The potential of PSMA-targeted alpha therapy in the management of prostate cancer

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.

KEYWORDS:

• Targeted alpha therapy
• prostate cancer
• theranostics
• prostate-specific membrane antigen
• apha emitters

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.

Additional information

Funding

This paper received no funding.