A Review of 177Lutetium-PSMA and 225Actinium-PSMA as Emerging Theranostic Agents in Prostate Cancer

Abstract

The development of prostate-specific membrane antigen (PSMA) ligands labeled with radionuclides is a ground-breaking achievement in the management of prostate cancer. With the increasing use of ⁶⁸Gallium-PSMA and ¹⁸F-DCFPyL (Pylarify) and their approval by the Food and Drug Administration (FDA), other PSMA agents and their unique characteristics are also being studied. Two other PSMA agents, namely ¹⁷⁷Lutetium-PSMA (¹⁷⁷Lu-PSMA) and ²²⁵Actinium-PSMA (²²⁵Ac-PSMA), are currently drawing the researcher's attention mainly due to their theranostic importance. Studies focusing on the essential characteristics of these two emerging radiotracers are relatively lacking. Hence, this review article, beginning with a brief introduction, intends to provide insights on the mechanism, efficacy, adverse effects, usefulness, including theranostic implications, and limitations of these two emerging PSMA agents. The ¹⁷⁷Lu-PSMA is commercially accessible, is well tolerated, and has been found to lower prostate-specific antigen (PSA) levels while improving patients' quality of life. It also reduces pain and the requirement for analgesics and is safe for advanced diseases. However, despite its potential advantages, around one-third of patients do not respond satisfactorily to this costly treatment; it is still challenging to personalize this therapy and predict its outcome. Similarly, ²²⁵Ac is compatible with antibody-based targeting vectors, releasing four extremely hazardous high-energy emissions with a longer half-life of 10 days. It has made ²²⁵Ac-PSMA therapy useful for tumors resistant to standard treatments, with a better response than ¹⁷⁷Lu-PSMA. Dosimetry studies show a good biochemical response without toxicity in patients with advanced metastatic castration-resistant prostate cancer (mCRPC). However, it can potentially cause significant damage to healthy tissues if not retained at the tumor site. Encapsulating radionuclides in a nano-carrier, hastening the absorption by tumor cells, and local delivery might all help reduce the harmful consequences. Both have advantages and disadvantages. The choice of PSMA agents may rely on desired qualities, cost, and convenience, among other factors. Further research is warranted in order to better understand their ideal use in clinical settings.

Keywords: 177lu-psma; 225ac-psma; [18f]fdg; pet/ct; prostate cancer; prostate-specific membrane antigen; psma.

Figure 1. Efficacy of 177Lutetium prostate-specific membrane antigen.

An 83-year-old patient with castration-resistant prostate cancer (Gleason score: 9) and an increasing prostate-specific antigen (PSA) level. He had a history of prostatectomy and radiation therapy on the prostate bed. The ⁶⁸Ga-PSMA PET scan showed diffuse bone and bone marrow involvement (a). Before the first cycle of ¹⁷⁷Lu-PSMA therapy, PSA and alkaline phosphatase (ALP) levels were 261 ng/mL and 659 U/L, respectively. The patient received two cycles of ¹⁷⁷Lu-PSMA, and the PSA level decreased continuously during cycles from 261 to 9.0 ng/mL (eight weeks after the second cycle). The ALP also reduced from 659 to 81 U/L (eight weeks after the second cycle). PSMA-PET (b) eight weeks after the second cycle showed a significant response with significant regression of PSMA. This research was originally published in Radiation Oncology. Awang ZH, Essler M, Ahmadzadehfar H. Radioligand therapy of metastatic castration-resistant prostate cancer: current approaches. Radiation Oncology. 2018;13(1):1-9 [13]

Figure 2. Efficacy of 225Actinium prostate-specific membrane antigen.

⁶⁸Ga-PSMA-11 PET/CT of a patient. Compared to initial tumor spread (A), restaging after two cycles of β-emitting ¹⁷⁷Lu-PSMA-617 presented progression (B). In contrast, restaging after the second (C) and third (D) cycles of α-emitting ²²⁵Ac-PSMA-617 gave an impressive response. This research was originally published in Journal of Nuclear Medicine. Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, Kopka K, Apostolidis C, Haberkorn U, Morgenstern A. 225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med. 2016;57(12):1941-4. © by the Society of Nuclear Medicine and Molecular Imaging, Inc. [51]