Abstract
Prostate cancer (PCa) is the most prevalent malignancy and leading cause of mortality in men. Despite the development of various drugs, such as novel androgen receptor signaling inhibitors and poly adenosine diphosphate-ribose polymerase inhibitors targeting homologous recombination repair-related genetic mutations, prognosis of metastatic castration-resistant prostate cancer remains unfavorable. However, recent advances in nuclear medicine have allowed for both imaging diagnostics and therapeutic interventions by targeting molecules specifically expressed in cancer cells with radioisotopes (RI). γ-rays are used in nuclear medicine imaging, whereas in therapy, α or β-emitting RIs are administered to target cells in radiation therapy. PCa, in particular, exhibits the characteristic features of radioligand therapy, as the membrane protein prostate-specific membrane antigen (PSMA) is proportionally highly expressed in malignancy compared to normal tissues. The administered RI-labeled compound binds to PSMA, enabling specific targeting of PCa for treatment. Unlike β-rays, α-rays have a shorter range and impart stronger energy to DNA, allowing α-particles to exhibit a higher linear energy transfer. Due to such characteristics, PSMA-targeted α radiotherapy is expected to have potent cytotoxic effects and fewer side effects on normal organs, making them more likely to be widely adopted in the future. However, reports on PSMA-targeted α radiotherapy differ in aspects, such as prior PSMA-targeted β radiotherapy, the administered doses, and the number of treatment cycles. Therefore, in this review, we compile the reports on treatments utilizing α-emitting isotopes targeting PSMA in patients with PCa.
Prostate cancer (PCa) was estimated to be the most commonly diagnosed malignant disease among American men in 2022 and the second leading cause of death after lung cancer (1). Surgery or radiation therapy is expected to result in a favorable prognosis for patients with localized PCa. However, if curative treatment is challenging, systemic pharmacological treatments, including androgen deprivation therapy (ADT), are the primary choice. ADT is highly effective in the early stages of PCa; however, as treatment duration increases, PCa acquires treatment resistance and almost always progresses to metastatic castration-resistant prostate cancer (mCRPC). Approximately 10% of patients diagnosed with PCa have bone metastases (2, 3), and within 2-3 years the disease progresses to mCRPC (4-6). Novel androgen receptor-targeted drugs, such as abiraterone acetate, enzalutamide, apalutamide, and darolutamide (7-10), along with taxane-based chemotherapeutic agents, such as docetaxel and cabazitaxel (11, 12), have been approved and widely used in the treatment of patients with CRPC. Furthermore, the polyadenosine diphosphate-ribose polymerase inhibitor olaparib was approved by the US Food and Drug Administration (FDA) for patients with mCRPC with BRCA mutations (13). In recent years, radioligand therapy (RLT) has achieved significant advancements in the treatment of multiple types of cancer. For instance, radium-223 accumulates in bone metastatic sites and primarily emits high-energy α radiation that has shown improvement in overall survival of patients with mCRPC with bone metastasis (14). In March 2022, the FDA approved the administration of β-ray 177Lu-PSMA-617 as a treatment for patients with mCRPC who tested positive on PSMA-PET-CT and had a history of treatment with androgen receptor pathway inhibitors and taxane-based chemotherapy. This approval was granted based on the observed improvement in overall survival (OS) compared to the standard care group (6).
PSMA is a type II transmembrane glycoprotein composed of 750 amino acids (15). Although PSMA is rarely expressed in normal human prostate epithelial cells, its expression in most PCa cells can exceed that in normal prostate epithelial cells by up to 100-1000 times (16, 17). Furthermore, PSMA overexpression is more prevalent in prostate cancers with a high Gleason score and in cases progressing to castration resistance (18, 19). Another specific aspect associated with PSMA expression is the internalization process in which proteins bound to PSMA on the cell surface undergo internalization. During this internalization process, radioactive isotopes labeled with PSMA-targeted compound enter the PCa cells, leading to increased DNA damage and apoptosis. Consequently, an efficient therapeutic effect of α-emitting isotopes is anticipated (20). However, as PSMA expression is observed in normal tissues other than the prostate, such as the salivary glands, lacrimal glands, renal proximal tubules, and duodenal mucosa, caution is required regarding organ-specific side effects when using PSMA-targeting radioligand therapy (17).
Visualization of lesion status based on the in vivo dynamics of drugs labeled with diagnostic radioisotopes (RI) and the subsequent administration of therapeutic drugs labeled with treatment-specific RI at the same site is expected to lead to the realization of personalized medicine. In recent years, this emerging field has been referred to as theranostics (therapy + diagnostics). To diagnose recurrence or metastatic sites, highly penetrative γ-rays are employed, whereas for therapy, cytotoxic α- and β-emitting radionuclides are used. Cellular damage is attributed to the energy kinetics of each particle, and α-rays, due to their short range and high energy compared to β-rays, can induce significant DNA double strand breaks across a smaller area, causing greater damage to cancer cells. Traditionally, we believe that in large tumors that are rich in stroma or have areas with low PSMA expression, the effect of α-rays is limited to the vicinity of tumor blood vessels, resulting in insufficient therapy compared to the β-ray therapy in which a cross-fire effect can be expected. For this reason, more studies have used β-rays than α-rays in RLT (21). The VISION trial, which demonstrated improved progression-free survival (PFS) and OS, led to the FDA approval of 177Lu-PSMA-617 radioligand therapy for the treatment of PSMA-positive patients with mCRPC (6). However, up to approximately 30% mCPPC never responded to 177Lu-PSMA-617 therapy (22) and, in 2016, Kratochwill et al. reported the promising therapeutic effects of PSMA-617 labeled with 225Ac in patients with mCRPC, marking the beginning of intensified research using α-emitting radionuclides (23). Generally, solid tumors can be treated with doses ranging from to 35-100 Gy. However, highly radiation-sensitive normal tissues, such as bone marrow, may experience radiation injury with doses exceeding 1.5 Gy, while organs like the lungs and kidneys may incur radiation damage at doses exceeding 20 Gy. After prostatectomy, many patients experience urinary incontinence, and reducing the radiation exposure risk of healthcare providers during nuclear medicine treatments for patients with mCRPC is a future challenge. Therefore, α-particles with a shorter range offer the advantage of reducing side effects compared to β-particles and the impact of secondary exposure of healthcare professionals to α-ray is extremely minimal (24). Given these considerations, the administration of drugs labeled with α-emitting radionuclides targeting the PSMA, which exhibits high specificity for PCa, is considered a well-matched and effective treatment although we need to pay attention to some potential side effects, such as xerostomia, related to physiological accumulation. The reports on PSMA targeted α-radiation therapy differ in the types of prior therapy, administered doses, and the number of treatment cycles. Therefore, this review compiles findings based on a literature search on PSMA targeted α-radiation therapy in patients with PCa using PubMed.
Type and Supply of RI that Emit α- and β-rays
Table I summarizes the characteristics of the radionuclides used in current clinical practice (25-28). Each type of radiation induces ionization based on its travel distance, leading to intracellular deposition and cell destruction. To achieve optimal target cell destruction while minimizing the ionizing interactions with healthy cells, it is essential to consider the travel length of the particles and the energy deposited in the cell. The energy delivered to the DNA of cells by α-particles is stronger and has a shorter effective range compared to β-particles. We specifically discussed the supply of 177Lu and 225Ac, the raw materials for 177Lu-PSMA-617 and 225Ac-PSMA-617, which are commonly used and researched in patients with CRPC.
Radioactive isotopes used in nuclear medicine therapy.
Almost all globally produced 177Lu is generated by irradiating precursor materials with neutrons in nuclear reactors and is utilized as 177Lu-PSMA-617 for CRPC and 177Lu-DOTATATE for neuroendocrine tumors (29). There is a potential shortage in the supply of 177Lu owing to increasing demand, and efforts to develop alternative manufacturing methods are underway, but have not yet reached practical implementation (30).
Currently, the production of 225Ac still relies on the extraction of 229Th. The global supply sources are limited to three locations worldwide: Oak Ridge National Laboratory in the United States (31), the Joint Research Centre of the European Commission in Karlsruhe, Germany (32), and the Institute for Physics and Power Engineering in Obninsk, Russia (33), resulting in a limited supply. Novel accelerator-based technologies, such as the nuclear fission of 232Th, proton and deuteron irradiation of 226Ra, and 226Ra irradiation based on photofission reactions, are being researched to increase the production of 225Ac. However, each of these technologies has limitations that require further development (34).
PSMA-targeted Radioligand Therapy Using 225Ac
Reports on prostate cancer treatment using 225Ac-PSMA-617 are summarized in Table II (23, 35-53). The first report on the treatment with 225Ac-PSMA-617 was published by Kratochwil C in 2016 (23). Remarkably, despite the advanced stages of mCRPC following multiple treatments (the first case was post-docetaxel, abiraterone, enzalutamide, and 223Ra therapy with a pre-RLT PSA of 2,923 ng/ml, and the second case was post-docetaxel, abiraterone, and enzalutamide therapy with a pre-RLT PSA of 294 ng/ml), the PSA levels dropped to less than 0.1 ng/ml. Almost all reports have consistently indicated that candidates for 225Ac-PSMA-617 therapy require high PSMA expression in lesions detected by 68Ga-PSMA-11 or 18F-PSMA-1007 PET/CT. Administration intervals are typically every eight weeks or two months, and treatment assessments involve monitoring via PSA follow-up and PSMA-PET/CT imaging.
Summary of prostate specific membrane antigen (PSMA) targeted α-radiation therapy in patients with metastatic prostate cancer.
When comparing the administered doses of 225Ac-PSMA-617 per cycle at 50, 100, 150, and 200 kBq/kg (body weight), it was observed that 100 kBq/kg resulted in the least side effects, with a recognized antitumor effect (35). Therefore, a dose of fixed 100 kBq/kg or initially 8 MBq/body, then tapering off is generally considered the standard.
Sathekge M reported the efficacy of 225Ac-PSMA-617 in a homogenized group of patients with CRPC, standardizing the patient treatment background to those who underwent ADT immediately after standard treatment (50). Among 53 patients, 48 (91%) showed a PSA reduction of ≥50% and multivariate analysis identified a PSA reduction of ≥50% as a predictor for both PFS and OS. The median OS for patients with a PSA reduction rate of <50% was nine months, whereas it was not reached for those with a reduction rate of ≥50% at the latest follow-up (median: 55 months). The median PFS was 22 months for patients with a PSA reduction rate of 50% or more and four months for those with a reduction rate of <50%. Despite differences in patient backgrounds, considering that the PSA reduction rates for patients with chemotherapy-naïve mCRPC treated with docetaxel, abiraterone, and enzalutamide after ADT are approximately 50%, 70%, and 80%, respectively, 225Ac-PSMA-617 appears to be a promising treatment option before chemotherapy (11, 54, 55). In patients without a history of taxane-based chemotherapy, only three cases (6%) showed grade III-IV renal toxicity, and no severe hematological toxicity was observed. For patients with mCRPC undergoing prolonged treatment with docetaxel, enzalutamide, or abiraterone, or those who have difficulty accessing regular clinic visits, 225Ac-PSMA-617 therapy may be particularly beneficial. In the TheraP trial, 177Lu-PSMA-617 demonstrated higher PSA response rates and fewer grade III or higher adverse events than did cabazitaxel in patients with mCRPC (56). Future research should compare 225Ac-PSMA-617 with cabazitaxel.
Sen reported that 225Ac-PSMA-617 was effective in patients with mCRPC following docetaxel treatment, and this treatment has been associated with an improved quality of life (47). As reported by Rosar, combination therapy with 177Lu-PSMA-617 and 225Ac-PSMA-617 was effective for mCRPC, showing significant OS improvement with minimal specific side effects of RLT (grade 3 or higher adverse events in 2 out of 15 cases) (48). However, there are also reports suggesting an increase in xerostomia (grade 2 or below) with combination therapy with 177Lu-PSMA-617 and 225Ac-PSMA-617, warranting further investigation (57).
Even after 177Lu-PSMA-617 therapy, which targets the same PSMA, 225Ac-PSMA-617 was effective with minimal side effects in patients with CRPC. Therefore, 225Ac-PSMA-617 may be useful in any treatment phase when PSMA is expressed in the tumor (43, 44, 46). Rosar reported that a single course of 225Ac-PSMA-617 (4MBq/body) and 177Lu-PSMA-617 (6GBq/body) therapy after 177Lu-PSMA-617 treatment failure for CRPC was effective and that this approach may reduce side effects by requiring lower doses and shorter treatment durations than multiple cycles of 225Ac-PSMA-617 monotherapy (49).
The effectiveness of 225Ac-PSMA-617 is not limited to patients with CRPC because it has shown efficacy in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Banba reported that in a small number of cases, PSA levels decreased by 90% or more in 100% of patients with mHSPC treated with 225Ac-PSMA-617 (51). The efficacy of 225Ac-PSMA-617 monotherapy in mHSPC is limited, with an OS of 31 months and 20 of 21 individuals (94%) experiencing grade II or lower xerostomia. No severe adverse events (grade III or above) were observed, likely because of the absence of a prior treatment history (53). Multivariate analysis results indicated favorable PFS and OS in patients with a PSA reduction of ≥50%. Despite differences in patient backgrounds and subsequent treatments, OS for mHSPC patients who underwent ADT plus docetaxel was 57.6 months (compared to 44.0 months with ADT monotherapy) (58), the 4-year OS for mHSPC patients receiving ADT plus enzalutamide was 71% (as opposed to 57% with ADT monotherapy) (59) and, the OS for mHSPC patients undergoing ADT plus abiraterone was 53.3 months, whereas it was 36.5 months with ADT monotherapy (60). Therefor it is not conclusive whether 225Ac-PSMA-617 monotherapy provides a better prognosis than standard treatments. Indeed, ADT and inhibition of the androgen receptor are essential for the treatment of mHSPC, and therapies solely targeting PSMA may be insufficient. Further investigations are needed to explore the combination of 225Ac-PSMA-617 and ADT in patients with mHSPC.
The AcTION trial, a prospective phase 1, open-label, dose escalation study, is currently assessing the safety of 225Ac-PSMA-617 in PSMA-positive patients with mCRPC (NCT04597411) who received a dose of 225Ac-PSMA-617 every 8 weeks for no more than six cycles. The TATCIST trial is a phase 2 study investigating the use of 225Ac-PSMA-I&T in patients with CRPC (NCT05219500) who received an initial dose of 100 kBq/kg at 8-week intervals for four doses, and additional doses were administered based on the PSA response.
Based on this review and summarizing the current investigation, the percentage of patients with mCRPC who experienced a 50% or greater reduction in PSA with 225Ac-PSMA-617 monotherapy was 66.9% (237/354), and the incidence of grade 3 or higher adverse events was 21.7% (80/368). Furthermore, for patients with mCRPC undergoing tandem therapy with 177Lu-PSMA-617 and 225Ac-PSMA-617, the PSA reduction rate of ≥50% was 50.0% (26/52), with a grade 3 or higher AE incidence of 15.4% (8/52). Tandem therapy with 177Lu-PSMA-617 and 225Ac-PSMA-617 may have exhibited a lower therapeutic effect and fewer side effects than 225Ac-PSMA-617 monotherapy, possibly due to fewer treatment cycles in the combined approach.
213Bi-PSMA-617
213Bi is one of the daughter nuclides of 225Ac with a short half-life of 46 min, undergoing branching decay to produce 213Po and 209Tl, emitting one α-particle per decay. It has been reported that seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with 90Y/177Lu-DOTATOC who were treated with 213Bi-DOTATOC showed enduring responses (61), but in patients with mCRPC, despite a higher accumulation in normal tissues, 213Bi-PSMA-617 did not demonstrate a significant superiority in therapeutic efficacy compared to 225Ac-PSMA-617, and no significant advantage was observed for cancer treatment (38).
Other Possible PSMA-targeted Alpha Radiotherapy in Patients With CRPC
225Ac is produced using 229Th or 226Ra as a parent nuclide or raw material, and handling of 229Th is challenging owing to the modification of 233U, which is a nuclear fuel. The worldwide production of 225Ac is limited, and it may be difficult to cover the global demand for patients with PCa with a high incidence in actual clinical practice (53). However, astatine is an α-emitter that can be produced with a natural bismuth target using a 30 MeV cyclotron at a reasonable cost and can be labeled onto small molecules and peptides (Table I) (62). Watabe reported the promising clinical potential of [211At]NaAt in patients with differentiated thyroid cancer refractory to standard [131I]NaI therapy (63, 64). Similarly, they developed a compound, 211At-PSMA-5, which binds to PSMA when labeled with astatine (65). Starting in 2024, we will be conducting clinical trials to assess the feasibility of using 211At-PSMA-5 for the clinical treatment of patients with CRPC.
Interestingly, darolutamide, a therapeutic agent for mCRPC, has the ability to increase the expression of PSMA and led to the suggestion that by inducing a PSMA-targeted thorium-227 conjugate (BAY 2315497), there could be an enhanced effect on DNA damage (66). A clinical trial evaluating the 227Th-BAY2315497 antibody with or without darolutamide in patients with mCRPC is currently underway (NCT03724747).
Conclusions and Future Perspectives
Treatment targeting PSMA with α-emitting agents for patients with mCRPC remained effective, even with a history of multiple treatments, including 177Lu-PSMA-617. However, given the current supply constraints, relying solely on 225Ac-PSMA-617 may not be feasible for all patients with mCRPC, because the production capacity of 225Ac is limited. Therefore, in the future, there is a need for infrastructure development aimed at increasing the production of 225Ac, along with the exploration of therapies utilizing α-emitting agents other than 225Ac, such as those expected in large-scale manufacturing, exemplified by 211At.
Combining 223Ra, the first radiopharmaceutical that emits α-particles, with abiraterone acetate plus prednisone or prednisolone, the frequency of fractures increased and additional 223Ra therapy is not recommended in patients with mCRPC (67). Considering such cases, it is crucial to investigate the efficacy and potential side effects of treatments targeting PSMA with α-emitting agents in patients with CRPC, particularly when used in combination with novel androgen receptor signaling inhibitors, taxane-based anticancer agents, and PARP inhibitors. In addition, the utility and side effects of combining this treatment with immunotherapy with the expectation of modulating the tumor microenvironment and inducing a systemic response, so-called abscopal effect, should be explored. Furthermore, prospective clinical studies comparing treatments targeting PSMA with α-emitting agents and existing upfront therapies in patients with mHSPC are anticipated. In a study using an mCRPC mouse model, albeit reported at the basic experimental stage, combination therapy with 225Ac-PSMA-617 and a programmed cell death protein 1 inhibitor achieved better tumor control than either agent alone owing to the abscopal effect; 225Ac altered the tumor microenvironment and induced systemic antitumor immune responses, which explains why immune checkpoint blockade enhances the therapeutic effect (68, 69).
Additionally, patients with CRPC treated with RLT whose PSA levels do not decrease by ≥50% have poor prognosis but in general, the usefulness of biomarkers for bone metastasis in PCa patients has not been established (70, 71). Therefore, the development of biomarkers to assess the effectiveness of treatment in individual patients before treatment initiation is crucial. For instance, there are reports indicating a correlation between PSMA expression levels before treatment and the efficacy of PSMA-targeted therapy (72-74).
Post-treatment targeting of PSMA with α-emitting agent interventions, such as salivary endoscopy, saline irrigation, and steroid injections may be effective in alleviating oral dryness (75). However, the invasiveness of these procedures renders their routine application impractical in clinical settings. Nevertheless, salivary gland protection remains a significant challenge for PSMA targeted α therapy, particularly in terms of preventing side effects. Although adverse effects such as hematologic toxicities are infrequent, bone marrow suppression in patients with mCRPC with a history of taxane-based treatment makes supportive measures, such as transfusion and infection control, important.
Given that treatments targeting PSMA are inherently effective only against tumors with high PSMA expression, there is a possibility that they may not be effective against neuroendocrine or prostate small cell cancers. Therefore, future research is eagerly awaited for the development of drugs such as darolutamide (66), which promote or sustain PSMA expression or new targeted radioligand therapy other than PSMA.
Footnotes
Authors’ Contributions
Gaku Yamamichi conceived the study and wrote the manuscript. Taigo Kato, Tadashi Watabe, Koji Hatano, Motohide Uemura, and Norio Nonomura supervised this study. All Authors have discussed, verified, and approved the final version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received December 31, 2023.
- Revision received January 24, 2024.
- Accepted January 25, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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