PSMA-targeted radioligand therapy in prostate cancer: current status and future prospects

ABSTRACT

Introduction

The prostate-specific membrane antigen (PSMA) targeted radioligand therapy (PRLT) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients has generated significant interest among the oncologic community, with several publications documenting good response rates and survival benefits with low toxicity profiles.

Areas covered

Indications, patient preparation, dose administration, post-treatment imaging, dosimetry, and side effect profiles of ¹⁷⁷Lu-PSMA-617 are discussed in this article. We also discuss results from prospective studies, major retrospective studies, meta-analyses, clinical trials, and mentioned major ongoing clinical trials on PRLT. We have also portrayed our own experiences and future perspectives on PRLT.

Expert opinion

For PRLT, PSMA-617 and PSMA-I&T molecules have revolutionized the theranostic approach in the management of advanced prostate cancer, with solid backing from several published articles showing favorable outcomes and an excellent safety profile of ¹⁷⁷Lu-PSMA-617. Improvement in quality of life and survival was seen in the majority of mCRPC patients after ¹⁷⁷Lu-PSMA-617 PRLT. Patients with good performance status, asymptomatic, only lymph node metastases, high PSMA expressing lesions, and no discordant FDG avid lesions have a longer survival after 177Lu-PSMA-617 PRLT than patients with poor performance status, symptomatic, hepatic, brain, and skeletal metastases, discordant PSMA, and FDG-avid lesions. Docetaxel and cabazitaxel are approved treatments for mCRPC patients. ¹⁷⁷Lu-PSMA-617 is approved as a third-line systemic treatment for mCRPC patients with failure to respond to androgen receptor pathway inhibitors and docetaxel therapy. PRLT is a safe and effective alternative to cabazitaxel (third-line systemic treatment), but it has a higher cost. ¹⁷⁷Lu-PSMA-617 could be a more efficient therapeutic option for mCRPC patients as first-line or combined therapy, and it may be a useful therapeutic option for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) patients. Several clinical studies and clinical trials on PRLT are currently underway. In the future, the results of these trials will be helpful in evolving treatment strategies for prostate cancer patients.

KEYWORDS:

• Prostate cancer
• prostate-specific membrane antigen (PSMA)
• metastatic castration-resistant prostate cancer (mCRPC)
• PSMA targeted radioligand therapy (PRLT)
• ¹⁷⁷Lu-PSMA-617
• theranostics

Article highlights

• A low level of PSMA expression is seen in normal prostate epithelium cells, and over-expression (up to 1000 times higher than normal) is seen in prostate cancer cells. The process of internalization allows the entry of PSMA labeled radionuclides within cells, which results in more DNA damage and apoptosis in cancer cells.

• The novel urea-based agents include PSMA-617 and PSMA-I&T. The molecular structures of ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA-I&T are built on different chelator agents, i.e. DOTA for ¹⁷⁷Lu-PSMA-617 and DOTAGA for ¹⁷⁷Lu-PSMA-I&T with comparable bio-distribution except for renal uptake. ¹⁷⁷Lu-PSMA-617 has lower renal uptake as compared to ¹⁷⁷Lu-PSMA-I &T.

• Presently, ¹⁷⁷Lu-PSMA-617 is recommended and FDA approved for mCRPC patients who have treatment failure with androgen receptor pathway inhibitors and docetaxel, show adequate PSMA uptake on pre-therapy PSMA PET/CT imaging, and possess adequate organ functions.

• PSMA uptake in tumor lesions higher than that of normal physiological liver uptake (as defined in the VISION trial) is a better and simpler approach for defining ‘adequate PSMA uptake’ on pre-therapy PSMA-PET/CT imaging for PRLT purposes.

• Post-¹⁷⁷Lu-PSMA-617 imaging is used for dosimetry, visualization of radioligand concentration in tumor lesions, and treatment response assessment. When post-¹⁷⁷Lu-PSMA-617 imaging is utilized for response assessment, there is no extra-radiation exposure to patients related to PET/CT or CT imaging for response assessment.

• Prostate Cancer Working Group 3 (PCWG3) provided a definition of responder or progression of disease by using serum PSA levels, where patients are considered PSA responders if they have achieved a ≥ 50% decrease in serum PSA level from baseline and PSA progression if they have achieved a ≥ 25% increase from the baseline value along with an increase in absolute value of ≥2 ng/mL after 12 weeks of treatment.

• Availability of ²²⁵Ac for clinical use is limited as production of ²²⁵Ac still relies on extraction from legacy stockpiles of thorium-229. The ²²⁵Ac decays to near-stable bismuth-209 via a cascade of six short-lived radionuclide daughters with emission of total energies ranging from 5.8 to 8.4 MeV, a tissue penetration of 47–85 μm, and gamma co-emissions (from disintegrations of francium-221 and bismuth-213).

• Administration of abiraterone acetate or enzalutamide in prostate cancers (i) increases PSMA expression and (ii) lowers testosterone levels, leading to inhibition of DNA repair mechanisms following damage by radiation therapy. These are the basis for the combination of PRLT with abiraterone acetate or enzalutamide.

• Immunotherapy may upregulate PSMA expression and in turn might enhance the effect of PRLT, which is the basis for combining PRLT with immunotherapy.

• More frequent non – life-threatening and unpleasant side effects of PRLT include nausea, vomiting, and xerostomia. Bone marrow toxicity is a rare but severe adverse event of PRLT.

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.