ASCO 2014: Cediranib Plus Olaparib Significantly Increases Progression-Free Survival in Women With Recurrent Ovarian Cancer
The combination of two investigational oral drugs, the PARP inhibitor olaparib and the antiangiogenic drug cediranib, significantly extended progression-free survival and increased the overall response rate compared to olaparib alone in a phase II study among women with recurrent, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. The results were presented at the 2014 ASCO Annual Meeting (Abstract LBA5500) by lead study author Joyce Liu, MD, MPH, instructor in medical oncology at Dana-Farber Cancer Institute in Boston.
The progression-free survival was 17.7 months with the combination treatment vs 9 months with olaparib alone (P = .001). The 8.7 month increase in progression-free survival among the patients receiving olaparib plus cediranib was “highly statistically significant with a P value of .005 and a hazard ratio of 0.42,” Dr. Liu noted at the ASCO press briefing on targeted therapies.
The overall response rate was markedly higher in the combination arm, 80% compared to 48% in the olaparib only arm. Five patients in the combination arm and two patients in the olaparib alone arm had complete responses.
Treated Until Disease Progression
Eligible patients had cancer recurrence at least 6 months after their last platinum-based chemotherapy. Other criteria included high-grade serous or endometroid histologic subtype, “although other high-grade histologic subtypes were allowed if the patient had a known prior BRCA germline mutation,” Dr. Liu explained. “Of note, the randomization was stratified for BRCA mutation status.” Of the 90 women enrolled at nine separate treatment centers, 48 were known BRCA carriers.
Trial participants had no prior treatment with antiangiogenic drugs in the setting of recurrent ovarian cancer or with PARP inhibitors. During the trial they received olaparib capsules at 400 mg twice daily, or cediranib at 30 mg daily and olaparib at 200 mg twice daily until disease progression as assessed by radiographic imaging.
Active in Patients Regardless of BRCA Mutation Status
“Prior studies have suggested that women with BRCA mutations may have increased sensitivity to PARP inhibitors. We looked at the activity of the cediranib/olaparib combination in both patients with and without a known BRCA mutation,” Dr. Liu noted.
“In patients with a BRCA mutation, there was a trend toward increased activity of the cediranib/olaparib combination, with a median progression-free survival going from 16.5 months in the single-agent arm to 19.4 months in the combination, with a P value of .16,” she said. “However, in patients without a mutation, or whose BRCA status was unknown, this difference was much more marked, with an increase in progression-free survival from 5.7 months on olaparib alone to 16.7 months on combination of cediranib and olaparib with a P value of .008.”
When asked by The ASCO Post if the results in patients without known BRCA mutations were surprising, Dr. Liu clarified: “In terms of the activity of the combination, if you look at the exact values, the combination has slightly more activity still in BRCA mutation carriers. What was I think unexpected to us to a certain degree, and keeping in mind that this is a post hoc subset analysis of a phase II trial, was that the most extensive difference was in the BRCA noncarrier/status unknown population. So that was a little unexpected, but it needs to be confirmed.”
Toxicities Higher but Manageable
The overall rate of grade 3/4 toxicity was higher for patients receiving the combination therapy, 70% vs 7% for those receiving olaparib alone. Specific differentially occurring toxicities included fatigue (27% for cediranib/olaparib vs 7% for olaparib alone), diarrhea (23% vs 0%), and hypertension (39% vs 0%).
“The toxicity profile of the cediranib/olaparib combination was acceptable,” Dr. Liu said. Toxicities “were overall manageable with aggressive symptom management and dose reductions.”
“The combination of cediranib plus olaparib resulted in a significantly higher response rate, though at the expense of higher toxicity. Whether this response translates into gains in survival needs further follow-up,” said Don S. Dizon MD, FACP, ASCO expert on gynecologic cancers and Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital in Boston. “However, this combination represents an oral, non–chemotherapy-based combination treatment option for women with high-grade serous or BRCA-mutation related ovarian cancers and definitely warrants further study.”
“We are actively exploring phase III designs to evaluate this combination further,” Dr. Liu noted.
The study was supported by the National Cancer Institute. The study authors reported no potential conflicts of interest.
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®.
