MolDX: Prolaris Prostate Cancer Genomic Assay for Men with Favorable Intermediate Risk Disease Comments and Responses

The comment period for the MolDX: Prolaris™ Prostate Cancer Genomic Assay for Men with Favorable Intermediate Risk Disease (LCD) DL37082 began on 02/08/17 and ended on 04/10/17. Comments were received from the provider community. The notice period begins 08/10/17 and ends 09/24/17. The LCD becomes final on 09/25/17.

Comment Response
The Prolaris test enables men and their practitioners to make informed decisions about whether to safely pursue active surveillance rather than a medical intervention by understanding the aggressiveness of the tumor. It is important for men to understand when they can safely choose active surveillance because some outcomes of treatment can result in side effects such as impotence and/or urinary incontinence. Such side effects have a personal and social impact on men that result in a lower quality of life, even leading to depression. We do not want any man to suffer, whether from cancer or treatment side effects, when it can be avoided. We therefore advocate for finalization of the draft LCD that expands access to Prolaris to men with intermediate favorable risk disease. Your supporting comments are noted.
Subsequent to publishing the draft LCD, NCCN posted its most recent update of the prostate cancer guidelines on February 21, 2017. We suggest updating the draft LCD to reference the current version (v2.2017) of the NCCN guidelines for prostate cancer. There have been no changes to the statements relevant to men with favorable intermediate risk disease. However, indications of Gleason grade group have been added to the description of the risk groups and changes have been made to the treatment options for the high risk group. We also noted that the treatment options listed in the draft LCD for intermediate risk patients were slightly inconsistent with NCCN. We believe that coverage of Prolaris for Medicare beneficiaries with favorable intermediate risk prostate cancer provides an opportunity to identify men who may safely pursue active surveillance and increase physician/patient confidence in that choice. Your supporting comments are noted. The slight changes in the NCCN Prostate Cancer (v2.2017) have been updated in the policy.
I have focused on the treatment of prostate cancer for my career, participating with numerous biomarker trials, risk stratification, controversies re: overtreatment/overutilization newly diagnosed PCa, as well as challenges and undertreatment of advanced prostate cancer (CRPC, etc). I am writing to support the favorable recommendation for Prolaris coverage support for patients with favorable risk intermediate disease who are newly diagnosed. Way too often, this patient population might be better served by considering an active surveillance option, and likewise, many of these patients, may be best suited for an interventional therapy. Unfortunately, both patient and physician are only able to rely upon historic metrics of PSA, DRE, and histopathology. The Prolaris score provides significant decision making value for patients and physician's when the treatment/surveillance decision is still unclear. I have participated in multiple prostate cancer biomarker and genomic assay trials, as well as have authored multiple publications on this topic. My work has involved: Prolaris, Oncotype Ox, Decipher, ConfirmDx, 4K, Exosome, etc. I have no stock or equity position in any of the companies associated with any of these tests. I have specifically used the Prolaris test both in research and post commercial approval to better counsel my patients and amplify patient-physician shared decision making. Your supporting comments are noted.
I am writing to you in support for the use of the Prolaris test for men diagnosed with the NCCN risk category Favorable Intermediate Disease. According to the 2017 NCCN Prostate cancer risk assignment, Favorable Intermediate is defined as Gleason score 3 + 4 = 7, and percentage of positive biopsy cores <50 percent, and no more than one NCCN intermediate risk factor. The NCCN continues to state that these patients may be considered for Active Surveillance (AS) as a treatment option. Although many of these men will, indeed, be potential candidates for AS, it is often difficult to determine who will actually be a good candidate.

I have been treating men with Prostate Cancer (PCa) for over twenty years as both a private practice and an academic Urologist. Because the decision of how to best treat (or not treat) a PCa patient can be very difficult, our group began to investigate the use of genomic markers to aid in appropriate treatment options. After studying the literature on all the available genomic markers, our group determined that the Myriad Prolaris test demonstrated superior science and clinical utility. We then engaged in the Prolaris clinical utility study to determine whether our physicians would actually use the test to guide their treatment decisions. Our doctors overwhelmingly used the results of the Prolaris test to help guide their treatment decisions. It was then that our practice adopted the test.

XXXXX Partners has been using the Prolaris test regularly for over 3 years and have ordered over 600 tests. Our physicians continue to use the results in their treatment decisions. In fact, we have incorporated the use of Prolaris into our treatment protocols over many NCCN risk categories. We have subsequently continued to assess the clinical utility of the test within our practice to confirm that the test remains useful in clinical decision-making. It has, indeed, remained a useful tool in our treatment algorithm

The decision for treatment of men in the Favorable Intermediate (FI) risk category continues to be difficult. In the past, most physicians would have offered definitive Active Intervention (AI) for all these men. Several studies have indicated, however, that many men within the FI risk category are excellent candidates for AS. The question remains on how to best determine which of these men would be appropriate candidates for AS versus AI. The Prolaris test provides a measure of tumor aggressiveness validated (in two independent studies) across all risk categories.		 Your supporting comments are noted.
The Myriad Prolaris Assay significantly helps inform the clinician and his or her patient on the major dilemma of counselling a prostate cancer patient with ANY RISK GROUP of localized disease: specifically, whether or not the cancer requires treatment, AND if so, whether monotherapies (surgery or radiation alone), or combined-modality therapies (surgery and adjuvant radiation, radiations combined with androgen deprivation therapies of various durations) are sufficient or required

Traditionally, physicians have used "risk-stratification" based solely on the parameters of biopsy Gleason Score, T-stage, and PSA level at diagnosis to help guide these decisions. This risk-strata approach initially proposed by Anthony D' Amico has been widely adopted and now modified and utilized by the NCCN treatment guidelines. It is my opinion that the NCCN treatment guidelines represent the most evidence-based expert consensus treatment guidelines available

The problem with existing risk-stratification schemes is that there is an incredibly wide variability of oncologic outcomes seen within these risk strata. It would also be a mistake to presume that the only relevant oncologic outcome of interest for prostate cancer patients is overall or disease specific-survival. In addition to death, prostate cancer patients suffer fates other than death. These include significant morbidity from metastatic disease, and significant morbidity from failing to achieve cure in men who may be put on indefinite systemic therapy that includes androgen deprivation therapies and chemotherapies. Systemic therapies to avoid death from prostate cancer take a significant toll on a patient's quality of life, cost payers including Medicare substantial sums, and cost our economy in terms of loss of productivity for otherwise able persons who can no longer work due to sequlae of living with metastatic disease and side effects of therapy

The EXISTING coverage for the Prolaris Assay limiting its use in only NCCN Very Low or low Risk indicates a misunderstanding of the role of the assay and the data supporting its routine clinical use. In addition, limiting the use of the Prolaris Assay by NCCN risk strata is inconsistent with the latest edition of the NCCN treatment guideline. In the NCCN guideline version 2.2017, the use of molecular based assays is to be considered as part of the "initial clinical assessment" pathway before NCCN risk stratification is completed. Although I cannot officially speak for the NCCN, as a writing committee member of this guideline I feel we placed this molecular testing recommendation prior to the NCCN risk stratification step by intent. It is there, and specifically there, because the Myriad Prolaris test (and others) provide import prognostic risk assessments for various oncologic endpoints that are INDEPENDENT of our historic risk stratification schemes. The exact current wording of the guideline is: "Men with clinically localized disease may consider the use of tumor based molecular assays. Retrospective case cohort studies have shown that molecular assays performed on biopsy or prostatectomy specimens provide prognostic information independent of NCCN risk groups. These include, but are not limited to, likelihood of death with conservative management, likelihood of biochemical progression after radical prostatectomy or external beam therapy, and likelihood of developing metastasis after radical prostatectomy or salvage radiotherapy

The scientific papers referenced in your Draft LCD in fact specifically support these conclusions. None of the studies validating the clinical utility of the assay isolated the utility to very low, low, or favorable intermediate risk groups

The test is already validated at prognosticating death from cancer in men choosing conservative management in any NCCN risk group. In addition, the test can accurately prognosticate biochemical failure after radiation therapy from biopsy tissue for all NCCN risk groups. In these patients, when pathologic or molecular parameters outside of those found in traditional risk strata are concerning, patients may benefit from either the addition or withdrawal of androgen deprivation therapy, as well as the addition or withdrawal of site-specific radiations (such as deciding on whether or not pelvic nodal radiotherapy or including the entirety of the seminal vesicles is warranted)

NCCN risk strata are based on the Gleason score, digital rectal exam, and PSA findings alone. In addition to those parameters, clinicians routinely use additional parameters such as the PSA doubling time, PSA density, and findings on imaging studies such as Bone Scan, CT and MRI, and predictive nomograms to guide treatment decisions specifically because the "one size fits all" approach of risk stratification is so poor. The Myriad Prolaris test is one of the only additional tests to be vigorously tested and validated on all NCCN risk groups, with hazard ratios and confidence intervals that are significant to predict outcomes better than any other parameter yet tested

I respectfully ask that you ACCEPT the draft to enable expanded coverage of the Prolaris test to men with "favorable intermediate risk" prostate cancer. I would also like to request that coverage be expanded to include any newly diagnosed prostate cancer patient who has localized disease. If Medicare limits the test to only those in the favorable intermediate risk, Low and Very Low risk populations as proposed, you will have taken away one of the only tools that has proven to prognosticate outcomes and alter clinical decision making since the Gleason Score was first described over forty years ago. In this comment to the draft I did not specifically reference the numerous peer-reviewed publications that support these conclusions, as those papers have already been included in the draft LCD. Nevertheless, I would be happy to offer a substantially more detailed analysis or serve as an expert consultant if requested.		 Your supporting comments are noted.
I have a large proportion of men within an active surveillance protocol and I encourage my partners to do the same for low risk disease. We have been utilizing the Prolaris test for these low risk men to help encourage appropriate choice of active surveillance as a treatment. This helps us avoid overtreatment and side effects of therapies that may not show survival benefit for this group of Medicare patients

We have been incorporating recent NCCN guideline changes and expanding active surveillance to low-intermediate risk patients. These patients have greater variation between low risk and higher risk outcomes. Genetic testing has been very beneficial for use in identifying men at higher risk that would benefit from therapy. Personally, I believe these tests are more beneficial in these intermediate risk patients instead of low risk men with inherently low risk disease. I find that the test changes management in these intermediate risk patients more often than in the low risk patients. I feel confident based on previously published data the Prolaris test means as much to outcome and risk as standard pathologic criteria such as Gleason score and PSA.		 Your supporting comments are noted.
Over the past 2 years our practice has gained significant experience with Prolaris, and we currently have standing orders with specific patient types. Prolaris provides an objective cell cycle progression score allowing us greater insight into the kinetics of the tumor. We combine that with PSA and Gleason in order to build a more predictive model of personalized tumor behavior. The result has allowed us to reduce outcome variability across patient types but especially in our Intermediate risk population

The level of evidence for Prolaris across all risk groups has distinguished itself in our group. Through our experience with nearly 500 tested patients about 50% of results demonstrate prostate tumors are either less aggressive or more aggressive than PSA, Gleason or other patient features suggest. Knowing the aggressiveness of the patients own tumor allows us to more effectively choose the right treatment for them at the right time. We have seen an overall increase in active surveillance in our practice as a result of utilizing the test, which is important due to the widespread concerns of overtreatment of prostate cancer

While there are several biomarker tests on the market, Prolaris is our test of choice and we believe an advancement in PCa risk stratification beyond typical clinical and pathologic features. Based on our experience, we strongly recommend that CMS provides coverage for Prolaris in Favorable Intermediate (Gleason 7(3+4)) patients. This risk group is challenging and we have found significant benefit when using Prolaris to determine the right treatment for this population.		 Your supporting comments are noted.
The current proposed expanded coverage of Prolaris would be consistent with current NCCN guidelines, which state that "men with favorable intermediate-risk prostate cancer can be considered for active surveillance", while acknowledging that such a choice "should be approached with caution, including informed decision-making and close monitoring for progression". As stated in the draft Local Coverage Determination, approval of Prolaris in this population is expected "to help determine which patients with favorable intermediate risk needle biopsy proven prostate cancer can be conservatively managed rather than treated with definitive surgery or radiation therapy". The use of Prolaris will allow the physician and patient to better assess cancer-risk than predicted by clinical features alone. Prolaris testing in this population will serve as a critical component of the informed decision-making process. Your supporting comments are noted.
I am a urologic oncologist with expertise in treating men with prostate cancer. As you know active surveillance (AS) is playing an increasingly prominent role in the management of low risk and more recently some intermediate prostate cancer. The recent NCCN guidelines have defined suitable parameters for AS in intermediate risk disease and support AS as a treatment option. Prolaris has proven itself in cases where there is some hesitancy re which option is optimal very useful as it provides further information independent of other clinical parameters. Both my patients and I have found this to be of great benefit in making what is frequently a very worrisome decision. Your supporting comments are noted.
I was one of the first to utilize the Prolaris test. I was relieved to have a test that supported, for most patients, the option of active surveillance. In addition, it helped me to focus my attention and skills on the patients with higher risk disease. I was most impressed by the tremendous volume of clinical data to support the mortality risk outcome. This was a well-designed and well-studied test. Patients were so relieved to see data to show their risk of dying from prostate cancer, often reported at 3% or less, at 10 years. This allowed for many of my patient to comfortably choose active surveillance, instead of rushing into treatment (surgery or radiation). As time has progressed, I feel more and more comfortable monitoring patients with higher risk disease. Recently the NCCN guidelines commented on active surveillance in favorable intermediate risk prostate cancer. I expect in the future we will continue to expand to include even more aggressive disease. Your supporting comments are noted.
Prolaris testing has proven quite useful in selected men with low to intermediate risk prostate cancer treated with active surveillance in whom there is a question of disease progression. Active surveillance includes careful and regular PSA monitoring, periodic prostate exam and periodic prostate biopsy. It is the preferred treatment modality for many men with low to intermediate risk prostate cancer given the fact that, even if untreated, the majority of these men will not suffer morbidity or mortality from prostate cancer. Some of these men, however, may be advised to move from active surveillance to active treatment if there is evidence of significant disease progression. What is often the case is that there is a significant change in PSA but no objective evidence of local or systemic progression on repeat biopsy, prostate exam, radiographic studies, etc. Under these circumstances, Prolaris often provides useful prognostic information as to whether or not the individual is likely to experience actual disease progression that could be prevented by moving from active surveillance to active treatment. The validity, use and interpretation of this test is well documented in the data that accompanied the LCD. It definitely has a place as described above and should be covered for its intended purpose. Your supporting comments are noted.
I am writing to you regarding: MolDX: Prolaris™ Prostate Cancer Genomic Assay for Men with Favorable Intermediate Risk Disease - DL37082 (Noridian) and DL37043 (Palmetto). I have focused on the treatment of prostate cancer for my career, participating with numerous biomarker trials, risk stratification, controversies re: overtreatment/overutilization newly diagnosed PCa, as well as challenges and under treatment of advanced prostate cancer (CRPC, etc.) I am writing now on my own personal behalf to support the favorable recommendation for Prolaris coverage support for patient with favorable risk intermediate disease who are newly diagnosed. Way too often, this patient population might be better served by considering an active surveillance option, and likewise, many of these patients, may be best suited for an interventional therapy. Unfortunately, both patient and physician are only able to rely upon historic metrics of PSA, DRE, and histopathology. The Prolaris score provides significant decision making value for patients and physician's when the treatment/surveillance decision is still unclear. I have participated in multiple prostate cancer biomarker and genomic assay trials, as well as have authored multiple publications on this topic. My work has involved: Prolaris, Oncotype Ox, Decipher, ConfirmDx, 4K, Exosome, etc. I have no stock or equity position in any of the companies associated with any of these tests. I have specifically used the Prolaris test both in research and post commercial approval to better counsel my patients and amplify patient-physician shared decision making. I would be happy to further discuss, if requested. Your supporting comments are noted.
I am commenting on the above LCD regarding Prolaris use for NCCN favorable intermediate risk prostate cancer. As already in use for low risk and very low risk prostate cancer, Prolaris has proven to be a very useful tool for verification of patients who by NCCN criteria (very low risk and low risk) may be appropriate candidates for active surveillance as the primary management for their prostate cancer. As practicing urologist with a subspecialty interest in prostate cancer, I have over 1000 active prostate cancer patients in my practice. I typically have diagnosed between 75 and 120 new patients with prostate cancer annually over the last decade. In recent years the numbers have decreased to the lower aspect of the range due to decrease in referral of patients for elevated PSA, which occurred following the US Preventative Task Force "D" rating on the use of PSA. One of the concerns that the USPSTF expressed was related to the potential overtreatment of prostate cancer leading to excess morbidity and mortality. As we continue to diagnose prostate cancer it is important that we use the best evidenced based scientific tools to help us stratify the risk related to the behavior of the cancer in order to determine treatment. Your supporting comments are noted.
In addition to its utility for patients with low risk and very low risk disease, the Prolaris test may be helpful for patients with favorable NCCN intermediate risk prostate cancer [predominant Gleason grade 3 (i.e. Gleason score 3+4=7), percentage of positive cores <50%, and no more than 1 NCCN intermediate-risk factor) NCCN intermediate risk factors include T2b-T2c, Gleason score 7, and PSA 10-20 ng/mL]. This group includes patients who have cancer with histopathologic features that make risk stratification even more challenging due to the wide variability in behavior. Some of these patients have cancer with biologic behavior that is more indolent than many low risk patients. Others have cancer that progresses to metastatic disease quickly and is lethal if not treated aggressively. However, random distribution of these patients to surveillance or treatment would lead to undesirable adverse oncologic outcomes and potential unnecessary treatment-related side effects. To be able to appropriately apportion patients in the right group based on risk of progression, would allow more patients to be identified for active surveillance with better safety. That improved risk stratification would help some patients avoid the overtreatment potential complications of radiation, surgery, and androgen deprivation. Similarly, patients who need immediate treatment would not be harmed or placed at risk of delay in potentially life-saving therapy. I hope that you consider the role of Prolaris in improving our treatment decisions for our favorable risk NCCN intermediate risk prostate cancer patients. Of note, my interest is magnified as the medical leader of a group of over 30 urologists who all share in this concern for how to best treat our patients. Your supporting comments are noted.
I am writing to you in support for the use of the Prolaris test for men diagnosed with the NCCN risk category Favorable Intermediate Disease. According to the 2017 NCCN Prostate cancer risk assignment, Favorable Intermediate is defined as Gleason score 3 + 4 = 7, and percentage of positive biopsy cores <50 percent, and no more than one NCCN intermediate risk factor. The NCCN continues to state that these patients may be considered for Active Surveillance (AS) as a treatment option. Although many of these men will, indeed, be potential candidates for AS, it is often difficult to determine who will actually be a good candidate. Your supporting comments are noted.
I have been treating men with Prostate Cancer (PCa) for over twenty years as both a private practice and an academic Urologist. Today I serve as the CEO and Chairman of the largest private Urology Practice in North Carolina and am intimately involved in our group's PCa protocol development and enforcement. Because the decision of how to treat best treat (or not treat) a PCa patient can be very difficult, our group began to investigate the use of genomic markers to aid in appropriate treatment options. After studying the literature on all the available genomic markers, our group determined that the Myriad Prolaris test demonstrated superior science and clinical utility. We then engaged in the Prolaris clinical utility study to determine whether our physicians would actually use the test to guide their treatment decisions. Our doctors overwhelmingly used the results of the Prolaris test to help guide their treatment decisions. It was then that our practice adopted the test

XXXXXX Partners has been using the Prolaris test regularly for over 3 years and have ordered over 600 tests. Our physicians continue to use the results in their treatment decisions. In fact, we have incorporated the use of Prolaris into our treatment protocols over many NCCN risk categories. We have subsequently continued to assess the clinical utility of the test within our practice to confirm that the test remains useful in clinical decision-making. It has, indeed, remained a useful tool in our treatment algorithm

The decision for treatment of men in the Favorable Intermediate (FI) risk category continues to be difficult. In the past, most physicians would have offered definitive Active Intervention (AI) for all these men. Several studies have indicated, however, that many men within the FI risk category are excellent candidates for AS. The question remains on how to best determine which of these men would be appropriate candidates for AS versus AI. The Prolaris test provides a measure of tumor aggressiveness validated (in two independent studies) across all risk categories

Because of our group's extensive experience with and trust in the Prolaris test, we are currently using it to help determine which men with FI disease would be good candidates for AS or AI. Other tests have not been validated in this risk category and offer no assistance in making appropriate treatment decisions. Our practice strongly supports the expansion of Medicare coverage of the Prolaris test to include those men with FI risk. We believe it will help provide the best information to help practitioners determine the most appropriate treatment for these men.		 Your supporting comments are noted.

 

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