Background: Immune checkpoint inhibitors have been incorporated to early-stage bladder carcinoma treatment recently. Durvalumab is a PD-L1 blocking antibody active in advance urothelial tumors and under evaluation in other settings of the disease. PARP inhibitors have shown activity in a variety of tumors with Homologous Recombination Deficiencies (HRD). The combination of Durvalumab plus Olaparib could present a synergistic effect, but its efficacy and potential biomarkers are under exploration. NEODURVARIB is a phase II clinical trial assessing the combination of Durvalumab plus Olaparib in MIBC (NCT03534492; SOGUG-2017-AIEC(VEJ)-2). Clinical activity and safety have been previously communicated by our group. Here we present the basal molecular profiles and their evolution under treatment with this combination. Methods: cT2-T4a MIBC aimed for cystectomy were treated during 6-8 weeks precystectomy. Pre- and post-treatment tumor and blood samples from 26 patients were collected. Pattern of immune infiltration was determined by IHQ. Genomics (mutational pattern, HRD and Tumor Mutation Burden [TMB]) and transcriptomics (differentially expressed loci, functional enrichment, molecular clustering and MIBC molecular subtyping) analysis were performed. Circulating immune populations were assessed using flow cytometry. Results: In basal (TURBT) samples, the frequency of mutations in genes commonly altered in MIBC (TP53, MLL2, ARID1A, FGFR3, among others), HRD and TMB were similar to previous reports in MIBC and did not differ between responders and non-responders. Additionally, mutational patterns remained stable between baseline (TURBT) and post-treatment (cystectomy) samples. Regarding transcriptomics, GSEA showed enrichment of Epithelial Mesenchymal Transition (EMT), TGFβ and inflammatory/infection related classes in resistant tumors. Interestingly, differentially expressed genes in responders vs. non-responders were significantly regulated by epigenetic factors (EZH2/Suz12/PRC2 network). Transcriptomic-based estimations of the stromal/immune infiltration and MIBC molecular subtyping also showed a switch of the tumor microenvironment due to the treatment (luminal to basal/squamous transitions), reinforced by significant changes in the expression of immune markers (higher PDL1 and FAP scores in cystectomies). Lastly, circulating senescent T-cells were correlated with pathological complete response. Conclusions: Genetic alterations remained unchanged in bladder cancers treated with Durvalumab plus Olaparib. However, an enrichment of EMT signatures and a switch towards basal/squamous phenotypes were observed in resistant tumors. These findings underscore the relevance of modifications in gene expression as potential mechanisms of resistance to this combination. Clinical trial information: NCT03534492.