Glutamate carboxypeptidase II, better known by its more commonly used name, prostate membrane specific antigen (PSMA), is an enzyme highly expressed on the prostatic epithelium1. In benign prostatic cells, the peptide is primarily expressed along the cytoplasmic surface; however, as malignant transformation occurs, the peptide begins to express an extracellular component which allows for ligand internalization. Additionally, prostate cancers have been shown to have up to a 1000x increase in PSMA expression compared to benign prostate tissue and non- prostatic tissues1. In this review, Dr Neal D. Shore, Director of Carolina Urologic Research Center, reviewed the literature and utility of PSMA PET/CT scans in prostate cancer, as well as therapeutic advances using radioligand therapy.
Dr Shore began his presentation by reviewing the multitude of ways that patients with suspected localized or metastatic prostate cancer can present to a urologist. Specifically, he reviewed the common sites of metastatic disease with up to 9/10 of patients presenting with osseous metastasis and less commonly, patients will present with lung, liver or adrenal metastatic disease as well.
After describing the background of his talk, Dr Shore shifted gears to discuss PSMA. He described several novel features of the PSMA receptor, including having both intracellular, transmembrane and extracellular components allowing it to serve as a target for PSMA- targeted radioligand therapy, a field now referred to as theranostics. Dr Shore remarked that PSMA serves as a novel biomarker for identification of micro-metastatic foci of prostate cancer and his presentation would focus on reviewing the applications and articles documenting this new modality. Namely, he expressed interest in utility of PSMA-targeted ligands in identifying extra- prostatic extension in patients with newly-diagnosed localized prostate cancer, detection of foci of prostate cancer in biochemical recurrence and utility in the castration resistant sphere with detection of disease undetectable on conventional imaging as well as utility in metastatic castration resistance. Dr Shore finalized his introduction by reiterating that despite the name prostate specific antigen, PSMA is hardly specific to the prostate. He explained that PSMA is expressed in a variety of other tissues including the salivary glands, kidneys and duodenum resulting in diagnostic and therapeutic potentials for those organs, as well as non-prostate related side effects for treatment of prostate cancer. It is important to note, however, that due to upregulation of PSMA expression in prostate cancer, the quantity of receptors between normal tissue and prostate cancer cells vary by a factor of up to 100-1000×1.
Dr Shore went on to discuss the role of conventional imaging for prostate cancer. According to conventional guidelines, bone scans and computed tomography (CT) are utilized for staging. Dr Shore mentioned that bone scans are widely available but often yield many false positives secondary to degenerative bone disease, trauma, or bone cysts. Regarding CT, he mentioned that CT is primarily useful for lymph nodes >1cm; however, are less useful when identifying soft tissue disease within the liver or lung. Finally, Dr Shore also mentioned that multiparametric prostate MRI has been shown to be useful in identifying extra prostatic extension (EPE); however, is less useful for staging pelvic lymph nodes. With regards to clinical scenarios, he mentioned that these conventional imaging models result in positive findings in less than 10% of patients with biochemical recurrence and the number falls even lower if the patient has a PSA less than 20.
These facts set the stage for discussing the utility of PSMA/PET in both a diagnostic and therapeutic capacity. Dr Shore mentioned that the majority of the focus in the prostate cancer realm has been using Gallium-68-PSMA ligand as well as Fluciclovine (18F) ligands in the diagnostic capacity; however, recent data including from the VISION trial, which his institution was a part of, will demonstrate the therapeutic capacity of PSMA-targeted ligands via Lutetium-177-PSMA. In the next segment of his talk, Dr Shore highlighted some of the core reasons why PSMA is an ideal imaging target. In addition to being upregulated in prostate cancer cells, there is a proven direct correlation between PSMA expression and Gleason scores, becomes upregulated in an androgen deprived state, and ligands that bind to the extracellular component of PSMA become internalized, allowing for intracellular therapeutic potential.
After reviewing the background of PSMA and its relationship to prostate cancer, Dr Shore shifted gears to discuss the role of PSMA PET/CT in the diagnostic workup process of prostate cancer. In the localized prostate cancer sphere, Dr Shore cited by Eiber, et al2 demonstrating the improved detection rate of EPE between mpMRI (66%) and PSMA-PET (92%) as well as the combined detection rate of 98%. To further elaborate on the improved diagnostic capabilities of PSMA PET/CT, Dr Shore cited the proPSMA trial demonstrating a substantially higher accuracy (92% vs. 65%) and sensitivity (85% vs. 38%) in identifying nodal metastasis compared to conventional imaging3. Up to 80% of lymph node metastatic disease is less than 8mm, explained Dr Shore; however, the low sensitivity of conventional imaging (<40%) inhibits clinicians from identifying these lesions early in the diagnostic process.
Heesakkers et al, demonstrated that PSMA-PET can identify nodal metastasis in up 2/3 patients that were negative on conventional imaging. Dr Shore explained that this increased diagnostic accuracy can provide valuable information to the clinician when informing a patient about treatment decisions as well as prognosis. The utility of increased diagnostic information can yield a change in the management strategy for a patient in up to 62% of cases,4 explained Dr Shore.
In the next segment of his presentation, Dr Shore discussed the utility of PSMA PET imaging in non- metastatic castration resistant prostate cancer (nmCRPC). Citing the well-known, SPARTAN, PROSPER and ARAMIS trials investigating the use of novel second generation androgen-receptor antagonists, Dr Shore explained that the diagnosis of nmCRPC is often based on negative findings on conventional imaging. This, however, is often an inaccurate diagnosis. Fendler et. al demonstrated in a retrospective trial including 200 patients with nmCRPC, 44% of patients had extra prostatic disease confined to the pelvis5. In metastatic castration resistant prostate cancer (mCRPC), Dr Shore remarked that several benefits, including improved ability to detect metastasis resulting in accurate upstaging of disease, as well as therapeutic potential in metastasis-directed radiotherapy. Despite the multitude of studies demonstrating the benefits of PSMA-PET, Dr Shore reiterated that there is a lack of level one evidence in this sphere and reemphasized the importance of waiting for the results of randomized clinical trials before applying PSMA PET/CT in the advanced prostate cancer setting. Dr Shore shifted gears to discuss the differences between Gallium-68 based PSMA ligands and how they compare to Fluciclovine based scans. Citing a study by Calais, et al, l comparing the two modalities, Dr Shore explained that Gallium-68 PSMA PET/CT yielded a substantial improvement in overall detection rate (56% vs. 26%) and had improved ability to detect extraprostatic disease. In terms of appropriate patient selection, Dr Shore emphasized that despite the many potential benefits, PSMA PET/CT can result in increased costs to the healthcare system, treatment burden and potential for healthcare disparities.
In the second half of the presentation, Dr Shore turned his attention to the evidence supporting therapeutic interventions utilizing PSMA ligands. The increased expression of PSMA in advanced prostate cancer allows for target directed delivery of radioactive ligands that emit cytotoxic alpha or beta particles, explained Dr Shore. The primary clinical trial supporting this area of therapeutic intervention is the Vision Trial, a phase 3 trial comparing the therapeutic effects of 6 cycles of 177-Lutetium-PSMA plus standard of care (SOC) versus SOC alone in patients with progressive mCRPC refractory to taxane chemotherapy or second-generation anti-androgen therapy. The results, presented at ASCO 2021, demonstrated that 177-Lutetium-PSMA radiotherapy prolonged overall survival (OS) (15.3 months vs. 11.3 months, HR 0.62, p <0.001) and extended radiographic progression free survival (rPFS) (8.7 months vs. 3.4 months, p < 0.001), explained Dr. Shore. Based on the results of the Vision trial, Dr Shore mentioned he is hopeful the FDA will approve this therapy sometime in 2022.
In summary, Dr Shore re-emphasized the important points regarding PSMA PET/CT. He remarked that it is a highly effective diagnostic modality in prostate cancer that frequently results in upstaging of the initial disease state often resulting in adjustment in management. Additionally, he remarked that it allows for identification of metastatic disease at lower PSA values compared to traditional imaging modalities. Despite the plethora of benefits, he re-iterated that the underlying biology and science especially behind theranostics will require further investigation before widespread use and ultimately, commonly used definitions may require modification as our diagnostic accuracy increases.
Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.
- Jones, Wallace, et al. “PSMA theranostics: Review of the current status of PSMA-targeted imaging and radioligand therapy.” Cancers 12.6 (2020): 1367
- Eiber, Matthias, et al. “Simultaneous 68Ga-PSMA HBED-CC PET/MRI improves the localization of primary prostate cancer.” European urology 70.5 (2016): 829-836.
- Hofman, Michael S., et al. “Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.” The Lancet395.10231 (2020): 1208-1216.
- Roach, Paul J., et al. “The impact of 68Ga-PSMA PET/CT on management intent in prostate cancer: results of an Australian prospective multicenter study.” Journal of Nuclear Medicine59.1 (2018): 82-88.
- Fendler, Wolfgang P., et al. “Prostate-specific membrane antigen ligand positron emission tomography in men with nonmetastatic castration-resistant prostate cancer.” Clinical Cancer Research 25.24 (2019): 7448-7454.