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With Accumulating Data, Interest Growing in Myriad's Prostate Cancer Prognostic Dx Prolaris

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Data recently published and presented on Myriad Genetics' prostate cancer prognostic test Prolaris is getting physicians and patients interested in learning how the multi-gene diagnostic can be used to gauge disease aggressiveness.

Myriad Genetics presented data at the American Society of Clinical Oncology's annual meeting last week from five studies involving its prostate cancer prognostic test Prolaris in various clinical settings. The retrospective studies, when considered together, suggested that the genetic test score, calculated from the expression of a panel of cell cycle progression genes, can accurately determine which prostate cancer patients are at risk of aggressive prostate cancer and which are likely to have indolent disease. The test was able to gauge progression in a variety of patient cohorts and provided information beyond standard clinical and pathological measures, the data showed.

Prolaris, which analyzes the expression of 31 cell cycle progression genes and 15 housekeeper genes, has so far been investigated in nine studies. Data from five of these studies were presented at ASCO, four of which have been published and one that has been accepted for publication.

In these studies, Prolaris was used to test samples from more than 300 patients conservatively managed after transurethral resection of the prostate; from more than 300 patients conservatively managed after needle biopsy; from two cohorts involving close to 800 patients who had received radical prostatectomy; and from more than 140 patients who had received external beam radiation therapy.

Because prostate cancer takes a long time to progress, the genomic analysis was done retrospectively and correlated with outcomes in the various trials. Patients in these original studies were followed for outcomes such as death from prostate cancer or biochemical recurrence with some patients followed for as long as 15 years.

The results of these investigations show that the Prolaris score "does predict outcomes in multiple cohorts in diverse clinical settings, provides independent information beyond classical clinicopathologic variables, and can help differentiate aggressive or indolent cancers," Jack Cuzick of the Wolfson Institute of Preventive Medicine in London, said during a presentation on Prolaris at ASCO. "Exactly how you use that [score] I think is still something that is being developed, but particularly for those with low-grade, Gleason 6, low-risk cancers, you can get a clear indication of those that are truly at low risk and those that need more aggressive therapy." Cuzick was the lead researcher in several of the studies involving Prolaris.

Additionally, in these studies, the Prolaris score proved to be "a highly significant predictor of outcome," Cuzick noted, adding that "it was the dominant predictor in all but one of the studies in the multivariate analysis."

There was some correlation in these studies between the Prolaris score and other prognostic measures such as prostate-specific antigen testing and Gleason Score. However, Cuzick described these correlations between the Prolaris score and PSA or Prolaris and Gleason Score as "weak" or "modest," noting that these are not measuring the same thing.

Likely due to the presentation of this data at ASCO and at other recent medical conferences, at least two prostate cancer specialists PGx Reporter spoke to – William Catalona at Northwestern University and John Davis at MD Anderson Cancer Center – said they're seeing growing interest in Prolaris, as well as in molecular diagnostics for prostate cancer prognosis in general, from fellow colleagues and their patients.

In urologic cancers, "we use essentially no genetic information relating to the tumor in order to tailor our therapies" and as such, "the bar is exceptionally low," Scott Tomlins from the University of Michigan Medical School said at ASCO in reviewing data on Prolaris and several other prostate cancer-related biomarker studies. "In terms of the [Prolaris] scores for prognostic biomarkers, I think this is of great interest both clinically and in the lay population that we often over-treat … and we really need to identify patients who can benefit from less or more therapy."

Prolaris and other prostate cancer molecular tests are entering the market at a time when currently available tools aren't specific enough to distinguish between men who have an aggressive form of prostate cancer and need invasive treatments, and those that are low risk and can do well with active surveillance. The NIH estimates that in 2010, the annual medical costs associated with prostate cancer in the US were $12 billion.

Approximately 240,000 men are diagnosed with prostate cancer and 30,000 men will die of the disease in the US each year. However, around one million men are biopsied for prostate cancer annually. Moreover, Myriad estimates that as many as 85 percent of prostate cancer patients are aggressively treated, which causes 30 percent of these men to experience complications such as incontinence and impotence.

Focus on cell cycle genes

In its strategy to diversify its molecular diagnostics pipeline beyond inherited cancers, Myriad is focused on bolstering the use of Prolaris, which it began developing six years ago. Taking into consideration published literature and institutional knowledge that the company has garnered through its work in breast cancer, Myriad's scientists decided to focus on cell cycle progression genes for the prostate cancer test.

"What the scientists at Myriad did … is look at the signatures available from the breast cancer literature and … [then do] an analysis of the informative genes in those panels. They concluded … that the most informative genes in these breast cancer signatures were the cell cycle progression genes," Michael Brawer, Myriad's VP of medical affairs, told PGx Reporter. "So, based really on that, they decided to begin looking at the genes within the cell cycle progression family."

Myriad's researchers started with 126 cell cycle genes and eventually narrowed that down to the 31 genes in the Prolaris test. "Cell cycle genes are those that regulate cell division, and [they are] such a fundamental hallmark of malignancy because cancer is unregulated cell growth, and because more importantly, the high division rate of cancer cells allows the mutations to be passed on to the daughter cells that … can give rise to the really aggressive [prostate cancer] phenotype," Brawer said.

The company has so far received more than 3,000 orders for Prolaris from 350 urologists. Myriad is marketing the test to urologists and radiation oncologists, who are primarily treating early stage disease. The test is indicated as a prognostic tool for men upon first cancer diagnosis and after they've had surgery to remove all or part of the prostate gland. At a list price of $3,400, these two indications present as much as a $1.2 billion annual market opportunity.

In the post-prostatectomy setting, Prolaris would be used to gauge which prostate cancer patients are at high risk of progression and should be followed more closely or treated with adjuvant external beam radiation therapy or systemic therapy.

Myriad in July last year launched Prolaris in the early prostate cancer setting, where the test is used to analyze biopsy samples at diagnosis to assess the risk of disease progression. The "much bigger population for this test is in the biopsy setting," Brawer said.

"This is really the test where we can identify who has a more indolent prostate cancer, a cancer best suited for conservative management" or "active surveillance," he noted, "as opposed to those who have a more aggressive cancer that may need definitive therapy and indeed need more than monotherapy, [such as] combination therapy."

Among the studies presented at ASCO was one in which researchers tested biopsy samples from 141 patients treated with electron beam radiation therapy and found that the test score was significantly associated with patients' outcomes and provided information about disease progression beyond standard clinical measures. Although this finding needs to be further validated in a larger patient cohort, the study authors concluded that Prolaris "could be used to select high-risk men undergoing electron beam radiation therapy who may need combination therapy for their clinically localized prostate cancer."

Based on data from this study, soon to be published, doctors can potentially use Prolaris to analyze patients' initial biopsy result, and assess early on "who is likely to fail monotherapy and may be much better served by combination therapy at initial presentation," Brawer noted.

Growing interest

Particularly in the prostate cancer setting, patients don't usually ask about molecular testing options. However, now, with the availability of a number of prognostic tests from Myriad and others, and the recent launch of Genomic Health's Oncotype DX prostate cancer test (PGx Reporter 5/15/2013), such diagnostics have become a hot topic of discussion in mainstream media outlets. All of sudden, physicians are receiving calls from patients asking if they can be tested.

However, given that these are still early days for molecular diagnostics for prostate cancer and these tests are expensive, doctors are being selective in deciding which tests to use, when to use them, and in what types of patients. Davis at MD Anderson has ordered Prolaris for approximately 10 patients deemed high risk by pathologic measures, and all have gotten low risk scores by the molecular test. As such, he has chosen to follow these patients with active surveillance instead of giving them costly radiation treatment.

Davis has a consulting agreement with Myriad to give talks on molecular markers for prostate cancer, but the company doesn't have control over the content of his presentations, he said.

Davis said he would recommend Prolaris to his colleagues. He also has written a letter to the Centers for Medicare & Medicaid Services to urge coverage of Prolaris. In that letter, Davis highlighted two patients for whom he used Prolaris in order to gain more guidance on how he might manage their disease.

For one 50-year-old, morbidly obese patient with a PSA of 4.5 and a Gleason Score of 3+3, testing with Prolaris yielded a value of -1.7. With this Prolaris score, the 10-year prostate cancer-specific mortality "was too low to calculate," Davis wrote in his letter to Medicare. Based on standard prognostic measures, he noted this patient would have requested radical prostatectomy, which could have been risky given his weight. With the Prolaris results, the patient is on active surveillance and is pursing weight loss measures.

"Traditionally, you think with a young guy with low-grade cancer, he's so young he needs surgery. But the guy weighs way too much," Davis told PGx Reporter. "You do the [molecular] test, and it shows highly favorable disease, so then maybe you can do surveillance and let him lose weight and do the test in the future."

Davis in the letter to CMS also highlighted the case of a 75-year-old with a PSA of 4.1, a Gleason Score of 3+4, and a history of diabetes, hypertension, deep vein thrombosis after hip replacement, and pulmonary embolism that requires chronic warfarin. Prolaris testing yielded a score of -1.7, the same as in the previous case. Although this patient was initially convinced he needed radical prostatectomy, after learning his Prolaris score, "he changed his mind and agreed to active surveillance." Given the Prolaris result, Davis said he was satisfied that this man's cancer is "unlikely to be lethal in his remaining life expectancy."

Prostate cancer patients, such as this elderly man, may provide a clear-cut opportunity to use molecular diagnostics, according to Davis. "Take someone who by biopsy criteria would normally get treated but they're old and has comorbidities … and then you do a molecular test that shows that the disease is highly non-aggressive," he said. "You could save someone unnecessary therapy and possible side effects."

As more tests are ordered, Davis hopes that he and his colleagues will begin to figure out the types of clinical scenarios in which Prolaris may be most informative. "I'm not out there saying everyone needs to test everybody," he said. "But find an area where you're uncertain and see if this helps."

Meanwhile, after several presentations were made on prostate cancer molecular diagnostics during the annual meeting of the American Urological Association last month, Catalona at Northwestern received a half dozen emails and phone calls from patients expressing interest in getting tested. His colleagues have said they've received similar requests from patients.

So far, Catalona has used Prolaris on one patient, but the test didn't change the planned treatment course. Based on the results of a biopsy, Catalona, a specialist in prostate cancer surgery and developer of the PSA screening test, recommended surgery for this patient. However, the patient wasn't convinced, hoping to be followed with active surveillance, and so he requested molecular testing.

"The patient's tumor by the Gleason Grade was a moderately aggressive tumor, not one that would be considered for active surveillance," Catalona said. "He had the [Prolaris] test and the score pretty much agreed with the Gleason Grade. So, in his case, it didn't change anything, but he felt better having two independent tests indicating that he really needed treatment."

Similarly, Davis acknowledged that molecular testing may not always help doctors make "an absolute change in management." Citing the example of his young patient with a weight problem, Davis noted that sometimes physicians already have an idea of what they want to do but they need some confirmation.

He pointed out that Myriad's test and the competing tests are all looking to answer somewhat different questions regarding prostate cancer progression. Davis chose Prolaris because the test has been out on the market the longest and there have been several published studies validating the test's performance. But he added that he might eventually try the other molecular tests for his patients when appropriate.

For Catalona to use Prolaris more broadly for his patients he would need to see more data. Noting that Myriad has a track record of performing reliable molecular tests, he characterized the currently available data on Prolaris as "not particularly compelling, but pretty good." However, if a prostate cancer patient made a reasonable case in requesting molecular testing, Catalona said he'd recommend testing if the out-of-pocket cost of the diagnostic wasn't an issue for the patient.

Convincing payors

With the publication of different studies involving Prolaris, Myriad is also in the process of building the evidence base to convince payors to reimburse for the test. According to Myriad's Brawer, some private payors are reimbursing for Prolaris. The test, however, isn't yet covered for Medicare patients — and the majority of prostate cancer patients, around 60 percent, are covered under Medicare.

Payors often require data from prospective studies showing that a particular treatment or intervention is clinically useful, but in prostate cancer this might be difficult. Brawer explained that given how slowly prostate cancer advances, it would take far too long to conduct a prospective analysis involving Prolaris. "You have to wait 10 or 15 years for outcomes," and within that time "the test will have morphed," he said. "In this setting, I don't anticipate anyone will be doing true prospective genomic testing in prostate cancer."

Short of following patients for oncologic outcomes, Myriad is conducting prospective studies, called PROCEED, in the commercial and academic setting, in which researchers are gauging the degree to which the Prolaris score changes physicians' treatment decisions. The company is hoping that this analysis, slated for completion next year, will convince the Centers for Medicare & Medicaid Services to cover Prolaris for the Medicare population. Industry observers have estimated that in order to garner Medicare coverage, Myriad will need to show that when doctors used Prolaris, they changed at least 20 percent of treatment decisions based on test results.

In his letter to CMS, MD Anderson's Davis urged for Medicare coverage of the test, noting that Prolaris "has the ability to change many default treatment paths for patients who may or may not be good candidates for active surveillance and the post-operative radiotherapy decision."

Without Medicare coverage, Davis estimated that his patients typically have an out-of-pocket charge of close to $400 for a test like Prolaris. "So far, I've not seen any prostate cancer patient to whom I've recommended [molecular testing] say 'no' based on cost," Davis noted. "So, in many ways, the rate limiting factor has been me."

Tomlins reflected during his review of the Prolaris data at ASCO that the broad adoption of prostate cancer biomarkers will require "buy-in" from a number of different stakeholders. In order for molecular diagnostics to be adopted in the management of prostate cancer, it will be particularly critical for Prolaris and other tests to show that they can be used to avoid costly treatment.

Given the cost of standard interventions for prostate cancer, Davis felt that the price of molecular prognostic tests are not out of line. He estimated that currently surgery and radiation can amount to $30,000 to $40,000. Moreover, standard procedures that physicians use to learn more about a prostate cancer patients' disease, such as MRI, can run up to $5,000. Even to re-biopsy a prostate cancer patient costs a few thousand dollars for ultrasounds, physicians, and pathology services.

Using molecular testing, "you only have to [avoid] a handful of adjuvant or primary radiation or surgeries to make up for that," said Davis.

In Catalona's view, however, a test with a $3,000 price tag may be too much to pay in order to give a patient peace of mind, particularly when test results don't change the treatment course the physician had originally planned. Still, Catalona ─ who is conducting genomic research to identify prostate cancer risk markers ─ is interested in seeing what molecular tests like Prolaris can do for patients who have been understaged by clinicopathological measures and are thought to have low-risk disease. By identifying high-risk patients earlier, molecular tests can also impact costs in downstream care.

Ultimately, the undeniable need for better prognostic tools to gauge prostate cancer is what's spurring Davis and other doctors to seek out molecular diagnostics like Prolaris. "I think there is a role for these tests, but there is a language barrier built into that," Davis said. "My personal interest is talking to other doctors about what that language is going to be and who are the people that need testing, and which treatment decisions are we going to make. I don't have all the answers right now but I'm interested in the area."

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