Coverage Policy Manual
Policy #: 2022043
Category: Laboratory
Initiated: March 2023
Last Review: December 2023
  Genetic Test: Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Prostate Cancer

Description:
Biomarker-targeted therapy has shown a clear survival benefit in individuals with metastatic prostate cancer. More recently, testing for tumor mutational burden (TMB) status to select individuals for immunotherapy has been proposed. Typically, the evaluation of biomarker status requires tissue biopsy. Circulating tumor DNA (ctDNA) or circulating tumor cell testing (also known as liquid biopsy) is proposed as a non-invasive alternative.
 
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 (Mateo, 2017).
 
Friends of Cancer Research convened a consortium addressing the lack of consistency in the way HRD is defined and measurement methods (Stewart, 2022). 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 (NCCN, 2023). 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.
 
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.
  
Regulatory Status
Below is a list of targeted treatments approved by the FDA for patients with prostate cancer, along with the approved companion diagnostic tests. This information 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.
 
Targeted Treatment for Metastatic Prostate Cancer and FDA Approved Companion Diagnostic Tests (FDA, 2022; FDA, 2022):
 
Niraparib + abiraterone acetate (AKEEGA) with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated metastatic castration-resistant prostate cancer.
 
    • Companion Diagnostic Tests:
      • FoundationOne CDx (Foundation Medicine, Inc.)
 
    • Biomarkers:
      • BRCA1 and BRCA2 alterations
 
    • Pivotal Studies
      • MAGNITUDE NCT03748641 (Chi, 2023)
 
Olaparib (Lynparza) in combination with abiraterone and prednisone or prednisolone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC).
 
    • Companion Diagnostic Tests:
      • BRACAnalysis CDx (Myriad Genetic Laboratories, Inc.)
      • FoundationOne Liquid CDx (Foundation Medicine, Inc.)
 
    • Biomarkers:
      • BRCA1 and BRCA2 alterations
      • BRCA1, BRCA2, and ATM alterations
 
    • Pivotal Studies
      • PROfound NCT02987543 (Hussain, 2020)
      • PROpel NCT03732820 (Clarke, 2022)
 
    • NCCN Recommendation Level/Guideline
      • 2A/Prostate Cancer (NCCN, 2023)
 
Olaparib (Lynparza) is also indicated for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone.
 
    • Companion Diagnostic Tests:
      • FoundationOne CDx (Foundation Medicine, Inc.)
 
    • Biomarkers:
      • Homologous recombination repair (HRR) genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L alterations
 
    • Pivotal Studies
      • PROfound NCT02987543 (Hussain, 2020)
 
    • NCCN Recommendation Level/Guideline
      • 2A/Prostate Cancer (NCCN, 2023)
 
Rucaparib (Rubraca) is indicated for adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy.
 
    • Companion Diagnostic Tests:
      • FoundationOne Liquid CDx (Foundation Medicine, Inc.)
 
    • Biomarkers:
      • BRCA1 and BRCA2 alterations
 
    • Pivotal Studies
      • TRITON2 NCT02952534 (Abida, 2020)
      • TRITON 3 NCT02975934 (Fizazi, 2023)
 
    • NCCN Recommendation Level/Guideline
      • 2A/Prostate Cancer (NCCN, 2023)
 
Talazoparib (Talzenna) in combination with enzalutamide is indicated for the treatment of adult patients with HRR gene-mutated metastatic castration-resistant prostate cancer.
 
    • Companion Diagnostic Tests:
      • None
 
    • Biomarkers:
      • HRR genes
 
    • Pivotal Studies
      • TALAPRO-2 NCT03395197 (Agarwal, 2023)
 
    • NCCN Recommendation Level/Guideline
      • 2A/Prostate Cancer (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 BRCA1/2 variant analysis for individuals with metastatic castrate-resistant prostate cancer (mCRPC) to select treatment with FDA-approved targeted therapies or immunotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
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 or immunotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
Tumor testing for microsatellite instability (MSI) or mismatch repair (MMR) to select treatment for unresectable or metastatic prostate cancer with FDA-approved targeted therapies or immunotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
BRCA1/2 and ATM variant analysis using ctDNA (liquid biopsy) for individuals with mCRPC to select treatment with FDA-approved targeted 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 BRCA1/2 variant analysis to guide prostate cancer 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, all other uses of germline BRCA1/2 variant analysis to guide prostate cancer targeted therapy or immunotherapy not addressed in this or other policies considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
All other uses of somatic testing for HRR gene alterations to guide prostate cancer 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, all other uses of somatic testing for HRR gene alterations to guide prostate cancer 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.
 
All other uses of tumor testing for MSI or MMR to guide prostate cancer targeted therapy or immunotherapy not addressed in this or other polices 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 tumor testing for MSI or MMR to guide prostate cancer targeted therapy or immunotherapy not addressed in this or other polices are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
All other uses of biomarker testing with ctDNA (liquid biopsy) to guide prostate cancer 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, all other uses of biomarker testing with ctDNA (liquid biopsy) to guide prostate cancer 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 (TMB) testing to guide prostate cancer targeted therapy or immunotherapy 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 (TMB) testing to guide prostate cancer targeted therapy or immunotherapy 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 prostate 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 prostate 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
Prostate 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 prostate cancer confirmed to have a BRCA1, BRCA2, or ATM alteration. Summarized below are the pivotal trials that supported the BRCA variant-related FDA-approved indications in prostate cancer.
 
Olaparib
Hussain et al published results from the open-label, multicenter, phase 3 PROfound trial (NCT02987543), which randomized individuals with metastatic castration-resistant prostate cancer (mCRPC) and disease progression following prior treatment with a next-generation hormonal agent to treatment with olaparib 300 mg twice daily (n=256) or investigator's choice of enzalutamide or abiraterone acetate plus prednisone (n=131) (Hussain, 2020). Study participants were divided into 2 cohorts based on their HRR gene mutation status. Specifically, individuals with mutations in BRCA1, BRCA2, or ATM were randomized to cohort A (n=245) and those with mutations in 12 other HRR pathway genes (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L) were randomized to cohort B (n=142). Participants with co-mutations were assigned to cohort A. The primary efficacy outcome was radiological progression-free survival (rPFS) in cohort A, which demonstrated a statistically significant improvement for olaparib compared to control with a median rPFS of 7.4 months versus 3.6 months (hazard ratio [HR], 0.34; 95% confidence interval [CI], 0.25 to 0.47; p <.0001). The median duration of OS in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (HR, 0.69; 95% CI, 0.50 to 0.97; p =.02). In cohort B, the median duration of OS was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months.
 
Rucaparib
Abida et al published results from the phase 2, multi-center, single-arm clinical trial of rucaparib in individuals with BRCA-mutated mCRPC that supported its accelerated FDA approval in 2020 (TRITON2) (Abida, 2020). This trial enrolled 115 participants who were treated with rucaparib 600 mg twice daily. For the efficacy population, median treatment duration was 8.1 months and median follow-up was 17.1 months. The primary endpoint of objective response rate, which was rated by blinded, independent radiology review, was 43.5% (95% CI, 31.0% to 56.7%). Median rPFS duration was 9.0 months (95% CI, 8.3 to 13.5). Anemia was the most frequent grade 3 or higher adverse event (25.2%). A key limitation of this trial is its lack of a control group. Continued approval for this indication for rucaparib may be contingent upon verification of progression-free survival in the ongoing confirmatory TRITON3 trial (NCT02975934), which is a randomized, controlled phase 3 trial evaluating rucaparib 600 mg twice daily versus physician’s choice of treatment in patients with mCRPC and a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation.
 
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 solid tumors, 6 of whom had prostate cancer. In the full cohort, the ORR was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival (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 Metastatic Prostate Cancer
The purpose of tumor mutational burden (TMB) testing in individuals with advanced prostate 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 prostate 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%; 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 prostate 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.
 
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 prostate 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 with prostate cancer.
 
Biomarker Testing with Circulating Tumor DNA (Liquid Biopsy) to Guide Treatment in Prostate Cancer
One purpose of liquid biopsy testing of patients who have advanced prostate cancer is to inform a decision regarding treatment selection (e.g., whether to select a targeted treatment or standard treatment). 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.
 
Olaparib
FoundationOne Liquid is an FDA-approved companion diagnostic to detect BRCA1, BRCA2, or ATM alterations in mCRPC patients who may benefit from treatment with olaparib (FDA, 2020). Approval was based on a retrospective analysis of data from participants enrolled in cohort A of the PROfound trial (i.e., patients who had a BRCA1, BRCA2, or ATM tumor variant). The sponsor conducted a clinical bridging study to demonstrate the concordance between variant status by the clinical trial assay used for enrollment and the FoundationOne Liquid CDx, and the effectiveness of olaparib in patients identified with a variant by the liquid test. The point estimates of PPA and NPA between FoundationOne® Liquid CDx and the F1 LDT CTA assay and the corresponding 95% confidence intervals were: PPA, 79.9% (72.2% to 86.2%); NPA, 91.8% (87.0, 95.2). Estimated radiological PFS HR and the corresponding 95% confidence intervals were 0.33 [0.21, 0.53] for the FoundationOne Liquid CDx ATM/BRCA1/BRCA2 positive and F1 LDT CTA ATM/BRCA1/BRCA2 positive population, which were comparable with the observed radiological PFS hazard ratio and the corresponding 95% confidence intervals of 0.34 [0.25, 0.47] for the F1 LDT CTA ATM/BRCA1/BRCA2 positive population.
 
Rucaparib
FoundationOne Liquid is an FDA-approved companion diagnostic to identify patients with BRCA1/2 alterations eligible for rucaparib treatment in prostate cancer (FDA, 2020).,There are no FDA-approved tissue-based companion diagnostic alternatives for this indication. Approval was based on results of the TRITON2 clinical trial (NCT02952534). The ORR in the primary efficacy population was 46.3% (95% CI, 30.7% to 62.6%) in BRCA-positive patients determined by FoundationOne Liquid CDx, which was comparable to the ORR of 43.5% (31.0% to 56.7%) in patients identified by the clinical trial assay (central plasma, central tissue, or local testing). Loehr et al reported confirmed ORR by enrollment assay in 62 evaluable participants with measurable disease and found overlapping confidence intervals for all 3 estimates (Loehr, 2021). Those enrolled by central tissue testing had an ORR of 55.0% (95% CI, 31.5% to 76.9%; 11/20), compared with 31.3% (95% CI, 11.0% to 58.7%; 5/16) in patients enrolled by central plasma test and 42.3% (95% CI, 23.4 to 63.1; 11/26) in patients enrolled by local test.
 
Clinical trials have evaluated the effectiveness of PARP inhibitor drugs in individuals with prostate cancer confirmed to have BRCA1, BRCA2, or ATM alterations as determined by FoundationOne Liquid.
 
American Society of Clinical Oncology
In 2022, the American Society of Clinical Oncology (ASCO) 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 on 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 tumor mutational burden (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
Germline Testing
The current National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer are version 4.2022 (NCCN, 2022). Guidelines are updated frequently; refer to the source for the most current recommendations.
 
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: intermediate-risk prostate cancer with intraductal/cribriform histology
 
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 testing for microsatellite instability-high (MSI-H) or dMMR is recommended in patients with metastatic castration-resistant prostate cancer and may be considered in patients with regional or castration-naïve metastatic prostate cancer.
 
TMB testing may be considered in patients with metastatic castration-resistant 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.
 
DNA analysis for MSI and immunohistochemistry (IHC) for MMR are different assays measuring different biological effects caused by dMMR function. If MSI is used, testing using a next-generation sequencing (NGS) assay validated for prostate cancer is preferred.
 
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 (e.g., BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2). Post-test genetic counseling to assess for the possibility of Lynch syndrome is recommended if MSI-H or dMMR is found.
 
Ongoing and Unpublished Clinical Trials
    • NCT02975934a TRITON3: A Multicenter, Randomized, Open Label Phase 3 Study of Rucaparib Versus Physician's Choice of Therapy for Patients With Metastatic Castration Resistant Prostate Cancer Associated With Homologous Recombination Deficiency has a planned enrollment of 405 and expected completion date of March 2023
    • NCT04019964 Nivolumab as a Non-Castrating Therapy for MMR-deficient and CDK12- Altered Prostate Cancer With PSA Recurrence After Local Therapy has a planned enrollment of 15 and an expected completion date of January 2025
 
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 2023, the American Urological Association and the Society of Urologic Oncology published amended guidelines on advanced prostate cancer (Lowrance, 2023). 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)
 
The current National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer are version 3.2023 (NCCN, 2023). Guidelines are updated frequently; refer to the source for the most current recommendations.
 
The guidelines include the following relevant recommendations:
 
Targeted Therapy
    • "Consider inclusion of olaparib in patients who have an HRR mutation and whose cancer has progressed on prior treatment with androgen receptor-directed therapy regardless of prior docetaxel therapy. Olaparib is a treatment option for patients with mCRPC and a pathogenic mutation (germline and/or somatic) in a homologous recombination repair gene (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L) who have been treated previously with androgen receptor-directed therapy."
    • "Consider inclusion of rucaparib 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. If the patient is not fit for chemotherapy, rucaparib can be considered even if taxane-based therapy has not been given."
    • "Olaparib with abiraterone is an option for patients with a pathogenic BRCA1 or BRCA2 mutation (germline and/or somatic) who have not yet received a novel hormone therapy or docetaxel."
    • "Talazoparib plus enzalutamide is a treatment option for patients with metastatic CRPC and a pathogenic mutation (germline and/or somatic) in a homologous recombination repair 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."
 
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.

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
0129UHereditary breast cancer related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis and deletion/duplication analysis panel (ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, and TP53)
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)
81301Microsatellite instability analysis (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed

References: Abida W, Patnaik A, Campbell D, et al.(2020) 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

Agarwal N, Azad AA, Carles J, et al.(2023) 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

Bonneville R, Krook MA, Chen HZ, et al.(2022) 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

Chi KN, Rathkopf D, Smith MR, et al.(2023) Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. Jun 20 2023; 41(18): 3339-3351. PMID 36952634

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