Medical Policy

Policy Num:      11.003.139
Policy Name:    Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency, NTRK)
Policy ID:          [11.003.139] [Ac / B / M+ / P+] [2.04.156]

Last Review:      October 22, 2025
Next Review:      October 20, 2026
 

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
11.003.026 - Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies
11.003.089 - Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)
11.003.134 - Molecular Testing for Germline Variants Associated with Ovarian Cancer (BRIP1, RAD51C, RAD51D, NBN)
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)
11.003.009 - Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, HER2, PD-L1, TMB)
11.003.004 - Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, and HER2)
11.003.011 - Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy (BRAF)
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 in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency, NTRK)

Summary

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.

Summary of Evidence

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer 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 NCCN recommendations.

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive somatic BRCA1/2 variant testing 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 advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive homologous recombination deficiency (HRD) testing using tumor tissue 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 advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive somatic BRCA1/2 variant testing using circulating tumor DNA testing (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 advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive NTRK gene fusion testing using tumor tissue to guide treatment with a tropomyosin receptor kinase (TRK) 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.

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 ovarian cancer.

Policy Statements

Germline BRCA1/2 variant analysis may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

Somatic BRCA1/2 variant analysis using tumor tissue may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

All other uses of germline and somatic BRCA1/2 variant analysis to guide targeted therapy for ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

Homologous recombination deficiency (HRD) analysis of tumor tissue may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

All other uses of HRD testing of tumor tissue to guide targeted therapy for ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

BRCA1/2 variant analysis using circulating tumor DNA (liquid biopsy) may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies when tissue-based analysis is not clinically feasible.

All other uses of circulating tumor DNA testing (liquid biopsy) to guide targeted therapy in individuals with ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

NTRK1, NTRK2, and NTRK3 gene fusion analysis of tumor tissue may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

All other uses of NTRK1, NTRK2, and NTRK3 gene fusion analysis of tumor tissue to guide targeted therapy for ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

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 (see Policy Guidelines).

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 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.

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)(https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-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.

This policy does not address germline testing for inherited risk of developing cancer.

Repeat Genomic Testing

There may be utility in repeated testing of gene variants for determining targeted therapy or immunotherapy in individuals with ovarian cancer, as a resistance mechanism to platinum-based chemotherapies and poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function (Lin et al 2019; PMID 30425037). American Society of Clinical Oncology (ASCO) currently suggests repeat genomic testing for patients 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 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 a patient 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 BRCA mutation evolution (reversion mutations) in individuals with ovarian cancer during PARP inhibitor therapy may be achieved with serial ctDNA sampling, and allow for earlier detection of resistance and selection of alternative therapies to reduce the risk of resistance. This testing strategy has not been fully studied and is not yet discussed in the NCCN guidelines for ovarian cancer.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG2). The Society's nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG3 shows the recommended standard terminology- "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"- to describe variants identified that cause Mendelian disorders.

Table PG2. Nomenclature to Report on Variants Found in DNA

Table PG3. ACMG-AMP Standards and Guidelines for Variant Classification

    ACMG-AMP: American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

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

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.^1,2,Poly adenosine 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 (Table 1).

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 BRCA1 and/or BRCA2 and/or a GIS above a defined threshold.^3,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%.^4,

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

Table 1 summarizes the targeted treatments approved by the FDA for individuals with ovarian cancer, along with the approved companion diagnostic tests. The information in Table 1 was current as of August 1, 2024. 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.^5,6,7, 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.

Table 1. Targeted Treatments for Ovarian Cancer and NTRK fusions with FDA-Approved Companion Diagnostic Tests

    Sources: Food and Drug Administration (2025 )21,; Drugs@FDA22,

    a Whole blood assays are approved for germline testing.

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 1, 2025.

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.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Population Reference No. 1

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

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer 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 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. 2

Somatic BRCA1/2 Variant Testing Using Tissue Biopsy to Select Targeted Treatment in Ovarian Cancer

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive somatic BRCA1/2 variant testing 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

Homologous Recombination Deficiency Testing to Select Targeted Treatment in Ovarian Cancer

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive homologous recombination deficiency (HRD) testing using tumor tissue 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

Somatic BRCA1/2 Variant Testing Using Liquid Biopsy to Select Targeted Treatment in Ovarian Cancer

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive somatic BRCA1/2 variant testing using circulating tumor DNA testing (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. 5

NTRK Gene Fusion Testing to Select Targeted Treatment in Ovarian Cancer

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive NTRK gene fusion testing using tumor tissue to guide treatment with a tropomyosin receptor kinase (TRK) 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.

Summary of Evidence

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer 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 NCCN recommendations.

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive somatic BRCA1/2 variant testing 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 advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive homologous recombination deficiency (HRD) testing using tumor tissue 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 advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive somatic BRCA1/2 variant testing using circulating tumor DNA testing (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 advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive NTRK gene fusion testing using tumor tissue to guide treatment with a tropomyosin receptor kinase (TRK) 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.

Supplemental Information

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

Practice Guidelines and Position Statements

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

American Society of Clinical Oncology

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.^4,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 [progression-free survival] benefit against possible OS [overall survival] 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.)"

National Comprehensive Cancer Network

The current NCCN guidelines for ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) are version 3.2025.^9, Guidelines are updated frequently; refer to the source for most current recommendations.

The guidelines include the following relevant recommendations on biomarker testing to guide targeted therapy in ovarian cancer:

• "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 deficiency (HRD) 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, HER2 status (by IHC), BRCA1/2, HRD status, MSI, MMR, TMB, FRa, RET, BRAF, and NTRK if prior testing did not include these markers.

• Molecular analyses may be performed on circulating tumor DNA (ctDNA or liquid biopsy) when tissue-based analysis is not clinically feasible.

• Validated molecular testing should be performed in a CLIA-approved facility."

Recommendations on the use of PARP inhibitors for ovarian cancer include the following:

Maintenance Therapy After Recurrence

• "PARP inhibitor options include niraparib, olaparib, or rucaparib.

• Niraparib is limited to those with a deleterious or suspected deleterious germline BRCA mutation.

• Olaparib and Rucaparib are limited to those with a deleterious or suspected deleterious BRCA mutation.

• Caution should be used when using maintenance PARP inhibitor for longer than 24 months.

• There are limited data on the use of a maintenance PARP inhibitor in patients who previously received a PARP inhibitor.

• Combination bevacizumab/PARP inhibitor is not recommended at this time for maintenance after recurrence therapy."

First-Line Maintenance Therapy

• "After first-line therapy with bevacizumab, data are limited on maintenance therapy with a single-agent PARP inhibitor (olaparib or niraparib ) for patients with a BRCA1/2 mutation. However, based on the magnitude of benefit of PARP inhibitor maintenance therapy for other subgroups, single-agent PARP inhibitors can be considered."

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." ^23,

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in August 2025 did not identify any trials that would likely influence this review.

References

1. National Cancer Institute. NCI Dictionaries: Homologous Recombination Repair Pathway. n.d. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/homologous-recombination-repair-pathway. Accessed August 1, 2025.
2. 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
3. Myriad Genetics. MyChoice CDX Myriad HRD Companion Diagnostic Test. 2024. https://myriad.com/genetic-tests/mychoicecdx-tumor-test/. Accessed August 1, 2025.
4. Tew WP, Lacchetti C, Kohn EC. Poly(ADP-Ribose) Polymerase Inhibitors in the Management of Ovarian Cancer: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. Nov 20 2022; 40(33): 3878-3881. PMID 36150092
5. AstraZeneca. Dear Healthcare Professional (Lynparza). 2023. https://www.lynparzahcp.com/content/dam/physician-services/us/590-lynparza-hcp-branded/hcp-global/pdf/solo3-dhcp-final-signed.pdf. Accessed August 1, 2025.
6. Clovis Oncology, Inc. United States Securities and Exchange Commission Report (Rubraca). 2022. https://d18rn0p25nwr6d.cloudfront.net/CIK-0001466301/017377a8-ad55-47da-ac40-91c5f2a5f69f.pdf. Accessed August 1, 2025.
7. GSK. Dear Health Care Provider Letter (Niraparib). 2022. https://www.zejulahcp.com/content/dam/cf-pharma/hcp-zejulahcp-v2/en_US/pdf/ZEJULA%20(niraparib)%20Dear%20HCP%20Letter%20November%202022.pdf. Accessed August 1, 2025.
8. 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
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