Description
Radiopharmaceuticals are composed of a radioisotope (i.e., a radioactive particle) bond to an organic molecule and are used for diagnostic and therapeutic purposes. The organic molecule acts as a targeting compound (ligand) that conveys the radioisotope to specific organs, tissues, or cells. Lutetium Lu 177 vipivotide tetraxetan (Pluvicto^TM), commonly abbreviated as Lu-177-PSMA-617, is a radioligand therapy that targets prostate-specific membrane antigen (PSMA), which is highly expressed on prostate cancer cells. Lu-177-PSMA-617 is indicated for use in adults with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have already been treated with other anticancer treatments, including androgen receptor (AR) pathway inhibition and taxane-based chemotherapy. Gallium Ga 68 gozetotide (Locametz^®) is a corresponding radioactive diagnostic agent for positron emission tomography (PET) of PSMA-positive lesions, including for the selection of patients with mCRPC for whom Lu-177-PSMA-617 therapy is indicated.

Background
Prostate cancer is the second leading cause of cancer-related deaths among American men with 268,490 new cases and 34,500 disease-related deaths estimated for 2022.¹ About 6 in 10 cases of prostate cancer are diagnosed in men who are ≥ 65 years of age, and the disease is rare in men < 40 years of age. Furthermore, prostate cancer disproportionally affects non-Hispanic Black men versus white men. Prostate cancer is typically suspected due to 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 are shown in Table 1.

Table 1. Prostate Cancer Grading Systems

Grade Group	Gleason Score (Primary and Secondary Pattern)	Cells
1	6 or less	Well-differentiated (low grade)
2	7 (3 + 4)	Moderately differentiated (moderate grade)
3	7 (4 + 3)	Poorly differentiated (high grade)
4	8	Undifferentiated (high grade)
5	9 – 10	Undifferentiated (high grade)

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 (PluvictoTM) 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.⁵

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 lutetium Lu 177 vipivotide tetraxetan PSMA-directed therapy is indicated.⁶

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.⁷

On Dec. 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.⁸

Policy
Therapeutic Radiopharmaceuticals for Prostate Cancer using Lu-177-PSMA-617, may be considered MEDICALLY NECESSARY for the treatment of adults with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) in 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.

Therapeutic Radiopharmaceuticals for Prostate Cancer using Lu-177-PSMA-617 is investigational/unproven therefore considered NOT MEDICALLY NECESSARY 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 (PluvictoTM) is 7.4 GBq (200 mCi) every 6 weeks for up to 6 doses.

Patients 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 patient develops any of the following:

• Recurrent Grade ≥ 3 myelosuppression after one dose reduction
• Grade ≥ 3 renal toxicity
• Recurrent renal toxicity after one dose reduction
• Recurrent Grade 3 dry mouth after one dose reduction
• Recurrent Grade ≥ 3 gastrointestinal toxicity after one dose reduction
• Aspartate aminotransferase or alanine aminotransferase > 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 > 4 weeks
• Any recurrent Grade 3 or 4 or persistent and intolerable Grade 2 adverse reaction after one 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

Grade	Description
1	Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
2	Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living and refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
3	Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living and refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
4	Life-threatening consequences; urgent intervention indicated.
5	Death related to adverse event.

Coding
See the Codes table for details.

Benefit Application
BlueCard^®/National Account Issues
State or federal mandates (e.g., 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.

Rationale
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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., people of color [African American, Asian, Black, Latino and Native American]; LGBTQIA [lesbian, gay, bisexual, transgender, queer, intersex, asexual]; women; and people with disabilities [physical and invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations..

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.⁹ There were 3 RCTs among the included studies. The first trial, VISION4,, 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.¹⁰ 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.¹¹

Table 2. SR and MA Characteristics

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Sadaghiani et al. (2022)9	Through June 2020	69	Participants with mCRPC treated with Lu-177-PSMA-617, Lu-177-PSMA-I&T*, or Lu-177-EB-PSMA-617*	4157 (5 to 393)	3 RCTs; 13 non-randomized prospective; 56 retrospective	NR

Lu-177-PSMA-617: lutetium Lu 177 vipivotide tetraxetan; MA: meta-analysis; mCRPC: metastatic castration-resistant prostate cancer; NR: not reported; RCT: randomized controlled trial; SR: systematic review.
*Product is not available in the U.S.
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 PSA decrease of 50% or more compared to controls.9, 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.

Table 3. SR and MA Results

Study	PSA decreasea ≥50%	OS according to pooled HRs for any PSA declineb	OS according to pooled HRs for ≥50% PSA declinec
Sadaghiani et al. (2022)9
Total N	483	353	590
Pooled effect (95% CI)	OR, 5.33 (1.24 to 22.90)	HR, 0.26 (0.18 to 0.37)	HR, 0.52 (0.40 to 1.28)
I2 (p)	92% (.0005)	21% (< .27)	0% (< .001)

CI: confidence interval; HR: hazard ratio; MA: meta-analysis; mCRPC: metastatic castration-resistant prostate cancer; NR: not reported; OR: odds ratio; OS: overall survival; PSA: prostate-specific antigen; RCT: randomized controlled trial; SR: systematic review. 
^aOutcomes pooled data from the VISION and TheraP RCTs.
^bOutcomes pooled data from 6 observational studies.
^cOutcomes pooled data from 10 observational studies. 

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 (rPFS) 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.

The phase 2 TheraP trial compared Lu-177-PSMA-617 (n = 99) to cabazitaxel (n = 101).¹⁰ 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).

Table 4. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Sartor (2021); VISION4	North America and EU	84 (52 in North America and 32 in EU)	June 2018 to October 2019	PSMA-positive mCRPC (≥ 1 metastatic lesion) previously treated with ≥1 AR pathway inhibitor and ≤2 taxane regimens (mean age, 71 years; ≥ 88% White men)	n = 551; Lu-177-PSMA-617 (7.4 GBq) administered by IV infusion every 6 weeks for a max of 6 cycles) plus investigator-chosen SOC	n = 280; investigator-chosen SOC
Hofman (2021); TheraP10	Australia	11	February 2018 to September 2019	PSMA-positive mCRPC previously treated with docetaxel and progressive disease defined by a rising PSA as per Prostate Cancer Working Group 3 criteria	n = 99; Lu-177-PSMA-617 administered by IV infusion every 6 weeks for a max of 6 cycles); starting dose was 8.5 GBq, and was decreased by 0.5 GBq/cycle	n = 101; cabazitaxel 20 mg/m2 IV, every 3 weeks for a max of 10 cycles

AR: androgen receptor; EU: European Union; IV: intravenous; mCRPC: metastatic castration-resistant prostate cancer; Lu-177-PSMA-617: lutetium Lu 177 vipivotide tetraxetan; PSA: prostate-specific antigen; PSMA: prostate-specific membrane antigen; RCT: randomized controlled trial; SOC: standard of care.

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

Study	OS (months)	rPFSa (months)	PSA PFSb	PSA responsec , %	Grade ≥3 adverse event, %
Sartor (2021); VISION4	Lu-177-PSMA-617 plus SOC (n = 551); SOC (n = 280)	Lu-177-PSMA-617 plus SOC (n = 385); SOC (n = 196)			Lu-177-PSMA-617 plus SOC (n = 529); SOC (n = 205)
Lu-177-PSMA-617 plus SOC	15.3	8.7			52.7
SOC	11.3	3.4			38.0
HR (CI); p-value	0.62 (95% CI, 0.52 to 0.74); < .001	0.40 (99.2% CI, 0.29 to 0.57); <.001			NR
Hofman (2021); TheraP10	Lu-177-PSMA-617 (n = 99); cabazitaxel (n = 101)
Lu-177-PSMA-617				66	33
Cabazitaxel				37	53
Treatment difference (CI); p-value		HR, 0.64 (0.46 to 0.88); = .007	HR, 0.60 (0.44 to 0.83); = .0017	Difference, 29 (16 to 42); <.0001	NR

CI: confidence interval; HR: hazard ratio; Lu-177-PSMA-617: lutetium Lu 177 vipivotide tetraxetan; NR: not reported; OS: overall survival; PFS: progression-free survival; PSA: prostate-specific antigen; rPFS: radiographic progression-free survival; RCT: randomized controlled trial; SOC: standard of care.
^aOnly includes data from patients randomized on or after March 5th, 2019, when rPFS was upgraded to an alternate primary outcome.
^bPSA PFS was 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.
^cPSA response was defined by a reduction of ≥50% from baseline.

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

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-upe
Sartor (2021); VISION4	4. Majority (≥88%) White men	1. Non-standardized protocol for SOC therapies; SOC treatments could not include chemotherapy or radium-233 5. PSMA-positive status was determined using gallium Ga 68 gozetotide exclusively	1. Non-standardized protocol for SOC therapies; SOC treatments could not include chemotherapy or radium-233	7. rPFS was upgraded to an alternate primary outcome after the trial was already underway
Hofman (2021); TheraP10	3. Not all enrolled patients (9.9% in cabazitaxel group and 8.1% in Lu-177-PSMA-617 group) were not previously treated with AR pathway inhibitors	5. PSMA-positive status was determined using both gallium Ga 68 gozetotide and FDG		1. Primary outcome focused on PSA response

AR: androgen receptor; FDG: 2-fluorine-18[18F]fluoro-2-deoxy-D-glucose; Lu-177-PSMA-617: lutetium Lu 177 vipivotide tetraxetan; PSA: prostate specific antigen; PSMA: prostate-specific membrane antigen; rPFS: radiographic progression-free survival; SOC: standard of care.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. 
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4. Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 7. Study Design and Conduct Limitations

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Sartor (2021); VISION4		1, 2. Open-label		7. Adverse events were measured only up to 30 days after the last dose of treatment
Hofman (2021); TheraP10		1, 2. Open-label

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

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.¹¹ 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).y (p = .94).

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%).

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 U.S. professional society, an international society with U.S. 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.

National Comprehensive Cancer Network
The National Comprehensive Cancer Network guideline for prostate cancer (v1.2023 ) provides the following relevant recommendations with regard to the use of lutetium Lu 177 vipivotide tetraxetan (Lu-177-PSMA-617):¹²

"The NCCN Panel recommends Lu-177-PSMA-617 as a category 1, useful in certain circumstances treatment option for patients with ≥ 1 PSMA [prostate-specific membrane antigen]-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. The NCCN Panel believes that both Ga-68 PSMA-11 or F-18 piflufolastat PSMA imaging can be used to determine eligibility."

U.S. Preventive Services Task Force Recommendations
Not available

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 8.

Table 8. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT04720157a	An International Prospective Open-label, Randomized, Phase III Study Comparing 177Lu-PSMA-617 in Combination with SoC, Versus SoC Alone, in Adult Male Patients with mHSPC (PSMAddition)	1126	Feb 2026
NCT04689828a	177Lu-PSMA-617 vs. Androgen Receptor-directed Therapy in the Treatment of Progressive Metastatic Castrate Resistant Prostate Cancer (PSMAfore)	450	Jan 2025
NCT04663997	A Randomized Phase II Study of 177 LuPSMA-617 vs Docetaxel in Patients With Metastatic Castration-Resistant Prostate Cancer and PSMA-Positive Disease	200	Jul 2025
NCT05150236	Phase II Study of Radionuclide 177Lu-PSMA Therapy Versus 177Lu-PSMA in Combination With Ipilimumab and Nivolumab for Men With Metastatic Castration Resistant Prostate Cancer (mCRPC)	110	Dec 2024

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

References

1. Prostate Cancer. American Cancer Society. Accessed June 27, 2023. https://www.cancer.org/cancer/prostate-cancer.html
2. Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep. Mar 1966; 50(3): 125-8. PMID 5948714
3. SEER Database. Accessed June 27, 2023. https://seer.cancer.gov/seerinquiry/index.php?page = view&id = 20170036&type = q
4. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. Sep 16 2021; 385(12): 1091-1103. PMID 34161051
5. Pluvicto [package insert]. Advanced Accelerator Applications USA, Inc; 2022.
6. Locametz [package insert]. Advanced Accelerator Applications USA, Inc; 2023.
7. Pylarify [package insert]. Progenics Pharmaceuticals, Inc.; 2021.
8. Illuccix [package insert]. Telix Pharmaceuticals US, Inc.; 2023.
9. Sadaghiani MS, Sheikhbahaei S, Werner RA, et al. 177 Lu-PSMA radioligand therapy effectiveness in metastatic castration-resistant prostate cancer: An updated systematic review and meta-analysis. Prostate. May 2022; 82(7): 826-835. PMID 35286735
10. 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
11. Calais J, Gafita A, Eiber M, et al. Prospective phase 2 trial of PSMA-targeted molecular RadiothErapy with 177 Lu-PSMA-617 for metastatic castration-reSISTant Prostate Cancer (RESIST-PC): efficacy results of the UCLA cohort. J Nucl Med. Oct 2021; 62(10): 1440-1446. PMID 34016732
12. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Prostate Cancer (version 1.2023).https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf NCCN. Accessed June 27, 2023.

Coding Section

Codes	Number	Description
CPT	N/A
HCPCS	A9607	Lutetium lu 177 vipivotide tetraxetan, therapeutic, 1 millicurie (eff 10/01/2022)
ICD10 CM	C61	Malignant neoplasm of prostate
	C79.82	Secondary malignant neoplasm of genital organs
	D07.5	Carcinoma in situ of prostate
ICD10 PCS		ICD10 PCS codes are for inpatient procedures only
Type of Service	Radiological
Place of Service	Outpatient/Inpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2024 Forward     

10/09/2024	Annual review, no change to policy intent. Updating rationale and references.
01/01/2024	New Policy