AN INTERESTING COMBINATION FOR OVARIAN CANCER

In a first-of-its-kind clinical trial, the combination of the oral antiangiogenic cediranib and the oral poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (both being developed by AstraZeneca) showed promising activity in patients with ovarian cancer, with manageable toxic effects.

The data are very early, but the combination achieved a 61% clinical benefit rate in patients with recurrent ovarian cancer. However, the combination's activity was not as strong in patients with metastatic triple-negative breast cancer.

Results of the trial were published online June 27 in theEuropean Journal of Cancer.

This combination has shown activity in epithelial ovarian cancer patients, so we wanted "to evaluate it in additional trials," said lead author Joyce Liu, MD, MPH, a gynecological oncologist at the Susan F. Smith Center for Women's Cancers at Dana-Farber/Brigham and Women's Cancer Center in Boston.

"We are in the process of conducting a phase 2 trial that compares the activity of this combination of olaparib plus cediranib with olaparib alone in women with platinum-sensitive recurrent ovarian cancer," she told Medscape Medical News.

Cediranib is a potent inhibitor of vascular endothelial growth factor, and is being evaluated in a number of cancers, including lung, kidney, and colon. Olaparib is currently being evaluated in breast, gynecologic, and colorectal cancers.

Study Details

PARP inhibitors and antiangiogenics have demonstrated activity in recurrent ovarian and breast cancer. However, to date, the effect of combining these agents in this population has not been reported. The authors note that antiangiogenic therapies have "proposed activity" in breast and ovarian cancers, and their toxic effects have limited overlap with PARP inhibitors. In addition, a phase 1 trial that combined olaparib with bevacizumab determined that the combination is well tolerated (Br J Cancer. 2012;106: 468-474).

In their phase 1 open-label trial, Dr. Liu and colleagues evaluated the safety, dosing, and preliminary effectiveness of the combination of olaparib plus cediranib in 20 patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer, and in 8 patients with metastatic triple-negative breast cancer.

The primary objectives of the study were to determine the dose-limiting toxicities and maximum tolerated dose of the combination. Secondary objectives included evaluating treatment-related toxicities and preliminarily assessing clinical activity (measured as response rate), the clinical benefit rate, and progression-free survival.

The study used a standard 3+3 dose-escalation design. Increasing doses of once-daily cediranib (starting at 20 mg) and twice-daily olaparib (starting at 100 mg) were administered continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity, or patient withdrawal from the trial.

All 28 patients enrolled in the study received at least 1 dose of olaparib and cediranib.

Among ovarian cancer patients, 12 (60%) had a known deleterious germline BRCA mutation, 3 (15%) had wild-type BRCA, and BRCA status was unknown in 5 (25%). Among breast cancer patients, 3 (38%) had a BRCA mutation, 1 (13%) had wild-type BRCA, and BRCA status was unknown in 4 (50%).

All 20 ovarian cancer patients had been previously treated with platinum/taxane therapy, and 1 ovarian cancer patient and 1 breast cancer patient had received adjuvant antiangiogenic therapy.

For the 18 ovarian cancer patients assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the overall response rate was 44% (1 complete response and 7 partial responses). When the 3 patients who had stable disease for at least 24 weeks were included in the analysis, the clinical benefit rate was 61%.

The 2 ovarian cancer patients assessed using Gynecologic Cancer InterGroup (GCIC) CA125 criteria both had stable disease, which lasted more than 24 weeks in 1 patient.

In the 11 ovarian cancer patients with a BRCA mutation, the overall response rate was 45% (1 complete response and 4 partial responses).

Limited Response in Breast Cancer

None of the breast cancer patients in the trial met RECIST 1.1 criteria for clinical response, although 2 had stable disease for at least 24 weeks.

Median progression-free survival was 8.7 months for ovarian cancer patients and 3.7 months for breast cancer patients.

"Given the small sample size and the study population, it is difficult to assess the activity of this combination in breast cancer patients," said Dr. Liu.

Maximum tolerated dose was determined to be 30 mg for cediranib and 200 mg for olaparib. An expansion cohort of 9 patients was subsequently enrolled at those doses.

All 28 patients experienced at least 1 treatment-related adverse effect, the most common of which were fatigue (93%), diarrhea (86%), nausea (57%), and hypertension (46%). Grade 3/4 events were occurred in 21 (75%) patients, the most common of which were hypertension (25%), fatigue (18%), and decreased neutrophil count (11%).

However, even though high-grade events occurred in 75% of patients, they were "anticipated and manageable."

This study was sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute and supported by a grant from the National Institutes of Health. The authors have disclosed no relevant financial relationships.

Eur J Cancer. Published online June 27, 2013. Abstract