In an interview with Targeted Oncology, Bobbie J. Rimel, MD, discussed the phase 2 NRG-GY012 results and the next step for cediranib plus olaparib as treatment of recurrent or metastatic endometrial cancer.
Combining cediranib (Recentin) with olaparib (Lynparza) did not demonstrate a significant improvement in progression-free survival (PFS) in patients with recurrent or metastatic endometrial cancer, treated in the phase 2 NRG-GY012 study. However, signals of efficacy warrant further exploration of the combination.
During a presentation of the data given by Bobbie J. Rimel, MD, during the Society of Gynecologic Oncology (SGO) Annual Meeting 2021, showed that cediranib plus olaparib achieved a median PFS of 5.5 months (HR, 0.7; 95% CI, 0.43-1.14 P = .06). In comparison, the arm that received cediranib alone had a median PFS of 3.8 months. The olaparib monotherapy arm underperformed with a median PFS of only 2.0 months (HR, 1.45; 95% CI, 0.91-2.30 P = .9).
NRG-GY012 is a study of 120 patients with recurrent or metastatic endometrial cancer who at baseline, had at least 1 prior chemotherapy regimen and 1 additional regimen for metastatic disease, as well as a non-cytotoxic/hormonal therapy for the management of recurrent or persistent disease. All patients had an ECOG performance status of 2 or lower, well-managed blood pressure, and no history of bowel obstruction. The study was 90% powered to detect a doubling of PFS to 7.2 months (HR, 0.5), but this was not demonstrated. The secondary end points of the study were overall survival, objective response rate, safety, and toxicity.
A further look at efficacy showed that 11 patients had partial responses to therapy. All responses occurred within the first 3 months of treatment. The longest response latest for more than 9 months, representing another signal of positive efficacy for the combination of cediranib and olaparib.
In an interview with Targeted Oncology™, Rimel, an assistant professor of Obstetrics and Gynecology at Samuel Oschin Cancer Center of Cedar Sinai, discussed the phase 2 NRG-GY012 results and the next step for cediranib plus olaparib as treatment of recurrent or metastatic endometrial cancer.
TARGETED ONCOLOGYTM: Can you explain the decision to combine cediranib with olaparib to treat patients with metastatic recurrent endometrial cancer?
Rimel: DNA damage repair is a very exciting molecular concept in cancers, especially in gynecologic cancers. For endometrial cancers specifically, data from The Cancer Genome Atlas Program and other studies demonstrated that there would be good rationale in pursuing a DNA damage repair strategy. As a PARP inhibitor, olaparib affects DNA damage repair in cells that have a weakened DNA damage repair mechanism. Hypoxia induced by anti-angiogenesis agents has also been hypothesized to create a worse DNA damage repair state, making the cell even more susceptible. So, the combination of a DNA damaging agent in addition to an agent, causing hypoxia, or anti-angiogenesis was likely synergistic. We had also seen some exciting results in ovarian cancer in the past.
Can you provide a brief overview of the study that you presented during the SGO Annual Meeting 2021?
Rimel: This is a platform study for metastatic recurrent endometrial cancer. It's the first one of its kind that was allowed to have more arms, so we have additional arms in the queue. We were extremely pleased to present the first 3 arms at the SGO Annual Meeting 2021. The study enrolled 120 women with metastatic recurrent endometrial cancer. Those patients were then randomized 1:1:1 to 3 arms. The first arm was cediranib alone, the second arm is olaparib alone, and the third arm was the combination of cediranib and olaparib
We expected to see toxicities of fatigue, diarrhea, and hypertension, and we did see all of those. There were no new safety signals seen and the control arm performed. We were also excited to see that in the combination arm, there were some very long-term responders greater than 12 months, and some even greater than 18 months. The study did not meet its primary end point with a P value of .06, but with the trend suggestive of the combination arm being effective, the olaparib-only arm was closed early due to futility. So, we are excited to see this study move forward to allow us to roll out 3 more arms.
What other thoughts do you have about the study results?
I think the results that we had so far were that the control arm of cediranib-alone arm performed exactly as expected, and it is always nice to see a confirmation. The olaparib-alone arm performed worse than I anticipated, and the combination arm performed better than expected with the durability of those patients who responded being 12 months or greater. That kind of durability is exciting for patients who otherwise have a median survival of less than 12 months.
What are the key takeaways from this research?
We’re one this was the fastest enrolling endometrial cancer study ever. We are incredibly grateful to the people that put patients on the study. I think that it was a rapid enrollment for multiple reasons. But capitalizing on that success was one of the incredible reasons that we were excited and able to hopefully take this forward as a to do more arms in the future. The second big takeaway was that the durability of the responses in the combination need further investigation and the translational end points that we've pre planned will help us hopefully get some idea of who might benefit from this combination in the future.
How does this study compare to other trials ongoing in the endometrial cancer space?
I think that this is going in the same direction as many other studies. The biology is going to help us determine how best to treat patients. But these kinds of smaller platform studies allow us to look at combinations that otherwise might not make it to a bigger trial. It also allows us, hopefully, to be able to turn through some exciting compounds and get to the good stuff, hopefully faster, to help patients find treatments that really work.
Bender D, Rimel BJ, Enserro D, et al. NRG-GY012: A randomized phase II study comparing single-agent olaparib, single-agent cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent or metastatic endometrial cancer. Presented at: Society of Gynecological Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-21, 2021; Virtual. Abstract 2073.