A Treatment Paradigm Shift: Targeted Radionuclide Therapies for Metastatic Castrate Resistant Prostate Cancer

Abstract

The recent approval of 177Lu PSMA-617 (Pluvicto®) by the United States Food and Drug Administration (FDA) is the culmination of decades of work in advancing the field of targeted radionuclide therapy for metastatic prostate cancer. 177Lu PSMA-617, along with the bone specific radiotherapeutic agent, 223RaCl2 (Xofigo®), are now commonly used in routine clinical care as a tertiary line of therapy for men with metastatic castrate resistant prostate cancer and for osseus metastatic disease respectively. While these radiopharmaceuticals are changing how metastatic prostate cancer is classified and treated, there is relatively little guidance to the practitioner and patient as to how best utilize these therapies, especially in conjunction with other more well-established regimens including hormonal, immunologic, and chemotherapeutic agents. This review article will go into detail about the mechanism and effectiveness of these radiopharmaceuticals and less well-known classes of targeted radionuclide radiopharmaceuticals including alpha emitting prostate specific membrane antigen (PSMA)-, gastrin-releasing peptide receptor (GRPR)-, and somatostatin targeted radionuclide therapeutics. Additionally, a thorough discussion of the clinical approach of these agents is included and required futures studies.

Nuclear Receptor Imaging In Vivo—Clinical and Research Advances

“…Androgen deprivation therapy remains a mainstay of treatment in mCRPC despite androgen insensitivity and is used in conjunction with bone-modifying agents and chemotherapy [ 89 ]. Advances in the field of targeted molecular imaging and radionuclide therapy for mCRPC has led to the widespread adoption of PET amino acids ( 18 F Fluciclovine; Axumin) and prostate-specific membrane antigen (PSMA) ligands ( 68 Ga PSMA-11; Locometz, Illucix) and radionuclide therapy including bone-specific radionuclide agents ( 223 Ra dichloride; Xofigo) and PSMA targeted radiotherapy ( 177 Lu PSMA-617; Pluvicto) [ 90 ]. PSMA imaging in particular has eclipsed the ability of androgen receptor (AR) imaging to identify mCRPC lesions Similar to ER and PR expression in breast cancer, AR expression is heterogeneous and expression can change over time, particularly when patients are placed on hormonal therapy.…”

Imidazolium‐methylene‐trifluoroborate: A novel radioprosthetic group validated with preclinical 18F‐Positron Emission Tomography imaging of Prostate Specific Membrane Antigen in mice

“…Propargyl-ImMBF 3 (3) was prepared by treating imidazole with propargyl bromide followed by iodomethyl-B (pin) and KHF 2 to give the corresponding trifluoroborate that was then reacted with a pendant azide borne on a EUK-scaffold. Briefly, imidazole was dissolved in MeCN under an argon atmosphere and was mixed with propargyl bromide to give the N-propargyl-imidazole in $88% yield.…”

“…Towards these ends, theranostic approaches that combine imaging and treatment are showing great promise for increasing patient survival and even enabling some patients to achieve long‐term remission. A prime example is prostate cancer (PCa), where diagnostic agents and companion therapeutics have increased patient survival; in just the past year, the FDA approved 18 F‐Pylarify™ 2 as a diagnostic agent for imaging the prostate‐specific membrane antigen (PSMA) to detect the metastatic spread of PCa and 177 Lu‐Pluvicto™ as a targeted radiotherapeutic that recognizes the same target 3 and is used to treat patients with end‐stage disease. In light of this success, a number of new PSMA‐targeting diagnostics, therapeutics, and theranostics are advancing in pre‐clinical and clinical trials 4–11 .…”

Synthesis of [68Ga]Ga-PSMA-11 using the iMiDEV™ microfluidic platform

“…[6][7][8][9][10] Moreover, two ready to use kits are commercially available, the first is developed by Isotopia Molecular Imaging Ltd. (isoPROtrace-11; Petach Tikva, Israel) 11,12 and the second one is from Telix Pharmaceuticals (TLX591-CDx, Illumet™ or Illuccix®; Melbourne, Australia). 12 The broadening of the theranostic approach and personalized medicine, particularly [ 177 Lu]Lu-PSMA-617 (Pluvicto®) for prostate cancer treatment, 13,14 revealed an emerging need for onsite and on-demand production of PET probes. Recently, different microfluidic devices have been developed to set up this new way of producing radiopharmaceuticals.…”