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Researchers Identify Biomarker of Response to New Ovarian Cancer Drug

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Key Points

  • Rucaparib treatment resulted in overall response rates of between 61% to 70% in women with BRCA1/2 mutations, with 83% of patients continuing on treatment.
  • In women with BRCA wild-type tumors, those with high genomic loss of heterozygosity had an overall response rate of between 32% to 40%, with 52% continuing on treatment.
  • Treatment was well-tolerated, and side effects were generally mild.

Researchers have found a way to identify which ovarian cancer patients are likely to respond well to a new anticancer drug called rucaparib. Previous clinical trials have shown that women with platinum-sensitive tumors with BRCA1/2 mutations respond well to rucaparib. In new findings presented today at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona (Abstract 215), researchers report that they have identified a biomarker that can predict which women without BRCA1/2 mutations will respond to the drug as well.

Rucaparib is designed to inhibit the poly(ADP-ribose) polymerase (PARP) protein, which is involved in repairing damaged DNA. Women with BRCA1/2-mutated 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.

In addition to identifying BRCA1/2 mutations, however, there are other indicators of defective DNA repair that could be used to predict responsiveness to PARP inhibitors, reported Elizabeth Swisher, MD, of University of Washington School of Medicine, Seattle. Dr. Swisher and her colleagues from research centers in the North America, Europe, and Australia have 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.

Phase II Trial

In the ARIEL2 phase II 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 treatments option,” Dr. Swisher said.

Women with platinum-sensitive ovarian cancer can be treated with platinum-based chemotherapies, which can be repeated should the cancer recur. However, the toxicity of the chemotherapy results in serious adverse side effects and, furthermore, it has to be given intravenously. Rucaparib is taken in pill form and is less toxic.

The ARIEL2 trial is enrolling women with platinum-sensitive, relapsed, advanced ovarian cancer and requires measurable disease and a pretreatment tumor biopsy tested for genomic LOH. The trial aimed to recruit more women with BRCA wild-type tumors in order to identify biomarkers indicating who would respond to the drug amongst this group; over 80% of the planned 180 patients on ARIEL2 will be have BRCA wild-type tumors.

Preliminary Findings

Patients were treated with rucaparib 600 mg twice a day until disease progression. To date, results have shown that not only do non–BRCA1/2 mutation carriers with high genomic LOH respond to rucaparib, but that testing for genomic LOH is an effective way of identifying those women who will respond to the drug.

Of the 121 women recruited to the trial by the end of October 2014, 25% had the BRCA1/2 mutations, 42% 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, partial response, or stable disease.

“We found that, as expected, rucaparib had the greatest clinical activity in the 23 women with the BRCA1/2 mutations. There was an overall response rate of between 61% to 70%, and 83% of the patients are continuing on the treatment,” Dr. Swisher said. “However, among the women without the BRCA1/2 mutations, the 25 with a high genomic LOH had an overall response rate of between 32% to 40%, with 52% continuing on treatment, while the 13 women without the LOH biomarker had an overall response rate of just 8%, with 38% continuing on treatment.

“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,” she said.

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.

Already, genomic LOH as a biomarker for predicting response to rucaparib has been incorporated into a test for a second clinical trial, ARIEL3, which is currently recruiting approximately 540 women with either serous or endometrioid platinum-sensitive, advanced ovarian, fallopian or primary peritoneal cancer. The effects of rucaparib vs placebo will be evaluated in groups of patients who have been molecularly defined according to their biomarker test.

The study was funded by Clovis Oncology.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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