The Anti-Cancer Role of Pterostilbene in Endometrial Cancer: A Phase II Prospective, Randomized, Window-of-Opportunity Clinical Trial with Megestrol Acetate

Pterostilbene (3,5-dimethoxy-40-hydroxystilbene) is a potent oral antioxidant with a promising role in anti-cancer treatment. In endometrial cancer (EC), in vitro studies demonstrated a synergistic antiproliferative effect of pterostilbene (PT) with megestrol acetate (MA), a common treatment for EC. This is a randomized phase II clinical trial (NCT03671811) of PT+MA vs. MA for three weeks prior to scheduled hysterectomy. The primary objective is to determine the antiproliferative effect of PT+MA vs. MA using Ki-67 index. The secondary objectives are toxicity, histological response, transcriptional changes, and lipid metabolism. A total of 44 patients were enrolled between January 2019 and November 2022 with 23 randomized to Arm 1 (PT+MA) and 21 to Arm 2 (MA). Toxicities included one G3 thromboembolic event (PT+MA) and one G3 hypertension event (MA). Histological responses were high in both arms (>90%). There was no difference in Ki-67 changes, although, when restricted to endometroid subtype, the relative decrease in Ki67 was 33.8% in PT+MA vs. 20.1% in MA alone (<i>p</i> = 0.14). Whole transcriptomic gene profiling of samples before and after PT+MA exposure demonstrated the activation of interferon alpha response pathway and suppression of mTORC1 signaling, hypoxia, oxidative phosphorylation, and IL2-STAT5 signaling. Lipid metabolism analyses did not reveal any significant changes between arms. PT is well-tolerated in the preoperative treatment of EC and demonstrated in vivo anti-cancer effects on the transcriptomic level.