CHICAGO--In light of encouraging data from a phase II trial reported at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), the National Cancer Institute (NCI) plans to conduct two phase III clinical trials to investigate the combined use of olaparib and cedirinab for the treatment of ovarian cancer.
In the phase II study, reported by Joyce Liu, MD, MPH, of the Dana-Farber Cancer Institute in Boston, patients with recurrent platinum-sensitive ovarian cancer had a 58% reduced risk of disease progression when treated with a combination of olaparib, a selective poly ADP ribose polymerase (PARP) inhibitor, and cediranib, a potent inhibitor of VEGFR -1, -2, -3, when compared to treatment with olaparib alone (Abstract LBA5500).
This marks the first time these two types of targeted drugs, both administered orally, have been combined. “The degree of activity supports additional clinical evaluation of the combination,” said Liu, who noted that both agents have previously shown activity in ovarian cancer when studied alone. In this phase II, multicenter, open-label study, patients were randomly assigned to receive olaparib 400 mg twice daily (n = 46), or a combination of olaparib 400 mg twice daily with cediranib 30 mg once daily (n = 44) 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. The primary endpoint was progression-free survival (PFS). Median follow-up was 16.6 months.
PFS was 17.7 months for patients who received the combination of cediranib and olaparib, compared with 9 months for patients who received olaparib alone (P = .005). The objective response rate was 80% for patients in the combination arm compared with 48% for patients on olaparib alone (P = .002). Five patients who received combination therapy had complete responses, and 30 had partial responses. Among patients who received olaparib alone, two had complete responses and 20 had partial responses.
Grade 3 or higher toxicities were seen more frequently among patients treated with the combination treatment than in the group treated with olaparib alone and included fatigue (27% vs 11%), diarrhea (23% vs 0%), and hypertension (41% vs 0%). “These toxicities were generally manageable with symptom management or by withholding or reducing the dose,” Liu said.
Although analysis of PFS based on BRCA status was not a pre-specified endpoint of the study, Liu said an exploratory analysis indicated 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 = .008).
Commenting on the findings, Jonathan A. Ledermann, MD, of the University College London Cancer Institute, United Kingdom, said use of the combination “may herald the beginning of treatments that avoid chemotherapy in some patients with recurrent ovarian cancer.” He said 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. 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 alone; P = .008), compared with BRCA-mutated cancer (PFS of 19.4 months in the combination arm vs 16.5 months with olaparib alone; P = .16).
Ledermann cautioned that the toxicity associated with the combination treatment is “not insignificant” and is directly related to the addition of cediranib. He noted, however, that toxicity with standard chemotherapy in this patient population is also not insignificant, he observed.
He said future long-term studies should take into account factors such as quality of life, dose interruptions, and dose reductions, in addition to reporting single episodes of adverse events. In the present study, dose reduction occurred in 77% of patients, but it was unclear whether this was related to one or both drugs, and even how patients were managed during this time.
He also suggested that a trial be designed to evaluate the combination of olaparib and cediranib against a chemotherapy-based combination, as well as whether maintenance therapy with olaparib would result in better outcomes than platinum-based chemotherapy and cediranib.
Both olaparib and cediranib are being developed by the MedImmune division of AstraZeneca. “We fully support the NCI plans to conduct two late-stage studies to further investigate the combination,” said Antoine Yver, head of oncology in the company’s global medicines development unit.