A randomized phase 2 clinical trial has evaluated the efficacy of the PARP inhibitor olaparib alone and in combination with the antiangiogenic agent cediranib compared to cediranib alone in patients with recurrent, persistent, or metastatic endometrial cancer. The study, published in January 2024 in the journal Cancer, found that while the olaparib/cediranib combination showed a trend toward improved progression-free survival, it did not meet statistical significance compared to cediranib alone.
The NRG-GY012 trial was an open-label, randomized, 3-arm phase 2 study conducted at multiple centers within the United States. It was led by NRG Oncology through the National Cancer Institute's National Clinical Trials Network. Funding was provided by National Cancer Institute grants to NRG Oncology, with drugs supplied by AstraZeneca.
The purpose of the study was to assess the efficacy of olaparib alone or in combination with cediranib compared to cediranib monotherapy in patients with advanced endometrial cancer. At the time the study was developed in 2016, treatment options for patients who had progressed on initial platinum-based chemotherapy were limited, with response rates under 20% and progression-free survival of approximately 3.5-4 months for available therapies.
A total of 120 patients were enrolled in the trial between September 4, 2018 and June 17, 2019. Eligible patients had histologically confirmed recurrent or persistent endometrial cancer that was refractory to established treatments. They must have received one previous chemotherapy regimen but no more than two, and have measurable or non-measurable disease according to RECIST v1.1 criteria. Patients were required to have an ECOG performance status of 0-2 and adequate organ and bone marrow function.
The median age of participants was 66 years (range 41-86). The majority (80.8%) were white, with 11.7% black patients. Most patients (67.5%) had an ECOG performance status of 0. In terms of histology, 39.2% had serous adenocarcinoma, while the remainder had various grades of endometrioid or other histologies. The majority (94%) had received prior platinum-based chemotherapy.
Patients were randomly assigned 1:1:1 to receive cediranib 30 mg once daily (reference arm), olaparib 300 mg twice daily, or the combination of cediranib 30 mg once daily plus olaparib 200 mg twice daily. Treatment was given in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival as assessed by the investigator.
At the time of the primary analysis, with a median follow-up of 18.3 months, the median progression-free survival was 3.8 months (95% CI 3.0-5.4) in the cediranib arm, 2.0 months (95% CI 1.8-4.7) in the olaparib arm (HR 1.45, 95% CI 0.91-2.3, p=0.935), and 5.5 months (95% CI 3.7-8.3) in the olaparib/cediranib arm (HR 0.7, 95% CI 0.43-1.14, p=0.064). While there was a trend toward improved progression-free survival with the combination, it did not reach statistical significance compared to cediranib alone.
The objective response rate was 24.1% for cediranib, 12.5% for olaparib, and 31.4% for the combination. Notably, four patients receiving the combination had a durable response lasting more than 20 months. Median overall survival was 12.4 months for cediranib, 13.4 months for olaparib, and 17.6 months for the combination, though the study was not powered for overall survival.
In terms of safety, 71.1% of patients in the cediranib arm experienced grade 3 or higher adverse events, compared to 47.5% with olaparib and 79.4% with the combination. The most common high-grade toxicities were hypertension (36%) and diarrhea (17.9%) with cediranib; anemia (12.5%) with olaparib; and hypertension (33.3%) and fatigue (20.5%) with the combination. No new safety signals were identified.
As part of the translational research objectives, the study evaluated homologous recombination deficiency (HRD) using the BROCA-GO sequencing panel on archival tumor samples. Only 5.2% of evaluable tumors had somatic mutations potentially producing HRD. Loss of heterozygosity (LOH) status, another potential marker of HRD, was only evaluable in 37.4% of samples due to insufficient tumor cellularity. Among evaluable samples, 35.6% were LOH-high.
The study had several important limitations. Due to a higher than expected number of consent withdrawals, particularly in the cediranib arm, the trial was unable to reach the pre-specified requirement of 39 progression-free survival events in the reference arm. This limited the statistical power of the primary analysis. Additionally, the low evaluability rate for LOH status hampered the ability to assess this as a potential predictive biomarker.
The authors concluded that single-agent PARP inhibition with olaparib did not warrant further exploration in this unselected endometrial cancer population. While the combination of olaparib and cediranib showed a trend toward improved progression-free survival, it did not meet statistical significance. However, the authors noted that the small subset of patients with durable responses to the combination merits further investigation to identify potential predictive biomarkers.
In their discussion, the investigators highlighted that this was the first randomized trial to investigate a PARP inhibitor alone and in combination with an antiangiogenic agent in pretreated metastatic endometrial cancer. The progression-free survival of 3.8 months observed with cediranib was consistent with prior studies of this agent and with chemotherapy in this setting. They noted that the lack of efficacy with single-agent olaparib aligns with the low frequency of BRCA1/2 mutations and other markers of HRD observed in this unselected endometrial cancer population.
The potential clinical impact of this study is multifaceted. First, it suggests that single-agent PARP inhibition is unlikely to be effective for most patients with recurrent endometrial cancer, in contrast to its established role in ovarian cancer. Second, while the olaparib/cediranib combination showed some promise, particularly in terms of durable responses in a subset of patients, further research is needed to identify predictive biomarkers that could select patients most likely to benefit. The authors suggest that future studies should consider stratification based on p53 mutational status rather than histology alone.
Additionally, the study highlights the ongoing challenge of developing effective therapies for recurrent endometrial cancer. Since this trial was initiated, the combination of lenvatinib and pembrolizumab has become a standard of care for many patients with advanced endometrial cancer based on the results of the KEYNOTE-775 trial. However, there remains a need for additional treatment options, particularly for patients who progress on or are ineligible for immunotherapy-based approaches.
The translational analyses conducted as part of this study provide important insights into the molecular landscape of recurrent endometrial cancer. The low frequency of HRD-associated mutations and the challenges in assessing LOH status in archival samples underscore the need for better definition of the HRD phenotype in endometrial cancer. This could inform future studies of PARP inhibitors or other agents targeting DNA damage repair pathways in this disease.
In conclusion, while the NRG-GY012 trial did not meet its primary endpoint, it provides valuable data to inform future research directions in recurrent endometrial cancer. The trend toward improved outcomes with the olaparib/cediranib combination, particularly the subset of patients with durable responses, suggests that further investigation of this approach may be warranted in biomarker-selected populations. As our understanding of endometrial cancer biology continues to evolve, studies like this one play a crucial role in refining treatment strategies and identifying novel therapeutic targets for this challenging disease.
References
Rimel BJ, Enserro D, Bender DP, et al. NRG-GY012: Randomized phase 2 study comparing olaparib, cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent, or metastatic endometrial cancer. Cancer. 2024;130(8):1234-1245. doi:10.1002/cncr.35151
