Neoadjuvant treatment of bladder cancer is evolving, with immunotherapy demonstrating promising activity. PARP inhibition combined with immune activation has been proposed as a synergistic strategy.
We conducted a comprehensive molecular characterization of tumors treated with this combination in the neoadjuvant setting to provide crucial results for rational development.
A phase II clinical trial was designed to evaluate the combination of anti-PDL1 inhibitor durvalumab and PARP inhibitor olaparib, focusing on biomarker dynamics in both pre- and post-treatment settings. A total of 29 patients were enrolled. Genomic and transcriptomic profiling, as well as analyses of immune cell populations, was conducted at baseline and at the time of cystectomy.
Of the 29 patients treated, a pathologic complete response was observed in 13 cases (44.8%). No major safety concerns were associated with the treatment, and 26 patients (90%) underwent cystectomy. Mutational patterns, tumor mutation burden, and homologous recombination deficiency remained stable throughout treatment and were not predictive of outcomes. However, a shift toward stromal phenotypes and increased expression of epithelial-mesenchymal transition signatures were observed following therapy, particularly in resistant tumors. Moreover, an increase in circulating CD4+ CD27- CD28- T cells was noted among responders.
The combination of neoadjuvant durvalumab and olaparib shows therapeutic activity in bladder cancer. Resistance mechanisms seem to be driven by transcriptional adaptations rather than the emergence of new mutations.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2025 Apr 29 [Epub ahead of print]
Juan F Rodríguez-Moreno, Guillermo de Velasco, Carlos Álvarez-Fernández, Ricardo Collado, Ricardo Fernández, Sergio Vázquez, Juan A Virizuela, Pablo Gajate, Albert Font, Nuria Lainez, Elena Sevillano-Fernández, Osvaldo Graña-Castro, Luis Beltrán, Rodrigo Madurga, Cristina Rodríguez-Antona, Pedro Berraondo, Sergio Ruiz-Llorente, Jesús García-Donas
Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain., Hospital Universitario 12 de Octubre, Madrid, Spain., Medical Oncology Service, Hospital Universitario Central de Asturias, Oviedo, Spain., Complejo Hospitalario de Cáceres, Cáceres, Spain., Medical Oncology Department, Hospital Universitario de Cruces, Barakaldo, Spain., Hospital Universitario Lucus Augusti, Lugo, Spain., Hospital Universitario Virgen Macarena, Sevilla, Spain., Hospital Universitario Ramón y Cajal, Madrid, Spain., Instituto Catalán de Oncología (ICO), Badalona, Spain., Complejo Hospitalario de Navarra, Pamplona, Spain., Department of Basic Medical Sciences, Institute of Applied Molecular Medicine (IMMA), Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Madrid, Spain., Department of Cellular Pathology, Barts Health NHS Trust, London, United Kingdom., Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain., Spanish National Cancer Research Center, Madrid, Spain., Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/40298406