A large randomized phase II/III clinical trial has found that the combination of cediranib and olaparib did not improve progression-free survival or overall survival compared to standard chemotherapy in patients with platinum-resistant or platinum-refractory ovarian cancer. The NRG-GY005 study, published on October 3, 2024 in the Journal of Clinical Oncology, was conducted at multiple centers in the United States, Canada, Japan, and Korea.
The study was funded by the US National Cancer Institute and supported in part by AstraZeneca and Merck. Its purpose was to assess the efficacy of cediranib (an oral VEGFR tyrosine kinase inhibitor), olaparib (a PARP inhibitor), and the combination of cediranib/olaparib compared to standard-of-care chemotherapy in platinum-resistant or platinum-refractory epithelial ovarian cancer.
NRG-GY005 was an open-label, four-arm, phase II/III superiority trial that enrolled patients with high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancers. Eligible patients had platinum-resistant recurrent disease (defined as progression within 6 months of receiving the last platinum therapy) or primary platinum-refractory disease (defined as progression while receiving platinum therapy). Patients were allowed to have received up to three previous lines of therapy.
Key exclusion criteria included previous receipt of a PARP inhibitor or receipt of antiangiogenic therapy in the recurrent setting. Patients were required to have measurable disease by RECIST 1.1 criteria for the phase II portion, while the phase III portion allowed either measurable or evaluable disease.
A total of 562 eligible patients were enrolled for the phase II/III portions of the trial. The median age was 64.2 years, and 96.7% of patients had high-grade serous carcinoma. Nearly one-third (31.6%) had primary platinum-refractory disease. Among those tested, 7.8% had either a germline BRCA1 or BRCA2 mutation.
Patients were randomized equally to receive either standard-of-care chemotherapy (weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin), cediranib alone, olaparib alone, or the combination of cediranib/olaparib. A preplanned interim futility analysis based on progression-free survival (PFS) was used to select treatment arms to advance to phase III.
Three arms met PFS criteria to carry forward to phase III: standard-of-care chemotherapy, cediranib/olaparib combination, and cediranib alone. The olaparib monotherapy arm was dropped due to insufficient activity.
At the final analysis, with a median follow-up of 42.2 months, the median PFS was 3.4 months for standard chemotherapy, 5.2 months for cediranib/olaparib, and 4.0 months for cediranib alone. The PFS hazard ratio estimates compared to chemotherapy were 0.796 (98.3% CI, 0.597 to 1.060) for cediranib/olaparib and 0.972 (98.3% CI, 0.726 to 1.300) for cediranib alone.
Median overall survival was 13.6 months for chemotherapy, 12.8 months for cediranib/olaparib, and 10.5 months for cediranib alone. The objective response rate among 443 patients with measurable disease was 8.6% for chemotherapy, 24.7% for cediranib/olaparib, and 13.1% for cediranib alone.
No new safety signals were identified. The most common adverse events in the cediranib-containing arms included diarrhea, fatigue, nausea, and hypertension. Approximately 18% of patients on the cediranib/olaparib arm and 27% on the cediranib arm discontinued treatment due to adverse events.
For the primary patient-reported outcome measure, there was no statistically significant difference on the NFOSI-DRS-P subscale between cediranib/olaparib and chemotherapy. Patients receiving cediranib alone reported worse scores during the first year of treatment compared to the other arms.
The study authors concluded that while the cediranib-containing arms demonstrated clinical activity based on PFS, they were not superior to standard-of-care chemotherapy. They noted that the combination of cediranib/olaparib showed evidence of durable clinical activity in some patients, highlighting the need for further investigation of biomarkers to identify those most likely to benefit.
Limitations of the study included a higher rate of early withdrawals from the chemotherapy arm, which could have introduced bias. The authors also noted that the underlying etiology for the slightly shorter overall survival with cediranib-containing regimens compared to chemotherapy was uncertain.
In terms of potential clinical impact, the results do not support the use of cediranib, olaparib, or the combination as standard treatment for platinum-resistant ovarian cancer at this time. However, the observed activity in subsets of patients suggests further research is warranted to identify biomarkers beyond homologous recombination deficiency that may predict response to these targeted therapies.
The findings add to the growing body of evidence on combination strategies with PARP inhibitors and antiangiogenic agents in ovarian cancer. While these approaches have shown promise in other settings, this large phase III trial demonstrates the ongoing challenges in treating platinum-resistant disease. As the authors note, the landscape of care for these patients continues to evolve, with recent approvals like mirvetuximab and ongoing development of novel antibody-drug conjugates and other targeted therapies.
For practicing oncologists, the results reinforce the continued role of single-agent chemotherapy as a standard approach for platinum-resistant ovarian cancer in the absence of specific biomarkers. However, they also highlight the heterogeneity of this patient population and the need for ongoing research to develop more personalized treatment strategies. The higher response rates seen with cediranib/olaparib, despite not meeting the primary endpoint, suggest this combination could potentially benefit select patients if predictive biomarkers can be identified.
In conclusion, while NRG-GY005 did not demonstrate superiority of cediranib-based regimens over chemotherapy, it provides important data to inform future research directions in this challenging disease setting. The results underscore the complexity of drug development in platinum-resistant ovarian cancer and the critical importance of biomarker-driven approaches to optimize patient outcomes.
References
Lee JM, Brady MF, Miller A, et al. Cediranib and Olaparib Combination Compared With Cediranib or Olaparib Alone, or Chemotherapy in Platinum-Resistant or Primary Platinum-Refractory Ovarian Cancer: NRG-GY005. J Clin Oncol. 2024;42(36):4305-4316. doi:10.1200/JCO.24.00683
