A surgical window trial evaluating medroxyprogesterone acetate with or without entinostat in endometrial cancer and validation of biomarkers of cellular response: An NRG Oncology study

Objectives: This surgical window of opportunity (window) study assessed the short-term effect of medroxyprogesterone acetate (MPA) alone vs MPA plus histone deacetylase (HDAC) inhibitor entinostat regulation of progesterone receptor (PR) in women with newly diagnosed endometrioid endometrial adenocarcinoma (EC). Methods: A multi-site, randomized, open-label surgical window study treated women intramuscularly on day 1 with 400 mg MPA. Entinostat given 5 mg by mouth (PO) on days 1, 8 and 15 was randomly assigned with equal probability. Surgery followed on day 21-24. Pre- and post-treatment slides were assessed for PR H-scores, Ki-67 levels and histologic response. Results: A total of 50 patients were accrued in 4 months; 22 and 20 participants had PR evaluable pre- and post-treatment slides in the MPA and MPA/Entinostat arms respectively. The median post treatment PR H-scores were significantly lower than pretreatment H-scores in both arms but did not differ significantly (MPA: 247 vs 27, MPA/Entinostat: 260 vs 23 respectively) p=0.87. Decreased Ki-67 was shown in 90% treated with MPA/Entinostat compared to 68% treated with MPA alone (p=0.13). Median PR H-score decreases were larger when Ki-67 was decreased (208) vs not decreased (45). The decrease in PR pre- vs post-treatment was associated with a loss of Ki-67 nuclear staining, consistent with reduced cellular proliferation (p Conclusions: This surgical window trial rapidly accrued in a multisite setting and evaluated PR as its primary endpoint and Ki67 as secondary. Despite no immediate effect of entinostat on PR in this short term study, lessons learned can inform future window and treatment trials.