Superior Efficacy Not Induced by the Addition of Olaparib to Cediranib in Advanced Endometrial Cancer

B.J. Rimel, MD

No statistically significant difference was seen with the combination of olaparib (Lynparza) and cediranib compared to cediranib alone in patients with recurrent, metastatic or persistent endometrial cancer, according to data from the phase 2 NRG-GY012 trial presented at the 2021 SGO Virtual Annual Meeting on Women’s Cancer.

“The progression-free survival observed in the ‘reference arm’ of cediranib was consistent with GOG 229 J and no new safety signals were identified. Olaparib was well tolerated but did not meet the primary end point. Based on the interim analysis the data monitoring committee recommended termination of this study arm,” B.J. Rimel, MD, assistant professor, obstetrics and gynecology, Cedars-Sinai Medical Center, said during a virtual presentation of the data.

In the randomized phase 2 NRG-GY012 trial, investigators randomized 109 women with recurrent endometrial cancer 1:1:1 to receive either oral cediranib monotherapy (30 mg daily; n = 34), oral olaparib monotherapy (300 mg twice daily; n = 39), or the combination of olaparib (300 mg twice daily) and cediranib (20 mg daily; n = 26) until disease progression.

Eligible patients had received at least 1 prior platinum-containing chemotherapy but no more than 2 prior lines of chemotherapy, had an ECOG PS of 2 or more; had well controlled blood pressure (≤ 140/90mmHg); and had no history of bowel obstruction in the last 3 months and were able to take oral medication. Prior treatment with biologic, hormonal, or immunotherapy was allowed. Moreover, patients were stratified by histology: serous versus endometrioid.

The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, and safety and toxicity.

Across the cediranib monotherapy, olaparib monotherapy, and combination arms, median age was 64.5 years (range, 41-79), 69 years (range, 58-86), and 65 years (range, 41-86), respectively. In total, 47 women (39.2%) had serous histology, 62 (51.7%) had endometrioid, and 8 (6.7%) had mixed histology. Rimel also noted that 12% of patients were non-White, most patients had only 1 prior chemotherapy, only about 10% of patients had prior immunotherapy, “but that reflects the time of the study conduct no doubt. And it should be noted that 50% of patients had prior radiation,” she said.

Median follow-up was 18.3 months. Patients underwent a median of 3 cediranib monotherapy cycles, 2 olaparib monotherapy cycles, and 3.5 cycles of the combination regimen.

Kaplan Meir estimated median PFS was 3.8 months for cediranib monotherapy, 2.0 months for olaparib monotherapy, and 5.5 months for the combination. When comparing cediranib versus olaparib, the one-sided P value stratified log rank test was 0.935 (HR, 1.45; 95% CI, 0.91-2.30). When comparing cediranib monotherapy with the combination regimen, it was 0.064 (HR, 0.7; (95% CI, 0.43- 1.14).

Across the cediranib monotherapy, olaparib monotherapy, and combination arms, progression was the reason for treatment discontinuation for 22 (55%), 33 (82.5%), and 17 (42.5%) patients, respectively, while adverse events led to discontinuation in 10 (25%), 5 (12.5%), and 10 (25%) patients.

No new safety signals were reported. The most common adverse events (AEs) across the cediranib monotherapy, olaparib monotherapy, and combination arms were hypertension (35.9% vs. 2.5% vs. 33.3%, respectively), diarrhea (17.9% vs. 0% vs. 2.6%), fatigue (10.3% vs. 0% vs. 20.5%), nausea (2.6% vs 0% vs. 5.1%), endocrine (2.6% vs. 0% vs. 5.1%), VTE (2.6% vs. 10% vs. 5.1%), anemia (2.6% vs. 12.5% vs. 2.6%), and febrile neutropenia (0% vs. 2.5% vs. 0%).

"Cediranib had more adverse events as anticipated and more withdrawals [from the trial],” Rimel said. “The data on withdrawals did not show a clear pattern with some patients withdrawing [because of] secondary social [issues] as well as quality of life issues.”

Four patients were still receiving the combination regimen at data cut-off.

Response rates to second-line chemotherapy for women with endometrial cancer is approximately 10% to 15%, Rimel noted, with an approximate PFS of 3 months. However, she added common genomic events like histology have suggested that targeting DNA repair could be an effective therapeutic strategy.

Cediranib, an oral multi-tyrosine kinase inhibitor, has previously demonstrated modest efficacy in patients with endometrial cancer, while olaparib, an oral PARP inhibitor, is approved in multiple settings for gynecologic malignancies.

“Potential synergy between these 2 agents and prior data suggests the combination may be active and tolerable in the treatment of endometrial cancer,” Rimel said.

She added that integrated biomarker analysis is in progress for the trial, which has been amended to include an additional 4 arms of study: retaining cediranib as the reference arm, olaparib plus capivasertib, olaparib plus durvalumab, and cediranib plus durvalumab.

_Reference:

_{Rimel BJ. 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: 2021 SGO Virtual Annual Meeting on Women’s Cancer; March 21, 2021; Virtual. Abstract 11636.}