Medical Policy

Policy Num:      03.003.001
Policy Name:    Therapeutic Radiopharmaceuticals for Prostate Cancer
Policy ID:          [03.003.001]  [Ac / B / M+ / P+]  [5.01.43]

Last Review:   November 05, 2025
Next Review:   November 20, 2026
 

Related Policies:

06.001.014 - Oncologic Applications of Positron Emission Tomography Scanning
06.001.063 - Therapeutic Radiopharmaceuticals for Neuroendocrine Tumors

Therapeutic Radiopharmaceuticals for Prostate Cancer

Summary

Summary of Evidence

For individuals with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have failed other anticancer therapies, including androgen receptor (AR) pathway inhibition and/or taxane-based chemotherapy, who receive lutetium (Lu) 177 vipivotide tetraxetan (Lu-177-PSMA-617), the evidence includes a systematic review and 2 randomized controlled trials (RCTs). Relevant outcomes are overall survival (OS), disease-specific survival, quality of life (QOL), and treatment-related mortality and morbidity. The systematic review, which included a heterogeneous population of patients with mCRPC, demonstrated a higher proportion of patients responding to PSMA-targeted radionucleotide therapy based on a prostate-specific antigen (PSA) decrease of 50% or more compared to controls; the review was also limited by the inclusion of mostly retrospective studies with small numbers of patients. The VISION RCT compared Lu-177-PSMA-617 plus investigator-determined standard of care (SOC) to SOC alone in patients with PSMA-positive mCRPC who had been treated with AR pathway inhibitors and taxane-based chemotherapy. Results demonstrated that Lu-177-PSMA-617 plus SOC significantly prolonged the median OS (15.3 vs. 11.3 months) and radiographic progression-free survival (rPFS) (8.7 vs. 3.4 months) compared to SOC alone. The incidence of Grade 3 or higher adverse events was greater with Lu-177-PSMA-617 than without (52.7% vs. 38.0%). The phase 2 TheraP trial compared Lu-177-PSMA-617 to cabazitaxel. Unlike the VISION trial, in TheraP, previous treatment with AR pathway inhibitors was not necessary for participation. Also, the TheraP trial used 2 positron-emission tomographic /computed tomography scans to identify PSMA-positive status, and excluded patients with discordant findings using gallium-68-labeled PSMA-11 and 2-fluorine-18[18F]fluoro-2-deoxy-D-glucose. The primary endpoint of PSA response, defined by a reduction of at least 50% from baseline, was achieved more often by patients who received Lu-177-PSMA-617 (66%) compared to cabazitaxel (37%). In this RCT, the incidence of Grade 3 or higher adverse events was greater with cabazitaxel (53%) compared to Lu-177-PSMA-617 (33%). In a subsequent publication of this study with a median follow-up of 35.7 months, the OS did not differ between treatment groups (19.1 vs. 19.6 months). Additional evidence has been published that supports the use of Lu-177-PSMA-617 in patients who are taxane-naive (and without advanced illness warranting consideration of taxane therapy a taxane) and have progressed on AR pathway inhibition. The PSMAfore trial demonstrated that treatment with Lu-177-PSMA-617 prolonged rPFS compared to switching to a different AR pathway inhibitor. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether the use of radiopharmaceuticals in adults with prostate cancer improves the net health outcome.

Policy statements

Therapeutic radiopharmaceuticals for prostate cancer using Lutetium (Lu) 177 vipivotide tetraxetan (Lu-177-PSMA-617), may be considered medically necessary for the treatment of adults with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) and with 1 or more PSMA-positive lesions and/or metastatic disease that is predominately PSMA-positive and with no dominant PSMA-negative metastatic lesions, who have been treated previously with androgen receptor-directed therapy and a taxane-based chemotherapy.

Therapeutic radiopharmaceuticals for prostate cancer using Lu-177-PSMA-617 is considered investigational for the treatment of prostate cancer when the above criteria are not met.

Policy Guidelines

Lutetium Lu 177 vipivotide tetraxetan

Lutetium Lu 177 vipivotide tetraxetan (Lu-177-PSMA-617) is a radiopharmaceutical and should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.

The recommended dose of Lu-177-PSMA-617 (Pluvicto^TM) is 7.4 GBq (200 mCi) every 6 weeks for up to 6 doses.

Recipients should be well-hydrated during treatment.

Refer to the prescribing information for Lu-177-PSMA-617 for recommended dosage modifications for adverse reactions. The management of adverse reactions may require temporary dose interruption (extending the dosing interval from every 6 weeks up to every 10 weeks), dose reduction, or permanent discontinuation of treatment with Lu-177-PSMA-617. The dose of Lu-177-PSMA-617 may be reduced by 20% to 5.9 GBq (160 mCi) once; the dose should not be re-escalated.

Lu-177-PSMA-617 should be discontinued permanently if the recipient develops any of the following:

• Recurrent Grade 3 or higher myelosuppression after 1 dose reduction

• Grade 3 or higher renal toxicity

• Recurrent renal toxicity after 1 dose reduction

• Recurrent Grade 3 dry mouth after 1 dose reduction

• Recurrent Grade 3 or higher gastrointestinal toxicity after 1 dose reduction

• Aspartate aminotransferase or alanine aminotransferase greater than 5 times the upper limit of normal in the absence of liver metastases

• Any unacceptable toxicity

• Any serious adverse reaction that requires treatment delay of greater than 4 weeks

• Any recurrent Grade 3 or 4 or persistent and intolerable Grade 2 adverse reaction after 1 dose reduction

Table PG1 describes the grading of severity used in the Common Toxicity Criteria for Adverse Events (version 4.03).

Table PG1. Common Toxicity Criteria for Adverse Events, Version 4.03

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage. 

Background

Prostate cancer is the second leading cause of cancer-related deaths among American men with 313,780 new cases and 35,770 disease-related deaths estimated for 2025.^1, About 6 in 10 cases of prostate cancer are diagnosed in men who are 65 years of age or older, and the disease is rare in men under 40 years of age. Prostate cancer disproportionally affects African American men and Caribbean men of African ancestry compared to men of other races. The disease is less common in Asian American, Hispanic, and Latino men than in non-Hispanic White men. The reasons for these racial and ethnic differences are not well understood. Typically, prostate cancer is suspected based on increased levels of prostate-specific antigen (PSA) upon screening.

Grading

Clinical staging is based on the digital rectal exam and biopsy results. T1 lesions are not palpable while T2 lesions are palpable but appear to be confined to the prostate. T3 lesions extend through the prostatic capsule, and T4 lesions are fixed to or invade adjacent structures. The most widely used grading scheme for a prostate biopsy is the Gleason system.^2, It is an architectural grading system ranging from 1 (well-differentiated) to 5 (poorly differentiated); the score is the sum of the primary and secondary patterns. A Gleason score of 6 or less is low-grade prostate cancer that usually grows slowly; 7 is an intermediate grade; 8 to 10 is a high-grade cancer that grows more quickly. A revised prostate cancer grading system has been adopted by the National Cancer Institute and the World Health Organization.^3, A cross-walk of these grading systems is shown in Table 1.

Table 1. Prostate Cancer Grading Systems

Treatment

Early localized disease can usually be treated with surgery and radiotherapy, although active surveillance may be adopted in men whose prostate cancer is unlikely to cause major health problems during their lifespan or for whom the treatment might be dangerous.^1, In patients with inoperable or metastatic disease, treatment consists of hormonal therapy and possibly chemotherapy. Androgen deprivation therapy (ADT) is generally the initial treatment for patients with advanced prostate cancer. Unfortunately, while ADT is effective at producing tumor response and improving quality of life, most patients' disease will eventually progress on ADT.

Castration-Resistant Prostate Cancer

Prostate cancer that progresses while the patient is on ADT is referred to as castration-resistant prostate cancer (CRPC).^1, Androgen pathways are important in the progression of CRPC, therefore, even after progression, continued ADT is generally used in conjunction with other treatments. Several drugs have been developed that either inhibit enzymes involved in androgen production or inhibit the androgen receptor, such as abiraterone and enzalutamide. Taxane chemotherapy with docetaxel or cabazitaxel may also be used after progression. Immunotherapy (sipuleucel-T) or radium 223 are additional options for select men.

Prostate-Specific Membrane Antigen–Positive Metastatic Castration-Resistant Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a transmembrane glutamate carboxypeptidase that is highly expressed on prostate cancer cells and high PSMA expression is an independent biomarker of poor prognosis.^4, Metastatic lesions are PSMA-positive in most patients with metastatic CRPC (mCRPC) and high expression has been independently associated with reduced survival. More recently, radioligand therapies such as lutetium Lu 177 vipivotide tetraxetan (Lu-177-PSMA-617) have demonstrated the ability to selectively target prostate cancer cells in patients who have PSMA-positive mCRPC.

Radionuclide Therapy: Lutetium Lu 177 vipivotide tetraxetan

Lu-177-PSMA-617 is a radioligand therapeutic agent with 2 components: a drug that delivers the therapy to cancer cells and a radioactive particle.^5, In the case of Lu-177-PSMA-617, the delivery vehicle is PSMA-617 and the radioactive component is lutetium-177. Upon binding of Lu-177-PSMA-617 to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing cells, as well as to surrounding cells, and induces DNA damage which can lead to cell death. Patients should be selected for treatment with Lu-177-PSMA-617 using gallium Ga 68 gozetotide or an approved PSMA-11 imaging agent based on PSMA expression in tumors.

Regulatory Status

On March 23, 2022, Lu-177-PSMA-617 (Pluvicto^TM) was approved by the U.S. Food and Drug Administration (FDA) for use in adults with PSMA-positive mCRPC who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy. In March 2025, this indication was updated to also include individuals with PSMA-positive mCRPC who have been treated with AR pathway inhibition and are considered appropriate to delay taxane-based chemotherapy.^6,

On March 23, 2022, gallium Ga 68 gozetotide (Locametz^®) was approved by the U.S. FDA as a radioactive diagnostic agent indicated for positron emission tomography (PET) of PSMA-positive lesions in men with prostate cancer: 1) with suspected metastasis who are candidates for initial definitive therapy; or 2) with suspected recurrence based on elevated serum PSA level; or 3) for selection of patients with metastatic prostate cancer, for whom PSMA-directed therapy is indicated.^7,

On May 26, 2022, piflufolastat F 18 (Pylarify^®) was approved by the U.S. FDA as a radioactive diagnostic agent indicated for PET of PSMA-positive lesions in men with prostate cancer with: 1) suspected metastasis who are candidates for initial definitive therapy or 2) suspected recurrence based on elevated serum PSA level.^8,

On December 17, 2021, gallium Ga 68 gozetotide (Illuccix^®) was approved by the U.S. FDA as a radioactive diagnostic agent indicated for PET of PSMA-positive lesions in men with prostate cancer with: 1) suspected metastasis who are candidates for initial definitive therapy or 2) suspected recurrence based on elevated serum PSA level.^9, The labeling was updated in March 2023 to include selection of patients with metastatic prostate cancer for whom treatment with Lu-177-PSMA-617 is indicated.

Rationale

This evidence review was created in August 2022 with a search of the PubMed database. The most recent literature update was performed through August 27, 2025.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Population Reference No. 1

Prostate-specific membrane antigen­–positive metastatic castration-resistant prostate cancer

Clinical Context and Therapy Purpose

The purpose of lutetium Lu 177 vipivotide tetraxetan (Lu-177-PSMA-617) in individuals with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with PSMA-positive mCRPC who have failed other anticancer therapies, including androgen receptor (AR) pathway inhibition and taxane-based chemotherapy.

Interventions

The therapy being considered is Lu-177-PSMA-617.

Comparators

The following therapies are currently being used to make decisions about PSMA-positive mCRPC: androgen-deprivation therapy (ADT) with or without: abiraterone, apalutamide, chemotherapy, enzalutamide, external beam radiation; surgery; observation.

Outcomes

The general outcomes of interest are overall survival (OS), disease-specific survival, quality of life (QOL), and treatment-related mortality and morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Table 2 summarizes the characteristics of a systematic review evaluating the efficacy of Lu-177-PSMA-617 in patients with mCRPC.

Sadaghiani et al (2022) published a systematic review with meta-analysis that included a total of 69 mostly retrospective studies and a total of 4157 participants; a crosswalk of the 56 studies that specifically evaluated Lu-177-PSMA-617 is found in Table A1 in the Appendix.^10, There were 3 RCTs among the included studies. The first trial, VISION^4,, evaluated Lu-177-PSMA-617 in a population of patients with PSMA-positive mCRPC who failed other anticancer therapies (including AR pathway inhibition and taxane-based chemotherapy) and were not suitable for additional chemotherapy. Details of the VISION trial are summarized in the section below. The second RCT, TheraP (also summarized below), evaluated Lu-177-PSMA-617 as an alternative to cabazitaxel in patients with mCRPC, regardless of prior use of AR pathway inhibitors.^11, The third RCT (RESIST-PC) compared 2 dosing strategies of Lu-177-PSMA-617 in patients with mCRPC; safety outcomes from this trial are summarized in the following section.^12,

Belabaci et al (2025) published a systematic review with meta-analysis that included 6 RCTs (N=2113) of participants with mCRPC to assess the safety and efficacy of Lu-177-PSMA-617.^13, Table A1 in the Appendix provides a crosswalk of the included RCTs. VISION and TheraP were both included, along with the ENZA-p trial,^14,15, an open-label RCT phase 2 trial conducted in Australia in patients with mCRPC that investigated enzalutamide plus Lu-177-PSMA-617 versus enzalutamide alone as first-line therapy, Satapathy et al (2022 and 2023),^16,17, a phase 2, open-label RCT non-inferiority trial comparing Lu-177-PSMA-617 to docetaxel in chemotherapy-naive mCRPC patiients, PSMAfore trial,^18, a phase 3 RCT comparing Lu-177-PSMA-617 to AR pathway inhibition in taxane-naive patients with mCRPC who had progressed on a previous AR pathway inhibition agent, and the SPLASH trial, a RCT in patients with mCRPC who had progressed while on AR pathway inhibition (not yet published). Details on the PSMAfore trial is summarized in the following sections.

Table 2. SR & MA Characteristics

Table 3 summarizes the results of the systematic review evaluating the efficacy of Lu-177-PSMA-617 in patients with mCRPC.

Sadaghiani et al (2022) demonstrated that PSMA-targeted radionucleotide therapy in mCRPC results in a higher proportion of patients responding to therapy based on a prostate-specific antigen (PSA) decrease of 50% or more compared to controls.^10, Furthermore, any PSA decrease demonstrated a statistically significant prolongation of survival. Analyses were limited by the inclusion of mostly retrospective studies with small numbers of patients, and heterogeneity with regard to dosing, number of cycles, prior therapies, and extent of the disease. Importantly, the authors did not identify the number of studies that specifically included patients with PSMA-positive mCRPC who failed other anticancer therapies, including AR pathway inhibition and taxane-based chemotherapy, nor were there subgroup analyses done for this relevant population.

In Belabaci et al (2025), patients treated with Lu-177-PSMA-617 had a significantly higher PSA response (defined as ≥50% PSA decrease) compared to controls.^13, Additionally, Lu=177-PSMA-617 also reduced the relative risk of radiographic progression-free survival (rPFS) by 43%, although no significant impact on OS was observed. There were no differences in Grade ≥3 adverse events between groups. The authors did not differentiate between patients who had previously failed other anticancer therapies, and there were no subgroup analyses conducted for these patients.

Table 3. SR & MA Results

Randomized Controlled Trials

Characteristics of RCTs evaluating Lu-177-PSMA-617 in patients with PSMA-positive mCRPC are summarized in Table 4.

The multinational, randomized, open-label, VISION trial (N=831) compared the efficacy and safety of Lu-177-PSMA-617 plus investigator-chosen standard of care (SOC) versus SOC alone.^4, The SOC treatments could not include chemotherapy or radium-233 (a radioisotope specifically used to treat bone metastases). PSMA-positive status was determined with the use of gallium-68-labeled PSMA-11 positron-emission tomographic (PET)-computed tomography (CT) imaging at baseline. Radiographic progression-free survival (PFS ) and OS were alternate primary outcomes, which meant that the trial would be deemed to be positive if the results with respect to either or both of these primary outcomes were significant at the allocated significance level of p=.025 for OS and p=.004 for rPFS. Of note, rPFS was added as an alternate primary endpoint in January 2019 (ie, after the trial had started) on the basis of discussions with the Food and Drug Administration (FDA). The analysis of OS was based on all randomized patients, while the analysis of rPFS was based on patients randomized on or after March 5th, 2019. The median follow-up was 20.9 months.

In a subsequent publication of the VISION trial, after a median follow-up of 7.8 months (interquartile range [IQR] 4.4 to 10.6), the incidence of any-grade treatment-emergent adverse events among patients receiving Lu-177-PSMA-617 was similar between cycles 1 to 4 (98%) and cycles 5 to 6 (99%).^19, The incidence of serious treatment-emergent adverse events was 42% during cycles 1 to 4, compared to 32% during cycles 5 and 6. No additional safety concerns were reported for patients who received more than 4 cycles of Lu-177-PSMA-617.

The phase 2 TheraP trial compared Lu-177-PSMA-617 (n=99) to cabazitaxel (n=101).^11, Unlike the VISION trial, in TheraP, previous treatment with AR pathway inhibitors was not necessary for participants, and 9.9% of those randomized to the cabazitaxel group and 8.1% of those randomized to Lu-177-PSMA-617 were not previously treated with these therapies. Also, the TheraP trial used 2 PET/CT scans to identify PSMA-positive status and excluded patients with discordant findings using gallium-68-labeled PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG). The primary endpoint of PSA response, defined by a reduction of at least 50% from baseline, was achieved more often by patients who received Lu-177-PSMA-617 (66%) versus cabazitaxel (37%), resulting in a between-group difference of 29% (95% confidence interval [CI], 16 to 42; p<.0001). Lu-177-PSMA-617 also delayed rPFS and PSA PFS (defined as the interval from randomization to first evidence of PSA progression; defined by an increase of ≥ 25% and ≥ 2 ng/mL after 12 weeks).

In a subsequent publication of the TheraP trial, after a median follow-up of 35.7 months (IQR , 31.1 to 39.2), 77 (78%) participants in the Lu-177-PSMA-617 group and 70 (69%) in the cabazitaxel group had died.^20, The OS was similar between groups (restricted mean survival time [RMST] 19.1 vs. 19.6 months; difference, -0.5 months; 95% CI, -3.7 to 2.7; p=.77). No new safety signals were identified.

Table 4. Summary of Key RCT Characteristics

The results of these trials are summarized in Table 5. Importantly, for the outcome of rPFS, similar results were found in an ad hoc analysis that included all the patients who had undergone randomization.

Table 5. Summary of Key RCT Results

The purpose of the study limitations tables (Tables 6 and 7) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 6. Study Relevance Limitations

Table 7. Study Design and Conduct Limitations

As previously noted, the RESIST-PC trial compared 2 Lu-177-PSMA-617 dosing regimens (6.0 GBq and 7.4 GBq) in patients with progressive mCRPC who previously received therapy with at least 1 AR pathway inhibitor and were either chemotherapy naïve or postchemotherapy.^12, The study took place at a single site in the US and included 51 patients. After a median follow-up of 24.8 months, improvement in bone pain occurred in 12 of 18 patients (67%) in the overall cohort, 6 of 7 patients (86%) in the 6.0 GBq dosing group, and 6 of 11 patients (55%) in the 7.4 GBq dosing group (p=.31). Pain PFS was 8.2 months (95% CI, 3.9 to 12.5), 5.4 months (95% CI, not reached), and 8.2 months (95% CI, 2.3 to 14.1) in the overall study population, 6.0 GBq dosing group, and 7.4 GBq dosing group, respectively (p=.94).

Taxane-Naive Patients

The indication for Lu-177-PSMA-617 was expanded in 2025 to include individuals with PSMA-positive mCRPC who have been treated with AR pathway inhibition and are considered appropriate to delay taxane-based chemotherapy.^5, Trials focused on that patient population are described below, with a summary of RCT characteristics in Table 8.

Randomized Controlled Trials

The PSMAfore trial,^18, a phase 3 RCT comparing Lu-177-PSMA-617 to AR pathway inhibition in taxane-naive patients with mCRPC who had progressed on a previous AR pathway inhibition agent, had primary and updated results published by Morris et al (2024). This open-label trial randomized patients 1:1 to Lu-177-PSMA-617 or a different AR pathway inhibitor. Crossover from the AR pathway inhibitor group to Lu-177-PSMA-617 was allowed after radiographic progression. Of the patients initially assigned to AR pathway inhibitor change, 134 (57%) eventually crossed over to receive Lu-177-PSMA-617. The primary endpoint was rPFS. The primary analysis was defined as the median time from randomization to first data cutoff of 7.26 months (IQR, 3.38 to 10.55). The updated analysis was defined as the median time from randomization to third data cutoff at 24.11 months (IQR, 20.24 to 27.40). In both the primary and updated analysis, treatment with Lu-177-PSMA-617 prolonged rPFS compared to change in AR pathway inhibitor. There was no significant difference in OS between groups at the updated analysis and grade ≥3 adverse events were similar between groups. The results of this trial are summarized in Table 9.

The final overall survival analysis of the PSMAfore trial was published by Fizazi et al (2025).^21, The median OS was 24.48 months with Lu-177-PSMA-617 versus 23.13 months with AR pathway inhibitor change (hazard ratio [HR], 0.91; 95% CI, 0.72 to 1.14; p=.20). Notably, results were likely confounded due to high rate of crossover. Dry mouth and anemia were more common with Lu-177-PSMA-617 than with change in AR pathway inhibitor and no new safety signals were identified.

Table 8. Summary of Key RCT Characteristics in Taxane-Naive Patients

Table 9. Summary of Key RCT Results in Taxane-Naive Patients

The purpose of the study limitations tables (Tables 10 and 11) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 10. Study Relevance Limitations

Table 11. Study Design and Conduct Limitations

Section Summary: Prostate-Specific Membrane Antigen­–Positive Metastatic Castration-Resistant Prostate Cancer

For individuals with PSMA-positive mCRPC who have failed other anticancer therapies, including AR pathway inhibition and taxane-based chemotherapy, who receive Lu-177-PSMA-617, the evidence includes a systematic review and 2 RCTs. The systematic review, which included a heterogeneous population of patients with mCRPC, demonstrated a higher proportion of patients responding to PSMA-targeted radionucleotide therapy based on a PSA decrease of ≥50% compared to controls; the review was also limited by the inclusion of mostly retrospective studies with small numbers of patients. The VISION RCT compared Lu-177-PSMA-617 plus investigator-determined SOC to SOC alone in patients with PSMA-positive mCRPC who had been treated with AR pathway inhibitors and taxane-based chemotherapy. Results demonstrated that Lu-177-PSMA-617 plus SOC significantly prolonged the median OS (15.3 vs. 11.3 months) and rPFS (8.7 vs. 3.4 months) compared to SOC alone. The incidence of Grade 3 or higher adverse events was greater with Lu-177-PSMA-617 than without (52.7% vs. 38.0%). The phase 2 TheraP trial compared Lu-177-PSMA-617 to cabazitaxel. Unlike the VISION trial, in TheraP, previous treatment with AR pathway inhibitors was not necessary for participants. Also, the TheraP trial used 2 PET/CT scans to identify PSMA-positive status and excluded patients with discordant findings using gallium-68-labeled PSMA-11 and FDG. The primary endpoint of PSA response, defined by a reduction of at least 50% from baseline, was achieved more often by patients who received Lu-177-PSMA-617 (66%) compared to cabazitaxel (37%). In this RCT, the incidence of Grade 3 or higher adverse events was greater with cabazitaxel (53%) compared to Lu-177-PSMA-617 (33%). In a subsequent publication of this trial with a median follow-up of 35.7 months, the OS did not differ between treatment groups (19.1 vs. 19.6 months). Additional evidence has been published that supports the use of Lu-177-PSMA-617 in patients who are taxane-naive (and not yet with advanced enough illness to require a taxane) and have progressed on AR pathway inhibition. The PSMAfore trial demonstrated that treatment with Lu-177-PSMA-617 prolonged rPFS compared to switching to a different AR pathway inhibitor.

For individuals with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have failed other anticancer therapies, including androgen receptor pathway inhibition and/or taxane-based chemotherapy, who receive lutetium (Lu) 177 vipivotide tetraxetan (Lu-177-PSMA-617), the evidence includes a systematic review and 2 randomized controlled trials (RCTs). Relevant outcomes are overall survival (OS), disease-specific survival, quality of life (QOL), and treatment-related mortality and morbidity. The systematic review, which included a heterogeneous population of patients with mCRPC, demonstrated a higher proportion of patients responding to PSMA-targeted radionucleotide therapy based on a prostate-specific antigen (PSA) decrease of 50% or more compared to controls; the review was also limited by the inclusion of mostly retrospective studies with small numbers of patients. The VISION RCT compared Lu-177-PSMA-617 plus investigator-determined standard of care (SOC) to SOC alone in patients with PSMA-positive mCRPC who had been treated with androgen receptor (AR) pathway inhibitors and taxane-based chemotherapy. Results demonstrated that Lu-177-PSMA-617 plus SOC significantly prolonged the median OS (15.3 vs. 11.3 months) and radiographic progression-free survival (rPFS) (8.7 vs. 3.4 months) compared to SOC alone. The incidence of Grade 3 or higher adverse events was greater with Lu-177-PSMA-617 than without (52.7% vs. 38.0%). The phase 2 TheraP trial compared Lu-177-PSMA-617 to cabazitaxel. Unlike the VISION trial, in TheraP, previous treatment with AR pathway inhibitors was not necessary for participation. Also, the TheraP trial used 2 positron-emission tomographic (PET)/computed tomography (CT) scans to identify PSMA-positive status, and excluded patients with discordant findings using gallium-68-labeled PSMA-11 and 2-fluorine-18[18F]fluoro-2-deoxy-D-glucose (FDG). The primary endpoint of PSA response, defined by a reduction of at least 50% from baseline, was achieved more often by patients who received Lu-177-PSMA-617 (66%) compared to cabazitaxel (37%). In this RCT, the incidence of Grade 3 or higher adverse events was greater with cabazitaxel (53%) compared to Lu-177-PSMA-617 (33%). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Clinical Oncology

The American Society of Clinical Oncology (ASCO) guideline on systemic therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) was updated in May 2025.^22, Relevant recommendations regarding lutetium Lu 177 vipivotide tetraxetan (Lu-177-PSMA-617) are below:

"For patients previously treated with ADT [androgen-deprivation therapy], ARPI [androgen receptor pathway inhibition], and docetaxel, and have progressive mCRPC, the Panel recommends Lu-177-PSMA-617 for PSMA [prostate-specific membrane antigen]-positive disease or chemotherapy using cabazitaxel (evidence quality: moderate; strength of recommendation: strong)."

The Panel also states that "currently, the role of PSMA PET [positron emission tomography]-CT [computed tomography] is limited to identify PSMA-expressing tumors for patients who will benefit with Lu-177-PSMA-617. In selected patients, PSMA PET can be used to stage patients with a rising PSA [prostate-specific antigen] and concern for progression not visualized on conventional imaging. Prospective data on using PSMA PET scans for response assessment are still emerging, and at this time, the Panel does not recommend their routine use."

In 2023, ASCO published a rapid recommendation update related to Lu-177-PSMA-617 based on the Food and Drug Administration (FDA) approval of F-18 flotufolastat.^23, Their updated recommendation stated:

"The panel recommends that either Ga-68 PSMA-11, F-18 piflufolastat, or F-18 flotufolastat be used as radiotracers to determine eligibility currently (type: informal consensus, benefits outweigh harms; evidence quality: low; strength of recommendation: weak)."

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) guideline for prostate cancer (v2.2025) provides the following relevant recommendations with regard to the use of Lu-177-PSMA-617 :^24,

"The NCCN Panel recommends Lu-177-PSMA-617 as a category 1, useful in certain circumstances treatment option for patients with ≥1 PSMA -positive lesion and/or metastatic disease that is predominately PSMA-positive and with no dominant PSMA-negative metastatic lesions who have been treated previously with androgen receptor-directed therapy and a taxane-based chemotherapy. PSMA-negative lesions are defined as metastatic disease that lacks PSMA uptake including bone with soft tissue components ≥1.0 cm, lymph nodes ≥2.5 cm in short axis, and solid organ metastases ≥1.0 cm in size. Although the FDA has approved Ga-68 PSMA-11 for use with Lu-177-PSMA-617, the panel believes that F-18 piflufolastat PSMA and F-18 flotufolastat PSMA can also be used in the same space due to multiple reports describing the equivalency of these imaging agents."

U.S. Preventive Services Task Force Recommendations

Not available.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 12.

Table 12. Summary of Key Trials

References

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11. Hofman MS, Emmett L, Sandhu S, et al. [ 177 Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. Feb 27 2021; 397(10276): 797-804. PMID 33581798
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14. Emmett L, Subramaniam S, Crumbaker M, et al. Overall survival and quality of life with [ 177 Lu]Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (ENZA-p): secondary outcomes from a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. Mar 2025; 26(3): 291-299. PMID 39956124
15. Emmett L, Subramaniam S, Crumbaker M, et al. [ 177 Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. May 2024; 25(5): 563-571. PMID 38621400
16. Satapathy S, Mittal BR, Sood A, et al. 177 Lu-PSMA-617 versus docetaxel in chemotherapy-naïve metastatic castration-resistant prostate cancer: a randomized, controlled, phase 2 non-inferiority trial. Eur J Nucl Med Mol Imaging. Apr 2022; 49(5): 1754-1764. PMID 34842950
17. Satapathy S, Mittal BR, Sood A, et al. [ 177 Lu]Lu-PSMA-617 Versus Docetaxel in Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: Final Survival Analysis of a Phase 2 Randomized, Controlled Trial. J Nucl Med. Nov 2023; 64(11): 1726-1729. PMID 37709534
18. Morris MJ, Castellano D, Herrmann K, et al. 177 Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. Sep 28 2024; 404(10459): 1227-1239. PMID 39293462
19. Chi KN, Armstrong AJ, Krause BJ, et al. Safety Analyses of the Phase 3 VISION Trial of [ 177 Lu]Lu-PSMA-617 in Patients with Metastatic Castration-resistant Prostate Cancer. Eur Urol. Apr 2024; 85(4): 382-391. PMID 38185538
20. Hofman MS, Emmett L, Sandhu S, et al. Overall survival with [ 177 Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial. Lancet Oncol. Jan 2024; 25(1): 99-107. PMID 38043558
21. Fizazi K, Chi KN, Shore ND, et al. Final overall survival and safety analyses of the phase III PSMAfore trial of [ 177 Lu]Lu-PSMA-617 versus change of androgen receptor pathway inhibitor in taxane-naive patients with metastatic castration-resistant prostate cancer. Ann Oncol. Jul 17 2025. PMID 40680993
22. Garje R, Riaz IB, Naqvi SAA, et al. Systemic Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Update. J Clin Oncol. Jul 10 2025; 43(20): 2311-2334. PMID 40315400
23. Garje R, Rumble RB, Parikh RA. Systemic Therapy Update on 177 Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. Nov 2024; 42(31): 3751-3752. PMID 37931186
24. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Prostate Cancer (version 2.2025).https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf NCCN. Accessed August 27, 2025.

Codes

Policy History