¹⁷⁷Lu-PSMA for prostate cancer: progress, challenges and future perspectives

Abstract

Prostate cancer is a malignant tumor posing significant threats to the health of men worldwide. In advanced stages, it frequently progresses to castration-resistant prostate cancer, which is characterized by complex mechanisms and poor prognosis. In such cases, conventional treatments have limited effectiveness. However, the emergence of radionuclide therapy has provided new hope. Lutetium-177-labeled prostate-specific membrane antigen (¹⁷⁷Lu-PSMA), currently the most promising radioligand in clinical research, received approval from the U.S. Food and Drug Administration (FDA) in 2022. This review comprehensively summarizes recent advancements, efficacy assessments, and safety evaluations of ¹⁷⁷Lu-PSMA therapy. Additionally, we analyze its current limitations and suggest future research directions for PSMA-targeted radioligand therapy (RLT). Undoubtedly, ¹⁷⁷Lu-PSMA-617 is transforming metastatic castration-resistant prostate cancer (mCRPC) treatment. However, challenges remain regarding its potential standardization for use in non-mCRPC cases, the optimal treatment sequence, standardized imaging/molecular biomarkers, and toxicity management, all of which require further prospective validation.

INTRODUCTION

Prostate cancer (PCa) is a major global health concern. In 2020, it ranked as the second most common cancer and the fifth leading cause of cancer-related deaths in men. It was the most frequently diagnosed cancer in men in 112 of 185 countries, with incidence rates varying from 6.3 to 83.4 per 100 000 across regions. Furthermore, PCa is the leading cause of cancer-related deaths in men in 48 countries.1 Although traditionally considered a low-incidence region, Asia is experiencing rapid increases in both the incidence and mortality of PCa.2

PCa progresses through several stages, including localized early-stage, locally advanced, and metastatic disease.3 Traditional treatments for localized PCa include active surveillance, radical prostatectomy, radiotherapy, and prostate cryoablation. Patients with localized recurrence after prostatectomy typically receive salvage radiotherapy and/or androgen deprivation therapy (ADT). Those with systemic recurrence are treated with ADT combined with chemotherapy or second-generation anti-androgens targeting the androgen receptor (AR) signaling pathway. Despite the use of ADT, advanced PCa often progresses to castration-resistant prostate cancer (CRPC), which has a poor prognosis and eventually develops into metastatic CRPC (mCRPC).4 Alterations in AR signaling in mCRPC result in sustained AR activation, leading to AR amplification, splice variants, and intratumoral androgen biosynthesis. Once depot resistance develops, the risk of PCa-specific mortality increases significantly.5 Although various therapeutic approaches are available for mCRPC, including chemotherapy, endocrine therapy, immunotherapy, and bone-targeted therapy, resistance to these agents is inevitable. Moreover, the complexity of resistance mechanisms significantly complicates mCRPC treatment.6

Recently, the emergence of radioligand therapy (RLT) for the treatment of PCa has offered new hope. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is highly and specifically expressed in PCa but minimally expressed in normal tissues. Its expression is correlated with tumor aggressiveness, making it a valuable diagnostic and therapeutic target.7 By exploiting this property, PSMA-targeting tracers can be labeled with various radionuclides. Upon accumulation at tumor sites, radioactive decay from α- or β-emitting radionuclides induces DNA strand breaks, leading to cell death. Among these, the small-molecule peptide, lutetium Lu 177 vipivotide tetraxetan (lutetium-177-labeled PSMA-617 radioligand [¹⁷⁷Lu-PSMA-617]), has shown the most significant clinical progress as a PSMA-targeted RLT. PSMA-targeted therapies demonstrate strong potential as precision medicine approaches.8

On March 23, 2022, the U.S. Food and Drug Administration (FDA) approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as ¹⁷⁷Lu-PSMA-617) for the treatment of adults with PSMA-positive mCRPC undergoing AR inhibition and paclitaxel-based chemotherapy. This approval has improved the prognosis of patients who previously had limited therapeutic options.9 Nevertheless, despite advances in ¹⁷⁷Lu-PSMA, numerous clinical and research challenges remain and require urgent attention. This review aims to systematically summarize recent advances in ¹⁷⁷Lu-PSMA therapy, evaluate its efficacy and safety, explore its limitations, and discuss future research directions.

Recent review articles on PSMA-targeted RLT often emphasize a single aspect, such as the efficacy of ¹⁷⁷Lu-PSMA in hormone-sensitive PCa or its toxicity in PCa management. In contrast, this article uniquely begins with the fundamental mechanism of action of ¹⁷⁷Lu-PSMA; reviews pivotal TheraP (a randomized phase 2 trial of lutetium-177 PSMA-617 theranostic treatment versus cabazitaxel in progressive metastatic castration-resistant prostate cancer) and VISION (lutetium-177 PSMA-617 for metastatic castration-resistant prostate cancer – an international, randomized, open-label, phase 3 study) trials; highlights recent clinical studies conducted over the past five years; and provides a comprehensive synthesis of efficacy, safety, biomarkers, limitations, and future directions. Thus, this article serves as an integrated reference for clinical decision-making.

FUNDAMENTAL PRINCIPLES OF ¹⁷⁷LU-PSMA

A transmembrane enzyme with a large extracellular domain is overexpressed in approximately 85% of prostate adenocarcinoma cells. In most cases, its expression level positively correlates with tumor grade as more aggressive tumors, especially metastatic and treatment-resistant types, have higher expression. An exception is seen in neuroendocrine-differentiated PCa, where PSMA expression may be heterogeneous.10 Another key reason for the value of PSMA-targeted therapy is that PSMA is expressed at low levels in normal tissues, making it an ideal target for both diagnosis and treatment of PCa.7,8

¹⁷⁷Lu is a medium-energy β-emitter with an average and maximum electron energies of 147 keV and 497 keV, respectively. This corresponds to a tissue penetration range of approximately 0.28 mm to 1.8 mm, with an average of 0.67 mm, sufficient to kill neighboring receptor-positive cells. Its physical half-life of 6.65 days aligns well with clinical treatment schedules. Additionally, ¹⁷⁷Lu emits low-energy γ-rays during decay, which are suitable for single photon emission computed tomography (SPECT) imaging or scintigraphy, enabling simultaneous diagnosis and therapy with ¹⁷⁷Lu-PSMA-617.10,11

PSMA-617 is a highly specific ligand that targets PSMA overexpressed in prostate tumors. Because PSMA expression is minimal in nonprostate tissues, background uptake in healthy tissue is low, reducing side effects and enhancing treatment safety. Compared with conventional chemotherapy, PSMA-617 offers higher specificity for PCa, minimizing collateral damage to surrounding tissues.11

When both ¹⁷⁷Lu and PSMA-617 are prepared, they can be chemically conjugated to form the radioligand ¹⁷⁷Lu-PSMA-617. This compound combines a therapeutic radionuclide with a PSMA-targeting molecule to enable targeted radionuclide therapy.12 Once bound to PSMA receptors, ¹⁷⁷Lu-PSMA-617 is internalized into PSMA-positive cells and retained intracellularly. During decay, it emits ionizing radiation that induces single- and double-strand DNA breaks, disrupting mitosis and promoting apoptosis in cancer cells.12,13 This therapeutic approach, known as RLT, delivers ionizing radiation specifically to tumor cells while sparing healthy tissue as much as possible.11 The schematic of ¹⁷⁷Lu-PSMA-617 for PCa treatment is shown in Figure 1.

Figure 1.

¹⁷⁷Lu-PSMA-617 disrupts mitosis and induces apoptosis in PCa cells. PSMA: prostate-specific membrane antigen; PSMA-617: prostate-specific membrane antigen-617 ligand; ¹⁷⁷Lu: lutetium-177; ¹⁷⁷Lu-PSMA-617: lutetium-177-labeled PSMA-617 radioligand; PCa: prostate cancer; β-emitter: beta-particle emitter; mCRPC: metastatic castration-resistant prostate cancer. This figure was created with the support of Biorender (http://www.biorender.com).

PROGRESS IN CLINICAL RESEARCH

This section highlights the TheraP and VISION trials, which have played significant roles in advancing the treatment of PCa with ¹⁷⁷Lu-PSMA. It also introduces recent relevant clinical trials from the past 5 years.

Efficacy of ¹⁷⁷Lu-PSMA-617 in the treatment of mCRPC is well established

The TheraP trial was a multicenter, open-label, randomized phase II study. A total of 183 patients with mCRPC were included. In total, 98 patients were randomly assigned to the ¹⁷⁷Lu-PSMA-617 group, and 85 patients were assigned to the cabazitaxel group. The primary endpoint was the prostate-specific antigen (PSA) response, defined as a ≥50% reduction from baseline. Compared with the cabazitaxel group, the ¹⁷⁷Lu-PSMA-617 group demonstrated higher PSA response rates and fewer grade 3 or 4 adverse events compared to the cabazitaxel group, supporting ¹⁷⁷Lu-PSMA-617 as an effective novel therapeutic option.14

The VISION trial was an international, open-label phase III study of ¹⁷⁷Lu-PSMA-617 in PSMA-positive mCRPC patients previously treated with at least one androgen receptor pathway inhibitor (ARPI) and one or two paclitaxel regimens. A total of 831 patients were randomly assigned in a 2:1 ratio to receive either ¹⁷⁷Lu-PSMA-617 plus protocol-permitted standard therapy, or standard therapy alone. The primary endpoints were radiographic progression-free survival (rPFS) and overall survival (OS). rPFS is defined as the duration from randomization to the first occurrence of radiological progression or death from any cause, whichever occurs first. OS is defined as the duration from randomization to death from any cause. Secondary endpoints included the objective response rate, disease control, and time to symptomatic skeletal events. The results demonstrated that ¹⁷⁷Lu-PSMA-617 combined with standard therapy significantly improved the rPFS (median: 8.7 months vs 3.4 months) and OS (median: 15.3 months vs 11.3 months), compared with standard therapy alone. The VISION trial provided strong evidence for the efficacy of ¹⁷⁷Lu-PSMA-617 in the treatment of advanced PSMA-positive mCRPC. These findings directly contributed to its approval by the FDA on March 23, 2022, for the treatment of advanced PSMA-positive mCRPC. ¹⁷⁷Lu-PSMA-617 is approved for the treatment of adult patients with PSMA-positive mCRPC who have received AR pathway inhibitors and paclitaxel-based chemotherapy.15

Interestingly, differences in OS were observed between the two large trials. In the VISION trial, ¹⁷⁷Lu-PSMA-617 combined with standard therapy significantly improved OS (median: 15.3 months vs 11.3 months). In contrast, the OS of patients in the TheraP trial was comparable between the ¹⁷⁷Lu-PSMA-617 and cabazitaxel groups (median: 19.1 months vs 19.6 months).16 These findings were supported by a recent secondary analysis of the TheraP and VISION randomized clinical trials conducted by Soon et al.17 The authors suggested that treatment crossover during the trials may have contributed to the observed differences in OS.17 An analysis of the VISION trial by Morris et al.18 revealed a close association between rPFS and OS. Similarly, Pathmanandavel et al.19 reported that both PSA progression and imaging progression were linked to shorter OS.18,19 In conclusion, the efficacy of ¹⁷⁷Lu-PSMA-617 in mCRPC, particularly in PSMA-positive patients who have received ARPI and paclitaxel-based chemotherapy, has been validated. However, its precise impact on OS requires further investigation. Future research should focus on optimizing RLT to improve long-term survival outcomes.

Feasibility and efficacy of ¹⁷⁷Lu-PSMA-617 in more clinical scenarios

The efficacy of ¹⁷⁷Lu-PSMA-617 in mCRPC has been established. It is now worth exploring whether this RLT could be applied beyond the current FDA-approved indication, which is limited to PSMA-positive mCRPC patients previously treated with ARPI and paclitaxel-based chemotherapy. Violet et al.20 reported that multiple prior lines of therapy before RLT are linked to poor prognosis. Similarly, Satapathy et al.21 reported that mCRPC patients who had not received paclitaxel analogs had significantly better outcomes following ¹⁷⁷Lu-PSMA-RLT than those who had received such treatment.20,21 An increasing body of evidence suggests that ¹⁷⁷Lu-PSMA-617 may have potential applications in additional clinical settings.

Emmett et al.22 recently conducted the ENZA-p ([¹⁷⁷Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer) phase II trial, enrolling mCRPC patients who had not received docetaxel or ARPI but were at high risk of early progression following enzalutamide therapy. These patients had a less complex treatment history compared with those in the VISION trial. The primary endpoint was PSA progression-free survival (PFS). The results showed that adding ¹⁷⁷Lu-PSMA-617 to enzalutamide improved outcomes, indicating that ¹⁷⁷Lu-PSMA-617 may enhance anti-tumour activity in mCRPC patients at risk of early progression on enzalutamide.22 This finding also indicates that combining ¹⁷⁷Lu-PSMA-617 with conventional chemotherapy or hormonal therapy is feasible and potentially more effective.

Similar to the ENZA-p trial, the phase III randomized controlled PSMAfore (¹⁷⁷Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer) trial by Morris et al.23 enrolled PSMA-positive mCRPC patients who had not received paclitaxel-based therapy but had progressed following one line of prior ARPI therapy. Patients were randomized into two groups: one received ¹⁷⁷Lu-PSMA-617, and the other (the “ARPI-switch group”) was switched to either abiraterone or enzalutamide. Patients in the ARPI-switch group were permitted to crossover to ¹⁷⁷Lu-PSMA-617 upon imaging-confirmed disease progression. The results revealed that the median rPFS was significantly longer in the ¹⁷⁷Lu-PSMA-617 group than that in the ARPI-switch group.23 Although prior ARPI exposure may have lowered sensitivity to subsequent treatments in the ARPI-switch group, potentially exaggerating the difference in rPFS, these findings still suggest that ¹⁷⁷Lu-PSMA-617 is not limited to heavily pretreated mCRPC patients who have received both ARPI and paclitaxel. In the future, it may also be incorporated into the standardized treatment regimens for patients with earlier stages of PCa.

Similarly, the phase II UpFrontPSMA trial led by Azad et al.24 is notable for evaluating ¹⁷⁷Lu-PSMA-617 administration prior to docetaxel in patients with newly diagnosed, high-volume metastatic hormone-sensitive prostate cancer (mHSPC). The results demonstrated that compared with patients treated with docetaxel alone, patients receiving the experimental regimen (¹⁷⁷Lu-PSMA-617 followed by docetaxel after six weeks) exhibited a significantly higher rate of undetectable PSA at 48 weeks. This finding indicates that the sequential use of ¹⁷⁷Lu-PSMA-617 followed by docetaxel enhances anti-tumour efficacy in patients with high-burden, newly diagnosed mHSPC compared with docetaxel alone.24 In the phase II CONSOLIDATE (¹⁷⁷Lu-PSMA-617 consolidation therapy after docetaxel in patients with synchronous high-volume metastatic hormone-sensitive prostate cancer) trial, Satapathy et al.25 used ¹⁷⁷Lu-PSMA-617 as consolidation therapy for residual lesions in patients with mHSPC following chemotherapy combined with hormonal therapy, demonstrating promising efficacy and safety results.25 These findings show that the efficacy of ¹⁷⁷Lu-PSMA-617 extends beyond mCRPC and highlight the need to define its optimal sequencing within standard PCa regimens. This question warrants further investigation using well-designed clinical trials.

Numerous ongoing open-label trials are currently investigating ¹⁷⁷Lu-PSMA-617. In a phase I trial, Golan et al.26 administered ¹⁷⁷Lu-PSMA to PCa patients prior to robot-assisted radical prostatectomy (RARP). The treatment appeared safe and feasible; however, its therapeutic efficacy remains uncertain.26 The ROADSTER (the use of lutetium-177 PSMA radioligand therapy with high dose rate brachytherapy for locally recurrent prostate cancer after previous definitive radiation therapy) trial, conducted by Mendez et al.,27 evaluated the addition of ¹⁷⁷Lu-PSMA RLT in patients with isolated local failure (ILF) following initial radical radiation therapy for PCa.27 Beheshti et al.28 proposed that ¹⁷⁷Lu-PSMA therapy could represent a promising option for patients with limited progressive PCa.28 Privé et al.29 recently updated the BULLSEYE (lutetium-177-PSMA in oligo-metastatic hormone-sensitive prostate cancer) trial, which investigated the efficacy of ¹⁷⁷Lu-PSMA RLT in the treatment of oligometastatic hormone-sensitive prostate cancer (oHSPC), aiming to prolong PFS and postpone the initiation of ADT. PFS is defined as the duration from randomization or treatment initiation to the first occurrence of disease progression (e.g., increased tumor volume or new lesions) or death from any cause, whichever occurs first.29

In conclusion, accumulating evidence suggests that ¹⁷⁷Lu-PSMA-617 may have broader clinical utility beyond PSMA-positive mCRPC previously treated with ARPI and taxane-based chemotherapy. In the future, it could become part of the standard of care (SoC) for a wider spectrum of PCa subtypes. However, the specific clinical scenarios in which ¹⁷⁷Lu-PSMA-617 enhances efficacy and improves patient prognosis remain unclear. Further randomized controlled trials are necessary to determine the optimal treatment sequence. A summary of the major recent clinical trials is presented in Table 1.

Table 1.

A review of recent clinical trials involving ¹⁷⁷Lu-PSMA therapy

Clinical trial	NCT number	Patient group	Study design	Primary endpoints	Result	Clinical implication
TheraP14	NCT03392428	mCRPC	177Lu-PSMA vs cabazitaxel	Proportion of patients exhibiting a ≥50% reduction in PSA levels	177Lu-PSMA demonstrates significantly superior efficacy and lower toxicity compared to cabazitaxel	177Lu-PSMA-617 is verified as a new class of effective therapeutic modalities
VISION15	NCT03511664	PSMA-positive mCRPC patients previously treated with ARPI and paclitaxel-based chemotherapy	177Lu-PSMA-617 combined with standard treatment vs standard treatment alone	rPFS and OS	The combination of 177Lu-PSMA-617 and standard therapy significantly extended rPFS and OS	Directly contributed to the FDA approval of 177Lu-PSMA-617 for the treatment of patients with advanced, pre-treated mCRPC
ENZA-p22	NCT04419402	mCRPC patients who have not received docetaxel or ARPI treatment	Enzalutamide combined with 177Lu-PSMA-617 vs enzalutamide alone	PSA PFS	Median PSA PFS: 13.0 months vs 7.8 months	Supports the use of 177Lu-PSMA-617 in mCRPC patients with risk factors for early enzalutamide progression
PSMAfore23	NCT04689828	PSMA-positive mCRPC patients without prior paclitaxel therapy	177Lu-PSMA-617 vs alteration of the ARPI dosing regimen	rPFS	rPFS: 9.3 months vs 5.55 months	Supports the use of 177Lu-PSMA-617 in mCRPC patients naïve to taxane treatment
UpFrontPSMA24	NCT04343885	Patients with newly diagnosed high tumour burden mHSPC	177Lu-PSMA-617 followed by docetaxel after 6 weeks of treatment vs docetaxel alone	Number of patients with undetectable PSA levels at week 48	25 out of 61 patients vs 10 out of 61 patients	Supports the use of 177Lu-PSMA-617 in the treatment of mHSPC patients
Golan et al. 26	-	RARP	Administration of 177Lu-PSMA-617 prior to RARP	Assessment of surgical complication rates, operative parameters, and postoperative functional outcomes	The procedure is considered safe and feasible; however, the effectiveness of the treatment remains uncertain	Demonstrates that administering 177Lu-PSMA prior to RARP is safe and feasible
ROADSTER27	NCT05230251	PCa following initial radical radiation therapy with an ILF	177Lu-PSMA RLT combined with HDR brachytherapy vs HDR brachytherapy alone	Evaluation of safety and feasibility	Currently ongoing	Explores a novel salvage therapy for ILF after primary radiotherapy with combined 177Lu-PSMA RLT and HDR brachytherapy
BULLSEYE29	NCT04443062	oHSPC	177Lu-PSMA-617-based MDT vs SoC	Evaluation using 18F-PSMA PET and whole-body MRI	Currently ongoing	Tests whether 177Lu-PSMA RLT is an effective therapeutic modality for oHSPC

ARPI: androgen receptor pathway inhibitor; FDA: U.S. Food and Drug Administration; mCRPC: metastatic castration-resistant prostate cancer; OS: overall survivial; PSA: prostate-specific antigen; PSMA: prostate-specific membrane antigen; rPFS: radiographic progression-free survival; ¹⁷⁷Lu: lutetium-177; ¹⁷⁷Lu-PSMA-617: lutetium-177-labeled PSMA-617 radioligand; HSPC: hormone-sensitive prostate cancer; oHSPC: oligometastatic hormone-sensitive prostate cancer; mHSPC: metastatic hormone-sensitive prostate cancer; RARP: robot-assisted radical prostatectomy; PCa: prostate cancer; ILF: isolated local failure; RLT: radioligand therapy; HDR: high-dose-rate; MDT: metastasis-directed therapy; SoC: standard of care; ¹⁸F-PSMA PET: fluorine-18 PSMA positron emission tomography; MRI: magnetic resonance imaging; PFS: progression-free survival; -: not available

SAFETY ANALYSIS

Safety and efficacy of ¹⁷⁷Lu-PSMA-617 at specific doses and cycles

Ha et al.30 recently assessed the biodistribution and dosimetry of ¹⁷⁷Lu in a phase I study involving mCRPC patients. The study indicated that a dosage of 3.7 GBq per cycle for 6 cycles is expected to be safe.30 In the phase II RESIST-PC (safety of PSMA-targeted molecular radioligand therapy with ¹⁷⁷Lu-PSMA-617) trial (NCT03042312), Calais et al.31 evaluated the safety of ¹⁷⁷Lu-PSMA-617 in 64 patients. They demonstrated that ¹⁷⁷Lu-PSMA-617 was safe and well tolerated at doses of 6.0 GBq and 7.4 GBq per cycle. Notably, the study enrolled patients with sufficient bone marrow reserve and normal renal function.31

In the VISION trial, compared with standard care alone, ¹⁷⁷Lu-PSMA-617 combined with standard-of-care treatment delayed the decline in health-related quality of life (HRQOL) and the onset of skeletal events.32 Chi et al.33 further analyzed the safety data from the VISION trial and reported that long-term exposure to ¹⁷⁷Lu-PSMA-617 combined with SoC treatment did not increase the risk of toxicity. The researchers suggested that the prolonged safety monitoring in the ¹⁷⁷Lu-PSMA-617 plus SoC group may have contributed to a higher rate of treatment-related adverse events (TEAEs). However, it should be noted that the two groups exhibited different trends for various types of TEAEs, and the rate of events associated with RLT remained higher in the ¹⁷⁷Lu-PSMA-617 group.33 Future standardized treatments need to address how to minimize the frequency of adverse events associated with RLT and how to manage TEAEs effectively.

Safety risks of ¹⁷⁷Lu-PSMA-617: a controversial issue

First, discrepancies exist between the VISION and TheraP trials. In the VISION trial, compared with the standard care group, the ¹⁷⁷Lu-PSMA-617 group had a significantly higher incidence of grade ≥3 adverse events (52.7% vs 38.0%).15 In contrast, the TheraP trial reported fewer grade 3–4 adverse events in the ¹⁷⁷Lu-PSMA-617 group. Additionally, no deaths were attributed to ¹⁷⁷Lu-PSMA-617 in the TheraP trial.14 However, in the larger VISION trial, five patients (1%) in the ¹⁷⁷Lu-PSMA-617 plus standard therapy group died from TEAEs, whereas no such deaths occurred in the standard therapy group.32 The TheraP and VISION trials differ primarily in the following aspects. In terms of inclusion criteria, the TheraP trial requires PSMA-positive disease with no metastatic disease sites and no discordance between fluorodeoxyglucose (FDG)-positive or PSMA-negative results; in contrast, patients in the VISION trial must have mCRPC and must have previously received at least one androgen receptor pathway inhibitor and one or two taxane-based therapies. With respect to the study design, patients in the TheraP trial were randomly assigned in a 1:1 ratio to receive either ¹⁷⁷Lu-PSMA-617 or cabazitaxel, with a PSA response as the primary endpoint. In contrast, patients in the VISION trial were randomly assigned in a 2:1 ratio to receive either ¹⁷⁷Lu-PSMA-617 plus protocol-permitted SoC or SoC alone, with the primary endpoints being rPFS and OS. This finding indicates that patients in the VISION trial have more stringent requirements regarding prior treatments, which increases the likelihood of cross-reactivity. Therefore, whether combining ¹⁷⁷Lu-PSMA-617 with other treatments increases the risk of adverse effects remains unclear.

In the UpFrontPSMA (sequential [¹⁷⁷Lu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer) trial, the most frequent grade 3–4 TEAEs were febrile neutropenia and diarrhea. Compared with the docetaxel-only group, the group receiving ¹⁷⁷Lu-PSMA-617 plus docetaxel did not exhibit a significantly higher rate of TEAEs, and no treatment-related deaths were reported.24 These findings suggest that adding ¹⁷⁷Lu-PSMA-617 may not increase toxicity. However, the results may be influenced by the limited sample size in this trial. In contrast, the PSMAfore trial reported a lower incidence of grade 3–5 adverse events in the ¹⁷⁷Lu-PSMA-617 group compared to the ARPI conversion group.23

In conclusion, compared with conventional hormone therapy or chemotherapy, ¹⁷⁷Lu-PSMA-617 is associated with a lower incidence of grade ≥3 adverse events. However, its safety profile when combined with other treatments remains controversial and requires further validation.

Common symptoms of adverse events

In the phase II RESIST-PC trial (NCT03042312), Calais et al.31 reported that the most common adverse events in patients treated with ¹⁷⁷Lu-PSMA-617, regardless of severity, were dry mouth, fatigue, nausea, and diarrhea, sequentially. The high incidence of dry mouth is attributed to the salivary glands having the highest dose coefficients for ¹⁷⁷Lu uptake among normal organs, followed by the kidneys, liver, and spleen.30 This symptom can be alleviated by administering polyglutamic acid tablets to reduce salivary gland uptake, along with the use of oral rinses.34,35 In contrast, long-term follow-up by Violet et al.20 revealed that the most common toxicities associated with ¹⁷⁷Lu-PSMA included self-limiting grade 1–2 dry mouth (66%), transient grade 1–2 nausea (48%), grade 3–4 thrombocytopenia (10%), and grade 3 anemia (10%).20

The adverse event profile varied when ¹⁷⁷Lu-PSMA-617 was administered in combination with other therapies. The ENZA-p trial revealed that patients receiving both ¹⁷⁷Lu-PSMA-617 and enzalutamide were more likely to experience fatigue and nausea compared with those receiving enzalutamide alone. Grade 3 adverse events observed only in the combination group included anemia and thrombocytopenia, which is consistent with findings from the VISION trial.15 In a study by Pathmanandavel et al.,36 combining ¹⁷⁷Lu-PSMA-617 with the radiosensitizer idronoxil for the treatment of mCRPC resulted in common adverse events such as anemia, fatigue, and xerostomia.36

Overall, ¹⁷⁷Lu-PSMA-617 frequently causes dry mouth and nausea, while anemia and fatigue are more common when it is combined with hormonal or other systemic therapies. Nevertheless, the adverse effects of ¹⁷⁷Lu-PSMA-617, whether used alone or in combination, were generally tolerable and demonstrated a favorable overall safety profile.

However, the precise mechanisms, extent, and severity of radiation-induced salivary gland toxicity remain poorly understood. Typically, to protect the salivary glands and mitigate radiation-related adverse effects, current strategies focus on reducing radioligand accumulation or accelerating radioactive clearance within the glands.37 Myelosuppression is another frequent treatment-related adverse effect. High bone tumor burden, prior taxane-based chemotherapy, and pretreatment grade 2 cytopenia are recognized as risk factors for clinically significant myelosuppression.38 Currently, symptomatic management is widely employed in clinical practice to alleviate these adverse reactions, although its efficacy remains suboptimal. Therefore, further exploration of strategies for alleviating, preventing, and treating adverse reactions such as xerostomia and myelosuppression is essential. Figure 2 summarizes the adverse reactions associated with ¹⁷⁷Lu-PSMA-617 observed in multiple clinical trials.

Figure 2.

Distribution of adverse reactions associated with ¹⁷⁷Lu-PSMA-617 across clinical trials (with incidence rates). PSMA-617: prostate-specific membrane antigen-617 ligand; ¹⁷⁷Lu-PSMA-617: lutetium-177-labeled PSMA-617 radioligand.

BIOMARKERS THAT PREDICT EFFICACY AND REFLECT PROGNOSIS

Imaging response

Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) significantly influences the staging and management of PCa because of its diagnostic capabilities and is frequently used alongside radiotherapy (RT).39,40,41 For treatment monitoring, PET tracers can also be employed to image patients.11 In the phase III PSMA-dRT trial (NCT04457245), Nikitas et al.42 reported that PSMA PET/CT could benefit 17% of patients by enabling more precise radiation therapy planning. Unfortunately, the trial was terminated prematurely for unspecified reasons, preventing the assessment of the impact of PSMA PET/CT on PFS.42

Pathmanandavel et al.19 also highlighted the value of posttreatment PET as an imaging biomarker. They reported that changes in PSMA total tumor volume (TTV) have strong prognostic potential for ¹⁷⁷Lu-PSMA-617 treatment.19 Additionally, in another trial combining ¹⁷⁷Lu-PSMA-617 with the radiosensitizer idronoxil, higher PSMA TTV was linked to worse OS.36

Conversely, Vlachostergios et al.43 reported that patients with high PSMA uptake and high radionuclide doses are more likely to respond to RLT.43 The standardized uptake value (SUV) quantifies the uptake of radiotracers, such as fluorine-18 fluorodeoxyglucose (18F-FDG), in tissues. In a secondary analysis of the VISION trial, Kuo et al.44 examined the role of quantitative gallium-68 prostate-specific membrane antigen-11 positron emission tomography (68Ga-PSMA-11 PET) in patients treated with ¹⁷⁷Lu-PSMA-617. They reported that the baseline whole-body mean SUV from 68Ga-PSMA-11 PET/computed tomography (CT) was the best predictor of efficacy. A 1-unit increase in the mean SUV was associated with a 12% reduction in rPFS and a 10% reduction in the risk of death.44 However, this finding is debated. A study by Pathmanandavel et al.19 revealed that changes in the PSMA SUVmax in patients treated with ¹⁷⁷Lu-PSMA-617 were not correlated with PSA PFS or OS.19 Only a higher mean PSMA SUV was associated with a treatment response.36 Therefore, controversy persists regarding whether the SUV influences long-term prognosis and its association with indicators such as rPFS or mortality risk, or whether it is solely linked to PSA response posttreatment. Exploring this question remains crucial. Additionally, the standardization of imaging endpoints in future trial designs remains a key challenge. Based on current research, prioritizing reporting PSMA TV or FDG-PET MTV over SUV alone is recommended. We recommend that future trials adopt a ≥30% change in PSMA TV as an exploratory threshold for imaging response and perform prospective correlation analysis with rPFS/OS.

In the TheraP trial, a mean PSMA-PET SUV of 10 or higher was confirmed as a predictive biomarker for response to ¹⁷⁷Lu-PSMA-617 in combination with cabazitaxel, outperforming cabazitaxel alone in predicting response in patients with mCRPC. These findings offer objective criteria for accurately identifying patients most likely to benefit from ¹⁷⁷Lu-PSMA-617 treatment. However, high FDG-PET metabolic tumor volume (MTV) is associated with poor response, regardless of the assigned treatment. Enhancing the response in patients with mCRPC and high tumor burden remains a challenge.45

Overall, PSMA-PET remains a valuable tool for managing and predicting outcomes in patients treated with ¹⁷⁷Lu-PSMA-617. Elevated PSMA TTV or FDG-PET MTV is linked to a reduced treatment response and worse overall survival. Although the relationship between the PSMA SUV and treatment outcomes remains unclear, an increased SUV generally indicates a positive therapeutic effect.

PSA response

The prognostic value of a decrease in the PSA concentration during ¹⁷⁷Lu-PSMA-617 therapy was confirmed by Armstrong et al.,46 who reported that greater decreases in the PSA concentration were associated with higher imaging response rates, longer median time to deterioration in health-related quality of life (HRQoL) and pain, and improved clinical outcomes.46 Giovanella et al.47 similarly reported that any decrease in the PSA concentration after 1–2 treatment cycles is a favorable prognostic indicator for OS.

Patient condition before treatment

Karimzadeh et al.48 reported that patients selected for PSMA RLT based on the TheraP trial’s inclusion criteria had better responses and outcomes. Interestingly, many patients who did not meet these criteria also exhibited high response rates.48 Satapathy et al.49 suggested that, among mCRPC patients treated with ¹⁷⁷Lu-PSMA RLT, visceral metastases predicted both a lower biochemical response rate and worse PFS and OS. von Eyben et al.50 reported that symptomatic patients and those with widespread metastases had shorter survival compared with asymptomatic patients or those with lymph node-only involvement. Zhang et al.51 reported a significant correlation between elevated baseline alkaline phosphatase (ALP) levels and poor OS and PFS in mCRPC patients prior to ¹⁷⁷Lu-PSMA RLT. Violet et al.20 reported that receiving multiple prior treatment regimens before RLT was associated with poor prognosis.50,51

In an interesting aspect of the phase II trial by Violet et al.,20 a subset of patients was followed over a prolonged period. Among 15 patients who experienced disease progression after an initial response to ¹⁷⁷Lu-PSMA therapy, 11 (73%) had a ≥50% reduction in the PSA level following retreatment. These findings support the efficacy of ¹⁷⁷Lu-PSMA retreatment, without unexpected adverse events reported.20 However, the trial’s small sample size and limited long-term follow-up data restrict the ability to further optimize ¹⁷⁷Lu-PSMA treatment regimens.

In conclusion, the patient’s condition prior to treatment, such as prior therapy, extent of metastasis, and biochemical markers, clearly influences treatment response. Identifying the criteria that predict favorable outcomes for ¹⁷⁷Lu-PSMA RLT remains an important area for further research.

In summary, based on the findings of the aforementioned clinical trials, the magnitude of PSA reduction and the presence, scope, and extent of distant metastases prior to ¹⁷⁷Lu-PSMA treatment have shown clinical relevance. However, the potential of indicators such as PSMA TTV, FDG-PET MTV and PSMA SUV as reliable biomarkers remains under investigation.

THERAPEUTIC LIMITATIONS AND CHALLENGES

Although ¹⁷⁷Lu-PSMA has significantly advanced mCRPC treatment, it continues to face several limitations and pressing challenges requiring resolution or improvement.

Mode of administration and dose optimization

Most previously reported clinical trials have employed intravenous administration for RLT delivery. However, the impact of selective prostatic arterial administration on primary tumor uptake remains unclear. Recently, Kohlbrenner et al.52 conducted a clinical trial (NCT04976257) and demonstrated that compared with intravenous infusion, selective prostatic arterial infusion produced a higher 68Ga-PSMA-11 tumor SUV. These findings highlight the need for further investigation into the intra-arterial delivery and localized activity of PSMA-targeted agents.52

In terms of dosage, a phase II trial by Calais et al.53 revealed that two active regimens, 6.0 GBq and 7.4 GBq, had comparable efficacy. However, real-world validation and additional clinical trials are necessary to refine ¹⁷⁷Lu-PSMA treatment protocols and enhance both radiation delivery and therapeutic efficacy.53 Jackson et al.54 described a simplified technique for dose estimation in ¹⁷⁷Lu-PSMA-617 therapy, offering a practical method that may support future dose-response modeling and optimization. Modifying the administration route or adjusting the dosage of ¹⁷⁷Lu-PSMA therapy may lead to improved prognosis and long-term clinical outcomes.

Dosing in special populations

In general, adequate hepatic and renal function is required in patients receiving ¹⁷⁷Lu-PSMA RLT, as it may cause severe radiation nephropathy due to thrombotic microangiopathy or elevated liver enzymes.55,56 However, Mahdi et al.57 demonstrated the safety of full-dose ¹⁷⁷Lu-PSMA in renal transplant recipients. Additionally, Usmani et al.58 reported a case involving a 74-year-old male mCRPC patient with diabetes mellitus, hypertension, and chronic kidney disease. To minimize renal radiation exposure, a reduced dose of ¹⁷⁷Lu-PSMA-617 (4 GBq) was administered, resulting in a marked decrease in PSA levels and clinical symptoms, along with stable kidney function.58 This case highlights that impaired renal function is not an absolute contraindication for radionuclide therapy and that dosage can be tailored based on a risk–benefit assessment. However, large-scale clinical trials are lacking to establish optimized dosing strategies for specific populations. Balancing the safety and efficacy of ¹⁷⁷Lu-PSMA RLT in these groups remains a significant challenge.

FUTURE DIRECTIONS AND PROSPECTS

Combination with conventional radiotherapy or hormonal therapy

Data from preclinical studies and early clinical trials suggest that combining external beam radiotherapy (EBRT) with PSMA-RLT dose escalation enhances tumor control and may prolong survival.59 van der Sar et al.60 are conducting a phase I PROQURE-I trial (NCT05162573) that combines EBRT and ADT with ¹⁷⁷Lu-PSMA-617 in PCa, aiming to assess tolerability and enhance efficacy.

Ma et al.61 planned a phase II trial to evaluate the efficacy of ¹⁷⁷Lu-PNT2002, a novel radiolabelled small molecule with high PSMA affinity, combined with stereotactic body radiotherapy (SBRT) versus SBRT alone in men with oligo-recurrent mHSPC.

Amanollahi Soudmand et al.62 conducted a preliminary study to evaluate the efficacy and safety of combining ¹⁷⁷Lu-PSMA-617 with radical prostatectomy and bilateral orchiectomy in patients with castration-sensitive metastatic PCa. The results indicated that radical prostatectomy and hormonal therapy combined with ¹⁷⁷Lu-PSMA-617 is a safe and effective treatment option, potentially benefiting specific patients with castration-sensitive metastatic PCa.62

Combination with radiosensitizers

In 2021, Crumbaker et al.63 proposed combining ¹⁷⁷Lu-PSMA-617 with the radiosensitizer idronoxil to overcome resistance in mCRPC, and demonstrated its safety and feasibility in a phase I/II trial. More recently, the same team reported that the PSMA SUVmean, PSMA-avid tumor volume, and the duration of androgen signaling inhibitor (ASI) treatment were independently associated with clinical outcomes.36 However, the enhanced efficacy of the combination strategy requires further validation. Kao et al.64 reported a case in which ¹⁷⁷Lu-PSMA-617 was combined with a radiosensitizer, leading to an excellent PSA response but also severe bone marrow radiotoxicity. This suggests that radiosensitizers act as a double-edged sword and must be used with caution in clinical settings.64

Combination with immunotherapy

In a phase I study, Lim et al.65 investigated the use of JNJ-63898081, a PSMA × CD3 bispecific antibody, for the treatment of metastatic desmoplasia-resistant PCa. This study demonstrated its feasibility and safety in overcoming immunosuppression and promoting antitumour activity; however, its long-term efficacy remains to be established. Nonetheless, it highlights a promising direction for future combination strategies.65

Similarly, Dorff et al.66 demonstrated that acapatamab, a PSMA × CD3 bispecific T-cell engager, was safe and well tolerated in mCRPC, although its durable antitumour activity was limited. Notably, PSMA × CD3 bispecific T-cell engagers may mediate resensitization to checkpoint inhibitors, thereby demonstrating unexpected efficacy.67 In conclusion, owing to their shared PSMA target, both bispecific T-cell engagers show considerable promise for future combination with ¹⁷⁷Lu-PSMA therapy.

Additional immunotherapy trials with the potential for synergistic use alongside RLT are currently ongoing. A phase I study (NCT02616185) by Autio et al.68 evaluated PF-06753512, a vaccine-based immunotherapy (PrCa VBIR), in patients with mCRPC and biochemical recurrence (BCR) of PCa. A first-in-human phase I trial (NCT03089203) by Narayan et al.69 evaluated CAR-T-cell relay immunotherapy for mCRPC and demonstrated its overall feasibility and safety. However, one patient died because of massive clonal CAR-T-cell expansion complicated by sepsis.69

Based on the aforementioned trials and current clinical practice, combining ¹⁷⁷Lu-PSMA-617 with conventional hormone therapy represents the most promising regimen at this stage. In contrast, combining ¹⁷⁷Lu-PSMA-617 with immunotherapy remains exploratory and is associated with considerable safety risks. Although its combination with radiosensitizers may enhance therapeutic efficacy, it concurrently amplifies radiation toxicity, potentially leading to unpredictable severe adverse effects. Balancing toxicity therefore remains a major challenge.

New-generation PSMA radiopharmaceuticals

As previously noted, the small-molecule radioligand ¹⁷⁷Lu-PSMA-617 has experienced the most significant clinical advancement among PSMA-targeted RLTs.8 In addition to ¹⁷⁷Lu-PSMA-617, other ¹⁷⁷Lu-labelled ligands have been developed. In 2019, Zang et al.70 conducted the first human study of ¹⁷⁷Lu-EB-PSMA-617 in patients with mCRPC and reported that it resulted in greater tumor accumulation compared with ¹⁷⁷Lu-PSMA-617.70 In a subsequent dose-escalation trial in 2020, the same team reported that a 2.12-GBq dose of ¹⁷⁷Lu-EB-PSMA-617 was safe and potentially effective for mCRPC treatment.71 In 2024, the team initiated a phase I trial (NCT05613738) of ¹⁷⁷Lu-PSMA-EB-01 (also known as ¹⁷⁷Lu-LNC1003), which demonstrated good tolerability across multiple treatment cycles. However, owing to limited patient enrolment, further studies are needed to evaluate the optimal dosing frequency, efficacy, and potential side effects of ¹⁷⁷Lu-LNC1003.72

Although no significant difference in absorbed dose was observed between ¹⁷⁷Lu-PSMA-I&T and ¹⁷⁷Lu-PSMA-617,73 Tauber et al.74 recently treated 80 elderly mCRPC patients (≥80 years old) with lutetium-177 prostate-specific membrane antigen imaging and therapy (¹⁷⁷Lu-PSMA-I&T) and confirmed its safety and efficacy. The observation that chemotherapy-naïve patients had better responses and longer treatment durations suggests that early RLT may be beneficial for mCRPC patients.74 van Golen et al.75 used ¹⁷⁷Lu-PSMA-I&T to treat mCRPC patients with peritoneal metastases and observed a strong PSA response.

Owing to its high linear energy transfer and short tissue penetration, actinium-225 (²²⁵Ac) induces double-stranded DNA breaks, making Ac-PSMA RLT a potentially safe and effective option for mCRPC patients.76,77,78 Yadav et al.79 used ²²⁵Ac-PSMA-617 to treat mCRPC patients refractory to ¹⁷⁷Lu-PSMA-617 RLT, achieving promising disease control with minimal toxicity. Wang et al.80 reported that ²²⁵Ac-PSMA may represent a promising therapy for mCRPC patients with extensive bone metastases. However, delayed nephrotoxicity, particularly tubulointerstitial nephritis, has been observed in some patients during clinical use.81

Tagawa et al.82 aimed to prolong mCRPC survival using ²²⁵Ac-labelled J591, an anti-PSMA monoclonal antibody, and demonstrated its safety and preliminary efficacy. Ling et al.83 recently launched a phase I dose-escalation study to assess the safety and efficacy of ²²⁵Ac-PSMA-I&T in mCRPC patients. Their findings suggest that ²²⁵Ac-PSMA may offer greater therapeutic promise than ¹⁷⁷Lu-PSMA-based RLT for mCRPC treatment.83 Additionally, compared with ¹⁷⁷Lu, terbium-161 (¹⁶¹Tb) emits more radiation, prompting Buteau et al.84 to incorporate it into the phase I/II VIOLET trial. The results indicated that ¹⁶¹Tb-PSMA-I&T is safe at the maximum administered dose of 7.4 GBq; however, further research in larger-scale randomized clinical trials is needed.84

Most new radiopharmaceuticals have entered clinical trials because of their additional advantages over ¹⁷⁷Lu-PSMA-617. Compared with ¹⁷⁷Lu-PSMA-617, ¹⁷⁷Lu-EB-PSMA-617 and ¹⁶¹Tb-PSMA-I&T accumulate more in mCRPC, potentially leading to improved therapeutic efficacy. Additionally, ¹⁷⁷Lu-PSMA-I&T shows a better therapeutic response and prolonged duration in chemotherapy-naïve patients. In contrast, ²²⁵Ac-PSMA-617 demonstrated a favorable disease control rate with reduced treatment-related toxicity. In conclusion, numerous novel radiopharmaceuticals are emerging for use in clinical RLT. However, whether they offer superior benefits over ¹⁷⁷Lu-PSMA-617 or serve mainly as salvage therapies remains uncertain and requires further clinical validation.

Precision medicine

In the phase II MEDCARE trial, Rans et al.85 demonstrated that targeting oligoprogressive lesions with progression-directed radiotherapy, compared with traditional SoC, delayed the initiation of new systemic therapy by 17 months in mCRPC patients. ¹⁷⁷Lu-PSMA-617 may serve as a progression-directed radiotherapy agent to delay disease progression and facilitate precision treatment.

A recent prospective trial by Chen et al.86 demonstrated that 68Ga-MY6349 PET/CT is a noninvasive technique for comprehensively evaluating trophoblast cell surface antigen 2 (Trop2), an emerging therapeutic target in PCa. Compared with 18F-FDG PET/CT and 68Ga-PSMA-11, 68Ga-MY6349 demonstrated greater tumor uptake and revealed intratumoral heterogeneity.86 These findings highlight the potential to develop improved imaging tools for identifying PSMA expression, which may enable personalized treatment strategies based on imaging phenotypes, PSMA expression, and genetic profiles. The future development prospects of PSMA-RLT and its potential combination therapies are illustrated in Figure 3.

Figure 3.

Future prospects of PSMA-RLT and its potential combination therapies. PSMA: prostate-specific membrane antigen; ¹⁷⁷Lu: lutetium-177; EBRT: external beam radiotherapy; ADT: androgen deprivation therapy; SBRT: stereotactic body radiotherapy; LuPIN: lutetium-PSMA-617 plus idronoxil trial; CD3: cluster of differentiation 3; EB-PSMA-617: albumin-binding (evans blue–modified) PSMA-617; I&T: imaging and therapy; ²²⁵Ac: actinium-225; ¹⁶¹Tb: terbium-161. This figure was created with the support of BioGDP (https://biogdp.com).

CONCLUSION

The therapeutic efficacy of ¹⁷⁷Lu-PSMA-617 in treating mCRPC is remarkable. When administered in combination with SoC, ¹⁷⁷Lu-PSMA-617 significantly extends rPFS and OS in patients with advanced mCRPC. Since its FDA approval for clinical use, an increasing number of phase I, II, and III trials have demonstrated its robust efficacy and favorable safety profile. Real-world studies have also supported these findings. This has been observed in various clinical settings, including mHSPC, both prior to conventional chemotherapy and in combination with hormonal therapy. With increasing knowledge of ¹⁷⁷Lu-PSMA-617, several biomarkers, such as the PSMA SUV and PSA response, have emerged as potential predictors of treatment efficacy and patient prognosis. Nevertheless, ¹⁷⁷Lu-PSMA-617 presents limitations, including uncertainties in its application to special populations, optimal dosing strategies, and the rare occurrence of serious adverse effects.

Additionally, ¹⁷⁷Lu-PSMA RLT shows strong potential for integration into combination regimens and precision medicine approaches. Further research is warranted to assess the long-term efficacy and safety of this therapy and to refine optimal dosing strategies and patient selection criteria. In summary, additional randomized controlled trials and extended follow-up data are essential to further optimize therapeutic regimens.

AUTHOR CONTRIBUTIONS

ZX and SYJ are co-first authors and contributed equally to this work. ZX was responsible for the detailed drafting of the manuscript. SYJ conducted a comprehensive search and initial screening of relevant and valuable literature. YZ and MHS further supplemented and refined the literature selection. QJ and GZJ are corresponding authors who provided critical revisions focusing on key intellectual content, supervised the research process, and finalized the manuscript for submission. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.