In two small phase II clinical trials, the drug olaparib, which blocks a DNA-repair enzyme called PARP, shrank tumors or stopped the progression of advanced breast and ovarian cancer in some women with inherited BRCA1 or BRCA2 gene mutations. Cancer cells with BRCA mutations are thought to be especially sensitive to PARP inhibition because they have a defect in another DNA repair pathway and therefore rely on the pathway that involves PARP. The results of both studies were published online July 6 in The Lancet.
In the breast cancer trial, Dr. Andrew Tutt of King’s College London School of Medicine and his colleagues enrolled 54 women with locally advanced or metastatic breast cancer and verified BRCA1 or BRCA2 mutations. All of the women had undergone at least one prior chemotherapy regimen. Half of the women received 400 mg of olaparib twice daily—the maximum tolerated dose—and the other half received 100 mg of olaparib twice daily, which preliminary studies showed is the minimum amount to have antitumor effects. Preliminary results were presented at the 2009 ASCO annual meeting.
Tumors shrank in 11 of the 27 women in the 400 mg group and 6 of the 27 women in the 100 mg group. The median duration of this response was 144 days in the former group and 141 days in the latter. Twelve women who participated in the study experienced temporary stabilization of their disease.
The women who received 400 mg had a median survival without disease progression of 5.7 months compared with 3.8 months in the 100 mg group. Forty-one percent of patients in the 400 mg group and 33 percent of patients in the 100 mg group experienced a high-grade side effect, including fatigue, nausea, and vomiting.
Similar results were seen in a parallel phase II trial of olaparib for recurrent ovarian cancer in women with BRCA1 or BRCA2 mutations. In that trial, led by Dr. M. William Audeh of Cedars-Sinai Medical Center in Los Angeles, 33 women received 400 mg of olaparib twice daily and 24 received 100 mg twice daily. Tumors shrank in 11 women in the 400 mg group (with a median response duration of 290 days) and 3 women in the 100 mg group (a median response duration of 269 days).
The authors of the breast cancer paper noted that women in both the breast and ovarian trials had received a median of three previous chemotherapy regimens, meaning their disease was highly resistant to treatment. Future trials should compare the efficacy and toxicity of olaparib with traditional cytotoxic chemotherapy, they said.
From the National Cancer Institute:
http://www.cancer.gov/ncicancerbulletin/071310/page3
Click here for the abstract of the ovarian cancer study
Click here to read an article in the Philadelphia Inquirer about this trial.
