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Myriad Reports New Data, Commercialization Updates for Tests New and Old

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Originally published June 17. This article has been corrected from a previous version to reflect that Myriad is developing the HRD test to guide platinum-based treatment decisions, and does not plan to launch BRACAnalysis in this setting.

NEW YORK (GenomeWeb) – This fall Myriad Genetics is planning to launch BRACAnalysis as a companion test that can pick out which breast cancer patients have BRCA1 and BRCA2 mutations, and therefore will respond to the PARP inhibitor olaparib.

Longer term, the company is also developing a next-generation sequencing based homologous recombination deficiency (HRD) test for picking out which breast cancer patients respond well to platinum based therapies.

Platinum-based chemo, such as cisplatin and carboplatin, are generic anti-cancer agents, and therefore drugmakers wouldn't be particularly eager to invest in the development of a companion test that identifies best responders to these drugs. However, in the absence of pharma support, Myriad has decided to step in and make the HRD test available as a lab-developed test that doctors can use to identify which breast cancer patients are likely to benefit from platinum-based regimens.

Studies show that triple-negative breast cancer patients have better responses when cisplatin is added to standard regimens. But there are significant toxicities associated with platinum treatment. "So, if you could do a better job of determining who would respond to platinum [agents], this would be a really important addition to the decision that goes into designing breast cancer chemotherapy," Richard Wenstrup, chief medical officer of Myriad Genetic Laboratories, told PGx Reporter recently.

In conjunction with the American Society of Clinical Oncology's annual meeting earlier this month, Myriad provided updates on its business plan for advancing BRACAnalysis as a companion diagnostic; the HRD test; the myRisk Hereditary Cancer test; and its myPath Melanoma test, a tissue-based test for differentiating benign and malignant skin lesions which represents Myriad's newest product. By the summer of next year, Myriad is planning to transition its flagship BRACAnalysis test into a companion diagnostic and consolidate its individual hereditary cancer risk testing into the NGS-based myRisk test.

At the meeting, the company reported new clinical data on all these diagnostics, including the first validation study for myPath.

BRACAnalysis CDx transition

With regard to BRACAnalysis, the company is hoping in the coming months to introduce it as a US Food and Drug Administration-approved companion test for AstraZeneca's PARP inhibitor olaparib. Myriad is calling the FDA-approved version BRACAnalysis CDx.

The FDA granted priority review status to AstraZeneca's new drug application for olaparib as an ovarian cancer treatment, putting it on track to receive a response from the agency by Oct. 3. In early April, Myriad announced the submission of its first premarket approval application module for BRACAnalysis as a companion test for olaparib.

Anticipating the simultaneous approval and launch of olaparib and BRACAnalysis CDx in the fall, Myriad officials have said they plan to educate physicians on the importance of testing ovarian cancer patients on BRACAnalysis before prescribing them the drug. The Society of Gynecological Oncologists currently recommends testing all ovarian and endometrial cancer patients for their hereditary risk of the diseases.

Myriad has additional companion diagnostic deals to study BRACAnalysis alongside AstraZeneca's olaparib as a treatment for breast cancer, BioMarin for its BMN-673, AbbVie's veliparib, and Tesaro's niraparib. All of these drugs are being evaluated in Phase III trials.

Also in the fall, Myriad is planning to launch a BRACAnalysis test that gauges mutations in tumor tissue. The current version of the test only assesses germline mutations in blood. A test that can gauge somatic mutations in patients' tumors will be particularly important for the adoption of BRACAnalysis as a tool that can inform cancer treatment decisions for patients.

However, Myriad will only launch the tumor BRACAnalysis version in Europe. "Right now there are no plans yet for a US launch of tumor BRCA [testing]," Wenstrup said. "The regulatory environment is different [in the US] and the FDA is mostly focusing on germline BRCA [mutations]."

Still, Wenstrup acknowledged that looking at tumor mutations will capture more patients likely to respond to PARP inhibitors, citing statistics that 14 percent of ovarian cancer patients have germline BRCA mutations, while 22 percent have somatic mutations.

Advancing HRD test

Ultimately, Myriad's HRD test stands to offer the most information to doctors when they're deciding whether a patient will respond to DNA-damaging agents. Myriad plans to launch the HRD test in 2015 as a tool for guiding treatment decisions for triple-negative breast cancer patients.

The HRD test gauges germline and somatic BRCA1/2 gene mutations, as well as a number of other markers involved in DNA repair. The test involves three assays that determine whole-genome tumor loss of heterozygosity (LOH) profiles, telomeric allelic imbalance (TAI), and large-scale state transitions (LST), and yields three scores.

Myriad believes that the combination of three scores will be a better gauge of homologous recombination deficiency and improve response prediction over BRCA testing. In a poster presentation at the San Antonio Breast Cancer Symposium last December, researchers led by Kirsten Timms and others from Myriad evaluated 213 invasive breast tumor samples and matched normal tissue samples spanning all breast cancer subtypes defined by estrogen receptor, progesterone receptor, and HER2 status. In the study, researchers from Myriad reported that all three scores are "highly correlated" with defects in BRCA1/2 and other pathway genes in breast or ovarian cancer, and can predict whether patients will respond to platinum agents.

At the ASCO meeting, Myriad added to the body of evidence on its HRD test, showing that the test, by characterizing different impaired pathways, is a more informative tool for guiding treatment strategies than testing for specific genetic markers. Myriad had previously analyzed data from the TBCRC009 study involving 86 metastatic triple-negative breast cancer patients who were treated with platinum-based therapies and tested for their BRCA mutation status. Researchers reported that nearly 55 percent of patients with BRCA1 and BRCA2 mutations responded to treatment while only 20 percent of those without these mutations responded.

Researchers led by Steven Isakoff from Massachusetts General Hospital Cancer Center reported new analysis at ASCO this year of the TBCRC009 cohort, comparing how well p63/p73 expression, PIK3CA mutations, p53 mutations, and the HRD test predicted patients' response to platinum therapy. While all the established markers failed to significantly identify responders, the HRD test yielded higher scores in BRCA mutation carriers versus non-carriers. Even in BRCA non-carriers, the HRD test was able to separate responders from non-responders.

The study shows that "as expected BRCA predicts response, but also that HRD ends up being the best predictor of response," Wenstrup said. Myriad is conducting a 160-patient randomized study to assess whether its HRD test can predict triple-negative breast cancer patients' responses to neoadjuvant cisplatin and paclitaxel-based chemo. The company will present data from this study later this year.

MyRisk data

The company also presented six studies involving its myRisk Hereditary Cancer test, which is currently available to early access clinicians. Wesntrup noted that by September all of Myriad's customers will be able to order myRisk. In anticipation of retiring all its single syndrome tests and moving fully to the myRisk panel by the summer of 2015, Myriad is focused on proving the benefit of NGS panel testing.

In one study presented at ASCO, researchers tested more than 1,000 patients with a history of hereditary colon cancer with myRisk and found that 27 percent had mutations in genes not usually linked to Lynch syndrome, and one-third of these additional mutations were in BRCA1/2 genes.

Another study looked at nearly 10,000 patients who were diagnosed with breast and ovarian cancers. According to myRisk results, 22 percent had BRCA1/2 mutations, but of these patients only 56 percent would have met guidelines for testing after their first cancer. Meanwhile, in 941 patients with colon and endometrial cancer who were evaluated, 28 percent had mutations in genes linked to hereditary colon cancer, but only 65 percent would have met guidelines for testing after their first cancer.

"These findings underscore the importance of diagnosing patients with hereditary cancer syndromes after their first cancer so that a second cancer can be prevented or identified early," Myriad said in a statement announcing the results.

MyPath Melanoma validation

Lastly, Myriad also presented data from a pivotal clinical validation study involving its 23-gene myPath Melanoma test. "This is the largest clinical validation study that's ever been done for a diagnostic for melanoma," Loren Clarke, VP of medical affairs at Myriad's dermatology unit, told PGx Reporter. Using the test, researchers from Myriad and elsewhere evaluated 437 pigmented lesions in patients samples from four academic medical centers. The aim of the study was to determine the extent to which expert dermatopathologists agreed with the test results.

Using current tools, there is significant variability in how pathologists determine whether a patients' skin lesion is malignant or benign. In the study, there was between 30 percent and 40 percent discordance among experts about the diagnosis of a particular sample. After performing myPath, there was much more insight into the difficult-to-treat cases and some lesions that experts thought were false-negatives were reclassified as true negatives.

"The problem that you have with any of these tests is that your endpoint is concordance among experts. What you have to rely on is concordance among experts on straight forward lesions," Clarke said. "That seems counterintuitive, because what you want the test for is ambiguous cases."

The company is planning to commercialize this test as a tool that doctors can use along with standard tools to evaluate difficult-to-classify skin lesions. "What you're doing with the straightforward cases is identifying the signature of a melanoma and identifying the signature of a benign mole," Clarke said, explaining the design of the validation trial. "You generate that signature and that can be used on ambiguous or difficult-to-diagnose cases."

The validation study showed myPath to have a sensitivity and specificity of around 90 percent. Myriad is also conducting a prospective trial evaluating how myPath impacts dermatopathologists' decisions for patients by comparing their pre- and post-test diagnosis.

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