Compared with olaparib alone, patients with recurrent platinum-sensitive ovarian cancer are at a 58% reduced risk of disease progression when treated with a combination of olaparib and cediranib. These data from a phase II study were presented at Saturday's Gynecologic Cancer Oral Abstract Session (Abstract LBA5500). “The degree of activity supports additional clinical evaluation of the combination of olaparib and cediranib in ovarian cancer,” said Joyce Liu, MD, MPH, of the Dana-Farber Cancer Institute. In published studies, inhibitors of PARP or poly (ADP-ribose) polymerase such as olaparib and antiangiogenic agents such as cediranib have shown activity in ovarian cancer.
In this multicenter, open-label study, patients were randomly assigned to receive olaparib 400 mg twice daily (46 patients) or a combination of olaparib 400 mg twice daily with cediranib 30 mg once daily (44 patients) until disease progression. Patients were required to have recurrent, platinum-sensitive, high-grade serous or BRCA-related ovarian cancer, measurable disease based on RECIST 1.1 criteria, and the ability to receive oral medicines. Progression-free survival (PFS) was the primary endpoint of the study.
The median follow up was 16.6 months. PFS was 17.7 months for patients who received the combination of cediranib and olaparib, a significant improvement compared with the 9 month PFS for patients who received olaparib alone (HR 0.42, 95% CI [0.23, 0.76]; p = 0.005; Fig. 1). The objective response rate was 80% for patients on the combination arm compared with 48% for patients on olaparib alone (p = 0.002). Complete responses were seen in 5 patients who recieved combination therapy, and partial responses in 30 patients from the same population; for patients who received olaparib alone, complete responses were seen in two patients and partial responses were seen in 20 patients. Grade 3 or higher toxicities associated with the combination treatment were fatigue (27% vs. 11% for olaparib), diarrhea (23% vs. 0% for olaparib), and hypertension (41% vs. 0% for olaparib). “These toxicities were generally manageable with symptom management or by withholding or reducing the dose,” Dr. Liu said.
Although patients in the study were stratified based on BRCA mutations, analysis of PFS based on BRCA status was not a prespecified endpoint of the study. In an exploratory analysis, Dr. Liu showed that patients with BRCA mutations showed improved PFS; in patients with wild-type BRCA or in whom BRCA status was unknown or nonexistent, PFS was significantly longer with combination therapy (p = 0.008; Fig. 2).
Discussant Jonathan A. Ledermann, MD, of the University College London Cancer Institute, United Kingdom, agreed that the combination arm showed excellent responses and said, “Combining olaparib and cediranib may herald the beginning of treatments that avoid chemotherapy in some patients with recurrent ovarian cancer.” The more intriguing observation was the greater differential effect seen with the combination in patients with wild-type BRCA or in whom BRCA status was unknown, he observed. The PFS is significantly augmented with cediranib in BRCA nonmutated/unknown cancer (16.5 months in the combination arm vs. 5.7 months for olaparib; p = 0.008) compared with BRCA-mutated cancer (PFS of 19.4 months in the combination arm vs. 16.5 months with olaparib; p = 0.16).
However, Dr. Ledermann indicated that the toxicity associated with the combination treatment was not insignificant. The additional toxicity in patients receiving the combination was directly related to cediranib. However, toxicity with standard chemotherapy in this patient population is also not insignificant, he observed. Dr. Ledermann indicated that for long-term maintenance studies it is important to look closely at quality of life, dose interruptions, and dose reductions in addition to reporting single episodes of adverse events. Dose reduction occurred in 77% of patients. However, it was difficult to know whether this related to one or both drugs, and how patients were managed during this time.
Dr. Ledermann questioned whether the combination of olaparib and cediranib might replace chemotherapy. He suggested that this could be tested in the patients with non-BRCA-mutated ovarian cancer. He suggested a trial that would test the combination of olaparib and cediranib against a chemotherapy-based combination. In addition, he suggested that it should test if maintenance therapy with olaparib would improve outcomes compared with platinum-based chemotherapy and cediranib.