Title XVIII of the Social Security Act (SSA), §1862(a)(1)(A), states that no Medicare payment shall be made for items or services that “are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.”

42 Code of Federal Regulations (CFR) §410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

CMS Internet Online Manual Pub. 100-02 (Medicare Benefit Policy Manual), Chapter 15, Section 80, “Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests”

This contractor will provide limited coverage for an Androgen Receptor splice variant 7 messenger RNA protein test (AR-V7) to help determine which patients with metastatic castrate resistant prostate cancer or other androgen receptor containing tumors may benefit from androgen receptor signaling inhibitor therapy and which may benefit from chemotherapy.

AR-V7 is covered as follows:

1. Patients will have progressive mCRPC as defined by the Prostate Cancer Working Group 2 guidelines (a minimum of 2 rising prostate-specific antigen (PSA) levels 1 or more weeks apart, new lesions by bone scintigraphy, and/or new or enlarging soft tissue lesions by computed tomography (CT) or magnetic resonance imaging (MRI)).
2. Patients will have failed one ARSi, (presently Enzalutamide (Xtandi), Apalutamide (Erleada), or Abiraterone (Zytiga) and future similar class drugs approved by the FDA) .
3. Patients will be considered appropriate for treatment by their treating physician for the alternative ARSi as a single
4. Circulating tumor cells (CTC) with nuclear expression of AR-V7 protein will be assessed prior to initiation of therapy.
5. Decision impact analysis: We expect that < 15% of nuclear AR-V7-positive patients will receive an
6. Efficacy analysis: Nuclear AR-V7-negative patients who receive an ARSi will have similar or better time on therapy than untested mCRPC patients (meeting above criteria) receiving

Other Androgen Receptor variant tests that demonstrate an equivalent analytical validity and clinical validity will be considered reasonable and necessary for similarthe listed diagnoses and criteria listed below. indications. Analytical and clinical validity will be assessed as part of a thorough and comprehensive technical assessment (TA) by the MolDx program and will similarly attain coverage for indications that are supported by the evidence and intended use within the scope of this policy.

Men with metastatic castration resistant prostate cancer (mCRPC) have multiple life extending, FDA- approved therapeutics options. However, there is no clear consensus on the therapeutic sequencing after initial exposure to an androgen receptor signaling inhibitors (ARSi), such as such as apalutamide, abiraterone, or enzalutamide or others to be developed. The response rate for a second ARSi, Abiraterone after Enzalutamide, or Enzalutamide after Abiraterone is lower than the initial exposure. Therefore, the most common clinical decision focuses on whether to start a second ARSi or taxane chemotherapy. It is therefore important to identify patients who will not respond to a 2nd ARSi in order to 1) avoid giving an ineffective therapy, and 2) delaying giving a more effective therapy, such as taxane chemotherapy, taxane combination therapies, Radium-223, PARP inhibitors, and platinum chemotherapy.

AR-V7 protein results from alternative androgen receptor (AR) mRNA splicing, which produces a constitutively active receptor that is associated with resistance to ARSi such as abiraterone and enzalutamide.^1,2 A growing body of evidence suggests that patients with AR-V7 positive mCRPC do not benefit from ARSi therapy but may respond to taxanes, such as docetaxel.^3-5 Supporting observations include that 1) AR-V7 positivity is associated with resistance to androgen receptor-targeted therapies⁴; 2) taxanes are equally effective in AR-V7–positive and AR-V7–negative mCRPC patients^3,5 ; and 3) AR-V7 status may change during therapy.⁶ For these reasons, the National Comprehensive Cancer Network (NCCN) suggests that AR-V7 is a biomarker that may help guide therapy in mCRPC. ⁷

AR signaling requires that the AR transcriptional elements bind to DNA within the nucleus of the cancer cell. Therefore, the nuclear localization of the AR-V7 truncated protein may improve the clinical specificity of predicting ARSi resistance.⁸ Analysis of AR-V7 localization scoring guides has demonstrated that currently only nuclear AR-V7 protein expression improves the clinical specificity of predicting ARSi resistance, and importantly, is associated with improved overall survival with taxane chemotherapy.⁹

Level of Evidence

Numerous prior Medicare coverage decisions have considered the evidence in the hierarchical framework of Fryback and Thornbury ¹¹where Level 2 addresses diagnostic accuracy, sensitivity, and specificity of the test; Level 3 focuses on whether the information produces change in the physician's diagnostic thinking; Level 4 concerns the effect on the patient management plan and Level 5 measures the effect of the diagnostic information on patient outcomes. To apply this same hierarchical framework to analyze an in vitro diagnostic test, we utilized the ACCE Model Process for Evaluating Genetic Tests.¹² The practical value of a diagnostic test can only be assessed by taking into account subsequent health outcomes. When a proven, well established association or pathway is available, intermediate health outcomes may also be considered. For example, if a particular diagnostic test result can be shown to change patient management and other evidence has demonstrated that those patient management changes improve health outcomes, then those separate sources of evidence may be sufficient to demonstrate positive health outcomes from the diagnostic test.