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Tumor BRCA Dx Could ID More Responders to PARP Inhibitors; Myriad Expects Initial Launch in Europe

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Originally published Sept. 30.

NEW YORK (GenomeWeb) – A comparison of germline BRCA mutation testing against a new diagnostic developed by Myriad Genetics that can gauge somatic mutations revealed that the latter was able to pick up 44 percent more deleterious markers in women with ovarian cancer.

In identifying additional mutation carriers, Myriad hopes its so-called Tumor BRACAnalysis CDx will be able to identify more responders PARP inhibitors. The company has long-term plans to launch somatic BRCA mutation testing as a companion diagnostic first in Europe and then in the US.

Germline mutations show up in all cells of the body, but a blood test that gauges just these mutations can miss some patients who acquire mutations only in their tumor. Gauging somatic mutations usually requires a test that analyzes markers in tumor tissue samples.

At the European Society for Medical Oncology's annual meeting in Madrid, Spain this week, researchers from Myriad and MD Anderson Cancer Center described a study analyzing approximately 130 previously untreated, high-grade ovarian cancer patients for germline BRCA mutations in blood samples and somatic mutations in tissue samples. In the study, the researchers also tested patients undergoing surgery for both of these types of mutations, and they performed germline testing using a custom amplicon assay and next-generation sequencing.

Of 92 patients who had testing for both germline and somatic markers, nearly 20 percent of patients were found to have germline mutations by blood testing. Meanwhile, testing with the Tumor BRACAnalysis CDx identified the 20 percent of patients with germline markers and an additional 8 percent of patients with a somatic BRCA1/2 mutation – marking a 44 percent increase in the number of mutations gauged.

Colin Hayward, Myriad's European medical director, said in a statement that the Tumor BRACAnalysis CDx "has the potential to greatly expand the number of ovarian cancer patients who may respond to treatment with PARP inhibitors."

Molecular diagnostics firms generally view the European market as being less onerous for commercializing new tests compared to the US. According to Myriad spokesperson Ron Rogers, the company expects to first launch the Tumor BRACAnalysis CDx in Europe around the time that AstraZeneca receives approval for olaparib. AstraZeneca submitted it market authorization application in September 2013 for olaparib as a treatment for BRCA-mutated platinum-sensitive, relapsed ovarian cancer.

The turnaround time for the tumor CDx is approximately two weeks and testing will be performed at Myriad's lab in Munich. According to Rogers, the VUS rate for the tumor CDx is similar to the germline test – below 3 percent.

Meanwhile, Myriad is currently studying germline BRACAnalysis as a CDx with drug developers in 13 Phase III studies in six different indications. Myriad has projected an annual market of 900,000 patients in the US for the CDx version of BRACAnalysis, six times the size of the current market for the test as a tool for gauging hereditary breast and ovarian cancer risk. The most advanced of its BRACAnalysis CDx efforts is with AstraZeneca for its drug olaparib.

In the US market, Myriad hasn't provided a definite timeline for when it plans to launch the tumor CDx; the firm intends to launch the germline BRACAnalysis CDx first, in line with the approval and launch of olaparib. However, the timeline for when the US Food and Drug Administration will decide olaparib's market approval has recently changed.

The FDA's Oncologic Drugs Advisory Committee (ODAC) in late June voted 11 to two against early approval of olaparib as maintenance therapy for platinum-sensitive relapsed ovarian cancer patients with germline BRCA mutations. The panel members felt that the agency should wait and see the impact olaparib has on patient outcomes compared to placebo in the Phase III SOLO-2 trial. AstraZeneca said it aims to report data from pivotal olaparib studies by the end of 2015.

Data from past studies have shown that olaparib improves progression-free survival by a median of seven months compared to placebo but ODAC members didn't find the trial provided clear indications that the drug improves overall survival. Several committee members felt that olaparib should extend survival compared to placebo in the maintenance setting, while others raised red flags about the rate of acute myeloid leukemias and myelodysplastic syndromes in olaparib-treated patients.

Although olaparib initially failed to show a survival advantage over placebo in a pharmacogenetically unselected ovarian cancer population in a trial called Study 19, AstraZeneca had hoped to show the drug's efficacy in BRCA mutated patients with retrospective analysis. At the 2013 American Society of Clinical Oncology annual meeting, AstraZeneca reported secondary analysis from the Phase II Study 19 showing that olaparib improved progression-free survival by a median of 7 months in BRCA mutated patients.

However, that trial did not report a survival advantage for olaparib over placebo when patients' germline BRCA mutation status was considered. This, according to researchers, may have been confounded by more than 30 percent of patients in the placebo arm being subsequently treated with another PARP inhibitor. But when the study investigators considered all patients with BRCA mutations (germline and somatic), the median overall survival was 34.9 months in the olaparib arm, compared to 31.9 months in the placebo arm, with a hazard ratio of 0.74. The finding wasn't statistically significant, but there was a "strong trend in favor of survival in patients taking olaparib," the lead study author said at the ASCO meeting last year.

After the June ODAC meeting, AstraZeneca submitted a major amendment to its olaparib application with the FDA, based on which the agency revised its projected approval date for the drug from Oct. 3 of this year to Jan. 3, 2015. During a second-quarter earnings call with market analysts and investors, Briggs Morrison, AstraZeneca's chief medical officer, said that the company is more optimistic based on conversations with the agency about olaparib's prospects and it is still hopeful it can net accelerated approval.

Myriad in April submitted the first premarket approval (PMA) module with the FDA for the BRACAnalysis germline test as a companion diagnostic for olaparib. Since the FDA ideally prefers that drugs and their companion tests are simultaneously approved and introduced on the market, the revised Prescription Drug User Fee Act (PDUFA) date for olaparib makes it likely that the CDx launch in the US will also be aligned to that timeframe.

Rogers noted that Myriad's CDx plans remain unchanged, and the company is still pursuing a PMA for germline BRACAnalysis as the companion test for olaparib.

The transition of BRACAnalysis into a companion test comes as the firm is also aiming to move all its hereditary cancer testing customers onto its next-generation sequencing myRisk Hereditary cancer panel by the summer of 2015. Eventually, Myriad's companion diagnostic suite will also feature an NGS assay, called the Homologous Repair Deficiency, or HRD, test.

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 profiles, telomeric allelic imbalance, and large-scale state transitions, and yields three scores.

According to Myriad, the HRD test stands to be a better gauge of homologous recombination deficiency and offer the most advanced prediction of responders to PARP inhibitors and DNA damaging agents compared to testing only for BRCA mutations. The company is hoping to launch the HRD test in June 2015 as a tool for predicting whether breast cancer patients will respond to platinum-based chemotherapies.

In the poster for the latest study presented at ESMO, researchers noted they are conducting additional studies to investigate homologous recombination defects with mutation and methylation data to fully characterize patient responses and outcomes to chemotherapy.

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