The WinPro trial: A window of opportunity study of endocrine therapy with and without prometrium in postmenopausal women with early stage hormone receptor-positive breast cancer.

513 Background: Preclinical evidence has shown that progesterone is a tumour suppressor in estrogen receptor positive (ER+) breast cancer. Prometrium is bioidentical to human progesterone, currently used for treating menopausal symptoms. Methods: The WinPro trial is a randomised, multi-centre, phase 2, window of opportunity trial of preoperative endocrine therapy in post-menopausal women with early-stage, ER+, progesterone receptor (PR) +, HER2- breast cancer. Patients (pts) were randomised 1:1:1 to letrozole (let) 2.5mg daily, letrozole 2.5mg daily + prometrium (pro) 300mg daily, or tamoxifen (tam) 20mg daily + prometrium 300mg daily for 11-17 days before surgery. The primary endpoint was the percent proportional reduction in Ki67 between biopsy and surgery (‘Ki67 suppression’) in let vs let + pro in the per protocol population. Other endpoints were safety, changes in ER, PR and androgen receptor (AR) via immunohistochemistry (IHC) and H-scores, spatial transcriptomics and RNA sequencing. Results: From Feb 2018 to June 2024,244 pts were enrolled across 6 Australian sites. 239 pts were randomised to let (n=78, 32.6%), let + pro (n=79, 33.1%), and tam + pro (n=82, 34.3%). 189 pts completed per protocol: let (n=66, 34.9%, let + pro (n=64, 33.9%), and tam + pro (n=59, 31.2%). Baseline characteristics were well balanced across arms. There was no significant difference in Ki67 suppression between let (88.2%) vs let + pro (89.2%) (p = 0.4). Ki67 suppression appeared inferior with tam + pro (61.5%). Treatments were well tolerated, with hot flushes less frequent in let + pro (13.3%) vs let (22.4%) or tam + pro (20.5%). IHC analyses showed no change in ER% after treatment, a decrease in PR% after treatment with let and let + pro, and a decrease in AR% after treatment in all groups. H-score, spatial transcriptomics, RNA sequencing and PAM50 analyses are underway. Conclusions: The WinPro trial showed that the addition of pro to let in post-menopausal women with ER+, PR+, HER2- breast cancer was safe, reduced hot flushes and led to similar reduction in Ki67 as let alone. Ongoing translational analyses are underway which will examine the changes in gene expression in malignant, immune and stromal cells at sub-cellular resolution and provide further insight into the mechanisms of response and resistance to endocrine therapy. Clinical trial information: ACTRN12618000928213 . Baseline Surgery Let N = 67 Let + pro N = 64 Tam + pro N = 60 Let N = 67 Let + pro N = 64 Tam + pro N = 60 Ki67% suppression, median (Q1, Q3) - - - 88.2(74.6, 93.0) 89.2(78.3, 93.9) 61.5(32.3, 75.9) Ki67%, median (Q1, Q3) 8.5(4.5, 16.0) 10.5(5.0, 16.3) 10.8(6.0, 17.0) 1.0(0.5, 2.5) 1.0(0.5, 2.0) 3.5(2.0, 7.5) ER%, median (Q1, Q3) 95(95, 95) 95(95, 95) 95(95, 95) 95(95, 95) 95(95, 95) 95(95, 95) PR%, median (Q1, Q3) 90(50, 95) 90(35, 95) 90(50, 95) 20(4, 70) 20(2, 70) 90(33, 95) AR%, median (Q1, Q3) 40(10, 90) 28(8, 80) 70(20, 90) 15(2, 60) 10(2, 75) 10(1.3, 45)