Comprehensive molecular characterization of muscle-invasive bladder cancer (MIBC) treated with durvalumab plus olaparib in the neoadjuvant setting: Neodurvarib trial.
Authors: Rodriguez-Moreno Juan Francisco , Ruiz-Llorente Sergio , De Velasco Guillermo , Alvarez-Fernandez Carlos , Collado Martín Ricardo , Fernandez Ricardo , Vazquez-Estevez Sergio , Virizuela Juan Antonio , Gajate Pablo , Font Albert , Lainez Nuria , Barquin Arantzazu , Beltran Luis , Rodriguez-Antona Cristina , Berraondo Pedro , García-Donas Jesús 
Published: February 2022

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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.