NEW YORK (GenomeWeb) – Myriad Genetics has filed the first module with the US Food and Drug Administration for its rolling premarket approval application for myChoice HRD, a test that drugmaker Tesaro used in studies to identify best responders to its PARP inhibitor niraparib.
However, based on FDA's feedback it's unclear whether the agency will view myChoice HRD as a companion or complementary test.
Myriad discussed these details during its second quarter earnings call this week, after a Phase III study last month showed that recurrent ovarian cancer patients benefitted from niraparib regardless of their BRCA mutation or homologous recombination deficiency status. In the NOVA study, published in the New England Journal of Medicine, median progression-free survival was 21 months in patients with germline BRCA mutations as determined by Myriad's BRACAnalysis CDx; 9.3 months in patients without such mutations, and 12.9 months in patients with homologous repair deficiency as determined by the myChoice HRD next-generation sequencing test.
Comparatively, patients receiving placebo had median progression-free survival of 5.5 months when they had germline BRCA mutations, 3.9 months when they didn't have such mutations, and 3.8 months when they were HRD positive. However, an exploratory analysis undertaken by Tesaro in HRD-negative patients showed that they also derived clinically meaningful benefit from niraparib, with median progression-free survival of 6.9 months on the PARP inhibitor compared to 3.8 months on placebo.
Myriad and Tesaro have interpreted these data differently. Following the release of the data last month, Tesaro said it is pursuing market approval for its drug in the overall recurrent ovarian cancer population. NOVA trial primary investigator Mansoor Raza Mirza from Copenhagen University Hospital in Denmark similarly told market analysts at the time that the results "warrant niraparib maintenance therapy to the whole study population, regardless of BRCA mutation status, regardless of HRD status."
"FDA will determine the test label," a Tesaro spokesperson told GenomeWeb.
Myriad, on the other hand, has focused on the ability of the HRD test to distinguish the magnitude of benefit in patients in the NOVA trial. Myriad CEO Mark Capone highlighted during the firm's second quarter earnings call yesterday that those with a positive HRD score and receiving niraparib saw a 9.1-month benefit in progression-free survival compared to those on placebo, while there was a 3.1-month benefit in the HRD-negative subset.
"This six-month difference in progression-free survival benefit is notable in a difficult-to-treat disease like ovarian cancer," Capone said, adding the data demonstrated the test's ability to delineate treatment benefit in a highly selected ovarian cancer population.
"In fact, in this particular study, approximately 70 percent of ovarian cancer patients had a positive myChoice HRD result, which makes differentiation from the overall group significantly more difficult," he explained.
But as PARP inhibitors like niraparib are approved in earlier cancer indications, Capone estimated that smaller subsets, between 25 percent and 40 percent, will have positive HRD scores. "In these indications, we believe that myChoice HRD test will be critical to identifying the subset of patients that will likely respond since the overall response will be much lower," Capone said during the earnings call.
In the meantime, Myriad is moving ahead with filing its rolling PMA application for myChoice HRD as a companion test for niraparib in the recurrent ovarian cancer population. It's uncertain though how the FDA's drug division will evaluate NOVA study data with the regard to the need for such a test.
For the time being, it seems the agency will be considering whether to greenlight myChoice HRD as a companion diagnostic, which is required for the safe and effective use of a drug, or as a complementary diagnostic, which isn't required but can be used to inform personalized treatment strategies. The agency has approved complementary tests alongside several recently launched PD-1/PD-L1 inhibitors.
During the earnings call, Capone quoted the agency as providing the following feedback: "Although, based on the clinical data available at this time, the BRACAnalysis CDx and myChoice HRD tests may be complementary diagnostics for use with niraparib, there is a possibility that niraparib will be approved for only the HRD positive and/or BRCA mutation positive subgroups. If this occurs, the devices will be indicated as companion diagnostics and it would be expected that the drug and devices are approved contemporaneously."
Myriad noted that the NOVA study results have piqued other drug firms' interest in myChoice HRD, and that it is in late-stage discussions with three pharmaceutical firms considering using the test for their PARP inhibitor or other therapeutic programs.
Capone highlighted that AstraZeneca has agreed to use its new myChoice HRD Plus test in an exploratory study involving its PARP inhibitor Lynparza (olaparib). The original myChoice HRD test detects whether patients have somatic mutations in BRCA1 and BRCA2 genes and other "genomic scars" by measuring heterozygosity loss, telomeric allelic imbalance, and large-scale state transitions. MyChoice HRD Plus also gauges mutations in 102 genes.
Over the summer, AstraZeneca announced it was working with Foundation Medicine to develop a next-generation sequencing based companion diagnostic for Lynparza that will detect alterations in a panel of genes associated with homologous recombination repair (HRR) pathways involved in fixing DNA double-stranded breaks. At the time, Susan Galbraith, VP of oncology at AstraZeneca, had explained to GenomeWeb that the drugmaker was interested in detecting the cause of HHR deficiency using Foundation's NGS panel, while Myriad's HRD test looked at "genomic scars" that are the result of the deficiency.
Although Myriad has maintained the superiority of its approach, the introduction of myChoice HRD Plus suggests the company is advancing a test that can characterize homologous recombination deficiency in patients in different ways, by assessing both genomic scars and alterations.
Myriad is also continuing to explore other indications for its BRACAnalysis CDx. The FDA approved BRACAnalysis CDx for the first time in 2014 alongside Lynparza as a treatment for advanced ovarian cancer patients who have received three or more prior chemotherapy agents.
Capone suggested that based on results from a recent study, called SOLO2, the test might be used to identify best responders to Lynparza in the recurrent ovarian cancer patient population. Additionally, there are 10 studies involving the BRACAnalysis CDx. One of these studies is investigating Lynparza in HER2-negative metastatic breast cancer patients. By the end of fiscal year 2018, the company is expecting results from several pivotal studies using the test to identify be responders to drugs for triple-negative breast, ovarian, and pancreatic cancer.