The effect of megestrol acetate ± pterostilbene in endometrial cancer: A prospective, randomized, window-of-opportunity clinical trial.

Abstract

5597 Background: Pterostilbene (3,5-dimethoxy-40-hydroxystilbene) is a potent oral antioxidant found naturally at highest concentrations in blueberries. Its anti-tumor effects in preclinical studies of various solid tumors include carcinogenesis, inflammation, reactive oxygen species (ROS) formation, and antiproliferative effects. In endometrial cancer (EC), in vitro and in vivo studies demonstrated a synergistic antiproliferative effect of pterostilbene (PT) in combination with megestrol acetate (MA). No clinical trials testing the potential therapeutic benefit of pterostilbene in cancer have been completed. Methods: We performed a prospective, window-of-opportunity, randomized phase 2 clinical trial (NCT03671811) in patients with EC. Eligible patients had to be surgical candidates for treatment with hysterectomy and not have received prior therapy. The primary objective was to determine the effect of MA plus PT versus standard treatment of MA alone on tumor proliferation as measured by the Ki-67 index during the preoperative window. Patients were randomized 1:1 to one of two arms: MA+PT PO BID versus MA PO BID, for 3 weeks. The Ki-67 index was measured via hot-spot and H-score methodology in the preoperative tumor and hysterectomy specimen by two blinded pathologists whose measurements were averaged. The net change between pre- and post-operative specimens was calculated for each patient and expressed as a percentage. Toxicity was assessed using CTCAE grading. Results: A total of 44 patients with EC of all histologies were recruited to the study and included in the toxicity analysis. Median age was 61.9 years. Baseline demographics were comparable between both arms. Median treatment duration was 21 days (14-56), similar in both arms. One G3 hypertension was encountered in the MA arm; one G3 thromboembolic event in the MA+PT arm. Of 35 patients with sufficient treatment duration (>10 days) and available pre-and post-treatment specimens, 29 patients with endometrioid histology were evaluated for the ki67 analysis: 14 in the MA arm and 15 in the MA+PT arm. The MA+PT group demonstrated a -41.1% change in Ki-67 index by Hot Spot Score compared to -27.5% in the MA-only group (p=0.17). A similar trend was observed for the Ki-67 index by H Score methodology (-41.6% vs -26.7%, MA+PT vs MA, p=0.17). Conclusions: The combination of MA + PT in preoperative treatment of endometrial adenocarcinoma is well tolerated. The addition of Pterostilbene demonstrates a trend towards decreased Ki-67 index in endometrioid EC patients. Molecular studies are pending to delineate biomarkers associated with response. Clinical trial information: NCT03671811 .