LEEP: A randomised, window of opportunity, neoadjuvant trial examining the pharmacodynamic effects of ribociclib prior to radical prostatectomy for high-risk, localised prostate cancer.
Authors: Tahlia Scheinberg, James G Kench, Peter Ferguson, Sarah Sutherland, Martin R Stockler, Kate Lynette Mahon, Phillip Stricker, Anthony M. Joshua, Henry Woo, Ruban Thanigasalam, Nariman Ahmadi, Gavin M. Marx, Ian D. Davis, Shomik Sengupta, Scott Leslie, Margaret M Centenera, Lisa Butler, Lisa Horvath
Journal: Journal of Clinical Oncology (2025)

392 Background: Prostate cancer (PCa) remains the second leading cause of cancer death in men. Neoadjuvant pharmacodynamic studies facilitate rational decisions about which therapies should progress to phase 2/3 trials. CDK4/6 inhibitors are effective in breast cancer, but have not demonstrated the same efficacy in metastatic PCa. LEEP assessed the pharmacodynamic effects of ribociclib, a highly selective oral CDK4/6 inhibitor, in hormone-naïve, high-risk, localised PCa. Methods: This open-label, window of opportunity trial randomised participants at 3 Australian sites in a 4:1 ratio to an experimental or control group. Participants in the experimental group were to be treated with ribociclib 400mg daily for 21 days prior to radical prostatectomy (RP). The primary endpoint was a 50% reduction in Ki-67 expression from the pre-treatment biopsy compared to the RP. Immune cell changes in peripheral blood and tissue were also examined. Results: Between November 2018 and October 2022,33 patients were randomised to either ribociclib or control. 17 participants in the ribociclib group and 7 in the control group were evaluable for response (9 not evaluable due to surgical delays (including COVID shutdowns) or insufficient cancer in the biopsy). When examining a random selection of cancer areas, 10/17 (58%) participants had a greater than 50% reduction in Ki-67, compared to only 2/7 (29%) in the control group. When examining hot spot areas of cancer (i.e. areas with the highest proportion of positive cells on low power estimation), only 5/17 (29%) participants had a greater than 50% reduction in Ki-67, compared to 0/7 (0%) in the control group. In peripheral blood, there were reductions in CD1c and CD141 dendritic cells and myeloid derived suppressor cells over 4 times points in the ribociclib (p&gt;0.05, 0.05 and 0.05 respectively) vs. control groups (p=0.46, 0.14 and 0.14). In patients treated with ribociclib, there was no difference in circulating regulatory T cells (p=0.67). Within the PCa tissue, there was a reduction in regulatory T cells in the ribociclib group compared to controls (p=0.07), but no change in adjacent non-cancerous tissue (p=0.701). There was no difference in M1 or M2 macrophages between the ribociclib and control groups (M1: tumour p=0.307, adjacent non-cancer p=0.334; M2: tumour p=0.168, adjacent non-cancer p=0.130). Conclusions: Following neoadjuvant treatment with ribociclib, &gt;50% reductions in Ki-67 were more frequent among those treated with ribociclib than controls. Reductions in Ki-67 were uncommon in more proliferative areas. Changes in the immune environment were consistent with breast cancer studies. We hypothesise that the more proliferative areas of cancer are less responsive to CDK4/6 inhibitors and this may in part explain the lower observed efficacy in mCRPC than metastatic breast cancer. Clinical trial information: ACTRN12618000354280 .