Researchers have found a way of identifying which patients with ovarian cancer are likely to respond well to the new anticancer drug rucaparib. These clinical trial results were presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, in Barcelona, Spain.
Results of clinical trials have shown that women with tumors that are sensitive to platinum-based chemotherapy and who carry inherited mutations in the BRCA1/2 genes respond well to rucaparib. The new findings identified a biomarker that can predict which women without BRCA1/2 mutations will respond to the drug as well.
Rucaparib is designed to inhibit poly (ADP-ribose) polymerase (PARP), which is a protein involved in repairing damaged DNA. Women with BRCA1/2 mutations who have developed ovarian cancer respond well to rucaparib because the genetic mutation has already affected one method of repairing damaged DNA in cells, and the PARP inhibitor attacks the cancer cells’ only other DNA repair mechanism.
Study leader Elizabeth Swisher, MD, from the University of Washington School of Medicine in Seattle, explained that there are other indicators of defective DNA repair that could be used to predict responsiveness to PARP inhibitors, in addition to BRCA1/2. The international research team has seen good responses to rucaparib in women with ovarian cancers exhibiting a form of cell damage called genomic loss of heterozygosity (LOH), in which an entire chromosomal region on one copy of the genome is lost.
In the ARIEL2 phase 2 clinical trial of rucaparib, which started in October 2013, preliminary data from 121 patients have shown responses to the drug in women with tumors that have high genomic LOH, as well as in patients with BRCA1/2 mutations.
“This is the first time that we have predictors to identify women with ovarian cancer other than those with a known BRCA1 or BRCA2 mutation who are likely to respond to a PARP inhibitor. This will allow more focused application of PARP inhibitors to the women most likely to benefit from treatment with a PARP inhibitor. The more we can identify responders to specific therapies, the better women and their doctors can select the most effective treatment option,” said Swisher.
More than 80% of the planned 180 patients on ARIEL2 will be non-BRCA1/2 mutation carriers.
Of the 121 women recruited to the trial by the end of October 2014, 25% had the BRCA1/2 mutations, 42% (the majority) did not have the mutations but had high genomic LOH, and 33% had neither. The overall response rate among the 61 patients who were evaluable by the end of October was 38%, with 77% of the women having a complete response (the tumor disappearing completely), a partial response (tumor shrinkage), or stable disease (the cancer remaining unchanged).
“In this early analysis it appears that our molecular predictors are working to identify women with better response rates from women unlikely to respond to rucaparib.”
Overall, 61% of the patients remain on the treatment, which has been well tolerated, with no patients having to stop it due to unacceptable side effects. Most of the adverse side effects were mild and included nausea, fatigue, liver problems, loss of taste and appetite, anemia, vomiting and constipation.