Abstract
PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.