Akhil Abraham Saji, MD

GU Oncology Now

In recent years, prostate-specific membrane antigen (PSMA)&mdash;also known as glutamate carboxypeptidase 2&mdash;has been a topic of great interest for clinicians and patients alike. Compared with traditional imaging modalities such as multiparametric magnetic resonance imaging or conventional computed tomography (CT), PSMA PET (in conjunction with CT) offers a more precise and targeted diagnostic modality for patients with prostate cancer.The underlying mechanism of PSMA is the overexpression of PSMA on the extracellular compartment and the upregulation of PSMA expression by anywhere from 100- to 1000-fold with the onset of prostate cancer.<a href="https://www.mdpi.com/2072-6694/12/6/1367" target="_blank" rel="noopener">1</a> Studies have shown that the degree of PSMA expression correlates with tumor stage and grade, with the notable exception of neuroendocrine tumors. The underlying biochemistry of the PSMA receptor facilitates the process of creating synthetic agents to bind the receptor, consequently providing diagnostic and therapeutic potential.Modern PSMA binding ligands are constructed with a urea molecular scaffold known as a PSMA pharmacophore, which has been the dominant molecular type for PSMA ligand synthesis since 2001. The first generation of PSMA binding ligands were monoclonal antibodies. They posed several limitations, including, but not limited to, slower target recognition and background clearance times.<a href="https://www.sciencedirect.com/science/article/abs/pii/S1078143912001573" target="_blank" rel="noopener">2</a> Comparatively, second-generation urea-based agents offer several advantages, including improved biological stability and resistance to extreme conditions such as temperature and pH.<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094430/" target="_blank" rel="noopener">3</a> These characteristics have enabled the creation of a variety of PSMA-directed, urea-scaffold-based pharmacophores that bind to the PSMA receptor with great affinity, facilitating both diagnostic and therapeutic effects.Several PSMA-directed agents have been created within the diagnostic sphere of prostate cancer, including 68Ga-PSMA-11 (produced by Telix Pharmaceuticals Limited and Isotopia Molecular Imaging) and 18F-DCFPyL (also known as piflufolastat F-18, or Pylarify by Lantheus). 68Ga-PSMA-11 was approved in December 2020 by the US Food and Drug Administration (FDA) for use in patients with suspected metastatic prostate cancer and those with biochemical recurrence (BCR) after primary therapy.<a href="https://content.govdelivery.com/accounts/USFDA/bulletins/2af2446" target="_blank" rel="noopener">4</a>Abghari-Gerst and colleagues conducted a prospective multicenter study to evaluate the performance of 68Ga-PSMA-11 in patients with suspected BCR after primary prostate cancer therapy.<a href="https://jnm.snmjournals.org/content/early/2021/07/29/jnumed.121.262412" target="_blank" rel="noopener">5</a> In their cohort of more than 2000 patients, close to half (50.8%) received prostatectomy, a further 29.6% received prostatectomy followed by radiation therapy, and 19.7% received primary radiation therapy. The study&rsquo;s primary end point was to identify the positive predictive value of 68Ga-PSMA-11 scans, which the authors confirmed using direct histopathology. Among the different cohorts evaluated for prostatic fossa disease, patients who had primary radiation had the highest rates of detection (64%) compared with prostate bed recurrence (20.6%) after prostatectomy. Pelvic nodal disease was more consistent across all patients, ranging in positivity rates from 42.7% to 38.8%.Axumin (18F-fluciclovine by Blue Earth Diagnostics), a former novel PET imaging technique, was approved by the FDA in May 2016 for BCR after primary therapy for prostate cancer.<a href="https://www.fda.gov/news-events/press-announcements/fda-approves-new-diagnostic-imaging-agent-detect-recurrent-prostate-cancer" target="_blank" rel="noopener">6</a> Its underlying mechanism is uptake by the L-amino acid transport system.<a href="https://e-century.us/files/ajnmmi/11/4/ajnmmi0133241.pdf" target="_blank" rel="noopener">7</a> How does Axumin compare with 68Ga-PSMA-11? In 2019, <a href="https://guoncologynow.com/author/jeremie-calais-md-msc" target="_blank" rel="noopener">Dr. J&eacute;r&eacute;mie Calais</a>, a GU Oncology Now editor, and colleagues published a single-center study evaluating the 2 modalities.<a href="https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30415-2/fulltext" target="_blank" rel="noopener">8</a>Their trial cohort included 50 patients who received both scans. The authors found that 68Ga-PSMA-11 had nearly double the detection rate (56%) compared with Axumin (26%). The largest differences between the modalities were seen in patients with low prostate-specific antigen levels.<a href="https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30415-2/fulltext" target="_blank" rel="noopener">8</a> The significant improvement provided by PSMA-targeted agents can facilitate identification of recurrent foci of prostate cancer earlier in the BCR process.PSMA is also a valuable therapeutic tool. By providing a biochemical target, molecular therapeutic agents can be created to selectively injure PSMA-expressing cancer cells. The field of PSMA-directed therapy is called radiotheranostics, and the most widely known radiotheranostic approach for prostate cancer involves 177Lu-PSMA-617 (Pluvicto by Novartis Pharmaceuticals). The premise of 177Lu-PSMA-617 involves utilizing the radionuclide lutetium-177 bound to the PSMA peptide to facilitate targeted emission of &beta; radiation&mdash;within a 2-mm radius, which induces single-stranded DNA damage&mdash;at the target sites.The phase 3 VISION trial investigated the use of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with chemotherapy or androgen pathway inhibitor agents.<a href="https://www.nejm.org/doi/full/10.1056/nejmoa2107322" target="_blank" rel="noopener">9</a> The trial demonstrated that 6 cycles of 177Lu plus standard of care (SOC) versus SOC alone prolonged overall survival (15.3 vs 11.3 months) and extended radiographic progression-free survival (8.7 vs 3.4 months). Ongoing and future studies will focus on using a radiotheranostic approach for the treatment of patients with earlier stages of disease, such as metastatic hormone-sensitive prostate cancer.Despite the evidence shown to date, PSMA technology is in its infancy and will need to overcome limitations related to cost, availability, and production prior to widespread dissemination. To promote adoption and due to compelling evidence, the American Urological Association/Society of Urologic Oncology advanced prostate cancer guideline recommends the use of PSMA PET imaging in patients with BCR after initial therapy in lieu of conventional imaging (Statement 6).<a href="https://www.auajournals.org/doi/10.1097/JU.0000000000003452" target="_blank" rel="noopener">10</a> The guideline also advocates for the use of PSMA-based imaging in patients with non-mCRPC at intervals of 6 to 12 months (Statement 21) and recommends that clinicians consider treating patients with mCRPC with Pluvicto to obtain PSMA-based diagnostic imaging prior to treatment.PSMA PET imaging is an exponential leap forward in the fight to cure prostate cancer. As the availability of diagnostic and theranostic capabilities expands across the United States, more patients will benefit from the higher diagnostic accuracy and therapeutic potential this technology can offer. Furthermore, PSMA PET is a valuable addition to the tools available to clinicians who care for patients with prostate cancer worldwide, allowing for more accurate data to facilitate treatment decision-making.Akhil Abraham Saji, MD, Fellow at the University of Southern California, is a urologist specializing in minimally invasive surgery and urologic oncology with an interest in technology-driven innovation within health care.&nbsp;References<ol>
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Assessing the Makeup and Utility of PSMA PET

Prostate Cancer Diagnostics

PSMA PET imaging is a leap forward in the fight to cure prostate cancer, especially as the availability of diagnostic and theranostic capabilities expands.