Summary
Findings from a phase III study showed that cediranib plus olaparib had similar activity to standard platinum-based chemotherapy in relapsed platinum-sensitive ovarian cancer, according to data presented at the ASCO 2020 Annual Meeting (Abstract 6003). However, the trial did not meet the primary endpoint, which was progression-free survival (PFS).
To explore additional resources offered by Oncology Times and to subscribe, visit https://journals.lww.com/oncology-times/pages/default.aspx
Original Article
Cediranib + Olaparib for Recurrent Platinum-Sensitive Ovarian Cancer
Oncology Times
By Catlin Nalley
Findings from a phase III study showed that cediranib plus olaparib had similar activity to standard platinum-based chemotherapy in relapsed platinum-sensitive ovarian cancer, according to data presented at the ASCO 2020 Annual Meeting (Abstract 6003). However, the trial did not meet the primary endpoint, which was progression-free survival (PFS).
In a phase II trial, the combination of cediranib and olaparib improved PFS in patients with relapsed platinum-sensitive high-grade ovarian cancer when compared to olaparib alone.
To further explore this combination, researchers conducted a randomized, open-label, phase III trial (NCT02446600) to assess whether combination cediranib plus olaparib, or olaparib alone, was superior to standard of care (SOC) platinum-based therapy in relapsed platinum-sensitive ovarian cancer.
Study Methodology
Patients eligible for the study included those with recurrent platinum-sensitive ( > 6-month platinum-free interval [PFI]) high-grade serous or endometrioid, or BRCA-related, ovarian cancer. One prior non-platinum therapy and unlimited prior platinum-therapies were allowed. Exclusion criteria included prior anti-angiogenics in the recurrent setting or prior PARP inhibitor therapy.
“Women with recurrent platinum-sensitive disease were randomized 1:1:1 to one of three arms: platinum-based chemotherapy, which consisted of investigators choice followed by observation; olaparib monotherapy at 300 mg twice daily; or the combination of cediranib 30 mg daily and olaparib 200 mg twice daily,” outlined study author Joyce F. Liu, MD, MPH, Director of Clinical Research in the Division of Gynecologic Oncology at Dana-Farber Cancer Institute, during her presentation.
The target sample size was 549 patients and the primary analysis occurred 2 years after the last patient enrolled. The primary endpoint was PFS.
“Type 1 error = 0.025 was controlled by a gatekeeping hierarchy that assessed cediranib plus olaparib versus SOC, then olaparib alone versus SOC, and finally cediranib plus olaparib versus olaparib,” the study authors wrote.
Key Results
Between February 2016 and November 2017, the study enrolled 565 patients (187 SOC, 189 olaparib, 189 combination), and 528 initiated treatment (166 SOC, 183 olaparib, 179 combination).
Patient characteristics were balanced across all three arms, according to Liu. “The majority of patients enrolled had a good performance status,” she explained. “Approximately two-thirds of patients had only one prior line of therapy with another 25 percent having had two prior lines of treatment.
“As expected, most patients had high-grade serous histology and just under 25 percent of patients had a deleterious germline BRCA mutation,” she continued. “The PFI was evenly divided between those patients who recurred within 6-12 months and those recurred more than 12 months after their last platinum-based therapy.”
The combination of cediranib and olaparib did not improve PFS compared to platinum-based chemotherapy with a HR of 0.856 (95% CI 0.66-1.11, p = 0.08, 1-tail), reported Liu. “The observed median PFS was 10.4 months for combination and 10.3 months for chemotherapy.”
Overall survival data are not currently mature. “At the time of this analysis, no difference in overall survival was observed between the three treatment arms,” Liu reported. “The response rate was 71.3 percent for chemotherapy, 69.4 percent for combination, and 52.4 percent for olaparib alone.
“There was no statistically significant difference in the response rates between combination and chemotherapy; however, the response rate to olaparib monotherapy was statistically lower than that to chemotherapy,” she further elaborated.
Among patients with a germline BRCA mutation, the median PFS was 10.5 months with chemotherapy compared to 18 months with the combination and 12.7 months with olaparib alone, according to Liu. “Response rates were 71 percent for chemotherapy, 89 percent for the combined cediranib plus olaparib, and 90 percent for olaparib.”
In terms of safety, Liu noted, “As expected hematologic AEs were highest in the chemotherapy arm, although rates of anemia were comparable to chemotherapy in the olaparib monotherapy arm. While the frequency of peripheral sensory neuropathy was highest in the chemotherapy arm, the frequency of other non-hematologic AEs was generally highest in the combination arm.
The most common AEs observed with combination cediranib and olaparib in other studies were also seen here. Fatigue, diarrhea, and hypertension were the most frequent adverse events associated with this combination, according to Liu, along with nausea.
Implications & Next Steps
While this study did not meet its primary endpoint, it still provides insight into the potential role of non-platinum therapies in this patient population.
“[This] is the first phase III trial to compare an all-oral, non-platinum regimen to platinum-based chemotherapy in platinum-sensitive ovarian cancer,” noted Liu. “Combination cediranib and olaparib did not meet the primary endpoint of improved PFS compared to platinum-based chemotherapy, although comparable clinical activity in terms of both PFS and ORR were observed. In patients with a germline BRCA mutation, both olaparib and the combination cediranib plus olaparib demonstrated substantial activity.”
In terms of safety, higher rates of hematologic AEs were observed with chemotherapy, but higher rates of non-hematologic AEs occurred with cediranib and olaparib. No new safety signals were identified for the combination, Liu summarized.
“Overall, although the study did not meet its primary endpoint, non-platinum therapies may still offer alternatives in women with recurrent platinum sensitive ovarian cancer,” she concluded. “[This study] demonstrated that these can be feasibly explored in future studies in this setting.”
Further investigation and biomarker subgroup analysis is ongoing.
Catlin Nalley is a contributing writer.