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Tesaro Using Myriad's BRCA Test to Characterize Response in Two Niraparib Phase III Trials

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Originally published June 25.

Through a partnership with Tesaro, Myriad Genetics this year will use BRACAnalysis to help the biotechnology firm better characterize whether the BRCA mutation status of ovarian and breast cancer patients impacts their ability to respond to the investigational PARP inhibitor niraparib.

Tesaro is moving niraparib into late-stage studies as a treatment for metastatic breast cancer and high-grade serous ovarian cancer. Myriad's BRCA test will be used to establish the germline BRCA mutation status for patients in two Phase III trials.

In mid-2013 Tesaro anticipates launching a Phase III study investigating niraparib in serous ovarian cancer. In partnership with the European Network of Gynecological Oncological Trial Groups, the firm will study niraparib in a double-blind, placebo-controlled trial involving 360 ovarian cancer patients who have high-grade serous histology and are sensitive to platinum-based therapy.

Myriad's BRACAnalysis test will be used to gauge study participants' germline BRCA mutation status and patients will be randomized to receive either niraparib or placebo. This trial will investigate whether niraparib as a maintenance therapy extends progression-free survival and overall survival in ovarian cancer patients compared to placebo, characterize the drug's safety, and evaluate these outcomes in the entire study population, as well as by BRCA mutation status.

“We are evaluating both germline BRCA mutation status and platinum sensitivity as potential predictors of clinical response in our Phase III study in ovarian cancer," Mary Lynne Hedley, president of TESARO, told PGx Reporter. "This trial is designed to enroll germline BRCA-positive and -negative patients, all of whom will be platinum sensitive, in two separate cohorts."

Tesaro sped the development program for niraparib into Phase III after seeing positive results in a two-part Phase I dose-finding trial, which, according to the company, particularly supported looking at platinum sensitivity and BRCA status as response predictors to niraparib in ovarian cancer patients. In the first part of this study involving 60 patients, three out of four patients with platinum-sensitive, high-grade serous ovarian cancer achieved a response by RECIST criteria on niraparib 300 mg. This dose, which will be used in Phase III trials, demonstrated a low rate of serious toxicities but commonly caused anemia, fatigue, and nausea.

Additionally, in this trial, 46 percent of patients across all niraparib dose levels (30 mg to 400 mg/daily) achieved a response, and 50 percent of those who had BRCA mutations and were platinum sensitive had a response by RECIST criteria. For platinum-sensitive, BRCA mutation-positive patients the median duration of response to niraparib was 431 days, while platinum-sensitive patients who didn't carry BRCA mutations had a median duration of response for 444 days.

The second part of this Phase I study involved 40 patients with platinum-resistant, high-grade serous ovarian cancer or castration-resistant prostate cancer. These patients received niraparib 300 mg/daily, and this second portion of the study allowed researchers to further evaluate the impact of the 300 mg/daily does in patients. Only preliminary data from this Phase I study was presented at the American Society of Clinical Oncology's annual meeting earlier this month.

Since Tesaro will be looking at both platinum sensitivity and BRCA mutation status as pharmacogenomic markers in the Phase III serous ovarian cancer study, it may turn out that one marker is more tightly linked to niraparib response than the other. The Phase III study will enable Tesaro to further refine the indication of niraparib in ovarian cancer, and discern whether the drug needs to be launched with a companion BRCA test.

"Regardless of BRCA status, because of the preponderance of homologous recombination deficiencies among platinum sensitive patients, both germline BRCA positive and negative patients could be sensitive to PARP inhibitors, and this study design will enable us to analyze responses in each of these groups," Tesaro's Hedley said.

In collaboration with the non-profit Breast International Group and the European Organization for Research and Treatment of Cancer, Tesaro is also advancing niraparib into a Phase III breast cancer study, which will enroll only those with germline BRCA mutations.

This trial, slated to launch in the second half of this year, will enroll approximately 300 BRCA mutation-positive patients with advanced metastatic breast cancer who have been previously treated with an anthracycline and a taxane. Study participants will be randomized to receive either niraparib or a number of chemotherapeutic agents chosen by the investigators. Researchers will follow patients to see whether niraparib meaningfully improves progression-free survival and overall survival compared to the chemo agents.

This latest collaboration with Tesaro marks one of several collaborations Myriad has inked with drug and biotech firms around the personalization of PARP inhibitors. For example, Myriad recently announced it had submitted an investigational device exemption application with the US Food and Drug Administration to use BRACAnalysis to pick out best responders to AstraZeneca's PARP inhibitor olaparib in Phase III ovarian cancer studies (PGx Reporter 6/5/2012). AstraZeneca is also using BRACAnalysis to gauge germline BRCA mutations in study participants.

BRCA genes are involved in repairing damaged DNA in cells, a function essential to cell survival. However, when patients have mutations in BRCA1 and BRCA2 genes, cells in their body have limited ability to repair DNA damage. Research suggests that those with BRCA 1/2 mutations are at greater risk for familial breast and ovarian cancer, but 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.

Based on this hypothesis, a number of drug developers are investigating whether PARP inhibitors in their pipeline will be more effective in BRCA mutation carriers. BioMarin Pharmaceuticals, Abbott Pharmaceuticals, and PharmaMar are also working with Myriad to study the effect of their PARP inhibitors in BRCA-mutated patients.

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