Abstract CT175: Neoadjuvant olaparib and cediranib in renal cancer: Outcomes of the WIndow-of-opportunity in REnal cancer (WIRE) Trial

Abstract Background: New therapies are needed for patients who experience primary or secondary resistance to renal cell cancer (RCC) treatment. Pre-clinical data suggests PARP inhibitors may be effective for RCC in combination with VEGF inhibitors. Neoadjuvant clinical trials offer an opportunity to understand the mechanisms of new therapies by comparing tumour and blood before and after treatment. Methods: WIRE is a window of opportunity, phase II, multi-centre, multi-arm, non-randomised, neoadjuvant clinical trial platform (NCT03741426). Arms 1-3 comprised: 1. cediranib (VEGF inhibitor), 2. cediranib + olaparib (PARP inhibitor), 3. olaparib. Eligible patients (pts) have cT1b+, cN0/1, cM0/1 clear cell RCC, planned for surgery, with no contraindication to IMP. A Bayesian adaptive design optimises recruitment to arms based on interim analyses of treatment effects. Pts receive 14-28 days of IMP to fit with the planned surgery date. Primary endpoint for arms 1-3 is a ≥30% reduction in DCE-MRI assessed capillary permeability (median Ktrans) post-treatment compared to baseline. Secondary endpoints include RECIST v1.1 primary tumour response and adverse events. Translational analysis will include blood profiling and multi-region tissue analysis by transcriptomics and digital pathology. Results: 29 pts were recruited (arm 1=6, arm 2=16, arm 3=7), 28/29 were male, median age 61y (range 48-75y). All pts were treatment naïve with ECOG PS of 0 or 1. 8/29 pts had M1 disease. All surgeries were completed within the planned window. 3/29 pts were not evaluable for the primary endpoint due to inadequate dose of IMP. The numbers of evaluable pts which met the primary endpoint were arm 1: 4/6 (67%), arm 2: 4/14 (29%), arm 3: 0/6 (0%). Table 1 shows changes in Ktrans, RECIST response and adverse events. Plasma angiogenic factors were significantly induced on treatment in the combination therapy arm 2. There was no correlation between angiogenic factor induction and Ktrans change. Conclusions: Positive responses in median Ktrans were observed in both the cediranib monotherapy and cediranib and olaparib combination therapy arms. Therapy was well tolerated, with no substantial toxicity or delays to surgery. Greater induction of angiogenic factors in the combination arm indicates possible synergy between cediranib and olaparib. Ongoing translational analysis of tissue and blood samples will investigate the mechanisms of response to these agents. Citation Format: James O. Jones, Ines Horvat Menih, Martin Thomas, Helen Mossop, Rebecca Wray, Maria Aquino, James Armitage, Harriet Baker, Carley Batley, James Blackmur, Sarah Burge, Anita Chhabra, Farhana Easita, Tim Eisen, Kate Fife, Angela Godoy, Richard Goodwin, Will Ince, Rose John, Alexander Laird, Natalia Lukashchuk, Athena Matakidou, Thomas J. Mitchell, Andrew N. Priest, Andrew Protheroe, Sreenidhi Ranjit, Anthony Riddick, Sulekha Said, Jamal Sipple, Amy Strong, Helen Su, Mark Sullivan, Silvia Tarantino, Gemma Tsang-Pells, Stephan Ursprung, Balaji Venugopal, Lauren Wallis, Anne Y. Warren, James Wason, Sarah J. Welsh, Younghwa Kim, John Stone, Mireia Crispin-Ortuzar, Ferdia A. Gallagher, Brent O'Carrigan, Grant D. Stewart, on behalf of the WIRE Trial Group. Neoadjuvant olaparib and cediranib in renal cancer: Outcomes of the WIndow-of-opportunity in REnal cancer (WIRE) Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT175.