Response to Comments: MolDX: Oncotype DX AR-V7 Nucleus Detect for Men with Metastatic Castrate Resistant Prostate Cancer (MCRPC)

On behalf of our patient centered organization we would like to communicate how pleased we are that MolDX has created a draft coverage policy for Oncotype DX ARV7 Nucleus Detect. We believe this draft LCD will expand access to the test for metastatic prostate cancer patients, who don’t have the luxury of time, to better understand their late stage disease and determine which therapy will provide the greatest impact on their disease. Recent data support that Oncotype DX AR-V7 Nucleus Detect is not only prognostic but also predictive, indicating that a patient has become resistant to ARSi therapy. This information plays a critical role in the sequencing of the advanced treatment options available for patients. Determining whether a patient should continue on to second line ARSi therapy or move to a taxane based chemotherapy. This ensures that patients are on a treatment that provides the greatest benefit and the best life extension.

For patients with advanced, late stage prostate cancer, coverage for ARV7 Nucleus Detect provides faster access to patients when there is simply no time for them to spend on treatments that are not effective. The improved and quicker access will truly have a beneficial impact on patient outcomes and survival. Thank you again for making this important tool, available to prostate cancer patients and for the opportunity to provide comment on this important coverage decision.

Thank you for the comment. We agree.

ZERO is a national nonprofit prostate cancer advocacy organization with a mission to end prostate cancer. ZERO advances research, inspires action, and improves lives the lives of men and families. In our work, we encounter men with advanced prostate cancer struggling to make optimal treatment decisions. These men lack the time and resources for suboptimal treatment.

As you know, the Oncotype Dx ARV-7 Nucleus Detect helps men with advanced prostate cancer and their physicians decide between a second androgen receptor signaling inhibitor (ARSi) or taxane chemotherapy. We are encouraged by the recent data presented at the American Society of Clinical Oncology Genitourinary Conference validating that overall survival increases in ARV-7 positive men when they use taxane chemotherapy following an ARSi. Decision making tools like ARV-7 are invaluable in that they allow men to confidently receive the therapy sequence that can give them more time with loved ones.

We encourage MolDx and the Centers for Medicare & Medicaid Services (CMS) to move expeditiously to finalize this draft LCD. Thousands of men are waiting to benefit from the life extending information that an ARV-7 test can reveal.

For that reason, we discourage MolDx from waiting for the review and later publication of the National Comprehensive Cancer Network (NCCN) guidelines in 2019. In the seven months between now and the guidelines publication, men who could have received a life-extending treatment sequence may be deceased by the time they could benefit from the new guidelines.

We appreciate MolDx being proactive and reviewing the most recent clinical utility data in an efficient manner. Men with advanced prostate cancer cannot wait for guidelines cycles because their cancers are lethal and on their own aggressive schedule.

Thank you for the comment. We agree.

Established in 1997, Biocept, Inc. is a San Diego-based CLIA licensed provider of liquid biopsy testing services that has developed minimally-invasive, blood-based methods to detect predictive cancer biomarkers (e.g., protein expression, gene fusions, gene amplifications, and oncogene mutations) utilizing circulating tumor cell (CTC), cell-free DNA (ctDNA).

We support all advancements towards providing coverage for CTCs AR-V7 as predictive test to identify the molecular characterization of a mCRPC patient’s cancer. Determining molecular signatures in blood as a complement to tissue testing is a critical benefit for some patients and their physicians in order to enable proper therapy selection.

Reimbursement coverage for the testing that provides such important information is necessary for the industry to continue advancements that improve patient outcomes while reducing cost. We would like to acknowledge the progress that Palmetto GBA has made in partnering with industry in working towards these goals.

Thank you for the comment.

Thank you very much for the coverage decision regarding Oncotype DX AR-V7 Nucleus Detect for patients who have failed enzalutamide or abiraterone and who are considering sequential AR-targeted therapy. This will be of benefit to many, many patients for both improved, directed patient care and overall health care cost savings.

I also wanted to request that you include patients who have failed apalutamide as well. This is a new AR-targeted therapy, similar to enzalutamide, which is FDA approved for treatment earlier in the disease process. Many more men will be exposed to this medication than either of the others covered under the draft indication, and there will be an even more important need to test them with the Oncotype DX AR-V7 Nucleus Detect assay to guide sequential therapy after failing apalutamide.

We have carefully considered this request. We agree that this test useful in decision making for a class of drugs, which now includes apalutamide. As such, we will expand coverage to include patients who have been treated with apalutatmide.

I support the coverage decision for ARV7, however as you know oncology is a moving target. Just last month apalutamide was approved by the FDA. for non-metastatic prostate cancer. I support your including this antiandrogen into the approval. Attached is a review article we just wrote on antiandrogens and you will see where this fits. Will be published in the Journal of Urology in 3 months.

We have carefully considered this request. We agree that this test useful in decision making for a class of drugs, which now includes apalutamide. As such, we will expand coverage to include patients who have been treated with apalutatmide.

I would like to submit two edits to the draft LCD:

1. The addition of the recently approved ARSI, Apalutamide (brand name Erleada) into the item #2 in the “Criteria for Coverage.” Apalutamide was recently FDA approved on February 14, 2018. Apalutamide is biochemically similar (only 1 atom difference, developed in the same lab) and clinically similar to enzalutamide.
   1. Current version of Criteria #2: Patients will have failed one ARSi, specifically Enzalutamide (Xtandi) or Abiraterone (Zytiga).
   2. Proposed version of Criteria #2: Patients will have failed one ARSi, specifically Enzalutamide (Xtand9), Abiraterone (Zytiga), or Apalutamide (Erleada).
2. The editing of the title and references of “metastatic castrate resistant prostate cancer” to “metastatic castration resistant prostate cancer”. This edit would be to align the commonly utilized nomenclature of “castration” vs. less utilized “castrate”.

We have carefully considered this request. We agree that this test useful in decision making for a class of drugs, which now includes apalutamide. As such, we will expand coverage to include patients who have been treated with apalutatmide.

ARV-7 measures a biological endpoint for the activity of the Androgen Receptor gene. When mutated (ie when ARV7 is expressed or exhibited), the activity of the androgen receptor is innately active and resistant to further endocrine therapy. Thus, when discovered, patients can avoid the effete and ineffective use of further endocrine therapy and, instead, move forward with immunotherapies, PARP inhibitors, cytotoxic chemotherapy, high dose testosterone, systemic bone-targeted radiation (alpharadin), or investigative measures.

I use the test to determine whether patients previously treated with enzalutamide, abiraterone, or apalutamide should move toward chemotherapy (if ARV7 is POSITIVE) or switch to a tertiary line of endocrine therapy (if ARV7 is NEGATIVE).

The test was discovered at Johns Hopkins and is clinically efficacious.

We agree that this test useful in decision making for a class of drugs, which now includes apalutamide. As such, we will expand coverage to include patients who have been treated with apalutatmide.

The AR-V7 test has been quite useful to several of my patients with advanced prostate cancer. By finding an AR-V7 mutation we were able to avoid useless therapy with further hormonal agents and move to more active therapy with chemotherapy. Given the cost and side-effects of all therapies, tools that can help refine treatment and avoid unnecessary treatment are crucial to move the field of oncology and prostate cancer forward.

Thank you for the comment. We agree.

I am writing to comment on the recent LCD for the AR-V7 assay. I am very pleased it has been approved for use for patients failing abiraterone or enzalutamide therapy, but there is additional need. Specifically, the recent (February 2018) approval of apalutamide (Erleada) for patients with non-metastatic disease creates an additional point where the AR-V7 test will be needed in the future. This drug has an identical mechanism of action as enzalutamide, and patients failing will by definition then be metastatic, castrate resistant prostate cancer patients, so they will be in an identical situation as the patients studied to gain approval. Please consider adding patients progressing on apalutamide to your LCD.

We agree that this test useful in decision making for a class of drugs, which now includes apalutamide. As such, we will expand coverage to include patients who have been treated with apalutatmide.

In my professional opinion, the AR-V7 CTC test may help provide clinical guidance on treatment decisions for men with metastatic castration resistant prostate cancer who have failed either abiraterone acetate or enzalutamide and who are candidates for further therapy. In conjunction with other clinical parameters, comorbidities, patient preferences, and available choices for next therapies, this assay can appropriately identify men less likely to benefit from further AR inhibition and could be more likely to benefit from alternative approaches such as docetaxel, cabazitaxel, radium-223, or investigational approaches. While the low prevalence of this test in the front line setting likely precludes its widespread use, in the second line setting (i.e. post-abi/enza), this can be useful particularly if positive. However, many men will test negative for AR-V7 by this test and still not respond to these hormonal therapies, so close clinical follow up is still needed.

Thank you and I have no conflicts of interest to report related to this topic other than research collaborations through Duke University with Epic Sciences, Janssen, and Johns Hopkins related to circulating tumor cell research.

Thank you for the comment.

I am very pleased with the coverage decision with regards to Oncotype DX ARV7 nucleus detect in patients with mCRPC who have failed enzalutamide or abiraterone and who are considering sequential AR targeted therapy. This is an important milestone for patients and there on going cancer care. I would also ask you to consider coverage of patients who have already received apalutamide a new ARSI for patients with nmCRPC and are considering another sequential AR targeted therapy. Determining patients receptor status helps physicians individualize patient treatment pathways, potentially avoiding medications that they might not benefit from.

Thank you for the comment.

I want to voice my support, as a prostate cancer oncologist who cares for about 400 men with prostate cancer at any given time, for the decision for coverage of the Oncotype DX AR-V7 Nucleus Detect test for prostate cancer patients with metastatic castration resistant disease. I have had the opportunity to use this assay on about 20 patients before it became fully commercially available, and have found it quite useful. It is quite helpful to have a test, which if positive, can predict with virtually 100% accuracy the futility of using and expensive drug, in this case abiraterone or enzalutamide.

I would like to suggest that a recent FDA approval of apalutamide for castration resistant prostate cancer without metastases should be addressed in your coverage decision for this new AR-V7 assay. Apalutamide and enzalutamide are both next generation androgen receptor inhibitors, have a similar biochemical structure, have the same mechanism of action, and have the same binding site on the androgen receptor. In fact both drugs came out of the same developmental lab. Since they are so similar, patients who have been exposed to apalutamide therapy and progressed should be eligible for this AR-V7 assay, just as are the patients who have progressed on enzalutamide. I hope you will consider language in your coverage decision that will include this new drug.

We agree that this test useful in decision making for a class of drugs, which now includes apalutamide. As such, we will expand coverage to include patients who have been treated with apalutatmide.

I am writing to confirm my support for CMS coverage of the Oncotype DX AR-V7 Nucleus Detect test (DL37701). The test addresses a critically important clinical decision in the day to day management of men with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on first line therapy. Specifically, who should be treated with an androgen receptor-signaling inhibitor given orally (ARSi) vs. taxane chemotherapy that is given intravenously. In our first study, we showed that the nuclear localized AR-V7 biomarker in circulating tumor cells detected with the Epic Sciences assay predicted an improved overall survival (OS) following treatment with taxane therapy over ARSi. Importantly, the test also predicted for improved outcomes for patients with AR-V7 negative CTCs by all the treatment endpoints recommended in PCWG2 (Prostate Cancer Working Group 2) including PSA changes, rPFS (radiographic progression free survival), time on therapy and overall survival. This specificity enables physicians to treat patients with a less toxic regimen to which they can benefit. We later showed in a follow-up study that the nuclear localized scoring guide was required to ensure the high specificity to non-response to ARSi.

More recently, we completed a blinded, multi-center study to validate our finding of nuclear localized AR-V7 as a predictive biomarker of patient survival. Attached is the poster presented at GU ASCO in February of this year highlighting the clinical results; the manuscript supporting the data has been accepted to JAMA Oncology and in press. The combined results of our initial and validation studies provide level 1 evidence as two Category B studies for the EPIC Sciences nuclear-localized AR-V7 as a treatment selection prediction biomarker for overall survival. These data show clearly that the nuclear AR-V7 test identifies patients who will have longer survival on taxane chemotherapy (AR-V7+) vs. longer survival on ARSi (AR-V7-). Importantly, we incorporated patient risk algorithms to demonstrate that the benefit of a gain in overall survival was not influenced by differences in patient risk and physician selection bias. In short, the test can aid physicians to maximize OS of an individual patient through better informed clinical decision making.

Thank you for the comment.

I am writing in support of the Oncotype Dx AR-V7 Nucleus Detect test. This test can fulfill an unmet need in the treatment of metastatic castrate resistant prostate cancer. Currently, there several therapies available for patients with metastatic prostate cancer which is resistant to androgen deprivation. For many patients, both chemotherapy and second line hormonal therapy (with agents like enzalutamide or abiraterone) may be reasonable options. From the data I have seen to date, the AR-V7 Nucleus Detect test is able to predict those who will respond poorly to second line hormonal therapy and may be better suited to go straight to chemotherapy. This has the potential to improve patient outcomes by forgoing unsuccessful therapy.

Thank you for the comment.

I am writing to you in support of a positive CMS coverage decision for the Oncotype Dx AR-V7 Nucleus Detect test (DL37701). The clinical question addressed by the test, who to give an ARSi vs. taxane chemotherapy, is a clear unmet need for which biomarkers are needed to guide therapy.

The clinical data linking the positivity of nuclear-localized AR-V7 to overall survival in the context of ARSi vs. taxane chemotherapy supports that the test has the potential of improving patient outcomes through utilization of the test. It is important that our Medicare patients gain access to the test to enable physicians the ability to make more informed therapy decisions.

Thank you for the comment.

The Oncotype Dx AR-V7 assay is such an important biomarker in thinking about secondary hormonal agents for our patients with metastatic prostate cancer, particularly the predictive value of not responding to another line of secondary hormonal agents in patients who have positive AR-V7 testing. I am glad that this biomarker test will be covered for our patients, to spare a subset of patients the cost and time of another line of treatment, if we know a priori from the AR-V7 test that it would be a futile treatment.

I would advocate to include coverage for this test in patients who have previously received apalutamide. This treatment is very similar to enzalutamide and was recently approved for non-metastatic castration resistant prostate cancer. Similarly to enzalutamide, exposure to apalutamide may lead resistance to other secondary hormonal agents through mechanisms like AR-V7. This AR-V7 test would be helpful in distinguishing which patients might benefit vs be resistant to another secondary hormonal therapy.

We agree that this test useful in decision making for a class of drugs, which now includes apalutamide. As such, we will expand coverage to include patients who have been treated with apalutatmide.

I am writing on behalf of the National Alliance of State Prostate Cancer Coalitions (NASPCC), a national 501(c)(3) entity comprised of more than 35 state prostate cancer coalitions across the country. NASPCC represents thousands of prostate cancer patients at the state and local level, working to obtain the best tests and treatments available to help those patients and their families.

NASPCC is extremely pleased to learn that MolDX has created a draft coverage policy for the Oncotype DX AR-V7 Nucleus Detect Test for men with metastatic castrate-resistant prostate cancer (CRPC), based in part on the recent data from Howard Scher et al that was presented at the 2018 ASCO GU Meeting. NASPCC is grateful to MolDX for expanding access to the AR-V7 Nucleus Detect Test to CRPC patients so that they can better understand their advanced stage of disease and, along with their physicians, decide their best options for treatment. Since the AR-V7 Nucleus Detect test is a predictive as well as a prognostic biomarker (Scher et al.), it is instrumental in helping to find which patents have become resistant to ARSi therapy, and thus which patients can reliably remain on ARSi therapy or should be moved to taxane therapy. Its use will thereby improve overall patient survival rates. AR-V7 as a biomarker helping to guide therapy in metastatic castrate-resistant prostate cancer can start saving lives now.

Thank you for the comment. We agree.

I was extremely pleased to learn about the Local Coverage Decision for the Oncotype DX AR-V7 Nucleus Detect assay for mCRPC patients who have failed enzalutamide or abiraterone and who are considering sequential AR-targeted therapy. This will improve our choice of sequencing for patients who have failed first line secondary hormone therapy. I am, however concerned that it did NOT also include apalutamide, Erleada, which recently got approval for M0 CRPC. These patients will often progress with PSA and/or radiographically and would benefit greatly from knowledge of their AR-V7 status.

We agree that this test useful in decision making for a class of drugs, which now includes apalutamide. As such, we will expand coverage to include patients who have been treated with apalutatmide.