Advances in PSMA-Targeted Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer

Introduction

Prostate cancer (PCa), a solid malignant tumor originating from the prostate epithelium, is the most common tumor affecting the male genitourinary system and represents a significant public health concern. In 2020, approximately 1.4 million new cases of PCa were diagnosed worldwide, including 288,300 new cases and 34,700 related deaths in the United States in 2023.^1,2 Despite numerous advances in the treatment of PCa, a substantial number of patients present with locally advanced or metastatic disease, contributing to ongoing mortality. There remains a critical need for novel, individualized, and effective targeted therapies to address the unmet medical needs of this population.

Although the exact function of prostate-specific membrane antigen (PSMA) in PCa is not fully understood, it is markedly overexpressed in PCa tissues compared to normal tissues.³ Notably, elevated PSMA expression is associated with increased prostate-specific antigen (PSA) levels, higher Gleason scores, and poorly differentiated, metastatic, and castration-resistant PCa, suggesting a potential role for PSMA in the differentiation and progression of metastatic castration-resistant prostate cancer (mCRPC).^3–6 PSMA has the ability to internalize bound molecules, making it a potential target for both diagnostic imaging and targeted therapeutic strategies.⁷ The FDA approved ⁶⁸Ga-PSMA-11 for staging and restaging of PCa in December 2020 and Lutetium-177 (¹⁷⁷Lu)-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC in March 2022. Numerous other PSMA-targeting molecules and antibodies are currently being investigated in preclinical and clinical studies. In this review, we summarize current research on PSMA and its applications in iatreusiology.

Current Clinical Experience with PSMA-Targeted RLT

β-Emitting Radionuclides

The β particle is an electron emitted from the nucleus of a decaying radioactive atom.⁸ DNA damage caused by β particles is dose-dependent; at low doses, the damage may be sublethal. However, owing to the relatively long range over which β particles deposit their energy, reactive oxygen species (ROS) produced from cytotoxic damage in adjacent non-tumor cells can also contribute to DNA damage.^9,10 Among the various β particles investigated for PCa targeted therapy, ¹⁷⁷Lu, Iodine-131, and Terbium-161 have shown potential.^11–16

Among all β-emitting radioisotopes, ¹⁷⁷Lu is the most commonly used in PCa treatment.^7,17 In 2015, 10 patients with metastatic castration-resistant prostate cancer (mCRPC) received one cycle of ¹⁷⁷Lu-PSMA-617.¹⁸ Following an eight-month follow-up, seven patients (70%) showed a decline in PSA levels, including six and five patients who experienced PSA reductions of ≥30% and ≥50%, respectively. Subsequent studies have confirmed the therapeutic benefits of ¹⁷⁷Lu-PSMA-617 in mCPRC.^19–21 In a meta-analysis of 1,338 patients, 44% of those treated with ¹⁷⁷Lu-PSMA radioligand therapy (RLT) had a ≥50% decline in PSA, compared with 22% of patients treated with enzalutamide or cabazitaxel (p = 0.0002).²¹ Another meta-analysis involving 3,958 patients across seven randomized controlled trials (RCTs) showed that ¹⁷⁷Lu-PSMA-617 treatment resulted in a 1.3-fold higher rate of ≥50% PSA decline compared to treatment with abiraterone, enzalutamide, mitoxantrone, or cabazitaxel (p < 0.001).²⁰ Despite these positive outcomes, several concerns remain. Most studies used PSA decline as the primary outcome rather than overall survival. Given that many enrolled patients had limited life expectancy, it is notable that only a few studies reported survival data. Subsequently, two large RCTs (VISON and TheraP trials) reported outcomes for ¹⁷⁷Lu-PSMA-617 in mCPRC treatment (Table 1). The VISON trial, an open-label Phase III trial, enrolled 581 patients in the treatment arm who had progressed after at least one androgen receptor pathway inhibitor and one or two taxane regimens. Patients treated with ¹⁷⁷Lu-PSMA-617 plus standard care had longer median imaging-based progression-free survival (PFS) (8.7 vs 3.4 months, p < 0.001) and overall survival (15.3 vs 11.3 months, p < 0.001) than those receiving standard care.²² These results were consistent with findings from a recent real-world study, which reported a median overall survival and PFS of 13.5 and 8.2 months, respectively, in mCRPC patients treated with ¹⁷⁷Lu-PSMA-617.²³ The TheraP trial, an open-label Phase II trial, enrolled 200 patients with mCPRC for whom cabazitaxel was considered the next appropriate standard treatment. In this trial, patients treated with ¹⁷⁷Lu-PSMA-617 showed a higher PSA response rate than those receiving cabazitaxel.^{24 177}Lu-PSMA RLT was well-tolerated, with no acute or subacute nephrotoxicity observed, even in patients with chronic renal failure, a single functioning kidney, or those who underwent 5–6 treatment cycles.^25–28 Only a small number of patients experienced grade 3/4 hematological toxicity, and no treatment-related deaths occurred.^{19,22,24,29,30} Hematological toxicity was typically transient and self-limiting, involving decreases in hemoglobin, neutrophil, and platelet levels. Grade 1/2 non-hematological events included xerostomia, nausea, vomiting, and bone pain.^24,30 Based on these findings, agencies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved ¹⁷⁷Lu-PSMA-617 as a third-line treatment for patients with mCRPC. However, the rigor of these RCTs has been questioned. In the VISON trial, three-quarters of patients in the control arm had previously received enzalutamide, a group unlikely to benefit from abiraterone—resulting in a suboptimal control group. Additionally, an updated analysis of the TheraP trial showed no significant difference in overall survival between the ¹⁷⁷Lu-PSMA-617 and cabazitaxel arms (19.1 vs 19.6 months).³¹ Concerns about long-term nephrotoxicity associated with ¹⁷⁷Lu-PSMA-617 have also emerged. A recent retrospective study reported that 45% (48/106) of patients receiving four or more cycles of ¹⁷⁷Lu-PSMA RLT experienced moderate decreases in estimated glomerular filtration rate (eGFR) one year after initiating treatment, and 24% (25/106) experienced severe eGFR decline.³²

Table 1 Current Active or Recruiting Phase III Prostate Cancer Trials Involving 177Lu-PSMA RLT

Several clinical trials have shown that earlier use of PSMA-targeted RLT in the mCRPC treatment yields better responses than when used after multiple prior treatments. Banda et al reported that 83% (15/18) of patients with metastatic hormone-sensitive prostate cancer (mHSPC) achieved a ≥50% PSA response following ¹⁷⁷Lu-PSMA-617 therapy.³³ However, it remains unclear whether PSMA-targeted RLT offers superior efficacy compared to currently approved first- or second-line agents. A clinical trial (PSMAfore, NCT04689828) is ongoing to evaluate whether ¹⁷⁷Lu-PSMA-617 improves radiographic PFS compared with a change in androgen deprivation therapy (ADT) in patients with mCRPC previously treated with an alternate ADT and not exposed to a taxane-containing regimen in the CRPC or mHSPC setting.³⁴ Preliminary results from the PSMAfore trial indicated a longer median radiographic PFS in the ¹⁷⁷Lu-PSMA-617 arm compared with the ADT-switch group (12.0 vs 5.6 months, p < 0.05). However, similar concerns apply: patients in the control arm who had already received enzalutamide were unlikely to respond favorably.

The urea-based small molecule PSMA I&T is another frequently used RLT agent. Recent studies have found no significant differences in survival outcomes between PSMA I&T and PSMA-617.^35–37 Whole-body and lacrimal gland absorbed doses were higher with ¹⁷⁷Lu-PSMA-617 than with ¹⁷⁷Lu-PSMA I&T, while renal absorbed doses were lower in patients treated with ¹⁷⁷Lu-PSMA-617.³⁸ Schäfer et al recently reported that three patients who underwent 8–10 cycles of ¹⁷⁷Lu-PSMA I&T developed radiation-induced nephropathy.³⁹ Therefore, the potential nephrotoxicity of ¹⁷⁷Lu-PSMA I&T must be carefully considered during treatment.

α-Emitting Radionuclides

The α particle—a ⁴He nucleus consisting of two neutrons and two protons—releases all its energy over a very short distance, resulting in higher efficiency against cancer cells and reduced toxicity to surrounding tissues compared with β particles.^40,41 Therefore, targeted α therapy is a promising alternative to β therapy, as it induces lethal DNA double-strand breaks with high efficacy.⁴² Unlike β particles, which may cause sublethal damage and depend on ROS produced by adjacent non-tumor cells, α particles kill cancer cells independently of oxygenation status or cell cycle phase, leading to enhanced therapeutic effectiveness.^43,44

Actinium-225 (²²⁵Ac) decays, through a series of daughter radionuclides, to Francium-221, Astatine-217, Bismuth-213 (²¹³Bi), and finally Bismuth-209, with a half-life of 10 days.^45,46 Owing to the nephrotoxicity associated with ²¹³Bi, ²²⁵Ac was previously limited in its clinical application for targeted α therapy.^47,48 However, since the development of stable chelators such as ²²⁵Ac-PSMA-617 and ²²⁵Ac-PSMA-I&T, ²²⁵Ac has significantly improved its potential for treating mCRPC.^49–51 These chelators facilitate rapid tumor uptake and efficient clearance of unbound conjugates from circulation, thereby reducing hematologic toxicity and nephrotoxicity. Furthermore, owing to its limited tissue penetration, ²²⁵Ac causes minimal hematologic toxicity, even in patients with bone marrow infiltration.

In 2016, Kratochwil et al reported the first clinical use of ²²⁵Ac-PSMA-617 in two patients, one who could not receive β-emitters owing to diffuse bone marrow involvement and another who was resistant to ¹⁷⁷Lu-PSMA-617. Both patients exhibited PSA levels below 0.1 ng/mL, with minimal hematological toxicity except for dose-dependent xerostomia.⁵² Since then, several studies have demonstrated the promising antitumor effects of ²²⁵Ac-PSMA-617.^53–57 In a retrospective study involving 73 patients with mCPRC who had exhausted standard therapies with ²²⁵Ac-PSMA-617,⁵⁷ 82% demonstrated a PSA response, with 70% achieving a 50% PSA decline. Xerostomia was the most common adverse event but was generally manageable and not severe enough to warrant treatment discontinuation. However, five cases of grade 3/4 renal failure have been reported. A meta-analysis of nine studies involving 263 patients demonstrated that 60.99% (95% confidence interval [CI], 54.92–66.83%) experienced a ≥50% PSA decline, with a mean PFS and mean overall survival of 9.15 and 11.77 months, respectively.⁵⁸ A multicenter retrospective study (WARMTH Act) involving 488 patients further confirmed the efficacy of ²²⁵Ac-PSMA RLT,⁵⁸ with a mean overall survival of 15.5 months and a mean PFS of 7.9 months.⁵⁹ However, notable toxicities included grade 3/4 anemia (13%), leukopenia (4%), thrombocytopenia (7%), and renal toxicity (5%). Another stable chelator, ²²⁵Ac-PSMA-I&T has shown an efficacy comparable to ²²⁵Ac-PSMA-617 in a recent retrospective analysis.⁶⁰

Generally, ²²⁵Ac-PSMA-617 is used as a salvage therapy for end-stage mCRPC or to overcome resistance to β-emitting radionuclides. Recent studies have explored its potential earlier in the treatment paradigm. In one study, 53 patients with mCRPC were treated with ²²⁵Ac-PSMA-617 immediately following ADT, and 91% exhibited a ≥50% PSA reduction.⁶¹ Notably, after a median follow-up of 55 months, overall survival had not yet been reached in patients with a ≥50% PSA reduction, suggesting that ²²⁵Ac-PSMA-617 may serve as an alternative to standard therapies such as enzalutamide or abiraterone post-ADT. Another retrospective study revealed that among 21 patients with mHSPC, 95% had a PSA response and 86% achieved a ≥50% PSA decline.^{62 225}Ac-PSMA-617 is not a substitute for ADT; however, its encouraging disease control rates suggest potential synergy when used in combination with ADT in HSPC. However, toxicity remains a major limitation in its routine clinical use. Xerostomia is currently the most common dose-limiting side effect for PSMA-targeted RLT. Salivary gland toxicity appears more frequent and severe following ²²⁵Ac-PSMA treatment. In a retrospective study involving 26 patients with mCPRC previously treated with ¹⁷⁷Lu-PSMA, all developed grade 1/2 xerostomia, with six discontinuing therapy due to the severity.⁵⁵ Another study reported grade 1/2 xerostomia in 94% of patients following ²²⁵Ac-PSMA-617 therapy.⁶² Previous studies indicate that the antitumor efficacy of RLT increases with higher radiation doses;^63,64 thus, severe toxicity may limit therapeutic intensification and reduce overall response. Currently, no RCT has documented that the benefits of ²²⁵Ac-PSMA outweigh its adverse effects.

Other α-targeted therapies have also been studied. ²¹³Bi-PSMA-617 has been administered to patients with progressive mCPRC despite conventional therapy; however, its clinical utility is limited by the short half-life of ²¹³Bi.⁶⁵ Thorium-227 (²²⁷Th), with a more suitable half-life for targeted α therapy, has shown promising preclinical results with the PSMA-targeted conjugate PSMA-TTC.^66,67 223Ra, another α-emitting radioisotope with a half-life of 11.4 days, emits 93.5% of its decay energy as α particles and eventually decays to stable lead-207 (²⁰⁷Pb). However, its clinical application is restricted to patients with PCa and osteoblastic metastases owing to its affinity for bone tissue.⁶⁸

Combination Therapy

Androgen Receptor Pathway Inhibitors

Although ¹⁷⁷Lu-PSMA RLT has demonstrated positive outcomes in mCPRC treatment, an increasing number of studies suggest that ¹⁷⁷Lu-PSMA RLT is not limited to third-line therapy. Several clinical trials are currently underway, evaluating PSMA-targeted RLT at various stages of PCa and in earlier lines of therapy. In an observational study comparing the efficacy of combined ¹⁷⁷Lu-PSMA-617 and abiraterone acetate versus ¹⁷⁷Lu-PSMA-617 monotherapy in patients with mCRPC, the combination group exhibited significant improvements in symptomatic response, PFS, and overall survival.⁶⁹ In a real-world study, patients receiving ¹⁷⁷Lu-PSMA-617 in combination with androgen receptor pathway inhibitors had a longer overall survival compared to those receiving ¹⁷⁷Lu-PSMA-617 alone; however, the difference was not statistically significant (18.2 vs 12.3 months, p = 0.265).²³

Docetaxel/Cabazitaxel

In a prospective study comparing the efficacy of ¹⁷⁷Lu-PSMA-617 and docetaxel in chemotherapy-naïve patients with mCRPC, 60% (9/15) of those receiving ¹⁷⁷Lu-PSMA-617 experienced a ≥50% PSA decline, while 40% (8/20) of patients treated with docetaxel showed a similar PSA response.⁷⁰ Moreover, ¹⁷⁷Lu-PSMA RLT demonstrated good tolerability. Grade 3/4 adverse events were less frequent in the ¹⁷⁷Lu-PSMA-617 group than in the docetaxel group, suggesting the potential of ¹⁷⁷Lu-PSMA-617 for use earlier in the disease course, rather than reserving it solely for advanced-stage treatment. An RCT (UpFrontPSMA, NCT04343885) is currently evaluating the efficacy of sequential treatment with ¹⁷⁷Lu-PSMA-617 followed by docetaxel versus docetaxel monotherapy in patients with metastatic hormone-naïve PCa.⁷¹

A prospective, single-arm clinical trial (LuCAB, NCT05340374) is also ongoing to determine the maximum tolerated dose, dose-limiting toxicities, and recommended phase II dose of cabazitaxel in combination with ¹⁷⁷Lu-PSMA-617 in patients with mCRPC.⁷²

Olaparib

A Phase I open-label clinical trial (LuPARP, NCT03874884) is underway to evaluate the safety and tolerability of combining olaparib with ¹⁷⁷Lu-PSMA-617 in patients with mCRPC.⁷³

Immunotherapy

A phase Ib trial (NCT03805594) is ongoing to evaluate the objective response of pembrolizumab in combination with ¹⁷⁷Lu-PSMA-617 in patients with mCRPC.⁷⁴ Similarly, a phase I/II trial (PRINCE, NCT03658447) is investigating the safety and tolerability of pembrolizumab administered every 3 weeks alongside ¹⁷⁷Lu-PSMA-617 every 6 weeks for up to six cycles, beginning at 8.5 GBq with 0.5 GBq dose reduction per cycle.⁷⁵

A phase II study (EVOLUTION, NCT05150236) was conducted to evaluate the activity and safety of ¹⁷⁷Lu-PSMA-617 alone and in combination with ipilimumab and nivolumab in patients with mCRPC.⁷⁶

Radium-223

A single-arm phase I/II trial (AlphaBet, NCT05383079) enrolled 36 patients to determine the maximum tolerated dose of ²²³Ra in combination with ¹⁷⁷Lu-PSMA I&T.⁷⁷

Radiosensitizer

The combination of ¹⁷⁷Lu-PSMA-617 with radiosensitizers has demonstrated enhanced survival benefit.^78,79 Among patients with mCRPC, 86% of those treated with ¹⁷⁷Lu-PSMA-617 and Idronoxil (NOX66) experienced a PSA reduction, while 61% achieved a maximum PSA decline of ≥50%.⁸⁰

β-Emitting and α-Emitting Radionuclides

Despite promising outcomes with targeted α and β therapies, a notable proportion (approximately 30%) of patients either do not respond to PSMA-targeted RLT or develop early resistance.^81,82 Furthermore, many patients cannot tolerate the associated adverse effects, with xerostomia currently being the most common dose-limiting side effect. Combination therapies employing β-emitting radionuclides have been proposed to minimize toxicity and overcome drug resistance. In a study involving 20 patients with mCRPC who showed no improvement with ¹⁷⁷Lu-PSMA monotherapy, a combination of low-activity ²²⁵Ac-PSMA-617 and full-activity ¹⁷⁷Lu-PSMA-617 was administered. Of these patients, 65% exhibited a maximum PSA decline of ≥50%, with a median PFS of 19 weeks and overall survival of 48 weeks.⁸³ Additionally, 17 patients who had progressed after ¹⁷⁷Lu-PSMA-617 monotherapy received one cycle of tandem therapy with ²²⁵Ac-PSMA-617 and ¹⁷⁷Lu-PSMA-617; 71% of these patients demonstrated partial remission or stable disease.⁷⁸

Characteristics Predicting Biochemical Response Following PSMA-Targeted RLT

A growing body of evidence suggests that RLT is not limited to advanced, end-stage diseases. Both ²²⁵Ac-PSMA-617 and ¹⁷⁷Lu-PSMA-617 have been investigated in patients with mHSPC, as well as in combination with other therapies such as abiraterone acetate.^62,69 However, a considerable number of patients still fail to respond to RLT.^59,79 Therefore, understanding the limitations and resistance mechanisms to RLT remains a critical challenge. While several promising studies have identified potential biomarkers and predictive characteristics, there remains an unmet need for optimal patient selection.

PSA remains the most prevalent biomarker to predict PCa recurrence and therapeutic response. A decline in PSA levels following RLT is generally considered an effective marker of response;^17,84–88 however, no consensus exists regarding the degree of PSA decline necessary to serve as a reliable prognostic marker. Most studies suggest that any PSA decline after the first RLT cycle is associated with prolonged overall survival.^84–86 A recent meta-analysis reported a pooled hazard ratio of 0.29 (0.18–0.46) for overall survival among patients with any PSA decline, and 0.67 (0.43–1.07) for those with >50% PSA decline.⁸⁶ Some studies have indicated that a PSA decline of ≥50% after the first RLT cycle is a strong predictor of prolonged overall survival.¹⁷ Assessing PSA changes six weeks after RLT initiation has also been proposed as an early predictor of long-term clinical outcomes. A PSA reduction of ≥30% at six weeks has been linked to a longer overall survival of 16.7 months, compared with 11.8 months in patients with stable PSA and 6.5 months in those with PSA progression.⁸⁹ However, this correlation has not been consistently observed.⁹⁰ For instance, Ahmadzadehfar et al reported that PSA declines of >50% or <50% after the first cycle did not significantly impact median overall survival, which was 14.3 and 13.9 months, respectively.⁷ Furthermore, a considerable proportion of patients (30–50%) who exhibited no PSA decline after the first cycle went on to show decreased PSA levels after the second or third cycle. This suggests that relying solely on PSA response after the first RLT cycle may exclude patients who ultimately derive significant long-term benefit. Variability in therapeutic dosages, patient characteristics, and the timing of PSA assessments contributes to heterogeneity across studies.

Ahmadzadehfar et al also reported that prior chemotherapy was a significant predictor of reduced overall survival, based on both univariate and multivariate analyses.⁷ The median overall survival was 10.9 months in patients who had received one round of chemotherapy with docetaxel and 8.9 months in those treated sequentially with docetaxel and cabazitaxel—both notably shorter than in patients without prior chemotherapy.⁷ Another retrospective study involving 167 patients with mCRPC revealed that prior taxane chemotherapy was associated with worse overall survival.⁹¹ However, the association was not significant in multivariate analysis, suggesting that poor baseline characteristics post-chemotherapy may influence prognosis. Another study verified that treatment with docetaxel or cabazitaxel did not affect survival or response rates to RLT.⁸⁷ Similarly, prior treatment with abiraterone, corticosteroids, or radiotherapy was not a predictor of PFS or overall survival in patients undergoing RLT.^87,92

Other factors, such as bone metastases, elevated lactate dehydrogenase, and alkaline phosphatase levels, have also been proposed as biomarkers for predicting RLT efficacy;^91,93,94 however, their predictive value remains controversial. Furthermore, most of these biomarkers are only measurable after treatment has already commenced, requiring patients to undergo expensive therapy prior to evaluation. Given the need for individualized treatment approaches, the identification of novel predictive biomarkers is urgently needed.

Advancements in whole-exome sequencing have led to the identification of numerous candidate biomarkers at the genomic, transcriptomic, proteomic, and metabolomic levels for evaluating RTL response. A 2021 study involving nine patients with mCRPC verified that PSMA protein expression in biopsy-confirmed metastatic lesions was an unreliable predictor of response to ¹⁷⁷Lu-PSMA-617.⁹⁵ Similarly, a retrospective analysis of 19 patients showed no correlation between PSMA expression and response to ¹⁷⁷Lu-PSMA-617.⁹⁶ However, the full-length androgen receptor and its splice variant AR-V7 were identified as prognostic biomarkers for predicting response to ¹⁷⁷Lu-PSMA-617.⁹⁶ Genomic instability, primarily associated with defects in DNA repair pathways, suggests that DNA damage-repair (DDR) mutations may serve as potential indicators of RLT response. Studies have shown that patients who are resistant to RLT despite PSMA positivity often carry DDR or checkpoint gene alterations.⁹⁷ Conversely, other research suggests that patients harboring DDR defects may experience longer overall survival following ²²⁵Ac-PSMA-617 treatment compared to those without such mutations. Additionally, decreased DDR gene expression, such as 53BP1 and γ-H2AX, has been associated with progressive PCa.⁹⁸

Discussion

Despite the demonstrated efficacy of PSMA-targeted RLT as a therapeutic option for patients with mCRPC, several challenges must be addressed before it can be widely adopted in clinical practice. Although α-emitting radionuclides exhibit superior cytotoxicity toward cancer cells and reduced toxicity to surrounding tissues compared to β particles, issues such as the variable chemistry of daughter radionuclides and the recoil effect must be carefully considered.⁹⁹ Toxicity remains a major limiting factor in the routine clinical use of α-emitting radionuclides. Many patients experience significant side effects from ²²⁵Ac-PSMA-617 treatment. While tandem treatments have been proposed to minimize toxicity, only a limited number of cases have been reported. The mechanism by which PSMA-targeted radioligands accumulate in the salivary glands is not yet fully understood. This accumulation does not appear to result primarily from PSMA-mediated uptake, thereby limiting available interventions for alleviating xerostomia.¹⁰⁰ Another major concern involves long-term side effects, including respiratory, hepatic, and renal failure, as well as the potential development of secondary malignancies and genetic disorders due to unintended radiation exposure to healthy tissues.¹⁰¹ Data on the nephrotoxicity of ¹⁷⁷Lu-PSMA-617 remain inconclusive, underscoring the need for caution when considering PSMA-targeted RLT in patients with early-stage mCRPC or HSPC. Discrepancies between preclinical and clinical studies also present significant barriers to broader RLT application. Differences in molecular expression patterns between human subjects and animal models can skew estimations of efficacy and toxicity.^102,103 For instance, PSMA-targeted radioligand accumulation in human salivary glands is notably higher than in mice and is often negligible in preclinical models, potentially leading to underestimation of toxicity risks in human applications.^89,104 Moreover, only those PSMA-targeted radioligands deemed optimal and safe in preclinical evaluations have progressed to clinical testing. This selective advancement may inadvertently exclude novel radioligands with promising clinical potential owing to incomplete preclinical assessments. In many RCTs, including VISON, TheraP, PSMAfore, UpFrontPSMA, PSMAddition, ANZUP2001, LuCAB, LuPARP, and AlphaBet, patients received a homogeneous dose and number of cycles: 7.4 GBq of ¹⁷⁷Lu-PSMA-617 or ¹⁷⁷Lu-PSMA I&T on Day 1 of every six-week cycle, for up to six cycles. However, the optimal dose and administration schedule of these agents remain undetermined. It also remains unclear whether PSMA RLT is superior to currently approved first- or second-line therapies. Furthermore, there are no validated biomarkers to predict RLT response, and the limited production capacity of ²²⁵Ac-PSMA has further constrained its clinical development.

To overcome these challenges, efforts must focus on reducing treatment-related side effects. One promising strategy is the development of novel radioligands and chelators that improve tumor uptake of targeting moieties while minimizing radiation exposure to healthy tissues. Several clinical trials are currently investigating the stability, efficacy, and toxicity of these ligands.^105–107 Other strategies include combination therapies and the use of salivary gland protectors to reduce toxicity;^82,108 however, further research is necessary to confirm the toxicity endpoints associated with these approaches and to evaluate the balance between therapeutic effectiveness and toxicity. Simultaneously, future studies should aim to elucidate the genotypic and phenotypic characteristics of patients, as well as their tumor immune microenvironments, to enable rational design of combination therapies that yield optimal clinical outcomes. Finally, innovative methods to increase the production of radioligands must be investigated to meet the growing demand.