Coverage Policy Manual
Policy #: 2022044
Category: Laboratory
Initiated: March 2023
Last Review: December 2023
  Genetic Test: Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Ovarian Cancer

Description:
Biomarker-targeted therapy has shown a clear survival benefit in patients with ovarian cancer. Typically, the evaluation of biomarker status requires tissue biopsy. Circulating tumor DNA testing (also known as a liquid biopsy) is proposed as a non-invasive alternative.
 
Biomarker Testing and Targeted Treatment in Ovarian 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 ovarian cancer (NCI, 2023; Mateo, 2017). Polyadenosine diphosphate-ribose polymerase (PARP) inhibitors are used to target tumor cells with alterations in the HRR genes BRCA1 and BRCA2. Currently, 3 PARP inhibitors are FDA-approved for use in ovarian cancer.
 
In ovarian cancer targeted therapies, HRD-positive status is generally defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. Myriad MyChoice® is an FDA-approved companion diagnostic for the assessment of tumor genomic instability score (GIS) and the detection and classification of variants in the BRCA1 and BRCA2 genes, for the selection of patients who are eligible for targeted treatment. A patient’s Myriad HRD status is determined by detecting single nucleotide variants (SNVs), variants in homopolymer stretches, insertions and deletions (indels), and large rearrangements (LRs) in the BRCA1 and BRCA2 genes and determining a genomic instability score (GIS) using DNA obtained from ovarian tumor tissue. A positive Myriad HRD Status result is due to either the presence of a pathogenic variant in BRCA1and/or BRCA2 and/or a GIS above a defined threshold (Myriad Genetics, 2023). Approximately 41% to 50% of epithelial ovarian cancers are estimated to exhibit HRD. Germline alterations in BRCA1 and BRCA2 genes have been identified in up to 17% of individuals diagnosed with epithelial ovarian cancer, and somatic mutations are found in an additional 7% (Tew, 2022).
 
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 can be used for genomic characterization of the tumor.
 
Regulatory Status
Below is a list of targeted treatments approved by the FDA for individuals with ovarian cancer, along with the approved companion diagnostic tests. This information was current as of August 30, 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.
 
Voluntarily Withdrawn Indications for Maintenance Therapy
In 2022, the manufacturers of all 3 PARP inhibitors used to treat ovarian cancer voluntarily withdrew indications for third-line or greater treatment in ovarian cancer (AstraZeneca, 2022; Clovis Oncology, 2022; GSK, 2022). The withdrawals were based on updated survival results from the ARIEL4 (NCT02855944), SOLO3 (NCT02282020), and QUADRA (NCT02354586) trials. The withdrawals did not affect other indications in ovarian cancer.
 
Targeted Treatments for Ovarian Cancer and FDA-Approved Companion Diagnostic Tests (FDA, 2022; FDA, 2022):
 
Targeted Treatment for Ovarian Cancer
Niraparib (Zejula )
    • Indication
      • Maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.
      • Maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Zejula
    • Companion Diagnostics
      • none for this indication
    • Biomarkers
      • none for this indication
    • Pivotal Studies
      • First-line maintenance treatment: PRIMA (NCT02655016) (Gonzalez-Martin, 2019; Gonzalez-Martin, 2023)
      • Maintenance treatment of recurrent germline BRCA-mutated ovarian cancer: NOVA (NCT01847274) (Mirza, 2016)
    • NCCN Recommended Level/Guidance
      • 2A Ovarian Cancer (V.2.2023) (NCCN, 2023)
 
Olaparib (Lynparza®)
    • Indication
      • Maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza.
      • In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with HRD-positive status defined by either:
        • a deleterious or suspected deleterious BRCA mutation, and/or
        • genomic instability
Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza.
      • Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are incomplete or partial response to platinum-based chemotherapy.
    • Companion Diagnostic Tests
      • BRACAnalysis CDx® (Myriad Genetic Laboratories, Inc.)
      • FoundationOne CDx (Foundation Medicine, Inc.)
      • Myriad myChoice CDx (Myriad Genetic Laboratories, Inc)
    • Biomarkers
      • BRCA1 and BRCA2 mutations
      • BRCA1 and BRCA2 alterations
      • BRCA1 and BRCA2 mutations and/or positive Genomic Instability Score
    • Pivotal Studies
      • First-line, maintenance BRCA-mutated advanced ovarian cancer: SOLO-1(NCT01844986) (Moore, 2018; DiSilvestro, 2023)
      • First-line maintenance treatment in combination with bevacizumab, HRD-positive advanced ovarian cancer: PAOLA-1 (NCT02477644) (Ray-Coquard, 2019)
      • Maintenance treatment of recurrent ovarian cancer: SOLO-2 (NCT01874353) (Pujade-Lauraine, 2017; Poveda, 2021)
      • Study 19 (NCT00753545) (Ledermann, 2012)
    • NCCN Recommended Level/Guidance
      • 2A Ovarian Cancer (V.2.2023) (NCCN, 2023)
 
Rucaparib (Rubraca®) (NCI, 2022)
    • Indication
      • Maintenance treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
    • Companion Diagnostic Tests
      • BRACAnalysis CDx (Myriad Genetic Laboratories, Inc.)
      • FoundationFocus CDxBRCA Assay (Foundation Medicine, Inc.)
      • FoundationOne CDx (Foundation Medicine, Inc.)
      • FoundationOne Liquid CDx (Foundation Medicine, Inc.)
    • Biomarkers
      • BRCA1 and BRCA2 mutations
      • BRCA1 and BRCA2 alterations
    • Pivotal Studies
      • ARIEL3 (NCT01968213) (Coleman, 2017)
    • NCCN Recommended Level/Guidance
      • 2A Ovarian Cancer (V.2.2023) (NCCN, 2023)
 
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.

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Germline and somatic BRCA1/2 variant analysis for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved therapies meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
Homologous recombination deficiency (HRD) analysis of tumor tissue for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved therapies meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
Microsatellite instability/mismatch repair (MSI/MMR) testing of tumor tissue for individuals with unresectable or metastatic ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved therapies meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
All other uses of germline and somatic BRCA1/2 variant analysis to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, all other uses of germline and somatic BRCA1/2 variant analysis to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
All other uses of HRD testing of tumor tissue to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, all other uses of HRD testing of tumor tissue to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Other uses of MSI/MMR testing of ovarian, fallopian tube, or primary peritoneal tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, other uses of MSI/MMR testing of ovarian, fallopian tube, or primary peritoneal tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Tumor mutational burden testing to predict response to immunotherapy in individuals with ovarian, fallopian tube, or primary peritoneal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, tumor mutational burden testing to predict response to immunotherapy in individuals with ovarian, fallopian tube, or primary peritoneal cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Simultaneous testing using liquid and tumor biopsies (outside of paired or concurrent somatic-germline testing) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, simultaneous testing using liquid and tumor biopsies (outside of paired or concurrent somatic-germline testing) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

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 15, 2022.
 
Biomarker Testing Using Tissue Biopsy to Select Targeted Treatment and Immunotherapy (BRCA1, BRCA2, Homologous Repair Deficiency, and Microsatellite Instability/Mismatch Repair)
Ovarian cancer treatment selection is informed by tumor type, grade, stage, patient performance status and preference, prior treatments, and the molecular characteristics of the tumor such as the presence of driver mutations. One purpose of biomarker testing of patients who have advanced cancer is to inform a decision regarding treatment selection (e.g., whether to select a targeted treatment or standard treatment).
 
Clinical trials have evaluated the effectiveness of poly adenosine diphosphate-ribose polymerase (PARP) inhibitor drugs in individuals with ovarian cancer confirmed to have a BRCA1/2 mutation. Summarized below are the pivotal trials that supported the BRCA variant-related FDA-approved indications in ovarian cancer.
 
Niraparib
FDA approval for niraparib for treatment of ovarian cancer was based on the QUADRA phase 2 clinical trial (Moore, 2019). QUADRA evaluated the safety and activity of niraparib in adult patients with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with 3 or more previous chemotherapy regimens. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with HRD-positive tumors (including patients with BRCA and without BRCA pathogenic variants) sensitive to their last platinum-based therapy who had received 3 or 4 previous anticancer therapy regimens (primary efficacy population). Thirteen of 47 patients (28%) in the primary efficacy population achieved an overall response according to RECIST (95% CI, 15.6% to 42.6%; p=.00053).
 
Olaparib
The effectiveness of olaparib as maintenance therapy in newly diagnosed advanced ovarian cancer was demonstrated in the phase 3 SOLO-1 RCT comparing olaparib to placebo in 391 individuals with newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation (Moore, 2018)). After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo (Kaplan-Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs. 27%; hazard ratio for disease progression or death, 0.30; 95% CI, 0.23 to 0.41; p<.001).
 
Rucaparib
Several companion diagnostic tests have been FDA-approved to select individuals with BRCA1/2 variants for treatment with rucaparib for ovarian cancer. Subsequently, however, the indication for rucaparib was changed to no longer require BRCA testing for this indication (FDA, 2022). The indication change was based on results from the ATHENA trial (NCT03522246) which showed improvement in progression-free survival (PFS) regardless of BRCA variant status (Monk, 2022).
 
Pembrolizumab
FDA approval of pembrolizumab was supported by the phase 2 KEYNOTE-158 study. The trial included a total of 233 previously treated participants with MSI-H/dMMR solid tumors, 15 of whom had ovarian cancer. In the full cohort, the overall response rate was 34.3% (95% CI, 28.3% to 40.8%). Median PFS was 4.1 months (95% CI, 2.4 to 4.9 months) and median OS was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%) (Marabelle, 2020).
 
Clinical trials have demonstrated clinical benefit when testing was used to identify individuals for treatment with FDA-approved therapies.
 
Tumor Mutational Burden Testing to Guide Treatment for Ovarian Cancer
The purpose of tumor mutational burden (TMB) testing in patients who have ovarian cancer is to inform a decision on whether patients should receive immunotherapy versus another systemic therapy. The goal of immunotherapy is to preferentially kill malignant cells without significant damage to normal cells so that there is improved therapeutic efficacy along with decreased toxicity.
 
FoundationOne CDx is FDA-approved as a companion diagnostic for use with pembrolizumab in patients with TMB-high ( 10 mutations per megabase) solid tumors. Approval was based on results of the KEYNOTE-158 study that enrolled patients with solid tumors, but none of the patients evaluated had ovarian cancer.
 
Marabelle et al reported the association of high TMB to response to pembrolizumab in patients with solid tumors enrolled in a prespecified exploratory analysis of the KEYNOTE-158 study (Marabelle, 2020). High TMB was defined as >10 mutations per megabase according to the FoundationOne CDx panel. The proportion of patients with an objective response in the TMB-high group was 29%. At a median follow-up of approximately 3 years, the median duration of response was not reached in the TMB-high group and was 33.1 months in the non-TMB-high group. Notably, TMB-high status was associated with improved response irrespective of programmed death-ligand 1 (PD-L1). Median PFS and OS did not differ between the high and non-high TMB groups. Objective responses were observed in 24 (35%; 95% CI, 24% to 48%) of 68 participants who had both TMB-high status and PD-L1-positive tumors (i.e., PD-L1 combined positive score of 1) and in 6 (21%; 95% CI, 8% to 40%) of 29 participants who had TMB-high status and PD-L1-negative tumors. Study eligible cancers were limited to anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar. Because no patients with ovarian cancer were included in these analyses, it is not possible to draw conclusions about the clinical validity and utility of TMB in this group of patients.
 
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. There is no direct evidence of clinical utility of TMB testing to guide ovarian cancer treatment.
 
Indirect evidence on clinical utility rests on clinical validity. Because the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
 
In a prespecified exploratory analysis of a nonrandomized trial of pembrolizumab in patients with various solid tumors, objective responses were observed in 35% of participants who had both TMB-high status and PD-L1-positive tumors and in 21% of participants who had TMB-high status and PD-L1-negative tumors. A TMB-high status was associated with improved response irrespective of PD-L1 status. Median OS and PFS survival were not significantly different between TMB groups. Because no patients with ovarian, fallopian tube, or primary peritoneal cancer were included in these analyses, it is not possible to draw conclusions about the clinical validity and utility of TMB in this group of patients. These results need to be confirmed in well-designed prospective studies enrolling patients in the relevant population.
 
Circulating Tumor DNA Testing (Liquid Biopsy) to Guide Treatment for Ovarian Cancer
One purpose of liquid biopsy testing of patients who have ovarian cancer is to inform a decision regarding treatment selection (e.g., whether to select a targeted treatment or standard treatment).
 
True-positive liquid biopsy test results lead to the initiation of appropriate treatment (e.g., targeted therapy) without a tissue biopsy. False-positive liquid biopsy test results lead to the initiation of inappropriate therapy, which could shorten PFS.
 
In patients able to undergo a tissue biopsy, negative liquid biopsies reflex to tissue testing. In patients unable to undergo a tissue biopsy, a negative liquid biopsy result would not change empirical treatment. Therefore, health outcomes related to negative test results do not differ between liquid biopsy and tissue biopsy.
 
In October 2020, FoundationOne Liquid was FDA-approved as a companion diagnostic to identify individuals with BRCA-mutated ovarian cancer to select patients for treatment with rucaparib (FDA, 2020). Approval was based on analysis of pre-treatment plasma samples from the phase 2 ARIEL2 study. Subsequently, in June 2022 the indication for rucaparib was changed to no longer require BRCA testing.
 
There are no other FDA -cleared or -approved liquid biopsy companion diagnostic tests for use in selecting targeted treatment or immunotherapy in individuals with ovarian cancer.
 
In 2018, the American Society of Clinical Oncology and College of American Pathologists jointly convened an expert panel to review the current evidence on the use of ctDNA assays (Merker, 2018). The literature review included a search for publications on the use of ctDNA assays for solid tumors in March 2017 and covers several different indications for the use of liquid biopsy. The search identified 1338 references to which an additional 31 references were supplied by the expert panel. Seventy-seven articles were selected for inclusion. Much of the literature on the use of ctDNA to guide treatment selection was for non-small-cell lung cancer, metastatic colorectal cancer, and breast cancer, The literature review did not specifically address ovarian cancer. The authors concluded that "There is little evidence of clinical validity and clinical utility to support the widespread use of ctDNA assays in most patients with advanced cancer, with the exception of those with demonstrated clinical utility or those with regulatory approval."
 
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. There is no direct evidence of clinical utility of ctDNA testing to guide ovarian cancer treatment.
 
The clinical utility of FoundationOne liquid was evaluated using plasma samples from participants in the ARIEL2 trial. However, BRCA testing is no longer indicated prior to rucaparib treatment in ovarian cancer and so the relevance of this evidence is uncertain.
 
The clinical utility of FoundationOne liquid was evaluated using plasma samples from participants in the ARIEL2 trial. However, BRCA testing is no longer indicated prior to rucaparib treatment in ovarian cancer and so the relevance of this evidence is uncertain. Clinical validity has not been demonstrated in multiple well-designed and conducted studies; therefore, a chain of indirect evidence to show clinical utility cannot be established.
 
American Society of Clinical Oncology
In 2022, the American Society of Clinical Oncology published a provisional clinical opinion on the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors (Chakravarty, 2022). The opinion notes the following:
 
PCO 1.1. Genomic testing should be performed for patients with metastatic or advanced solid tumors with adequate performance status in the following 2 clinical scenarios:
    • When there are genomic biomarker–linked therapies approved by regulatory agencies for their cancer.
    • When considering a treatment for which there are specific genomic biomarker–based contraindications or exclusions (strength of recommendation: strong).
PCO 1.2.1. For patients with metastatic or advanced solid tumors, genomic testing using multigene genomic sequencing is preferred whenever patients are eligible for a genomic biomarker–linked therapy that a regulatory agency has approved (strength of recommendation: moderate).
PCO 1.2.2. Multigene panel–based genomic testing should be used whenever more than one genomic biomarker is linked to a regulatory agency–approved therapy (strength of recommendation: strong).
PCO 2.1. Mismatch repair deficiency status (dMMR) should be evaluated in patients with metastatic or advanced solid tumors who are candidates for immunotherapy. There are multiple approaches, including using large multigene panel–based testing to assess microsatellite instability (MSI). Consider the prevalence of dMMR and/or MSI-H status in individual tumor types when making this decision (strength of recommendation: strong).
PCO 2.2. When TMB may influence the decision to use immunotherapy, testing should be performed with either large multigene panels with validated TMB testing or whole-exome analysis (strength of recommendation: strong).
PCO 4.1. Genomic testing should be considered to determine candidacy for tumor-agnostic therapies in patients with metastatic or advanced solid tumors without approved genomic biomarker–linked therapies (strength of recommendation: moderate).
 
National Comprehensive Cancer Network
The current NCCN guidelines for ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) are version 4.2022 (NCCN, 2022). Guidelines are updated frequently; refer to the source for most current recommendations.
 
In the up-front setting, choice of somatic testing should, at a minimum, optimize identification of molecular alterations that can inform use of interventions that have demonstrated benefit in this setting, including BRCA1/2, loss of heterozygosity (LOH), or homologous recombination (HR) status in the absence of a germline BRCA mutation.
 
In the recurrence setting, tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit including, but not limited to, BRCA1/2, HR status, MSI, MMR, TMB, BRAF, and NTRK if prior testing did not include these markers.
 
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in August 2022 did not identify any trials that would likely influence this review.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2022, the American Society of Clinical Oncology published updated recommendations on poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in the management of ovarian cancer (Tew, 2022). The recommendations included the following:
 
Newly Diagnosed Ovarian Cancer
"Recommendation 2.1. Patients with newly diagnosed stage III-IV EOC [epithelial ovarian cancer] who are in complete or partial response to first-line platinum-based chemotherapy should be offered PARP inhibitor maintenance therapy in high-grade serous or endometrioid ovarian cancer. For those with germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes, options should include olaparib (300 mg orally every 12 hours for 2 years), niraparib (200-300 mg orally daily for 3 years) or rucaparib (600 mg twice a day for 2 years). Longer duration could be considered in selected individuals after discussion of risks. For those who are HRD [homologous recombination deficiency] positive, determined using FDA-approved companion diagnostic tests, rucaparib and niraparib are options. Niraparib or rucaparib may be offered for non-BRCA mutated/HRD negative patients. (Type: Evidence-based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong.)"
 
Recurrent Ovarian Cancer: Second-Line or Greater Maintenance and Treatment
"Recommendation 3.0. PARP inhibitor monotherapy maintenance (second-line or more) may be offered to patients with EOC who have not already received a PARP inhibitor and who have responded to platinum-based therapy regardless of BRCA mutation status; treatment is continued until progression of disease or toxicity despite dose reductions and best supportive care. Options include olaparib 300 mg every 12 hours, rucaparib 600 mg every 12 hours or niraparib 200-300 mg once daily. (Type: Evidence-based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong.) Maintenance treatment with niraparib for patients without germline or somatic BRCA mutation should weigh potential PFS benefit against possible OS decrement. (Type: Evidence-based, benefits outweigh harms; Evidence quality: Low; Strength of recommendation: Moderate.)"
"Recommendations 3.1/3.2. PARP inhibitor monotherapy should not be routinely offered to patients for the treatment of recurrent platinum sensitive EOC. (Type: Evidence-based, benefits outweigh harms; Evidence quality: Intermediate; Strength of recommendation: Moderate.) Evidence on PARP inhibitor use in this setting is evolving and data are continuing to emerge. Any decision to proceed with PARP inhibitor treatment in select populations (BRCA mutation, No prior PARP inhibitor use, Platinum Sensitive, Advanced Lines of Treatment) should be based on individualized patient and provider assessment of risks, benefits, and preferences."
"Recommendation 3.3. PARP inhibitor monotherapy is not recommended for treatment for patients with either BRCA wild-type or platinum-resistant recurrent EOC. (Type: Evidence-based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong.)"

CPT/HCPCS:
0037UTargeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden
0172UOncology (solid tumor as indicated by the label), somatic mutation analysis of BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) and analysis of homologous recombination deficiency pathways, DNA, formalin fixed paraffin embedded tissue, algorithm quantifying tumor genomic instability score
0239UTargeted genomic sequence analysis panel, solid organ neoplasm, cell free DNA, analysis of 311 or more genes, interrogation for sequence variants, including substitutions, insertions, deletions, select rearrangements, and copy number variations
81162BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis and full duplication/deletion analysis (ie, detection of large gene rearrangements)

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Bonneville R, Krook MA, Chen HZ, et al.(2020) Detection of Microsatellite Instability Biomarkers via Next-Generation Sequencing. Methods Mol Biol. 2020; 2055: 119-132. PMID 31502149

Chakravarty D, Johnson A, Sklar J, et al.(2022) Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion. J Clin Oncol. Apr 10 2022; 40(11): 1231-1258. PMID 35175857

Clovis Oncology, Inc.(2022) United States Securities and Exchange Commission Report (Rubraca). https://shorturl.at/cjwP5. Accessed September 3, 2023.

Coleman RL, Oza AM, Lorusso D, et al.(2017) Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinumtherapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Oct 28 2017; 390(10106): 1949-1961. PMID28916367

DiSilvestro P, Banerjee S, Colombo N, et al.(2023) Overall Survival With Maintenance Olaparib at a 7-yr Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and BRCA Mutation: The SOLO1/GOG 3004 Trial. J Clin Oncol. Jan 20 2023; 41(3): 609-617. PMID 36082969

Food and Drug Administration (FDA).(2020) FoundationOne Liquid CDx. Premarket Approval Number (PMA Number P00006). 2020. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=p200006. Accessed September 6, 2022

Food and Drug Administration (FDA).(2022) 2022. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed August 28, 2022.

Food and Drug Administration (FDA).(2022) 2022. List of Cleared or Approved Companion Diagnostic Devices (In 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 29, 2022.

Food and Drug Administration (FDA).(2022) Rubraca (Rucaparib) Product Label. June 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2 022/209115s011lbl.pdf. Accessed August 30, 2022.

Gonzalez-Martín A, Pothuri B, Vergote I, et al.(2019) Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. NEngl J Med. Dec 19 2019; 381(25): 2391-2402. PMID 31562799

Gonzalez-Martín A, Pothuri B, Vergote I, et al.(2023) Progression-free survival and safety at 3.5years of follow-up: results from the randomised phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer. Eur J Cancer. Aug 2023; 189: 112908. PMID 37263896

GSK.(2022) Dear Health Care Provider Letter (Niraparib). https://shorturl.at/rAGMZ. Accessed September 3, 2023.

Ledermann J, Harter P, Gourley C, et al.(2012) Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. NEngl J Med. Apr 12 2012; 366(15): 1382-92. PMID 22452356

Marabelle A, Le DT, Ascierto PA, et al.(2020) Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. Jan 01 2020; 38(1): 1-10. PMID 31682550

Mateo J, Boysen G, Barbieri CE, et al.(2017) DNA Repair in Prostate Cancer: Biology and Clinical Implications Eur Urol. Mar 2017; 71(3): 417-425. PMID 27590317

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