Medical Policy
Policy Num: M3.001.001
Policy Name: Therapeutic Radiopharmaceuticals for Prostate Cancer
Policy ID: [M3.001.001] [Ac / MA / M+ / P+] [5.01.43]
Last Review: August 22, 2024
Next Review: August 20, 2025
Related Policies: None
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Radiopharmaceuticals are composed of a radioisotope (ie, 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 (PluvictoTM), 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.
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.
Not applicable.
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.
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.
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 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).
| 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. |
Pluvicto is a radioligand therapeutic agent indicated for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy.
Recommended Dosage: The recommended PLUVICTO dosage is 7.4 GBq (200 mCi) intravenously every 6 weeks for up to 6 doses, or until disease progression, or unacceptable toxicity.
Recommended dosage modifications of PLUVICTO for adverse reactions are provided in Table 1. 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 PLUVICTO. If a treatment delay due to an adverse reaction persists for > 4 weeks, treatment with PLUVICTO must be discontinued. The dose of PLUVICTO may be reduced by 20% to 5.9 GBq (160 mCi) once; do not re-escalate dose. If a patient has further adverse reactions that would require an additional dose reduction, treatment with PLUVICTO must be discontinued 14..
Dosage Modifications of PLUVICTO for Adverse Reactions
| Adverse reaction | Severity | Dosage modification |
| Myelosuppression (Anemia, thrombocytopenia, leukopenia, or neutropenia) [see Warnings and Precautions (5.2)] | Grade 2 | Withhold PLUVICTO until improvement to Grade 1 or baseline. |
| Grade ≥ 3 | Withhold PLUVICTO until improvement to Grade 1 or baseline. Reduce PLUVICTO dose by 20% to 5.9 GBq (160 mCi). | |
| Recurrent Grade ≥ 3 myelosuppression after one dose reduction | Permanently discontinue PLUVICTO. | |
| Adverse reaction | Severity | Dosage modification |
| Renal toxicity [see Warnings and Precautions (5.3)] | Defined as: • Confirmed serum creatinine increase (Grade ≥ 2) • Confirmed CLcr < 30 mL/min; calculate using Cockcroft-Gault with actual body weight | Withhold PLUVICTO until improvement. |
| Defined as: • Confirmed ≥ 40% increase from baseline serum creatinine and • Confirmed > 40% decrease from baseline CLcr; calculate using Cockcroft-Gault with actual body weight | Withhold PLUVICTO until improvement or return to baseline. Reduce PLUVICTO dose by 20% to 5.9 GBq (160 mCi). | |
| Grade ≥ 3 renal toxicity | Permanently discontinue PLUVICTO. | |
| Recurrent renal toxicity after one dose reduction | Permanently discontinue PLUVICTO. | |
| Dry mouth [see Adverse Reactions (6.1)] | Grade 2 | Withhold PLUVICTO until improvement or return to baseline. Consider reducing PLUVICTO dose by 20% to 5.9 GBq (160 mCi). |
| Grade 3 | Withhold PLUVICTO until improvement or return to baseline. Reduce PLUVICTO dose by 20% to 5.9 GBq (160 mCi). | |
| Recurrent Grade 3 dry mouth after one dose reduction | Permanently discontinue PLUVICTO. | |
| Gastrointestinal toxicity [see Adverse Reactions (6.1)] | Grade ≥ 3 (not amenable to medical intervention) | Withhold PLUVICTO until improvement to Grade 2 or baseline. Reduce PLUVICTO dose by 20% to 5.9 GBq (160 mCi). |
| Recurrent Grade ≥ 3 gastrointestinal toxicity after one dose reduction | Permanently discontinue PLUVICTO. | |
| Fatigue [see Adverse Reactions (6.1)] | Grade ≥ 3 | Withhold PLUVICTO until improvement to Grade 2 or baseline. |
| Electrolyte or metabolic abnormalities [see Adverse Reactions (6.1)] | Grade ≥ 2 | Withhold PLUVICTO until improvement to Grade 1 or baseline. |
| AST or ALT elevation [see Adverse Reactions (6.1)] | AST or ALT > 5 times ULN in the absence of liver metastases | Permanently discontinue PLUVICTO. |
| Other non-hematologic toxicity [see Adverse Reactions (6.1)] | Any unacceptable toxicity | Permanently discontinue PLUVICTO. |
| Any serious adverse reaction that requires treatment delay of > 4 weeks | Permanently discontinue PLUVICTO. | |
| Any recurrent Grade 3 or 4 or persistent and intolerable Grade 2 adverse reaction after one dose reduction | Permanently discontinue PLUVICTO. |
Prostate cancer is the second leading cause of cancer-related deaths among American men with 288,300 new cases and 34,700 disease-related deaths estimated for 2023.1, 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. 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.
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.
| 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) |
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.
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 (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.
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.
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 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.8, 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.
The safety and efficacy of PLUVICTO have not been established in females. Based on its mechanism of action, PLUVICTO can cause fetal harm. There are no available data on PLUVICTO use in pregnant females. No animal studies using lutetium Lu 177 vipivotide tetraxetan have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including PLUVICTO, have the potential to cause fetal harm.
The safety and efficacy of PLUVICTO have not been established in females. There are no data on the presence of lutetium Lu 177 vipivotide tetraxetan in human milk or its effects on the breastfed child or on milk production.
Contraception
Based on its mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment with PLUVICTO and for 14 weeks after the last dose.
Infertility
The recommended cumulative dose of 44.4 GBq of PLUVICTO results in a radiation absorbed dose to the testes within the range where PLUVICTO may cause temporary or permanent infertility.
The safety and effectiveness of PLUVICTO in pediatric patients have not been established.
Of the 529 patients who received at least one dose of PLUVICTO plus BSoC in the VISION study, 387 patients (73%) were 65 years or older and 143 patients (27%) were 75 years or older. No overall differences in effectiveness were observed between patients ≥ 75 years of age and younger patients. Serious adverse reactions occurred in 11% of patients ≥ 75 years of age and in 11% of younger patients. Grade ≥ 3 adverse reactions occurred in 40% of patients ≥ 75 years of age and in 31% of younger patients.
Exposure of lutetium Lu 177 vipivotide tetraxetan is expected to increase with the degree of renal impairment. No dose adjustment is recommended for patients with mild (baseline CLcr 60 to 89 mL/min by Cockcroft-Gault) to moderate (CLcr 30 to 59 mL/min) renal impairment; however, patients with mild or moderate renal impairment may be at greater risk of toxicity. Frequently monitor renal function and adverse reactions in patients with mild to moderate renal impairment. The pharmacokinetics and safety of PLUVICTO have not been studied in patients with severe (CLcr 15 to 29 mL/min) renal impairment or end-stage renal disease.
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.
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.
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."
Not available.
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.
Some currently unpublished trials that might influence this review are listed in Table 8.
| 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 |
NC Medicaid Division of Health Benefits. (2022, November). Lutetium Lu 177 Vipivotide Tetraxetan Injection, for Intravenous Use (PluvictoTM) . New HCPCS Code A9607. https://medicaid.ncdhhs.gov/blog/2022/11/01/lutetium-lu-177-vipivotide-tetraxetan-injection-intravenous-use-pluvictotm-new-hcpcs-code-a9607
National Cancer Institute. (2018). Surveillance, Epidemiology, and End Results Programs. Pluvicto. https://seer.cancer.gov/oncologytoolbox/canmed/ndconc/69488-0010/
| Codes | Number | Description |
| HCPCS | A9607 | Lutetium lu 177 vipivotide tetraxetan, therapeutic, 1 millicurie |
| 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 |
| Date | Action | Description |
|---|---|---|
| 08/22/2024 | Committe Review | Policy presented at the Utilization Management Committee MA. |
| 07/10/2024 | Policy Creation | Policy created with literature review through July 09. 2024. 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 when criteria is met. |