognosis and treatment assessment of prostate cancers, as well as for targeted endoradiotherapy.

High PSMA expression was also observed in the neovasculature of most solid tumors, notably breast, lung and gastrointestinal cancers. 68Ga-PSMA-PET was reported to allow high-uptake detection of nonprostate cancers. More recently, a preliminary clinical report showed that breast cancers can readily be imaged using 68Ga-PSMA, with the highest detection rate observed in the triple-negative subtype. As such, while 68Ga-PSMA was mainly explored in prostate cancers until now, rising evidence demonstrates its applicability to most solid cancers as well.

In the last few years, many peptidomimetic compounds were designed as PSMA-specific ligands, such as PSMA-11, PSMA-617 and PSMA-1007. The latter is radiolabeled covalently with a 18F, whereas most other molecules depend upon their chelator moiety for labeling with a radiometal such as 64Cu or 68Ga. The main advantages of using a chelator-bearing compound include ease of labeling and purification along with the potential to alternatively label with therapeutic radiometals such as 177Lu or 225Ac to form a theranostic pair with PET-capable isotopes with the same molecular frame. Notably, PSMA-617, labeled with 68Ga for PET imaging and with 225Ac for therapy, showed astonishing potential in a cohort of advanced prostate cancer.