Abstract CT173: Neoadjuvant durvalumab and olaparib in resectable urothelial bladder cancer- Impact on its molecular profile and efficacy: Neodurvarib trial

Abstract BACKGROUND: PARP inhibition by olaparib and immune system activation due to PD-L1 binding with durvalumab have been suggested as synergistic strategies. Thus, a comprehensive molecular characterization of tumors treated with this combination could support its rational development. Neoadjuvant bladder cancer could serve as an ideal setting for this purpose. METHODS: We designed a phase II trial with durvalumab plus olaparib to analyze the dynamics of biomarkers in both pre- and post-treatment settings. Twenty-nine patients were enrolled. Genomic and transcriptomic profiles, as well as immune cell populations, were assessed at baseline and cystectomy. RESULTS: The combination was well tolerated, with 26 (90%) patients undergoing cystectomy. Among the 29 patients treated, a pathological complete response was observed in 13 cases (44.8%). Mutational patterns, tumor mutation burden, and homologous recombination deficiency did not vary throughout treatment and did not correlate with outcomes. However, a shift towards stromal phenotypes and an overexpression of epithelial-mesenchymal transition signature were observed after therapy and in resistant tumors. Additionally, an increase in circulating CD4+ CD27- CD28- T cells was observed in responders. CONCLUSION: Neoadjuvant durvalumab plus olaparib appears to be active in bladder cancer. Transcriptional adaptations, rather than new mutations, could be a key mechanism of resistance. Citation Format: Juan F. Rodriguez Moreno, Guillermo de Velasco, Carlos Alvarez, Ricardo Collado, Ricardo Fernandez, Sergio Vazquez, Juan Antonio Virizuela, Pablo Gajate, Albert Font, Nuria Lainez, Elena Sevillano, Osvaldo Grana Castro, Luis Beltran, Rodrigo Madurga, Cristina Rodriguez-Antona, Pedro Berraondo, Sergio Ruiz-Llorente, Jesus Garcia-Donas. Neoadjuvant durvalumab and olaparib in resectable urothelial bladder cancer- Impact on its molecular profile and efficacy: Neodurvarib 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 CT173.