August 23, 2011 — The experimental drug olaparib (AstraZeneca) looks like a promising treatment for a wide range of ovarian cancers, not just those associated with BRCA1 and BRCA2 genetic mutations, according to a new study published online today in Lancet Oncology.
"To the best of our knowledge, this is the first study demonstrating activity of a PARP inhibitor in patients with high-grade serous ovarian cancer without germline BRCA1 or BRCA2 mutations," write lead study author Karen A. Gelmon, MD, of the BC Cancer Agency, Vancouver, British Columbia, Canada, and colleagues.
A Noteworthy Study
The study is noteworthy because it shows, for the first time, activity of a PARP inhibitor as monotherapy in women with advanced high-grade serous ovarian cancer who do not have a germline BRCA1 or BRCA2 mutation, writes Melinda L. Telli, from Stanford University School of Medicine, Stanford, California, in an accompanying editorial.
"This finding not only suggests new therapeutic possibilities for women with this aggressive type of ovarian cancer but also importantly confirms the hypothesis that subpopulations of patients with common sporadic tumors can be targeted effectively with PARP inhibitor therapy," Dr. Telli writes.
This "important finding" of activity against such a serious cancer "marks a new beginning in what will hopefully be a long and fruitful future for PARP inhibitors as they make their move beyond BRCA," she added.
Activity in Mutation Carriers
Olaparib, an investigational oral poly (ADP-ribose) polymerase inhibitor, has already shown efficacy in BRCA1 and BRCA2 mutation carriers with breast and ovarian cancer in phase 1 and phase 2 studies.
Most recently, in a study presented at the American Society of Clinical Oncology 2011 Annual Meeting, patients with platinum-sensitive relapsed serous ovarian cancer who received olaparib as maintenance therapy had a median progression-free survival of 8.4 months, compared with 4.8 months in patients who received placebo.
Dr. Gelmon and her team wanted to see whether olaparib might also have potential in a broader group of breast and ovarian cancer patients without these mutations.
"There was preclinical evidence that there may be some of the same defects in triple negative breast cancer and high-grade ovarian cancer that are in BRCA cancers, so the question was whether we could treat these non-BRCA cancers with the same drugs used in the BRCA cancers," Dr. Gelmon told Medscape Medical News.
Clinical Trial Results
In this open-label, nonrandomized trial, 65 patients with advanced high-grade serous or undifferentiated ovarian cancer and 26 patients with triple-negative breast cancer received olaparib, 400 mg twice daily for 4 weeks. They were stratified according to whether they had a BRCA1 or BRCA2 mutation or not.
The primary endpoint of the study was objective response rate by RECIST.
Of the 63 ovarian cancer patients with target lesions, confirmed objective responses were seen in 7 of 17 patients (41%) with BRCA1 or BRCA2 mutations and in 11 of 46 patients (24%) without mutations.
No confirmed objective responses were reported in patients with breast cancer. This could be due to chance because of the small sample size or to the fact that the breast cancer patients were heavily pretreated, Dr. Gelmon suggested.
Olaparib was generally well tolerated. Most adverse effects were mild and included fatigue, nausea, vomiting, and decreased appetite.
"Further studies should be done to validate this result and also to start taking it to earlier ovarian cancers," Dr. Gelmon said. "We would like to combine it with other agents. This has been tried but not very successfully. We are trying to understand which cancers will respond or not in the lab just now."
The study was funded by AstraZeneca. Dr. Gelmon reported a financial relationship with AstraZeneca. Dr. Telli has disclosed no relevant financial relationships.
Lancet Oncol. 2011;12:852-861. Abstract Editorial
"To the best of our knowledge, this is the first study demonstrating activity of a PARP inhibitor in patients with high-grade serous ovarian cancer without germline BRCA1 or BRCA2 mutations," write lead study author Karen A. Gelmon, MD, of the BC Cancer Agency, Vancouver, British Columbia, Canada, and colleagues.
A Noteworthy Study
The study is noteworthy because it shows, for the first time, activity of a PARP inhibitor as monotherapy in women with advanced high-grade serous ovarian cancer who do not have a germline BRCA1 or BRCA2 mutation, writes Melinda L. Telli, from Stanford University School of Medicine, Stanford, California, in an accompanying editorial.
"This finding not only suggests new therapeutic possibilities for women with this aggressive type of ovarian cancer but also importantly confirms the hypothesis that subpopulations of patients with common sporadic tumors can be targeted effectively with PARP inhibitor therapy," Dr. Telli writes.
This "important finding" of activity against such a serious cancer "marks a new beginning in what will hopefully be a long and fruitful future for PARP inhibitors as they make their move beyond BRCA," she added.
Activity in Mutation Carriers
Olaparib, an investigational oral poly (ADP-ribose) polymerase inhibitor, has already shown efficacy in BRCA1 and BRCA2 mutation carriers with breast and ovarian cancer in phase 1 and phase 2 studies.
Most recently, in a study presented at the American Society of Clinical Oncology 2011 Annual Meeting, patients with platinum-sensitive relapsed serous ovarian cancer who received olaparib as maintenance therapy had a median progression-free survival of 8.4 months, compared with 4.8 months in patients who received placebo.
Dr. Gelmon and her team wanted to see whether olaparib might also have potential in a broader group of breast and ovarian cancer patients without these mutations.
"There was preclinical evidence that there may be some of the same defects in triple negative breast cancer and high-grade ovarian cancer that are in BRCA cancers, so the question was whether we could treat these non-BRCA cancers with the same drugs used in the BRCA cancers," Dr. Gelmon told Medscape Medical News.
Clinical Trial Results
In this open-label, nonrandomized trial, 65 patients with advanced high-grade serous or undifferentiated ovarian cancer and 26 patients with triple-negative breast cancer received olaparib, 400 mg twice daily for 4 weeks. They were stratified according to whether they had a BRCA1 or BRCA2 mutation or not.
The primary endpoint of the study was objective response rate by RECIST.
Of the 63 ovarian cancer patients with target lesions, confirmed objective responses were seen in 7 of 17 patients (41%) with BRCA1 or BRCA2 mutations and in 11 of 46 patients (24%) without mutations.
No confirmed objective responses were reported in patients with breast cancer. This could be due to chance because of the small sample size or to the fact that the breast cancer patients were heavily pretreated, Dr. Gelmon suggested.
Olaparib was generally well tolerated. Most adverse effects were mild and included fatigue, nausea, vomiting, and decreased appetite.
"Further studies should be done to validate this result and also to start taking it to earlier ovarian cancers," Dr. Gelmon said. "We would like to combine it with other agents. This has been tried but not very successfully. We are trying to understand which cancers will respond or not in the lab just now."
The study was funded by AstraZeneca. Dr. Gelmon reported a financial relationship with AstraZeneca. Dr. Telli has disclosed no relevant financial relationships.
Lancet Oncol. 2011;12:852-861. Abstract Editorial
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