Lynparza Long-Term Responders Likely to have Deficient DNA Repair

Lynparza Long-Term Responders Likely to have Deficient DNA Repair
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Long-term, progression-free survival in women with ovarian cancer treated with Lynparza (olaparib) is likely linked to deficient DNA repair mechanisms, particularly those caused by mutations in the BRCA genes.

In addition to that finding, the study, “Long-term responders on olaparib maintenance in high-grade serous ovarian cancer: Clinical and molecular characterization,” showed that patients who had a complete response to chemotherapy had a better chance of not developing resistance to the treatment. The report was published in the journal Clinical Cancer Research.

Because about 70% of women with high-grade serous ovarian cancer relapse despite good responses to initial treatment, researchers are seeking ways to prevent  patients from relapsing.

Lynparza is a PARP inhibitor drug that improved progression-free survival — from 4.8 months to 8.4 months — in an earlier trial (NCT01081951), when used as a maintenance treatment after chemotherapy.

To assess which characteristics might predict a longer response to the treatment, researchers at the Princess Margaret Cancer Centre in Canada and AstraZeneca, analyzed the features of patients who had not progressed for at least two years. The patients were participating in another clinical trial (NCT00753545), comparing Lynparza with placebo.

Researchers compared 37 patients with a long-term response to 61 who had relapsed after less than three months. Of the long-term responders, only five were on placebo, while 32, or 86.5%, had received Lynparza. Among short-term responders, only 34.4% were treated with Lynparza.

Among long-term responders, 56% had a complete response to chemotherapy, which was predictive of a long-term response. In contrast, only five of those who relapsed quickly had a complete response.

In their search for molecular features linked to a long-term response, the research team found that 73% of Lynparza-treated patients with a long progression-free survival had mutations in either the BRCA1 or BRCA2 genes. In addition, all five of those receiving placebo, who did not progress in two years, had such mutations.

In contrast, methylation of the BRCA genes was not linked to treatment response. Methylation of a gene acts to silence it, and can, therefore, mirror mutation effects.

In addition, the analyses indicated that DNA repair deficiency was more common among long-term Lynparza responders, but the difference between long- and short-term responders was statistically insignificant.

To verify if the observed correlations held true in another patient group, the research team ran the same analyses on patients from the earlier trial. All patients with a long progression-free survival in the trial had received Lynparza. The team also could confirm that the presence of BRCA gene mutations correlated to long-term response. All 11 of those who progressed within three months did not carry BRCA mutations.

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