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Readying HRD Test for Early-Access Launch, Myriad Reports Data to Strengthen Predictive Claims

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SAN ANTONIO, TX – Researchers presented fresh data on Myriad's MyChoice HRD test supporting previous studies that have shown it can predict response to platinum-based treatments in triple-negative breast cancer (TNBC) and suggesting for the first time that the test could also be a predictive tool in the broader subset of early-stage HER2-negative breast cancer patients. 

MyChoice HRD is a key part of Myriad's companion diagnostics portfolio, alongside BRACAnalysis CDx and Tumor BRACAnalysis CDx. The next-generation sequencing, tissue-based HRD test measures the ability of a patient's cancer cells to repair DNA damage and predicts response to PARP inhibitors and platinum-based chemotherapies.

Myriad has so far conducted seven studies involving myChoice HRD to predict response to platinum drugs in ovarian cancer and TNBC patients. Researchers from the company were involved in the two breast cancer studies presented at the San Antonio Breast Cancer Symposium this week.

The new data come as Myriad is getting ready to provide a select group of physicians early-access to myChoice HRD. Johnathan Lancaster, chief medical officer of Myriad Genetic Laboratories, told GenomeWeb at SABCS that the company is in the process of identifying academic sites that see ovarian cancer patients who are commonly treated with platinum-based therapies.

"There are academic investigators who may have interest in helping us understand some of the operational details and challenges of a tumor-based HRD assay in the gynecologic malignancy space," Lancaster said. "Investigators may also have an interest in identifying patients who may benefit from DNA-damaging agents."

The firm has put in a lot of work to figure out when and how ovarian cancer patients are biopsied, and what the processes are for accessing patients' tissues. Lancaster said the early-access program will provide operational insights on top of this work. "We want to make sure that when we go live, even [for] things that we didn't anticipate, we've identified and ironed out the hiccups," he noted.

Although Myriad will initially introduce the test through its CLIA-certified lab, the company has previously indicated it will submit with the US Food and Drug Administration an investigational device exemption and a premarket approval application for the HRD test in Fiscal Year 2016. Toward that end, Myriad is building a lab in which it will run myChoice HRD according to FDA regulations. This lab, which will be completed in the second quarter of FY2016, will enable Myriad to submit data from Phase III studies where myChoice HRD is being used as a companion diagnostic for PARP inhibitors and other drugs.

As the test gets closer to commercialization, Myriad seems focused on building a strong evidence base for myChoice HRD, and the studies presented at SABCS add foundation.

In the first study, researchers led by Melinda Telli from Stanford University Cancer Centers pooled data from six previously conducted Phase II trials in order to investigate whether TNBC patients treated with neoadjuvant platinum-based chemotherapy responded better when their tumors were homologous recombination deficient compared to patients whose tumors were not. Approximately two-thirds of 267 patients were deemed to be homologous recombination deficient based on if they had a myChoice HRD score of 42 or higher or mutations in BRCA1 or BRCA2 genes.

This is the largest study involving myChoice HRD to date, according to Lancaster. And although the pooled analyses included studies that used different treatment regimens, the data consistently showed that TNBC patients with homologous repair deficiency have a greater likelihood of benefitting from platinum treatments than patients who don't, he observed.

Patients with a positive myChoice HRD score had a five-fold increase in pathologic complete response than those with a negative score. Moreover, researchers found that patients with homologous recombination deficient tumors were more likely to experience pathologic complete response compared to patients without this deficiency, regardless of BRCA mutation status.

Myriad is in the process of completing a second validation study for myChoice HRD involving around 400 TNBC patients. The company is hoping this study will establish the ability of the test to predict whether TNBC patients will experience a pathologic complete response to platinum agents and convince professional societies to recommend the test in guidelines.

In the second study presented at SABCS, researchers led by Roisin Connolly from Johns Hopkins School of Medicine gauged the ability of myChoice HRD to predict pathologic complete response in a broader subset of early-stage breast cancer patients. The original TBCRC008 trial involved 62 patients who received preoperative carboplatin and paclitaxel, plus or minus Zolinza (vorinostat). The latest analysis was based on homologous recombination deficiency status and pathologic complete response information from 48 patients 30 were hormone receptor-positive and 18 had TNBC (negative for ER, PR, and HER2).

The researchers found that 50 percent of patients with homologous repair deficient tumors — defined as having an HRD score of 42 or more or BRCA mutations — achieved pathologic complete response compared to around 8 percent of those without homologous repair deficiency. Researchers reported similar efficacy in both hormone receptor-positive and TNBC patient subsets. Even when researchers considered 40 patients without BRCA mutations, 64 percent of those with a high myChoice HRD score had pathologic complete response compared to 8 percent of those with a low score.

This study supports prior data showing that Myriad's test predicts response to platinum-containing treatment in TNBC. However, this is the first study to suggest that the test could also be a predictive tool for hormone-receptor-positive, HER2-negative breast cancer patients, which comprises 70 percent of newly diagnosed cases.

"We're now starting to see the benefit [of the HRD test] outside of triple-negative breast cancers," Lancaster said, which is "causing us to question where else in breast cancer and other tumors types does homologous recombination deficiency have a potential to help physicians guide therapy."

Myriad developed the HRD test in order to capture the DNA scars that are the telltale signs of homologous recombination deficiency (HRD). Each cell in the human body experiences thousands of DNA damaging events a day, and homologous recombination is a key mechanism by which cells repair this damage. When the homologous repair mechanism isn't working as it should, DNA damage builds up and can cause cancer. However, studies have shown that drugs like PARP inhibitors and platinum agents that also break and damage DNA, are particularly lethal against cancer cells in patients who already have hobbled DNA repair capabilities.

Lancaster acknowledged that researchers haven't yet pinpointed all the reasons why a tumor might have HRD. "So it would be counterintuitive for any lab to design a test that identifies the causes. By definition, you're going to leave stuff on the table because you don't know all the causes," he said. "We're more interested in identifying as many tumors as possible that have HRD, rather than saying this is why they got there."

Myriad's HRD test score comprises measurements of whole-genome tumor loss of heterozygosity profiles, telomeric allelic imbalance, and large-scale state transitions. BRCA genes are also crucial to homologous recombination, and having mutations in BRCA1 and BRCA2 impairs DNA repair capabilities.

As such, when the myChoice HRD test is commercially launched, patients' BRCA status will be reported along with the HRD score as part of the testing service. "The nature of the HRD assay is such that BRCA testing is integral," Lancaster said.

A year ago, the FDA approved the first PARP inhibitor, Lynparza (olaparib), in advanced, heavily pretreated ovarian cancer patients who have BRCA1/2 germline mutations. AstraZeneca worked with Myriad to launch the drug with a companion diagnostic, the BRACAnalysis CDx. 

When it looked like AstraZeneca might pull the plug on the Lynparza development program due to lackluster efficacy a few years ago, this was devastating news for patients, who had been waiting eagerly for new treatment options in ovarian cancer. "It wasn't just [AstraZeneca's] PARP inhibitor, but a whole class of drugs, that was going away," Lancaster recalled.

With the approval of Lynparza alongside BRACAnalysis CDx, there is renewed hope for PARP inhibitors. "This idea of a biomarker that rescues a drug, there's no better story for precision medicine and companion diagnostics," said Lancaster.

Before deciding on BRACAnalysis CDx, AstraZeneca was initially thinking about using an HRD test to identify best responders to Lynparza, but this didn't pan out. Myriad spokesperson Ron Rogers said that the diagnostic firm has discussed its HRD test with AstraZeneca, but wouldn't elaborate. 

Publicly, Myriad has announced CDx collaborations for the myChoice HRD with a number of drug companies advancing PARP inhibitors, including BioMarin and Tesaro. Lancaster said that there is a growing appreciation among drugmakers that while BRCA testing is a good test for identifying best responders, "there is more to be gained" from assessing HRD.

After taking BRACAnalysis CDx through premarket review, Myriad feels more confident in the agency's regulatory process, Lancaster noted. As an NGS assay, the HRD test will involve different regulatory requirements, but the experience with BRACAnalysis CDx "has given us an exposure to the process and an appreciation for how high a bar the FDA sets," he said.

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