ABSTRACT
Introduction
Alpha emitters present several advantages for cancer therapy. The radiopharmaceutical 223Ra-dichloride has been recently introduced for the targeted alpha therapy (TAT) of metastastic castration-resistant prostate cancer (mCRPC). However, since 223Ra-dichloride targets only skeletal lesions, its use in clinical practice is recommended only in subjects without visceral metastases. To overcome this, several efforts have been made to develop radiopharmaceuticals suitable for TAT and specifically directed toward the biomarker prostate specific membrane antigen (PSMA), overexpressed by both skeletal and visceral metastases from mCRPC.
Areas covered
The radiobiological principles concerning TAT applications are covered, with particular emphasis on its pros and cons, especially in comparison with beta-emitter radionuclide therapy. Furthermore, the role of PSMA as a theranostic target for imaging and therapy is reviewed. Lastly, the pre-clinical and clinical applications of TAT through 225Actinium (225AC) and 213Bismuth (213Bi) are discussed.
Expert opinion
PSMA-based TAT holds the promise of becoming a powerful tool for the management of mCRPC. Nevertheless, several issues have still to be addressed, especially concerning TAT toxicity. Furthermore, several efforts have to be made for identifying the more adequate alpha-emitter (225Ac vs 213Bi) with a view to the patient’s tailored therapeutic approach.
Article highlights
Metastatic castration resistant prostate cancer (mCRPC) represents an aggressive disease, with limited therapeutic options
Targeted alpha therapy (TAT) with 223Ra-dichloride was demonstrated to provide a significant survival benefit in mCRPC, but its effectiveness is only limited to bone metastases
PSMA has emerged as a crucial target for the imaging and therapy of prostate cancer, through the utilization of radiolabeled PSMA-inhibitors, capable of binding to the extracellular domain of the PSMA molecule
PSMA-targeted therapy with beta-emitters has been applied in patients with promising results, although the majority of cases did not reach complete or long-term response
PSMA TAT with 225Ac and 213Bi holds the promise to represent a powerful tool since alpha-emitters are high LET radiations and produce tumoricidal effects independently from oxygenation and cell cycle
Preliminary clinical experiences suggest that TAT with 225Ac/213Bi-PSMA-617 may have a role in the managment of mCRPC, being severe xerostomia the most relevant adverse event
Optimization of dose regimen and an accurate patients’ selection might be useful for improving PSMA TAT, also minimizing adverse effects
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.