NRG-GY012 Study Tests Multiple Olaparib Combinations in Endometrial Cancer

BJ Rimel, MD

A phase 2 study (NCT03660826) is investigating treatment with single-agent olaparib (Lynparza) vs single-agent cediranib (Recentin; AZD2171), vs cediranib combined with olaparib, olaparib combined with durvalumab (Imfinzi), cediranib with durvalumab, or olaparib with capivasertib in patients with recurrent, persistent, or metastatic endometrial cancer.

The NRG-GY012, multicenter, randomized, 4-arm study is evaluating patients with recurrent, metastatic, or persistent endometrial cancer to test various combinations that may lower the chance of endometrial cancer growing or spreading when compared with usual treatment options.

Patients will be randomized in a 1:1:1:1 ratio to receive cediranib orally once a day at 30 mg, oral olaparib 300 mg daily twice a day with capivasertib 400mg 4 day on/3 off schedule, oral olaparib 300 mg twice daily with durvalumab 1500 mg every 28 days, or the combination of oral cediranib 20 mg given on days 1-28 and durvalumab 1500 mg on day 1. All treatment cycles are 28 days.

Investigators are evaluating the primary end point of progression free survival (PFS) with secondary end points of overall survival, objective tumor response, and incidence of adverse events. Other end points include mutations in deoxyribonucleic acid homologous repair genes and markers of angiogenesis in serial plasma samples.

A total of 40 patients will be enrolled per arm. Those eligible for enrolment in the trial are patients with endometrioid, serous, and mixed endometrial cancer who have received at least 1 prior line of chemotherapy, and have an ECOG performance status of 0,1, or 2. If patients have received previous endocrine or immunotherapy alone, they are eligible for enrollment. However, patients who have had prior treatment with lenvatinib (Lenvima) and pembrolizumab (Keytruda) will be excluded.

In an interview with Targeted Oncology^TM, BJ Rimel, MD, gynecologic oncologist at Cedars Sinai Medical Center in Los Angeles, California, discussed the rationale, methods, and design of this phase 2 study for patients with endometrial cancer.

Targeted Oncology: What does the current treatment landscape look like for endometrial cancer?

Rimel: The current treatment landscape for endometrial cancer has changed significantly in the last few months with the new opportunities for using immunotherapy and the upfront setting with the results of NRG GYO18 [NCT03914612] and RUBY studies [NCT03981796].

Can you discuss this trial in progress in endometrial cancer?

I'm a part of a trial and progress which is the second 4 arms of GYO12, which is a phase 2 study looking at the use of cediranib vs olaparib, durvalumab vs cediranib, durvalumab vs olaparib, and olaparib vs capivasertib. This 4-arm study is designed to examine these individual treatment options for patients with recurrent, metastatic, or progressive endometrial cancer who’ve had prior chemotherapy, but have not received lenvatinib or pembrolizumab.

What was the rationale behind this study?

This is the second four arms of a platform study designed to examine quickly and in succession, several different options for patients with endometrial cancer. Endometrial cancer second-line treatments have evolved quickly over the last few years, and our goal with this study was to allow patients to have an opportunity to examine these other treatment strategies.

Can you discuss the methods and design of the study?

This is an NRG oncology sponsored study. We are fortunate to be the first and so far, only platform study design. Our first 3 arms resulted in 2020. Our second 4 arms are in progress now. Our initial 3-arm study demonstrated that cediranib was equivalently effective to cediranib and olaparib, and that olaparib was not as effective as cediranib. That was in our first 3 arms, and we were able to then take cediranib as our reference arm and add the other 3 arms that I mentioned.

Great and what are your overall hopes for this trial and for the future of this space?

Our overall hopes are that we'll find a second- or third-line therapy for patients with endometrial cancer that allows them to have another standard of care. [This year] I am [also] looking forward to talking to my colleagues, and especially to new data around antibody drug conjugates.

REFERENCE:

Testing the combination of olaparib and durvalumab, cediranib and durvalumab, olaparib and capivasertib, and cediranib alone in recurrent or refractory endometrial cancer following the earlier phase of the study that tested olaparib and cediranib in comparison to cediranib alone, and olaparib alone. ClinicalTrials.gov. Updated June 29, 2023. Accessed June 30, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03660826