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Review
. 2019 Nov 1;30(11):1728-1739.
doi: 10.1093/annonc/mdz270.

Advances in targeted alpha therapy for prostate cancer

G De Vincentis  1 , W Gerritsen  2 , J E Gschwend  3 , M Hacker  4 , V Lewington  5 , J M O'Sullivan  6 , M Oya  7 , M Pacilio  8 , C Parker  9 , N Shore  10 , O Sartor  11 ; Targeted Alpha Therapy Prostate Working Group
Affiliations
Review

Advances in targeted alpha therapy for prostate cancer

G De Vincentis et al. Ann Oncol. .

Abstract

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.

Keywords: prostate cancer; prostate-specific membrane antigen (PSMA); radium-223; targeted alpha therapy (TαT).

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Figures

Figure 1.
Figure 1.
PSMA TαT is complementary to existing therapies for prostate cancer. Depicted is a suggested clinical sequencing, in which PSMA TαTs would be considered after a failure of a first-line therapy for mCRPC and PSMA expression was confirmed positive. ADT, androgen deprivation therapy; CT, computed tomography; mHSPC, metastatic hormone-sensitive prostate cancer; mCRPC, metastatic castration-resistant prostate cancer; NAH, novel antihormonal; nmCRPC, non-metastatic castration-resistant prostate cancer; PET, positron emission tomography; PSMA, prostate-specific membrane antigen; TAT, targeted alpha therapy.
Figure 2.
Figure 2.
PSMA as a potential therapeutic target for prostate cancer. PSMA is a transmembrane protein overexpressed in prostate cancer. The extracellular domain of PSMA is internalized after ligand binding, allowing intracellular delivery of conjugated therapeutic agents, such as actinium-225. PSMA, prostate-specific membrane antigen.
Figure 3.
Figure 3.
Schematic representation of 227Th-PSMA-IgG1. An N-hydroxysuccinimide-activated 3,2-hydroxypyridinone chelator is coupled to the PSMA antibody and radiolabeled with the thorium-227 radionuclide. PSMA, prostate-specific membrane antigen.
See this image and copyright information in PMC

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