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

Abstract

Objectives: The Cancer Genome Atlas and others identified genomic events suggesting that endometrial cancer (EC) should be susceptible to DNA repair inhibition. Data from pre-clinical models suggest poly ADP-ribose polymerase (PARP) inhibitors alone or in combination with other targeted agents may be an effective therapeutic strategy in EC. Combinations of angiogenic inhibitors and PARP inhibitors have demonstrated synergistic effects and have been well tolerated in other tumor types. This study compared two experimental arms exploring DNA repair inhibition versus cediranib alone which has previously shown promising activity in GOG 229J. Methods: A 1:1:1 randomized phase II study comparing cediranib (C) versus olaparib (O) or the combination of olaparib and cediranib (OC) for women with recurrent EC. Eligible patients had received at least 1 prior platinum containing chemotherapy but ≤2 prior lines of chemotherapy for recurrent EC. Cediranib was administered 30 mg PO daily, olaparib 300 mg PO BID and in the combination cediranib 20 mg PO daily / olaparib 300 mg PO BID. One cycle in all arms was 28 days. Primary endpoint was progression free survival (PFS) by RECIST1.1. Patients were stratified by histology (serous vs. endometrioid). Results: 120 patients were enrolled. 109 patients were treated: 34 patients C: 39 O and 36 OC. 10 patients withdrew consent prior to treatment. Median age was 66 years (range 41-86); 47 (39.2%) serous, 62 endometrioid (51.7%) and 8 (6.7%) mixed histology. The Kaplan Meir estimated median PFS was 3.8 months for C; 2.0 months O and 5.5 months for OC. The one-sided p value stratified log rank test comparing O vs. C was 0.935: HR 1.45 (95% CI 0.91-2.3) and C vs. OC 0.064; HR 0.7 (95% CI: 0.43-1.14). No new safety signals were reported. Conclusions: The combination of cediranib and olaparib demonstrated modest efficacy in patients with recurrent, metastatic or persistent EC, but was not significantly different compared to cediranib alone. The combination was safe with no unexpected toxicity. Single agent olaparib demonstrated insufficient efficacy to warrant further investigation as monotherapy in this patient population. The Cancer Genome Atlas and others identified genomic events suggesting that endometrial cancer (EC) should be susceptible to DNA repair inhibition. Data from pre-clinical models suggest poly ADP-ribose polymerase (PARP) inhibitors alone or in combination with other targeted agents may be an effective therapeutic strategy in EC. Combinations of angiogenic inhibitors and PARP inhibitors have demonstrated synergistic effects and have been well tolerated in other tumor types. This study compared two experimental arms exploring DNA repair inhibition versus cediranib alone which has previously shown promising activity in GOG 229J. A 1:1:1 randomized phase II study comparing cediranib (C) versus olaparib (O) or the combination of olaparib and cediranib (OC) for women with recurrent EC. Eligible patients had received at least 1 prior platinum containing chemotherapy but ≤2 prior lines of chemotherapy for recurrent EC. Cediranib was administered 30 mg PO daily, olaparib 300 mg PO BID and in the combination cediranib 20 mg PO daily / olaparib 300 mg PO BID. One cycle in all arms was 28 days. Primary endpoint was progression free survival (PFS) by RECIST1.1. Patients were stratified by histology (serous vs. endometrioid). 120 patients were enrolled. 109 patients were treated: 34 patients C: 39 O and 36 OC. 10 patients withdrew consent prior to treatment. Median age was 66 years (range 41-86); 47 (39.2%) serous, 62 endometrioid (51.7%) and 8 (6.7%) mixed histology. The Kaplan Meir estimated median PFS was 3.8 months for C; 2.0 months O and 5.5 months for OC. The one-sided p value stratified log rank test comparing O vs. C was 0.935: HR 1.45 (95% CI 0.91-2.3) and C vs. OC 0.064; HR 0.7 (95% CI: 0.43-1.14). No new safety signals were reported. The combination of cediranib and olaparib demonstrated modest efficacy in patients with recurrent, metastatic or persistent EC, but was not significantly different compared to cediranib alone. The combination was safe with no unexpected toxicity. Single agent olaparib demonstrated insufficient efficacy to warrant further investigation as monotherapy in this patient population.