This story has been updated to add information from Jonathan Ledermann's presentation at the ASCO annual meeting. Originally published June 1.
CHICAGO -- Myriad Genetics has submitted its first investigational device exemption application with the US Food and Drug Administration for BRACAnalysis, laying the regulatory groundwork for the test to be studied in five pivotal trials to pick out best responders to AstraZeneca's PARP inhibitor olaparib.
If these trials are successful, Myriad will be able to apply to garner premarket approval of BRACAnalysis as a companion test to olaparib.
AstraZeneca spokesman David Ginivan told PGx Reporter that the company will start two Phase III trials involving olaparib in BRCA-mutated ovarian cancer in the third quarter of this year. One study will investigate olaparib maintenance therapy in the first-line setting in ovarian cancer patients with BRCA mutations, and the second trial will assess the drug in platinum-sensitive, relapsed ovarian cancer patients who harbor these mutations. According to AstraZeneca's R&D pipeline posted on the firm's website, the company is also investigating olaparib in breast cancer patients with BRCA mutations.
Myriad spokesman Ron Rogers told PGx Reporter that this is the first IDE that the company has filed for BRACAnalysis. The company, however, has a number of deals with drug developers, including Abbott Laboratories, Cephalon, BioMarin, and PharmaMar, to use BRACAnalysis to pick out best responders to investigational PARP inhibitors.
AstraZeneca has recently said that it plans to start Phase III studies for olaparib later this year. In Europe, the company has filed a letter of intent with the European Medicines Agency and expects to submit data on the drug within the year.
At the American Society of Clinical Oncology's annual meeting this week, AstraZeneca released data from a pharmacogenomic subgroup analysis of a randomized, double-blind, placebo-controlled Phase II trial, which had originally failed to show an overall survival advantage for olaparib compared to placebo.
Originally, to participate in this trial, patients didn't have to have their BRCA mutation status analyzed, but mutation status was already known for 97 of 265 patients. These patients "appeared to have better survival than other patients in this trial," lead author Jonathan Ledermann of University College London Cancer Institute said during a presentation at the meeting. This led investigators to hypothesize that olaparib might yeild a progression-free survival and overall survival benefit in those harboring BRCA mutations.
For this retrospective analysis, researchers from AstraZeneca and elsewhere led by Ledermann determined germline BRCA mutation status from the blood samples of patients who had consented and somatic BRCA tumor mutation status from archived tissue samples, and identified 136 patients in total who had a BRCA mutation.
Patients who inherit germline BRCA mutations carry the alteration in all the cells of their body, while those that do not inherit such a mutation may acquire a somatic mutation only in their tumor cells. BRACAnalysis was used to test for germline mutations in this Phase II study.
According to AstraZeneca, researchers worked with the diagnostic firm Foundation Medicine to determine somatic BRCA mutations in patients' tumors. Foundation Medicine uses next-generation sequencing-based technologies to profile tumors for many cancer-related genes, and is working with a number of drug developers to stratify patients in clinical trials and inform drug development portfolios.
Patients in the study with germline BRCA mutations who were treated with olaparib experienced median progression-free survival of 11.2 months, compared to 4.1 months for those who received a placebo. Patients with somatic mutations treated with olaparib similarly lived for a median of 11.2 months without their cancer progressing, compared to 4.3 months in the placebo arm.
Interim overall survival analysis in the two treatment arms didn't appear to change when analyzed according to germline BRCA mutation status, yielding a hazard ratio of 0.85 in patients with germline mutations and 0.84 in those without germline mutations. However, the study authors noted that 13 out of 37 patients with germline BRCA mutations were treated with a subsequent PARP inhibitor which could have confounded the overall survival analysis in this subset of patients.
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. When looking at overall survival by BRCA mutation status "we see a strong trend in favor of survival in patients taking olaparib," even though it was not significant, Ledermann said at the meeting.
In the PGx subanalysis, researchers also considered a new endpoint, dubbed progression-free survival 2, in which they looked at how long patients lived without their tumors progressing from the time they were randomized to when they started a second PARP inhibitor after failing on olaparib or placebo, and then failed on that second treatment. This analysis yielded a hazard ratio of 0.46 for patients with BRCA mutations and PFS2 was extended from 15.3 months to 23.8 months.
Ledermann said that this showed that a "clinically meaningful benefit for the effect … of olaparib is carried over beyond progression and beyond the time that [patients] failed to the time that they failed a second subsequent therapy." He added that because so many patients switched over to another PARP inhibitor, this made is difficult to gauge an overall survival benefit.
There was no statistically significant difference in the quality-of-life parameters between the treatment arms among those with BRCA mutations. Treatment related side effects were also similar between mutation carriers and non-carriers, and low grade nausea and fatigue were the most common side effects in the study. Of the 33 patients in this trial who received olaparib for more than three years, 22 had a BRCA mutation.
Based on the findings from this PGx substudy, "olaparib maintenance treatment led to the greatest clinical benefit in patients with a BRCA mutations," the study authors concluded. Ledermann and colleagues recommended that data from this subset analysis should be confirmed in Phase III trials.
AstraZeneca had previously tried, unsuccessfully, to advance olaparib as an ovarian cancer treatment without a pharmacogenomic strategy. In December 2011, AstraZeneca nixed plans to move olaparib into Phase III studies for the treatment of serous ovarian cancer after interim analysis of the Phase II trial (the same study in which they conducted this latest retrospective PGx analysis) showed that patients treated with the drug didn't appear to live longer than those on placebo. Data from this study, published in the New England Journal of Medicine last year, showed that at interim analysis, 101 patients had died, 52 in the olaparib arm and 49 in the placebo arm.
However, AstraZeneca is now restarting its olaparib development program in ovarian cancer with a PGx strategy after seeing data from the subset analysis. "Based on these data, Myriad will collaborate with AstraZeneca to deliver BRCA testing for its pivotal clinical studies," the company said in a statement.
BRCA genes are involved in repairing DNA damage in cells, a function essential to cell survival. However, when patients have mutations in BRCA1 and BRCA2 genes, cells in their body lose this repair ability. Although patients with BRCA1/2 mutations have a higher predisposition for breast and ovarian cancer, research suggests that they are also more likely to respond to the PARP inhibitor class of drugs. PARP inhibitors block cells' ability to repair DNA damage, so in BRCA mutated tumors that are already DNA-repair deficient, the cancer cells are inundated with faulty DNA and die.
AstraZeneca is currently in discussions with the FDA about the clinical development program for olaparib, but could not provide a timeline for when it might file a new drug application for the treatment.
“In the US, we will be using Myriad's BRACAnalysis test as a companion diagnostic test for olaparib in the Phase III studies. AstraZeneca and Myriad are jointly exploring the regulatory pathway for both the drug and companion diagnostic,” AstraZeneca's Ginivan said. "Prospective recruitment of the Phase III studies will be based on assessment of germline BRCA mutation status only."
Myriad's BRACAnalysis test is currently available as a laboratory-developed test and is performed by the firm's CLIA certified laboratory. The test is sold as a tool that doctors can use to gauge inherited germline BRCA mutations in patients and determine if they have a heightened risk of familial breast and ovarian cancer. Carriers of germline BRCA1 or BRCA2 mutations have up to an 87 percent risk of developing breast cancer and up to a 44 percent chance of developing ovarian cancer by age 70.
Recently, Myriad announced plans to retire BRACAnalysis, which currently comprises the majority of the firm's product revenues, and phase out its other hereditary cancer tests by the summer of 2015. In place of these tests, Myriad will launch a 25-gene, next-generation sequencing-based hereditary cancer panel, called myRisk Hereditary Cancer. Slated for launch by the end of the year, the myRisk test will gauge many of the hereditary risk markers currently assessed by Myriad's existing tests.
As part of this evolution, BRACAnalysis will also transition from a hereditary breast and ovarian cancer risk test to a companion diagnostic for various PARP inhibitors. "While Myriad will be replacing the BRACAnalysis test with myRisk Hereditary Cancer for hereditary cancer testing, the company plans to offer BRACAnalysis testing as a companion diagnostic – following review by FDA – to help select patients who are likely to respond to PARP inhibitors," the company said in a statement.
Myriad's various companion diagnostic collaborations with pharma companies represent a fast-growing segment of the company's revenues. For the quarter ended March 31, Myriad's companion diagnostics revenues grew by 25 percent from the previous year's quarter to $8.1 million. Revenues from this segment contributed 5 percent of total revenues during this period.