Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.
Bibliographical noteFunding Information:
MH received consultancy fees from Bayer, ITM, and Janssen; grants from Siemens, Eli Lilly, Roche, BMS, Ipsen, ITM, and EZAG; and payment for lectures from Siemens, Bayer Healthcare, and GE Healthcare.
This work was supported by Bayer, Whippany, New Jersey, USA. Bayer provided review for medical accuracy, to ensure the balance of statements, and to confirm that content was correctly referenced during the development of the manuscript. The authors would like to emphasize that this manuscript was written independently and is their own intellectual work. No grant number is applicable.
MO received research funding from Astellas and honoraria from Astellas, Sanofi, Janssen, AstraZeneca, and Takeda.
OS has stock and other ownership interests in Eli Lilly, GlaxoSmithKline, and Noria; received consulting fees from Bayer, Bellicum Pharmaceuticals, Johnson & Johnson, Sanofi, AstraZeneca, Dendreon, Endocyte, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Celgene, Bavarian Nordic, OncoGenex, EMD Serono, Astellas Pharma, and Progenics; received research funding from Bayer, Johnson & Johnson, Sanofi, Endocyte, Innocrin Pharma, Merck, and Invitae; provided expert testimony for Sanofi; and received travel/accommodations/expenses support from Bayer, Johnson & Johnson, Sanofi, AstraZeneca, and Progenics.
WG received speaker fees from Bayer and MSD; consultant fees from Bristol-Myers Squibb, Astellas, Bayer, Sanofi, and Amgen for participation in advisory boards; and research grants from Bayer, Astellas, and Janssen-Cilag.
© 2019 THE AUTHORS
Copyright 2020 Elsevier B.V., All rights reserved.
- prostate cancer
- prostate-specific membrane antigen (PSMA)
- targeted alpha therapy (TαT)
ASJC Scopus subject areas