Myriad Asks FDA to Approve myChoice CDx to Find Potential Lynparza Candidates

Myriad Asks FDA to Approve myChoice CDx to Find Potential Lynparza Candidates

Myriad Genetics submitted an application to the U.S. Food and Drug Administration (FDA) seeking approval of its myChoice CDx test to identify ovarian cancer patients likely to benefit from first-line maintenance therapy with Lynparza (olaparib) in combination with bevacizumab.

The supplementary premarket approval (sPMA) application follows the FDA’s granting of priority review status to a request by AstraZeneca and Merck to approve Lynparza and bevacizumab for women with advanced ovarian cancer who respond to first-line platinum-based chemotherapy. Merck is known as MSD outside the U.S. and Canada.

Both submissions were supported by positive results from the PAOLA-1 Phase 3 trial (NCT02477644), which showed that the combination significantly delayed disease progression or death compared with bevacizumab alone, and that women with defects in homologous recombination — a DNA repair mechanism — benefited the most from the treatment.

Myriad’s myChoice CDx identifies these DNA repair defects in tumors by assessing mutations in the BRCA1 and BRCA2 genes, along with three biomarkers of genomic instability (a high frequency of mutations within the genome).

These three biomarkers are loss of heterozygosity, when one of the two copies of a gene is deleted, telomeric allelic imbalance, meaning a significant difference in the length of the end regions of chromosomes, and large-scale state transitions, or large breaks in DNA resulting in misalignments.

Because tumors with homologous recombination defects are more dependent on other DNA repair mechanisms involving the PARP enzyme — a DNA damage sensor — they are more likely to respond to treatments that block PARP activity (PARP inhibitors) such as Lynparza.

Lynparza is an oral PARP inhibitor developed by AstraZeneca and Merck. It is approved for the maintenance treatment of women with recurrent ovarian cancer responding to second-line or later platinum-based chemotherapy and for the treatment of BRCA-mutated advanced ovarian cancer that failed at least three prior chemotherapy regimens.

Lynparza is also approved as a first-line maintenance treatment for advanced ovarian cancer patients, but only for those with BRCA mutations. The companies expect approval will be extended to first-line maintenance, in combination with bevacizumab, to all women, regardless of BRCA status.

PAOLA-1 was designed to compare a combination of Lynparza plus bevacizumab against bevacizumab and a placebo as maintenance treatment for women newly diagnosed, advanced ovarian cancer who were in response to platinum-based chemotherapy.

It included 806 participants, with or without BRCA mutations, who received twice-daily tablets of either Lynparza (537 patients) or a placebo (269) for up to two years, in combination with bevacizumab, given every three weeks for up to 15 months.

About half of the women (48%) had HRD-positive tumors, based on a score of 42 or higher in the myChoice CDx test or the presence of BRCA mutations.

PAOLA-1 results demonstrated that Lynparza extended the time patients lived without disease worsening from 16.6 months to 22.1 months, lowering patients’ risk of disease progression or death by 41%.

Women with BRCA mutations saw a 69% reduction in risk of disease progression or death; in women with homologous recombination defects (which also included mutations in BRCA genes), the figure was 67%; and women with defects in homologous recombination other than BRCA mutations had a 57% decline in risk.

The findings suggest that, by detecting women with either BRCA mutations or homologous recombination defects, MyChoice CDx will be able to identify ovarian cancer patients more likely to benefit from Lynparza.

“This regulatory submission represents another important milestone for the myChoice CDx test,” Nicole Lambert, president of Myriad Oncology and Women’s Health, said in a press release. “Our goal is to improve patient care through precision medicine and ensure that women with advanced ovarian cancer have access to targeted therapies.”

MyChoice CDx is approved by the FDA to identify patients eligible for late-line treatment with another PARP inhibitor called Zejula (niraparib), and is being reviewed as a diagnostic test for the identification of women more likely to benefit from Zejula first-line maintenance treatment.