Status of PSMA-targeted radioligand therapy in prostate cancer: current data and future trials

Abstract

Metastatic prostate cancer continues to be an incurable disease. Despite all the novel therapies approved in the past two decades, overall patient outcomes remain relatively poor, and these patients die on a regular basis. Clearly, improvements in current therapies are needed. Prostate-specific membrane antigen (PSMA) is a target for prostate cancer given its increased expression on the surface of the prostate cancer cells. PSMA small molecule binders include PSMA-617 and PSMA-I&T and monoclonal antibodies such as J591. These agents have been linked to different radionuclides including beta-emitters such as lutetium-177 and alpha-emitters such as actinium-225. The only regulatory-approved PSMA-targeted radioligand therapy (PSMA-RLT) to date is lutetium-177–PSMA-617 in the setting of PSMA-positive metastatic castration-resistant prostate cancer that has failed androgen receptor pathway inhibitors and taxane chemotherapy. This approval was based on the phase III VISION trial. Many other clinical trials are evaluating PSMA-RLT in various settings. Both monotherapy and combination studies are underway. This article summarizes pertinent data from recent studies and provides an overview of human clinical trials in progress. The field of PSMA-RLT is rapidly evolving, and this therapeutic approach will likely play an increasingly important role in the years to come.

Molecular Design of 68Ga- and 89Zr-Labeled Anticalin Radioligands for PET-Imaging of PSMA-Positive Tumors

“…with an accumulation of 2.2 ± 0.4% ID/g for Dfo and of 2.5 ± 0.4% ID/g for FsC, which is doubled compared to the increased tumor uptake of 1.2% ID/g for 68 Ga·NODAGA-A3A5.1 at t = 60 min. This is comparable to published PET-imaging studies with nanobodies , or Anticalins directed against other tumor targets , and is in agreement with previous studies of PASylated Fab fragments. ,, Admittedly, the performance only poorly competes with the recently approved 177 Lu-PSMA-617 (lutetium-177 vipivotid tetraxetan, Pluvicto), a small-molecule radioligand developed on the basis of a urea-type enzyme inhibitor of the glutamate carboxy­peptidase 2 (GCPII = PSMA), which shows fast and exceptional tumor accumulation and only low persistence in the kidneys. ,, Nevertheless, the findings from our study provide valuable guidance for the development of protein-based radioligands against other tumor markers that cannot be efficiently addressed by small molecules.…”

“…21,55,56 Admittedly, the performance only poorly competes with the recently approved 177 Lu-PSMA-617 (lutetium-177 vipivotid tetraxetan, Pluvicto), a small-molecule radioligand developed on the basis of a urea-type enzyme inhibitor of the glutamate carboxypeptidase 2 (GCPII = PSMA), which shows fast and exceptional tumor accumulation and only low persistence in the kidneys. 3,57,58 Nevertheless, the findings from our study provide valuable guidance for the development of proteinbased radioligands against other tumor markers that cannot be efficiently addressed by small molecules.…”

“…While PSMAtargeted tumor imaging is established in the clinic since 1996 after the FDA approval of the first antibody tracer, 111 In capromab pendetide (ProstaScint), radiopharmaceuticals based on small-molecule inhibitors have recently outcompeted antibodies. 2,3 Apart from the ongoing high interest as an established PCa biomarker, PSMA also represents a model cell surface tumor marker for protein-based tracers in general.…”

“…In the last few years, tremendous progress has been made by introducing the concept of theranostics and by targeting the prostate-specific membrane antigen (PSMA) as a tumor marker in PCa for both diagnostics and therapeutic intervention. While PSMA-targeted tumor imaging is established in the clinic since 1996 after the FDA approval of the first antibody tracer, 111 In capromab pendetide (ProstaScint), radiopharmaceuticals based on small-molecule inhibitors have recently outcompeted antibodies. , Apart from the ongoing high interest as an established PCa biomarker, PSMA also represents a model cell surface tumor marker for protein-based tracers in general. Hence, we set out to investigate the PSMA-specific Anticalin A3A5.1, which possesses sub-nanomolar affinity, as a novel type of radioligand.…”

LC–MS/MS Bioanalysis of Radioligand Therapeutic Drug Candidate for Preclinical Toxicokinetic Assessment

“…3 Radioligand therapy (RLT) is a novel therapeutic method that has gained significant momentum in recent years in the diagnosis, treatment, and monitoring of cancer. 4 As a form of precision nuclear medicine for patients with advanced cancers, RLT uses radioactive substances, i.e., radioligands, to bind specifically to the receptors expressed on cancer cells, delivering radiation to tumor in a direct and precise way while preserving the surrounding healthy tissues. One successful example of RLT is PLUVICTO ( 177 Lu-PMSA-617), which was approved in 2022 as the first prostate-specific membrane antigen-targeted radioligand therapy demonstrating clinical benefits in patients with prostate cancer.…”