Medical Policy

Policy Num:     11.003.138
Policy Name:   Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Prostate Cancer (BRCA1/2, Homologous Recombination Repair Gene Alterations) 
Policy ID:         [11.003.138]  [Ac / B / M+ / P+]  [2.04.155]

Last Review:   October 08, 2024
Next Review:   October 20, 2025
 

Related Policies:

11.003.030 - Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2)
11.003.028 - Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes
11.003.022 - Genetic Testing for Li-Fraumeni Syndrome
11.003.051 - Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management
11.003.026 - Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies
11.003.089 - Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)
11.003.135 - Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer

11.003.140 - Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB)
11.003.034 - Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer
11.003.009 - Molecular Analysis (Including Liquid Biopsy) for Targeted Therapy or Immunotherapy of Non-Small-Cell Lung Cancer
11.003.004 - Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, MMR/MSI, HER2, and TMB)
11.003.011 - Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy or Immunotherapy
11.003.016 - Genetic Testing for PTEN Hamartoma Tumor Syndrome
11.003.064 - Genetic Cancer Susceptibility Panels Using Next Generation Sequencing
05.001.034 - Tropomyosin Receptor Kinase Inhibitors for Locally Advanced or Metastatic Solid Tumors Harboring an NTRK Gene Fusion

Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Prostate Cancer (BRCA1/2, Homologous Recombination Repair Gene Alterations, NTRK Gene Fusion)

Summary

Description

Biomarker-targeted therapy has shown a clear survival benefit in individuals with metastatic prostate cancer. Typically, the evaluation of biomarker status requires tissue biopsy. Circulating tumor DNA (ctDNA) (also known as liquid biopsy) is proposed as a non-invasive alternative.

Summary of Evidence

For individuals with metastatic castrate-resistant prostate cancer (mCRPC) who receive germline BRCA1/2 variant testing to guide treatment with a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor, the evidence includes FDA-approved therapeutics with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and National Comprehensive Cancer Network (NCCN) recommendations.

For individuals with mCRPC who receive somatic testing for homologous recombination repair (HRR) gene alterations (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) using tissue biopsy to guide treatment with a PARP inhibitor, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with mCRPC who receive somatic testing for BRCA1, BRCA2, and ATM alterations using circulating tumor DNA (ctDNA; liquid biopsy) to guide treatment with a PARP inhibitor, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with mCRPC who receive NTRK gene fusion testing to select treatment with FDA-approved therapies, the evidence includes pooled results from single-arm studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, medication use, and treatment-related morbidity. For larotrectinib, 3, single-arm studies evaluating the efficacy of larotrectinib in 159 pediatric and adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion are ongoing. Pooled results of the first 55 sequentially enrolled patients have been published. All patients were required to have progressed on systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. The ORR by the Institutional Review Committee (primary study endpoint) was 79% (95% CI, 72% to 85%); complete response 16%; and partial response 63%. Responses observed were independent of age, tumor type, NTRK gene, or fusion partner. For entrectinib, integrated data from 54 adult patients with NTRK fusion-positive, locally advanced or metastatic solid tumors from 3, single-arm ongoing studies who had completed a minimum of 6 months of follow-up were reviewed. The ORR by blinded independent central review was 57.4% in patients with NTRK fusion-positive solid tumors. The median DOR was 10.4 months. Results were similar in a Phase 2 trial of children and adolescents with NTRK fusion-positive tumors, with an ORR of 60.0%. 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 summarize the evidence and guidelines on biomarker testing to select targeted treatment for individuals with metastatic prostate cancer.

Policy

Germline BRCA1/2 variant analysis for individuals with metastatic castrate-resistant prostate cancer (mCRPC) to select treatment with FDA-approved targeted therapies may be considered medically necessary.

All other uses of germline BRCA1/2 variant analysis to guide prostate cancer targeted therapy are considered investigational.

Somatic testing using tissue biopsy for homologous recombination repair (HRR) gene alterations (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) to select treatment for mCRPC with FDA-approved targeted therapies may be considered medically necessary.

All other uses of somatic testing using tissue biopsy for HRR gene alterations to guide prostate cancer targeted therapy are considered investigational.

Somatic testing using circulating tumor DNA testing (liquid biopsy) for BRCA1, BRCA2, and ATM alterations to select treatment for mCRPC with FDA-approved targeted therapies may be considered medically necessary.

All other uses of somatic testing using circulating tumor DNA testing (liquid biopsy) to guide prostate cancer targeted therapy are considered investigational.

Simultaneous testing using liquid and tumor biopsies (outside of paired or concurrent somatic-germline testing) to guide treatment in individuals with prostate cancer is considered investigational (see Policy Guidelines).

Testing of NTRK gene fusions in individuals with mCRPC to select treatment with FDA-approved targeted therapies may be considered medically necessary.

Testing for other variants may become available between policy updates.

Policy Guidelines

Plans may need to alter local coverage medical policy to conform to state law regarding coverage of biomarker testing.

Testing for other variants may become available between policy updates.

Testing for individual genes (not gene panels) associated with Food and Drug Administration (FDA)-approved therapeutics for therapies with NCCN recommendations of 2A or higher are not subject to extensive evidence review. Note that while the FDA approval of companion diagnostic tests for genes might include tests that are conducted as panels, the FDA approval is for specific genes (such as driver mutations) and not for all of the genes on the test panel.

For expanded panel testing, see evidence review 2.04.115.

For somatic biomarker testing related to use of immune checkpoint inhibitor therapy (BRAF, microsatellite instability/mismatch repair [MSI/MMR], PD-L1, tumor mutational burden [TMB]), see evidence review 2.04.157.

Note that TMB is often included in panel tests and might not have separate coding; Plans with coverage for panels might consider local decision for TMB.

FDA approves tests in between policy review cycles. As such, newly approved tests might need to be considered per local Plan discretion. For guidance on testing criteria between policy updates, refer to the FDA's List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) () for an updated list of FDA-approved tumor markers and consult the most current version of NCCN management algorithms.

Note: Extensive evidence review is not included for somatic tests of individual genes (not gene panels) associated with FDA-approved therapies with NCCN recommendations of 2A or higher. The pivotal evidence is included in Table 1 for informational purposes. Additionally, no evidence review is provided for somatic tests of individual genes that do not have associated FDA-approved therapies regardless of NCCN recommendations, as these off-label therapies are deemed investigational per the Blue Cross and Blue Shield Association Medical Policy Program Policies and Procedures.

Repeat Genomic Testing

There may be utility in repeated testing of gene variants for determining targeted therapy or immunotherapy in individuals with prostate cancer, as tumor molecular profiles may change with subsequent treatments and re-evaluation may be considered at time of cancer progression for treatment decision-making (See NCCN PROS-B 3 of 3). The American Society of Clinical Oncology (ASCO) currently suggests repeat genomic testing for individuals on targeted therapy with suspected acquired resistance, especially if choice of next-line therapy would be guided. The ASCO guidance is not tumor specific, and it cautions to consider clinical utility (Chakravarty et al, 2022; PMID 35175857).

Paired Somatic-Germline Testing

Testing for genetic changes in tumor tissue assesses somatic changes. Some somatic testing involves a paired blood analysis in order to distinguish whether findings in tumor tissue are acquired somatic changes or germline changes. Some laboratories offer paired tumor sequencing and germline sequencing which is done at the same time and in the same laboratory. The goal of this paired testing is to identify truly somatic changes to guide treatment. However, paired testing can also identify potential germline changes that might indicate an inherited cancer syndrome. These results would need to be confirmed through germline testing if personal and family cancer history is consistent with an inherited cancer syndrome (see evidence reviews related to inherited cancer syndromes, 2.04.02, 2.04.08, 2.04.88, 2.04.101).

Paired genetic testing is different than concurrent somatic-germline testing. In concurrent testing, the germline results are not used to filter the somatic results. Rather, the laboratories perform large, separate panels of germline and somatic variants. The goal is to identify options for genome-informed treatment and to identify hereditary cancer risk. For concurrent panel testing, see evidence review 2.04.93 - Genetic Cancer Susceptibility Panels Using Next Generation Sequencing for germline panel, and see evidence review 2.04.115 - Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies for somatic panel.

Concurrent Somatic Liquid-based and Tissue-based Genomic Testing

Liquid biopsy testing uses blood samples and assesses cancer DNA and non-cancer DNA in the same blood sample. The goal is to identify options for genome-informed treatment. Some providers will order a liquid biopsy test and a tissue biopsy test at the same time, not for filtering or for comparison as in the paired genetic testing section above, but to hasten time to treatment. If the intent of concurrent testing is to follow an individual over time for resistance mutations/response to therapy, then consideration could be given to doing liquid biopsy at diagnosis with the tissue biopsy to make sure that whatever mutations are going to be followed longitudinally can be detected by the liquid biopsy. For example, monitoring of BRCA mutation evolution (reversion mutations) in individuals with prostate cancer during poly adenosine diphosphate-ribose polymerase (PARP) inhibitor therapy may be achieved with serial circulating tumor DNA (ctDNA) sampling, and allow for earlier detection of resistance and selection of alternative therapies to reduce the risk of resistance (Goodall et al, 2017; PMID 28450425). This testing strategy has not been fully studied, and is not yet discussed in the NCCN guidelines for prostate cancer

Genetic Counseling

Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing or have state mandates for biomarker testing coverage.

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

Targeted Treatment in Metastatic Castrate Resistant Prostate Cancer

DNA damage happens daily, and most are repaired to allow normal cell functioning. Double strand breaks (DSB) in the DNA are particularly damaging. Repair of DSB utilizes the homologous recombination repair (HRR) pathway. Many types of cancer, however, are unable to repair DNA damage. This leads to the accumulation of genetic errors, such as loss of DNA, rearrangements in the DNA, and loss of entire genes. The consequence of these errors is genomic instability. The loss of the HRR and associated genomic instability is called homologous recombination deficiency (HRD). HRD is associated with several types of cancer including prostate cancer, where estimates as high as 30% of metastatic castrate-resistant prostate cancer (mCRPC) tumors have genetic changes that result in the loss of DNA repair capacity.^1,

Friends of Cancer Research convened a consortium addressing the lack of consistency in the way HRD is defined and measurement methods.^2, They proposed the following definition: “HRD is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the HRR pathway.” Additionally, they encourage the use of “HRD” and “HRP” to reflect homologous recombination deficiency and homologous recombination proficiency. While the consortium did not explicitly define how to measure homologous recombination repair status, they acknowledge that it might involve gene variant testing as well as genomic instability measurement and call for transparency and standardization.

Specific to prostate cancer, the National Comprehensive Cancer Network (NCCN) prostate cancer guideline gives examples of HRR genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L). Germline and somatic alterations in these genes may be predictive of the clinical benefit of PARP inhibitors in mCRPC..^3,Olaparib (Lynparza) and rucaparib (Rubraca) were the first PARP inhibitors to receive FDA approval for the treatment of mCRPC. In 2023, niraparib in combination with abiraterone acetate (marketed as Akeega) and talazoparib (Talzenna) were also approved for use in mCRPC (see Table 1).

Circulating Tumor DNA (Liquid Biopsy)

Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA. Cell-free DNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or circulating tumor cells. Unlike apoptosis, necrosis is considered a pathologic process and generates larger DNA fragments due to incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. Circulating tumor DNA (ctDNA) can be used for genomic characterization of the tumor.

Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion Testing

The presence of NTRK gene fusion can be detected by multiple methods including next-generation sequencing, reverse transcription-polymerase chain reaction, fluorescence in situ hybridization and immunohistochemistry.^4, Next-generation sequencing provides the most comprehensive view of a large number of genes and may identify NTRK gene fusions as well as other actionable alterations, with minimal tissue needed. The fluorescence in situ hybridization using break-apart probes can detect gene rearrangements in DNA that may generate a fusion transcript. The immunohistochemistry techniques have generally been used in the research setting. Reverse transcription-polymerase chain reaction is designed to identify only known translocation partners and breakpoints and cannot identify novel breakpoints or novel fusion partners.

Regulatory Status

Table 1 summarizes the targeted treatments approved by the FDA for individuals with prostate cancer, along with the approved companion diagnostic tests. The information in Table 1 was current as of August 21, 2023. An up-to-date list of FDA cleared or approved companion diagnostics is available at https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools.

Table 1. Targeted Treatments for Metastatic Prostate Cancer and FDA Approved Companion Diagnostic Tests

NCCN: National Comprehensive Cancer Network.

Sources: Food and Drug Administration ( 2023);10, Drugs@FDA (2023)11, 

Laboratory-Developed Tests

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed under CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.

Rationale

This evidence review was created in September 2022 with a search of the PubMed database. The most recent literature update was performed through August 6, 2024.

Testing for individual genes (not gene panels) associated with Food and Drug Administration (FDA)-approved therapeutics for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive evidence review. The pivotal evidence is included in Table 1 for informational purposes. Note that while the FDA approval of companion diagnostic tests for genes might include tests that are conducted as panels, the FDA approval is for specific genes (such as driver mutations) and not for all of the genes on the test panel.

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.

Population Reference No. 1

Germline BRCA1/2 Variant Testing to Select Targeted Treatment in Prostate Cancer

For individuals with metastatic castration-resistant prostate cancer (CRPC) who receive germline BRCA1/2 variant testing to guide treatment with a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor, the evidence includes FDA-approved therapeutics with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher and was not extensively evaluated.

For individuals with metastatic castrate-resistant prostate cancer (mCRPC) who receive germline BRCA1/2 variant testing to guide treatment with a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor, the evidence includes FDA-approved therapeutics with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and National Comprehensive Cancer Network (NCCN) recommendations.

Population Reference No. 2

Somatic Testing for Homologous Recombination Repair Gene Alterations Using Tissue Biopsy to Select Targeted Treatment in Prostate Cancer

For individuals with mCRPC who receive somatic testing for homologous recombination repair (HRR) gene alterations (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) using tissue biopsy to guide treatment with a PARP inhibitor, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

For individuals with mCRPC who receive somatic testing for homologous recombination repair (HRR) gene alterations (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) using tissue biopsy to guide treatment with a PARP inhibitor, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Population Reference No. 3

Somatic Testing for BRCA1, BRCA2, and ATM Alterations Using Liquid Biopsy to Select Targeted Treatment in Prostate Cancer

For individuals with mCRPC who receive somatic testing for BRCA1, BRCA2, and ATM alterations using ctDNA (liquid biopsy) to guide treatment with a PARP inhibitor, the evidence includes FDA-approved therapeutics with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher and was not extensively evaluated.

For individuals with mCRPC who receive somatic testing for BRCA1, BRCA2, and ATM alterations using circulating tumor DNA (ctDNA; liquid biopsy) to guide treatment with a PARP inhibitor, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Population Reference No. 4

Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion Testing to Select Targeted Treatment

Clinical Context and Test Purpose

The purpose of tropomyosin receptor kinase (TRK) inhibitors such as larotrectinib and entrectinib for individuals with locally advanced or metastatic solid tumors that 1) have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, 2) are metastatic or where surgical resection is likely to result in severe morbidity, and 3) have no satisfactory alternative treatments or have progressed following treatment, is to provide a treatment option that is 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 mCRPC to select treatment with FDA-approved therapies.

Interventions

The test being considered in this review is NTRK gene fusion testing.

Comparators

The comparator of interest is no NTRK gene fusion testing to guide treatment.

Outcomes

The overall outcomes of interest are overall survival (OS), disease-specific survival, change in disease status, medication use, resource utilization, and treatment-related morbidity.

Study Selection Criteria

For the evaluation of clinical validity of the NTRK gene fusion test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores).

• Included a suitable reference standard.

• Patient/sample clinical characteristics were described.

• Patient/sample selection criteria were described.

Testing for individual genes (not gene panels) associated with FDA-approved therapeutics (ie, as companion diagnostic tests) for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive evidence review. Note that while the FDA approval of companion diagnostic tests for genes might include tests that are conducted as panels, the FDA approval is for specific genes (such as driver mutations) and not for all of the genes on the test panel.

Clinically Valid and Clinically Useful

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse). A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Review of Evidence

Clinical trials have evaluated the effectiveness of using NTRK gene fusion testing to identify individuals with solid tumors for treatment with FDA-approved therapies. The incidence of NTRK fusions is below 1% for most common cancers such as lung, prostate, and colon cancer. NTRK fusion cancers are rare and therefore conducting randomized trials would be challenging. A limitation in relevance is related to the generalizability of its results to populations that were not well represented in the pivotal study due to the small numbers of patients. Although the efficacy of larotrectinib and entrectinib is largely unknown in such cases, in settings where no treatment is available or where available treatment would result in significant morbidity or where the clinical effects of available treatments are modest, it is plausible to assume that larotrectinib or entrectinib may provide an advantage over available therapy for patients with NTRK fusion solid tumors. As per the FDA review, there was strong nonclinical support of the antitumor activity of larotrectinib across multiple cell lines and NTRK fusion partners, and clinically, durable tumor shrinkage occurred in a consistent fashion in patients with a variety of tumors harboring a diverse array of NTRK fusions. In light of these factors, the FDA review teams concluded that pooling of results from patients with NTRK fusion-solid tumors was warranted and supported a tissue agnostic indication.

Currently, the only FDA approved companion diagnostic test for larotrectinib and entrectinib is the FoundationOne^® CDx (Foundation Medicine).^15, Multiple commercial laboratories currently offer testing for NTRK1, NTRK2, and NTRK3 gene fusions.^4,

Larotrectinib

FoundationOne Liquid is an FDA-approved companion diagnostic to detect NTRK gene fusion in patients who may benefit from treatment with laratrectinib.^15, Approval was based on pooled results of 3, single-arm prospective studies.^11, The ORR was 79% (95% confidence interval [CI], 72% to 85%). At the time of data cutoff (February 19, 2019), in 108 participants with confirmed response, the median duration of response (DOR) was 35.2 months (95% CI, 22.8 months to not estimable). Depending on the cancer site, ORR ranged widely from 0 to 100%. The safety population included 260 patients treated with larotrectinib. regardless of NTRKfusion status. Adverse event were primarily Grade 1 or 2, and were similar in pediatric and adult patients. Grade 3 adverse events occurred in 39% of patients, and Grade 4 events occurred in 17% of patients. Serious adverse events included pneumonia, pyrexia, abdominal pain and diarrhea, all occurring in 2% of included patients. Assessment of a causal relationship between larotrectinib and adverse events is limited due to the single-arm design of the study.

Entrectinib

FoundationOne Liquid is an FDA-approved companion diagnostic to detect NTRK gene fusion in patients who may benefit from treatment with entrectinib.^15, In the integrated analysis of STARTRK-1, STARTRK-2, and ALKA-372-001 data,the median age was 58 years (range, 21 to 83 years), 89% had an ECOG performance score of 0 or 1, 63% had received prior anticancer therapy (20% received 1, 43% received ≥2) and 22% had CNS disease at baseline.^12, Median duration of follow-up was 12.9 months (interquartile range, 8.8 to 18.8 months). In 54 adult patients with NTRK fusion-positive solid tumors, the objective response rate was 57% and median DOR was 10.4 months. The safety population included 68 patients with NTRK fusion-positive solid tumors who had received any dose of entrectinib; median treatment duration for the safety evaluation was 7.9 months. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria. Serious treatment-related adverse reactions were reported in 10% of patients. Permanent discontinuation due to treatment-related adverse events occurred in 4% of patients. Assessment of a causal relationship between entrectinib and adverse events is limited due to the single-arm design of the study.

Phase 2 results from the STARTRK-NG trial included 27 children and adolescents, 15 of whom had NTRK fusion-positive solid tumors.^14, The cut-off date for data analysis was September 2020. The objective response rate was 60% after a median duration of 11 months follow-up. Among the total Phase 2 population, 85% (23/27) had a Grade 3 or higher adverse event, most commonly weight gain (33% [9/27]) and a decrease in neutrophil count (22% [6/27]). The STARTRK-NG trial is ongoing, with expected completion in 2027.

Section Summary:

Clinical trials have demonstrated clinical benefit when testing was used to identify individuals for treatment with FDA-approved therapies. For larotrectinib, 3, single-arm studies evaluating the efficacy of larotrectinib in 159 pediatric and adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion are ongoing. Pooled results of the first 55 sequentially enrolled patients have been published. All patients were required to have progressed on systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. The ORR by the Institutional Review Committee (primary study endpoint) was 79% (95% CI, 72% to 85%); complete response 16%; and partial response 63%. Responses observed were independent of age, tumor type, NTRK gene, or fusion partner. For entrectinib, integrated data from 54 adult patients with NTRK fusion-positive, locally advanced or metastatic solid tumors from 3, single-arm ongoing studies who had completed a minimum of 6 months of follow-up were reviewed. The ORR by blinded independent central review was 57.4% in patients with NTRK fusion-positive solid tumors. The median DOR was 10.4 months. Results were similar in a Phase 2 trial of children and adolescents with NTRK fusion-positive tumors, with an ORR of 60.0%.

For individuals with mCRPC who are being considered for targeted treatment with a PARP inhibitor.

For individuals with mCRPC who receive NTRK gene fusion testing to select treatment with FDA-approved therapies, the evidence includes pooled results from single-arm studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, medication use, and treatment-related morbidity. For larotrectinib, 3, single-arm studies evaluating the efficacy of larotrectinib in 159 pediatric and adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion are ongoing. Pooled results of the first 55 sequentially enrolled patients have been published. All patients were required to have progressed on systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. The ORR by the Institutional Review Committee (primary study endpoint) was 79% (95% CI, 72% to 85%); complete response 16%; and partial response 63%. Responses observed were independent of age, tumor type, NTRK gene, or fusion partner. For entrectinib, integrated data from 54 adult patients with NTRK fusion-positive, locally advanced or metastatic solid tumors from 3, single-arm ongoing studies who had completed a minimum of 6 months of follow-up were reviewed. The ORR by blinded independent central review was 57.4% in patients with NTRK fusion-positive solid tumors. The median DOR was 10.4 months. Results were similar in a Phase 2 trial of children and adolescents with NTRK fusion-positive tumors, with an ORR of 60.0%. 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 Urological Assocation/Society of Urologic Oncology

In 2023, the American Urological Assocation and the Society of Urologic Oncology published amended guidelines on advanced prostate cancer.^12, The guidelines included the following relevant recommendation (level of evidence) on the treatment of mCRPC:

• In patients with mCRPC, clinicians should offer germline (if not already performed) and somatic genetic testing to identify DNA repair deficiency, microsatellite instability (MSI) status, tumor mutational burden, and other potential mutations that may inform prognosis and familial cancer risk, as well as direct potential targeted therapies.(Clinical Principle)

National Comprehensive Cancer Network

The current National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer are version 4.2024.^3, Guidelines are updated frequently; refer to the source for the most current recommendations.

The guidelines include the following relevant recommendations:

Targeted Therapy

• "Olaparib is an option for patients with mCRPC who have an HRR mutation and whose cancer has progressed on prior treatment with androgen receptor-directed therapy regardless of prior docetaxel therapy based on results of a randomized phase 3 study in patients with HRR mutations. Radiographic PFS was improved over physician's choice of abiraterone or enzalutamide. In the pre-docetaxel setting, olaparib is a preferred treatment option for patients with a pathogenic mutation (germline and/or somatic) in BRCA1 or BRCA2, and is also an option in this setting for patients with other HRR gene alterations (ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L)."

• "Rucaparib is an option for patients with mCRPC and a pathogenic BRCA1 or BRCA2 mutation (germline and/or somatic) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy based on results from a phase 2 trial."

• "Olaparib with abiraterone is an option for certain patients with mCRPC (PROS-16) and a pathogenic BRCA1 or BRCA2 mutation (germline and/or somatic) who have not yet received a novel hormone therapy and who have not yet had treatment in the setting of CRPC based on results of an international, doubleblind, phase 3 trial."

• "Talazoparib plus enzalutamide is a treatment option for patients with mCRPC and a pathogenic mutation (germline and/or somatic) in an HRR gene (BRCA1, BRCA2, ATM, ATR, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) who have not yet had treatment in the setting of CRPC, depending on prior treatment in other disease settings (PROS-16) based on results from a randomized, double-blind, phase 3 trial."

Germline Testing

The Principles of Genetics section (PROS-B) provides appropriate scenarios for germline genetic testing in individuals with a personal history of prostate cancer.

Germline testing is recommended in patients with a personal history of prostate cancer in the following scenarios related to the tumor: metastatic, regional (node-positive), very-high risk localized, high-risk localized prostate cancer.

Germline testing may be considered in patients with a personal history of prostate cancer in the following scenarios related to the tumor: intermediate-risk prostate cancer with intraductal/cribriform histology; or a prior personal history any of the following cancers: of exocrine pancreatic, colorectal, gastric, melanoma, upper tract urothelial, glioblastoma, biliary tract, and small intestinal.

Somatic Testing

Tumor testing for alterations in homologous recombination DNA repair genes, such as BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, and CDK12, is recommended in patients with metastatic prostate cancer. This testing can be considered in patients with regional prostate cancer.

Tumor Specimen and Assay Considerations

The panel strongly recommends a metastatic biopsy for histologic and molecular evaluation. When unsafe or unfeasible, plasma ctDNA assay is an option, preferably collected during biochemical (PSA) and/or radiographic progression in order to maximize diagnostic yield.

Caution is needed when interpreting ctDNA-only evaluation due to potential interference from clonal hematopoiesis of indeterminate potential (CHIP), which can result in a false-positive biomarker signal.

The preferred method of selecting patients for rucaparib treatment is somatic analysis of BRCA1 and BRCA2 using a ctDNA sample.

Post-Test Considerations

Post-test genetic counseling is recommended if pathogenic/likely pathogenic variant (mutation) identified in any gene that has clinical implications if also identified in germline (eg, BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2).

U.S. Preventive Services Task Force Recommendations

Not applicable.

MEDICARE NATIONAL COVERAGE

The Centers for Medicare & Medicaid Services (CMS) National Coverage Determination on Next Generation Sequencing (90.2) states:

"Effective for services performed on or after March 16, 2018, [CMS] has determined that Next Generation Sequencing (NGS) as a diagnostic laboratory test is reasonable and necessary and covered nationally, when performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, when ordered by a treating physician, and when all of the following requirements are met:

a. Patient has:

1. either recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer; and
2. not been previously tested with the same test using NGS for the same cancer genetic content; and
3. decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

b. The diagnostic laboratory test using NGS must have:

1. Food & Drug Administration (FDA) approval or clearance as a companion in vitro diagnostic; and,

2. an FDA-approved or -cleared indication for use in that patient’s cancer; and,

3. results provided to the treating physician for management of the patient using a report template to specify treatment options. ^18,

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 2.

Table 2. Summary of Key Trials

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

References

1. Mateo J, Boysen G, Barbieri CE, et al. DNA Repair in Prostate Cancer: Biology and Clinical Implications. Eur Urol. Mar 2017; 71(3): 417-425. PMID 27590317
2. Stewart MD, Merino Vega D, Arend RC, et al. Homologous Recombination Deficiency: Concepts, Definitions, and Assays. Oncologist. Mar 11 2022; 27(3): 167-174. PMID 35274707
3. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Prostate Cancer. Verson 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed August 7, 2024.
4. TRK Fusion Cancer (Testing). https://trkcancer.com/testing. Accessed August 7, 2024.
5. Chi KN, Rathkopf D, Smith MR, et al. Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. Jun 20 2023; 41(18): 3339-3351. PMID 36952634
6. Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. Dec 10 2020; 383(24): 2345-2357. PMID 32955174
7. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, Oya M, Shore N, Loredo E, Procopio G, et al for the PROpel Investigators. 2022. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. NEJM Evid 2022;1(9). https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200043. Accessed August 7, 2024.
8. Abida W, Patnaik A, Campbell D, et al. Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol. Nov 10 2020; 38(32): 3763-3772. PMID 32795228
9. Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or Physician's Choice in Metastatic Prostate Cancer. N Engl J Med. Feb 23 2023; 388(8): 719-732. PMID 36795891
10. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. Jul 22 2023; 402(10398): 291-303. PMID 37285865
11. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. Apr 2020; 21(4): 531-540. PMID 32105622
12. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. Feb 2020; 21(2): 271-282. PMID 31838007
13. Drilon A, Siena S, Ou SI, et al. Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. Apr 2017; 7(4): 400-409. PMID 28183697
14. Desai AV, Robinson GW, Gauvain K, et al. Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro Oncol. Oct 03 2022; 24(10): 1776-1789. PMID 35395680
15. Food and Drug Administration. 2024. List of Cleared or Approved Companion Diagnostic Devices ((n Vitro and Imaging Tools). https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools. Accessed August 7, 2024.
16. Food and Drug Administration. 2024. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed August 7, 2024.
17. Lowrance W, Dreicer R, Jarrard DF, et al. Updates to Advanced Prostate Cancer: AUA/SUO Guideline (2023). J Urol. Jun 2023; 209(6): 1082-1090. PMID 37096583
18. Centers for Medicare & Medicaid Services. 2020. National Coverage Determination 90.2: Next Generation Sequencing. https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=372&ncdver=2&NCAId=296&bc=ACAAAAAACAAA&. Accessed August 7, 2024.

Codes

Applicable Modifiers

As per correct coding guidelines   

Policy History