PSMA Targeted Molecular Imaging and Radioligand Therapy for Prostate Cancer: Optimal Patient and Treatment Issues

Theranostics (therapy + diagnosis) targeting prostate-specific membrane antigen (PSMA) is an emerging therapeutic modality that could alter treatment strategies for prostate cancer. Although PSMA-targeted radioligand therapy (PSMA-RLT) has a highly therapeutic effect on PSMA-positive tumor tissue, the efficacy of PSMA-RLT depends on PSMA expression. Moreover, predictors of treatment response other than PSMA expression are under investigation. Therefore, the optimal patient population for PSMA-RLT remains unclear. This review provides an overview of the current status of theranostics for prostate cancer, focusing on PSMA ligands. In addition, we summarize various findings regarding the efficacy and problems of PSMA-RLT and discuss the optimal patient for PSMA-RLT.


Introduction
Prostate cancer is the second most commonly diagnosed malignant disease and the fifth leading cause of death among men in the world [1]. Localized prostate cancer has a good prognosis with treatment such as surgery and radiation, but recurrent or metastatic cancer leads to a lethal disease called castration-resistant prostate cancer (CRPC). Drugs, such as second-generation antiandrogens (enzalutamide [2], abiraterone [3], apalutamide [4], darolutamide [5]), taxanes (docetaxel [6], cabazitaxel [7]), PARP inhibitors (olaparib [8]), and radium-223 [9], have prolonged prognosis in CRPC patients, but CRPC remains difficult to cure. However, the situation is changing with the recent discovery of a cancer-specific protein called prostate-specific membrane antigen (PSMA). There has been remarkable development in "theranostics", in which antibodies or small molecular compounds that bind to PSMA are coupled with the diagnostic emitter or therapeutic alphaor beta-emitters to diagnose or treat prostate cancer, respectively. Then, in March 2022, the US Food and Drug Administration (FDA) approved 177 Lu-PSMA-617, a radioligand therapy for PSMA (PSMA-RLT), based on the results of the VISION trial [10]. In the VISION trial, 177 Lu-PSMA-617 extended prognosis in heavily pretreated CRPC patients. However, although 177 Lu-PSMA-617 offers a longer-term prognosis for some patients, the overall survival difference was only 4 months compared to the control group, and hence CRPC remains a fatal disease. In addition, despite the inclusion of only PSMA-positron emission tomography (PET) positive patients in this study, some patients do not show an adequate treatment response. Therefore, 177 Lu-PSMA-617 does not always benefit all CRPC patients, and it is unclear which patients would benefit from this therapy. This review provides an overview of the current status of diagnostic and therapeutic agents and milestone studies in the rapidly developing PSMA-RLT. We also review the therapeutic effects and side effects of PSMA-RLT and outline the currently developing PSMA therapies, including combination

18 F-PSMA-1007
In general, agents using 18F have a longer half-life than 68 Ga agents, making them suitable for image evaluation at later time points and mass production. 18 F is generally synthesized in cyclotrons and has a longer half-life than 68 Ga [21], which may be superior in production and supply, but production facilities are limited due to the need for huge cyclotrons. 18 F-PSMA-1007 is characterized by biliary excretion and low urinary excretion, which is considered an advantage in the evaluation of local lesions [22]. However, it is highly concentrated in the liver, which may mask liver metastatic lesions, and may not be suitable for patients with severe hepatic dysfunction [23]. Some reports suggest that it is advantageous in the diagnosis of recurrence after total prostatectomy because of its lower urinary excretion compared to other agents, but others report that there was no difference in diagnostic performance [22]. Although this drug has not been approved by the FDA and EMA, it is currently being compared to Ga-PSMA-11 [24] and is a promising agent for future approval. 18 F-DCFPyL is an agent approved by the FDA in 1/DEC/2020 as piflufolastat TM ; it is not yet approved by the EMA. The indications are the same as for 68 Ga-PSMA-11, which is approved for the diagnosis of recurrence after radical therapy, staging of localized prostate cancer, and metastatic prostate cancer. It is excreted from the urine and liver, but its accumulation in the liver is reported to be milder than that of 18 F-PSMA-1007, and it may be safer than 18 F-PSMA-1007 in patients with hepatic dysfunction [23]. Most of the current reports of PSMA-PET were performed using PSMA-PET/CT. PSMA-PET has a lot of evidence for primary staging evaluation in localized intermediateand high-risk prostate cancer and diagnosis of biochemical recurrence (BCR) after radical prostatectomy (RP) or radiotherapy, but there are many challenges for diagnosis in metastatic prostate cancer and CRPC. In a prospective phase III trial of 764 intermediateand high-risk prostate cancer patients with RP, the diagnostic sensitivity and specificity of 68 Ga-PSMA-11 PET/CT for lymph node metastatic stage were 0.40 (95% CI: 0.34-0.46) and 0.95 (95% CI: 0.92-0.97), respectively [25]. In another meta-analysis of 37 studies on the primary staging by 68 Ga-PSMA-11 PET/CT, the sensitivity and specificity for the diagnosis of lymph node metastases were 77% and 97%, respectively, in a patient-based analysis [26]. PSMA-PET for local staging in the primary staging of prostate cancer is not approved and is still experimental. PSMA-PET/MRI has been reported to be more effective than PET/CT for primary staging [27] and has been noted to have better diagnostic ability for T3a and T3b [28]. If PSMA-PET/MRI enables TNM classification staging in a single scan, it should be potentially beneficial to patients, and future studies are warranted. We are currently evaluating a prospective comparative study of multi-parametric MRI and PSMA-PET/MRI for preoperative evaluation of local staging for localized prostate cancer (jRCTs022220021), and the results will be reported in the future. An attempt to fusion-biopsy using PSMA-PET/MRI for men with elevated PSA (NCT03187990) is ongoing, and future results are expected. With regard to the primary staging of bone metastases, 12 studies, including a systematic review, reported that the sensitivity and specificity of PSMA-PET/CT for the primary staging of high-risk localized prostate cancer were better than CT/bone scintigraphy on both sensitivity (median sensitivity per lesion 33-92% and per patient 66-91%) and specificity (median specificity per lesion 82-100% and per patient 67-99%) [29]. In a prospective comparative trial (ProPSMA) of 302 patients with high-risk localized prostate cancer prior to RP or radiation therapy, the diagnostic accuracy for lymph node or distant metastasis of 68 Ga-PSMA-11 PET/CT was 27% (95% CI: 23-31) higher than CT and bone scan (92% (95% CI: 88-95) vs. 65% (95% CI: 88-95)) [30]. Thus, in localized prostate cancer, Ga-PSMA-PET has a high metastasis detection rate, but it remains unclear whether reclassification of the clinical stage based on these imaging results alters the patient's post-treatment prognosis. In persistently elevated PSA after RP patients, the detection rate of metastasis of PSMA PET/CT was 42, 58, 76, and 95% in patients with PSA levels of 0-0.2, 0.2-1, 1-2, and >2 ng/mL, respectively [26]. In a prospective multicenter study of 323 patients with BCR, PSMA PET/CT significantly reduced the number of patients with unknown recurrence sites (77 vs. 19%, p < 0.001) and significantly increased the number of patients with metastatic disease (11 vs. 57%) compared to conventional imaging (CT and bone scan), and as a result, the treatment plan was changed in 62% of patients [31]. PSMA-PET was indicated to have a potentially important role in treatment planning for salvage radiation therapy after curative treatment [32], but further reports are needed. The optimal use of PSMA-PET as a pre-treatment patient selection tool for metastatic prostate cancer prior to PSMA-RLT remains unclear. In the TheraP phase II trial [33] of 177 Lu-PSMA-617 treatment for CRPC patients, 29 of 291 patients (10%) were excluded from the trial due to low 68 Ga-PSMA-11 accumulation. Due to tumor heterogeneity in metastatic prostate cancer, PSMA-PET accumulation is expected to differ between patients and tumors. There are no established criteria for deciding which metastatic lesions are eligible for PSMA-RLT, and therefore, it is necessary to explore the optimal selection criteria based on actual clinical studies in the future.

Development of Standardized Image Interpretation
As PSMA-PET has become more widely used, discrepancies in findings between radiologists have increased due to uptake in benign lesions and non-prostatic malignancies [34][35][36][37][38][39]. Three guidelines (criteria) are currently reported to resolve this problem: PROMISE criteria [40], PSMA-RADS [41], and EANM criteria [17]. The external validity of these criteria has recently been evaluated, and although they have good reproducibility in the assessment of 68 Ga-PSMA-11, there are factors that cause disagreement among readers, and further research is needed to standardize the reading of PSMA-PET imaging [42]. Based on these studies, the EANM standardized reporting guidelines v1.0 for PSMA-PET (E-PSMA guideline) were suggested [23]. The guideline recommends that PSMA accumulation be described on a four-point scale ( Table 1) and that TNM stages be described by molecular imaging TNM (miTNM) classification according to the PROMISE criteria ( Table 1). The guidelines also indicate that PSMA-PET can be positive in other malignancies such as renal, lung, breast, and liver cancers, as well as in ganglia, benign bone lesions, benign neurogenic tumors, and sarcoidosis. Despite these efforts to standardize reading, it is important to understand that these guidelines are primarily intended for biochemical recurrence and not for metastatic prostate cancer. No local tumor miT2 Organ-confined tumor miT3a Non-organ-confined tumor (extracapsular extension) miT3b Non-organ-confined tumor (seminal vesicles invasion) miT4 Tumor invading adjacent structures (other than seminal vesicles) miTr Presence of local recurrence after radical prostatectomy Regional nodes (N) miN0 No positive regional lymph nodes miN1 Positive regional lymph nodes No distant metastases miM1a Extra-pelvic lymph nodes miM1b Bone metastasis miM1c Non-nodal visceral metastasis: report involved organ(s) (B)

Class Description
Local tumor (T) miT0 No local tumor Non-organ-confined tumor (extracapsular extension) miT3b Non-organ-confined tumor (seminal vesicles invasion) miT4 Tumor invading adjacent structures (other than seminal vesicles) miTr Presence of local recurrence after radical prostatectomy Regional nodes (N) miN0 No positive regional lymph nodes miN1 Positive regional lymph nodes No distant metastases miM1a Extra-pelvic lymph nodes miM1b Bone metastasis miM1c Non-nodal visceral metastasis: report involved organ(s) Adapted from [40].

PSMA-PET Imaging in Metastatic Prostate Cancer
The role of PSMA-PET imaging in the treatment of progressive prostate cancer is under development. In non-metastatic CRPC (nmCRPC) with conventional imaging modalities, PSMA-PET has been proven to detect metastatic sites [43], but it is unclear whether this subgroup can help identify who would benefit from the stratification of patients with this imaging PSMA-PET is also currently being investigated for use in the evaluation of treatment of metastatic prostate cancer, and the PSMA PET progression (PPP) criteria have been suggested [44]. This set of criteria defines treatment responses in three distinct phases: (1) the appearance of two or more new PSMA-positive distant lesions; (2) the appearance of one new PSMA-positive lesion plus consistent clinical or laboratory data and recommended confirmation by biopsy or correlative imaging within 3 months of PSMA PET; and (3) an increase of ≥30% in size or uptake plus consistent clinical or laboratory data and confirmation by biopsy or correlative imaging within 3 months of PSMA PET. This criteria set should be considered when reporting PSMA-PET in patients receiving systemic therapy, but its efficacy needs to be validated in the future. PSMA-PET is also used for pre-treatment evaluation of RLT for advanced prostate cancer, but there are no clear criteria at present. Two prospective comparative studies on PSMA-RLT have been completed at this time: the VISION trial [10] and the TheraP trial [33]. Both trials used PSMA-PET/CT to identify patients with high PSMA expression, but the thresholds used to define indications differed among the trials, and no fixed criteria have been established; thus, future studies are needed.

PSMA-Radioligand Therapy (PSMA-RLT)
The increasing use of PSMA-PET imaging for diagnosis has shown that it is possible to identify PSMA-PET tracer uptake in many prostate cancer metastatic lesions. Therefore, there have been attempts to replace a radioisotope (RI) for diagnosis with a therapeutic RI that emits αor β-rays (theranostics; therapy + diagnosis). Although αand β-rays provide high energy to the tumor, their range is short [45], and a large number of radionuclides must be taken up in the target tissue to achieve a therapeutic effect. For this reason, LMW PSMA ligands with excellent tissue translocation [46,47] are often used for RLT. This is also a factor in the use of LMW PSMA ligands since poor clearance of PSMA ligands and prolonged residence of RI in the blood can lead to the appearance of strong hematologic toxicity. Comparing αand β-rays, α-rays have higher energy than β-rays and can cause efficient DNA double-strand breaks (DSB). However, the disadvantage of α-rays is that they can only destroy accumulated cells and, thus, cannot be expected to have the crossfire effect that β-rays have, which can damage PSMA-negative cells adjacent to PSMA-positive cells [45]. The typical αand β-ray emitting nuclides, including those in the basic research stage, are listed in Table (Table 2). The current PSMA-RLT process is to identify therapeutic targets in CRPC patients with diagnostic tracers ( 68 Ga-PSMA-11 or 18 F-DCFPyL) and to treat metastatic sites with PSMA ligands (PSMA-617, PSMA I&T, etc.) conjugated with β ([177]-lutetium, 177 Lu) or α ([225]-actinium, 225 Ac) emitter. Here, we summarize the current efficacy, effectiveness, and problems with PSMA-RLT, focusing on 177 Lu-PSMA-617, which was recently approved by the FDA and had the best therapeutic results, and introduce the currently developed therapies.  177 Lu-PSMA-617 The radiopharmaceutical for PSMA-RLT that is supported by the most solid data is 177Lu-PSMA-617. This agent was first started in patients in 2014 [48] and has shown promising results in CRPC patients with multiple treatment histories [49]. There are two milestone studies on this agent.
The TheraP trial, a randomized phase II trial, was first conducted by the Hofman, M. S. et al. group in Australia [33]. Since cabazitaxel was considered the next appropriate standard of care (SoC) after docetaxel in this trial, CRPC patients highly selected by 68 Ga-PSMA-11 and 18 F-FDG PET/CT scans were randomized to receive 177 Lu-PSMA-617 (6 GBq intravenous injection every 6 weeks for up to 6 cycles) or cabazitaxel (20 mg/m 2 for up to 10 cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. Primary endpoints have been achieved ( 177 Lu-PSMA-617 group vs. cabazitaxel group, PSA responses; 66 vs. 37% by intention to treat; difference 29% (95% CI: 16-42; p < 0·0001; and 66 vs. 44% by treatment received; difference 23% ; p = 0·001)). However, the study results require careful interpretation because the primary endpoint of the study was at least a 50% reduction in PSA; in addition, the dose of 20 mg/m 2 cabazitaxel was lower than the 25 mg/m 2 in the TROPIC [7] and CARD trials [50].
An open-label phase III trial (VISION trial) was subsequently conducted by Sartor, O. et al. in the United States. This study compared 177 Lu-PSMA-617 radioligand therapy with SoC in metastatic CRPC (mCRPC) patients with metastases expressing PSMA on PET/CT and previously treated with at least one androgen receptor axis-targeted therapy agent (ARAT) and one or two taxanes. Imaging-based progression-free survival (PFS) and overall survival (OS) were alternative primary endpoints. Eligible patients had at least one PSMA-positive metastatic lesion that exceeded liver parenchymal uptake on 68 Ga-PSMA-11 PET/CT, a lymph node with a short axis greater than 2.5 cm, a metastatic solid organ lesion with a short axis greater than 1.0 cm, and a metastatic bone lesion with a soft tissue component greater than 1.0 cm in the short axis. More than 800 patients were randomized. 177 Lu-PSMA-617 significantly prolonged both imaging-based PFS by 5.3 months (median, 8.7 vs. 3.4 months) and OS by 4 months (median, 15.3 vs. 11.3 months) compared to SOC. Although more Grade 3 or higher adverse effects (AEs) occurred with the 177 Lu-PSMA-617 group than the SoC group (52.7 vs. 38.0%), there was no significant effect on the quality of life. 177 Lu-PSMA-617 was shown to be a valuable treatment option in this mCRPC population. These results led to FDA and EMA approval of 177 Lu-PSMA-617. Clinical trials are currently underway for 177 Lu-PSMA-617, including an open-label randomized controlled trial for patients with metastatic hormone-sensitive prostate cancer (NCT04720157) and a phase II trial for castration-sensitive prostate cancer with oligo metastases (NCT04443062, NCT05079698), and the indication is expected to expand.

Predictors of Treatment Effectiveness of 177 Lu-PSMA-617 and Limitations
In the VISION study, 177 Lu-PSMA-617 prolonged the prognosis of heavily pretreated CRPC patients, but the prolonged duration was only 4 months. In addition, despite the inclusion of only patients with PSMA-PET uptake, 20-40% of the patients showed little benefit. In the TheraP trial, with more restrictive inclusion with respect to PSMA uptake compared to the VISION trial, 68 Ga-PSMA-11 and 18 F-FDG PET/CT scans were performed simultaneously, and 80 of 291 (27%) patients with low PSMA-PET accumulation (SUVmax of lesions less than 20, or SUVmax less than 10 with lesions of more than 10 mm) or FDGpositive were excluded for reasons of having lesions with higher FDG uptake than PSMA uptake. Despite this high selection, 36% of patients did not have an adequate PSA response. Buteau et al. reported a sub-analysis in the TheraP trial and discussed that patients with lower mean 68Ga-PSMA-11 uptake in tumor lesions (PSMA mean) and higher total amount of 18F-FDG uptake in tumor lesions (metabolic tumor volume; MTV) had a lower treatment response [51]. Ferdinandus, J., et al. similarly found that the results of the LuPSMA phase II trial of 177 Lu-PSMA-617 revealed MTV, mean intensity of PSMA tumor uptake, bone scan index (BSI), ALP, and LDH as biomarkers prognostic of overall survival [52]. Gafita, A., et al. generated a nomogram predicting 177 Lu-PSMA-617 treatment prognosis using information on 414 177 Lu-PSMA-617-treated patients from six studies [53]. The nomogram identified seven factors as prognostic indicators after 177 Lu-PSMA-617 treatment, including the PSMA mean of the tumor ( Table 3). The results of these studies suggest that low tumor PSMA accumulation (PSMA mean) is associated with lower efficacy of Lu-PSMA treatment, but other factors remain to be determined. 18 F-FDG uptake could be a possible predictor of treatment response, but further studies are needed. Other biochemical (ALP, LDH) and imaging (BSI) parameters that increase with tumor volume correlated with prognosis, but it might simply indicate a selection of patients with a poor prognosis. Thus, although 177 Lu-PSMA-617 is a promising treatment for CRPC patients, it is difficult to obtain sufficient therapeutic effects even in highly selected patients. Approaches to this problem have included the development of different PSMA ligands, α-ray emitter therapy, and combinations with other agents. Table 3. Prognostic factors after treatment with 177 Lu-PSMA-617. 1 Time since diagnosis (years) 2 Chemotherapy status previous chemotherapy (yes/no) 3 Haemoglobin (g/dL) 4 Tumor SUVmean of PSMA-PET 5 Number of lesions (<20/≥20) 6 Bone metastases (yes/no) 7 Liver metastases (yes/no) Adapted from [53]. SUV = standardized uptake value.

PSMA-RLT with β-ray Emitting Radionuclides
Therapeutics with β-ray emitting radionuclides other than 177 Lu-PSMA-617 are still in the basic or clinical research phase. Clinical trials are underway using different LMW PSMA ligands with PSMA I&T and other short half-life antibodies. In particular, 177 Lu-PSMA-I&T has been reported to show safety, pharmacokinetics, and tumor uptake comparable to 177 Lu-PSMA-617 in patients with CRPC, and to prolong the prognosis of HSPC patients with oligometastasis in a small case randomized trial [54]. Open-label randomized controlled phase III trials comparing Lu-PSMA I&T and ARAT in mCRPC patients (NCT04647526) are currently in progress, and results are awaited. 90 Y-PSMA-617, which employs the β-ray emitting radionuclide 90 Y, holds the potential to reduce xerostomia and blood toxicity in comparison to 177Lu-PSMA-617 [55]. This suggests that it may be superior in terms of mitigating side effects. We eagerly anticipate future studies to further explore and validate this promising possibility.

PSMA-RLT with α-ray Emitting Radionuclides
Compared to β-rays, α-rays have a shorter range and higher energy, inducing more efficient DSB and causing cancer cell death [45]. Although some case reports have shown dramatic effects [56,57], treatment with α-emitters is still in development regarding safety and availability [58], and we discuss development agents and current issues. 225 Ac-PSMA-617 has been administered in many treatment-resistant cases of 177 Lu-PSMA-617 and is the commonly reported agent in PSMA-RLT with α-emitter [59]. In 2016, the first report with Ac-PSMA-617 was published by Kratochwil, C. et al. In this report, two patients with a history of intensive CRPC treatment were treated with 6.4 MBq (100 kBq/kg) of Ac-PSMA-617 for 2-3 cycles, which resulted in a reduction of PSA to less than 0.1 ng/mL [57]. Although there have been some reports of dramatic efficacy, there are few reports evaluating PFS and OS [60]. In addition, it is difficult to evaluate the efficacy of 225 Ac-PSMA-617 at this time because the number of doses is not stable in each study because of the discontinuation of 225 Ac-PSMA-617 due to xerostomia and hematologic toxicity [60]. Phase I/II studies with 225 Ac-PSMA-617 (NCT04597411) and 225 Ac-PSMA-I&T (NCT04597411, NCT05219500) are currently ongoing, which will clarify the effectiveness, actual frequency of AEs, and dose-limiting toxicity. Furthermore, the supply of 225 Ac is very small [58] and its dissemination is limited, and 225 Ac produces toxic daughter nuclides in the decay process [45], which leads to dose limitation due to blood toxicity xerostomia. To overcome the limitations of 225 Ac, other α-ray RLTs, such as 161 Tb-PSMA-I&T (NCT05521412) and 277 Th-PSMA-I&T (NCT03724747) are being evaluated in phase I trials. In terms of productivity and safety, the focus is on 211 At, 213 Bi, and 212 Pb as promising nuclides [45,61].

Combination Therapies
To enhance the therapeutic effect of PSMA-RLT, several trials are underway in combination with various agents. ARATs are one of the most important agents in mHSPC and mCRPC, but at present, the efficacy and safety of the combination with PSMA-RLT agents have not been fully established. Currently, the phase 3 trial of 177 Lu-PSMA-617 + SoC (including ARAT) in mHSPC (NCT 04720157, PSMAddsion) and the phase 1/2 trial of 177 Lu-PSMA-617 + enzalutamide in mCRPC (NCT 04419402, ENZA-P) are expected to evaluate the efficacy and safety of the combination therapy. Phase 1/2 trials for combination with taxanes, which are key drugs for CRPC treatment, and ARATs, are also in progress for mCRPC patients (NCT04343885, NCT05340374).
Furthermore, the characteristics of PSMA-RLT as radiotherapy are utilized for combination therapy with other agents. One of the trials was a combination therapy of olaparib, a PARP inhibitor, and 177 Lu-PSMA-617 (NCT03874884, LuPARP). 177 Lu causes DNA single-strand breaks by β-rays [45], and PARP contributes to this damage repair [8,62,63]. Therefore, the use of olaparib and 177Lu-PSMA-617 is expected to have a synergistic antitumor effect. It has been reported that PSMA expression correlates with DNA damage repair (DDR) mutation [64], and since patients with DDR mutation are more radiosensitive [65] and effective to olaparib [8,62,[66][67][68], synergistic effects between both agents could be expected. Clinical trials of combination therapy aimed to exploit the "abscopal" effect, which is a benefit of radiotherapy, are also ongoing. The abscopal effect is considered a therapeutic response to irradiated tumor metastasis. It is caused by the induction of anti-tumor immunity due to exposure to tumor antigens following tumor disruption caused by irradiation of the focal tumor [69]. Therefore, combination therapies of radiation and immune checkpoint inhibitors are being developed to increase the abscopal effect [70,71]. Phase 2 clinical trials for progressive mCRPC patients are currently underway for 177 Lu-PSMA-617 in combination with pembrolizumab, a PD-1 inhibitor (NCT03658447, PRINCE), and nivolumab and ipilimumab, a PD-1 inhibitor and CTLA4 inhibitor, respectively (NCT05150236, ANZUP2001).

Off-Target Effects
β-and α-emitters have high cytotoxicity and are capable of causing serious damage to normal healthy tissues. The PSMA-RLTs currently in use accumulate mainly in blood, salivary glands, and kidneys [77][78][79]; consequently, disturbances to these tissues need to be considered. Xerostomia is the most typical side effect of PSMA-RLT and has been reported frequently, especially in patients treated with 225 Ac-PSMA-617 [60,80]. Several attempts have been made to reduce the uptake of radionuclides into the salivary glands, but xerostomia has led to dose limitation in many patients [60]. Hematologic toxicity should also be considered. In the VISION trial, anemia, leukopenia, and thrombocytopenia Grade 3 or 4 were observed in 12.9, 2.5, and 7.9% of patients treated with 177 Lu-PSMA-617, respectively [10]. An analysis of 106 patients treated with 225 Ac-PSMA-617 reported Grade 3 or higher anemia, leukopenia, and thrombocytopenia in 0.9, 2.8, and 1.9% of patients, respectively [81]. However, it should be considered that the median cycle is 4 cycles, and the dosage was reduced to 4-6 MBq after the third cycle, while the first two cycles were 8 MBq in this report. It has also been reported that hematologic toxicity appeared more frequently in patients with renal dysfunction. In addition, there is concern about renal dysfunction because 177 Lu-PSMA-617 and 225 Ac-PSMA-617 accumulate in the kidneys and are excreted via the urinary tract. The over Grade 3 renal dysfunction frequency was 0.6% and 7% higher for 225 Ac-PSMA-617 than for 177 Lu-PSMA-617, respectively [59]. For 225 Ac-PSMA-617, many reports of a relatively small number of cycles have been reported, and future studies are needed.

Supply of α-and β-Emitters
Until recently, 177 Lu has been most widely used in the production of 177 Lu-DOTA-TATE for the treatment of neuroendocrine tumors. However, after the positive results of the VISION trial, the demand for 177 Lu has drastically increased. Most of the 177 Lu produced worldwide is used for both 177 Lu-PSMA-617 and 177 Lu-DOTATATE, and a large amount of 177 Lu is produced in a nuclear reactor through irradiation of source material

PSMA-Targeted Nanoparticles
Nanoparticles (NPs) such as polymers, DNA polyplexes, lipid particles, liposomes, metals, and proteins have been developed in regard to ligand molecules that target PSMA [72]. NPs targeting PSMA with metals such as iron oxide [73] and gold [74], polymers [75], and liposomes [76] have been developed and are expected to be used clinically in the future.

Off-Target Effects
βand α-emitters have high cytotoxicity and are capable of causing serious damage to normal healthy tissues. The PSMA-RLTs currently in use accumulate mainly in blood, salivary glands, and kidneys [77][78][79]; consequently, disturbances to these tissues need to be considered. Xerostomia is the most typical side effect of PSMA-RLT and has been reported frequently, especially in patients treated with 225 Ac-PSMA-617 [60,80]. Several attempts have been made to reduce the uptake of radionuclides into the salivary glands, but xerostomia has led to dose limitation in many patients [60]. Hematologic toxicity should also be considered. In the VISION trial, anemia, leukopenia, and thrombocytopenia Grade 3 or 4 were observed in 12.9, 2.5, and 7.9% of patients treated with 177 Lu-PSMA-617, respectively [10]. An analysis of 106 patients treated with 225 Ac-PSMA-617 reported Grade 3 or higher anemia, leukopenia, and thrombocytopenia in 0.9, 2.8, and 1.9% of patients, respectively [81]. However, it should be considered that the median cycle is 4 cycles, and the dosage was reduced to 4-6 MBq after the third cycle, while the first two cycles were 8 MBq in this report. It has also been reported that hematologic toxicity appeared more frequently in patients with renal dysfunction. In addition, there is concern about renal dysfunction because 177 Lu-PSMA-617 and 225 Ac-PSMA-617 accumulate in the kidneys and are excreted via the urinary tract. The over Grade 3 renal dysfunction frequency was 0.6% and 7% higher for 225 Ac-PSMA-617 than for 177 Lu-PSMA-617, respectively [59]. For 225 Ac-PSMA-617, many reports of a relatively small number of cycles have been reported, and future studies are needed.

Supply of αand β-Emitters
Until recently, 177 Lu has been most widely used in the production of 177 Lu-DOTATATE for the treatment of neuroendocrine tumors. However, after the positive results of the VISION trial, the demand for 177 Lu has drastically increased. Most of the 177 Lu produced worldwide is used for both 177 Lu-PSMA-617 and 177 Lu-DOTATATE, and a large amount of 177 Lu is produced in a nuclear reactor through irradiation of source material with neutrons [82]. There is a possibility of a deficit supply of 177 Lu due to increasing demand, and some efforts are underway to develop a different production method, but it is not yet at a practical stage [83]. Currently, the production of 225 Ac still relies on extraction from 229 Th, with only three sources in the world (Directorate for Nuclear Safety and Security of the JRC of the European Commission in Karlsruhe, Germany (formerly known as the Institute for Transuranium Elements) [84], Oak Ridge National Laboratory (ORNL), US [85], and at the Institute of Physics and Power Engineering (IPPE) in Obninsk, Russia) [58], thus, supplies are still limited. New accelerator-based techniques (spallation of 232 Th, proton and deuteron irradiation of 226 Ra, and 226 Ra irradiation based on photonuclear reactions) are being explored to increase 225 Ac production, but each technique still has its limitations and requires further development [58].
Under current supply circumstances, due to limited production of both 177 Lu and 225 Ac, 177 Lu-PSMA and 225 Ac-PSMA-RLT will not be able to replace the classical treatment of mCRPC for all patients. Infrastructure development, including strengthening of the supply chain, will be necessary in the future. 177 Lu-PSMA-617 is an agent with low toxicity and excellent therapeutic efficacy, but previous reports suggest that it is not suitable for some patients. In 2019, the European Association of Nuclear Medicine (EANM) published a guideline for 177 Lu-PSMA-RLT [86]. The guideline was aimed at patient safety and radiation protection of medical staff based on the Declaration of Helsinki for the unapproved 177 Lu-PSMA-RLT agents. The guideline identifies six contraindications to the administration of 177 Lu-PSMA-RLT (Table 5). The majority of clinical trials for 177 Lu-PSMA-RLT are designed according to this guideline, and the efficacy and safety of PSMA-RLT have not been established in patients not meeting these criteria. When actually administering 177 Lu-PSMA-RLT to the patient, these contraindications need to be confirmed. Especially in patients with uncontrolled urinary tract obstruction, hydronephrosis, or at risk for urinary retention, delayed excretion of 177 Lu-PSMA-RLT possibly leads to nephrotoxicity and other side effects. In addition, drug interactions between 177 Lu-PSMA-RLT and other CRPC drugs have not been validated, and more than four weeks is recommended between the last dose of chemotherapy, ARAT, or bone tracer and administration of 177 Lu-PSMA-RLT.

Safety and Radiation Protection
Patients with urinary incontinence are more difficult to manage from the viewpoint of radiation protection. In these patients, because most 177 Lu-PSMA-RLT agents are excreted in the urine, there is the possibility of increased risk of exposure to health care providers and caregivers compared to other patients. Strategies to prevent this problem need to be fully considered prior to introducing treatment.

Patients with Better Indications for PSMA-RLT Agents
PSMA-RLT is difficult to adapt to all imaging-selected CRPC patients due to supply limitations at present. Therefore, it is preferred to be able to highly select patients who are more likely to benefit from PSMA-RLT. High PSMA-PET and low FDG-PET accumulation are considered to be promising selection criteria. It is impossible to determine from current reports at which stage of prostate cancer PSMA-RLT should be administered.  177 Lu-PSMA-RLT in the EANM procedure guideline. 1 Life expectancy is less than 6 months (ECOG performance status > 2); unless the main objective is alleviating suffering from disease-related symptoms.
2 Unacceptable medical or radiation safety risk for isolation on a nuclear medicine therapy unit (if required by national regulations).
3 Unmanageable urinary tract obstruction or hydronephrosis; in patients with diagnosed or who are at high risk of urinary retention, 99mTc-MAG3 or 99mTc-DTPA renal scintigraphy should be considered as a baseline exam.

4
Progressive deterioration of organ function (GFR < 30 mL/min or creatinine > 2-fold upper limit of normal (ULN); liver enzymes > 5-fold ULN). 5 Myelosuppression: a. Total white cell count less than 2.5 × 10 9 /L b. Platelet count less than 75 × 10 9 /L 6 Conditions that require timely interventions (radiation therapy, surgery), e.g., spinal cord compression and unstable fractures, PSMA-RLT might be performed afterward upon the patient's condition. Borderline cases should be evaluated within the multidisciplinary tumor board for the individual benefit-to-risk ratio.
The use of these agents should also be considered from a safety perspective. Because of urinary excretion, 177 Lu-PSMA-617 is not safe to administrate in patients with uncontrolled urinary tract obstruction, hydronephrosis, or at risk for urinary retention due to delayed excretion. There are also still unclear drug interactions, and it is necessary to carefully check concomitant medications. It should be considered that the metabolization of PSMA-RLT has the potential to change depending on the type of nuclide and ligand, and that a wide variety of agents are expected to be developed in the future, and their administration should take into account the patient's condition. Finally, in terms of radiation protection, we believe that the possibility of increased exposure risk to medical personnel and caregivers should be fully considered in patients who present with severe urinary incontinence.

Conclusions and Future Directions
Recently, PSMA-RLT has dramatically altered the treatment of mCRPC and is a feasible alternative to conventional treatment. As a result, the development of agents targeting PSMA is expected to accelerate in radiopharmaceutical research. The approval of 68 Ga-PSMA-11 and 177 Lu-PSMA-617 as a therapeutic by the FDA and EMA should accelerate this trend. Several clinical trials are still underway to develop treatments with different PSMA ligands, such as 177 Lu-PSMA-I&T and short-lived antibodies, as well as α-emitters. However, there are problems that must be overcome in the current PSMA-RLT. In particular, issues of supply, side effects, and the type of patients to whom PSMA-RLT should be applied are critical to its future development. It will be necessary to address these problems through the development of various agents and clinical trials in the future.  Acknowledgments: We gratefully acknowledge the authors and their respective research papers for allowing us to cite the tables (Tables 1, 3 and 5). The citation has been performed strictly in accordance with the guidelines provided in each paper. We greatly value the substantial contribution their work has made to our research. We acknowledge their diligence and effort in creating and presenting the valuable data that has informed our study. We hope that our work continues to uphold the academic integrity they have exemplified, and we appreciate the continuous development of knowledge they represent. I would like to express my deepest gratitude to Yoshiyuki Kojima, whose invaluable guidance and expertise have immensely contributed to the realization of this research paper. Thank you for your mentorship and inspiration.

Conflicts of Interest:
The authors declare no conflict of interest.