Academic Background and Problem Statement

Epithelial Ovarian Cancer (EOC) remains one of the leading causes of death among gynecologic malignancies. Although the incorporation of molecularly targeted therapies, such as bevacizumab and PARP inhibitors, has improved Progression-Free Survival (PFS) and, in some cases, Overall Survival (OS), many patients still develop primary platinum-refractory or platinum-resistant recurrent ovarian cancer (PROC). The prognosis for PROC patients is poor, and treatment options are limited, primarily relying on cytotoxic monotherapies such as pegylated liposomal doxorubicin (PLD), weekly paclitaxel, and topotecan. While the AURELIA study demonstrated that adding bevacizumab to chemotherapy significantly improved PFS and Objective Response Rate (ORR) in PROC, there remains a need for alternative therapies.

Cediranib, a VEGFR tyrosine kinase inhibitor, and Olaparib, a PARP inhibitor, have both shown single-agent antitumor activity in recurrent ovarian cancer. Cediranib inhibits tumor angiogenesis, while Olaparib kills tumor cells by inhibiting DNA repair. Preclinical studies suggest that the combination of Cediranib and Olaparib may synergistically increase DNA damage and inhibit tumor angiogenesis. Based on these findings, the NRG-GY005 study aimed to evaluate the efficacy of Cediranib, Olaparib, and their combination in PROC patients, comparing them to Standard of Care (SOC) chemotherapy.

Source and Author Information

This study was conducted by Jung-Min Lee and colleagues from the National Cancer Institute (NCI), NRG Oncology, Sunnybrook Health Sciences Centre in Canada, and other institutions. The paper was published on October 3, 2024, in the Journal of Clinical Oncology (JCO), with the DOI: https://doi.org/10.1200/jco.24.00683.

Study Design and Process

NRG-GY005 was an open-label, four-arm, phase II/III superiority trial designed to assess the efficacy of Cediranib, Olaparib, and their combination in PROC patients. The study enrolled patients with high-grade serous or endometrioid ovarian cancer who had received one to three prior therapies. Key exclusion criteria included prior receipt of PARP inhibitors or antiangiogenic therapy in the recurrent setting.

The study was divided into two phases: Phase II and Phase III. In Phase II, patients were randomized to one of four treatment arms: SOC (weekly paclitaxel, topotecan, or PLD), Cediranib monotherapy, Olaparib monotherapy, or Cediranib/Olaparib combination therapy. During a preplanned interim futility analysis, the Olaparib monotherapy arm was discontinued due to insufficient activity, and the remaining three arms advanced to Phase III. The primary endpoints for Phase III were PFS and OS, with secondary endpoints including ORR and Patient-Reported Outcomes (PROs).

Main Results

A total of 562 eligible patients were enrolled, with 510 patients included in the Phase III analysis. The median follow-up duration was 42.2 months. The median PFS for the SOC, Cediranib/Olaparib, and Cediranib monotherapy arms were 3.4 months, 5.2 months, and 4 months, respectively. The hazard ratios (HRs) for PFS comparing Cediranib/Olaparib and Cediranib monotherapy to SOC were 0.796 (98.3% CI, 0.597-1.060) and 0.972 (98.3% CI, 0.726-1.300), respectively. The median OS for the three arms was 13.6 months, 12.8 months, and 10.5 months, respectively. Among 443 patients with measurable disease, the ORR was 24.7% for Cediranib/Olaparib, 13.1% for Cediranib monotherapy, and 8.6% for SOC.

In terms of safety, no new safety signals were identified. Adverse events (AEs) related to Cediranib, such as diarrhea, fatigue, and hypertension, were common but within expected ranges. Patient-reported outcomes indicated no significant differences in disease-related symptoms between the Cediranib/Olaparib and SOC arms.

Conclusions and Significance

The study demonstrated that the Cediranib/Olaparib combination showed clinical activity in terms of PFS and ORR but was not superior to SOC. Although the combination did not meet the primary endpoints, its efficacy in certain patient subgroups warrants further investigation. Future research should focus on identifying biomarkers to select patients who are most likely to benefit from this combination therapy while minimizing toxicity in those unlikely to respond.

Highlights of the Study

1. Innovation: This is the first Phase III trial to compare an all-oral, non-chemotherapy regimen with chemotherapy in PROC patients.
2. Clinical Significance: While the Cediranib/Olaparib combination did not significantly improve PFS or OS, its efficacy in certain subgroups provides insights for future personalized treatment approaches.
3. Safety: No new safety signals were identified, and the safety profile of the Cediranib/Olaparib combination was manageable.

Future Research Directions

Future studies should further explore biomarkers to identify patients who may benefit from the Cediranib/Olaparib combination. Additionally, the mechanisms of resistance to antiangiogenic agents and PARP inhibitors need to be investigated to optimize treatment strategies.