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546 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.

TPS503 Background: Perioperative treatment of muscle-invasive bladder carcinoma (MIBC) remains cisplatin-based chemotherapy, but recent evidences suggest that immune checkpoint inhibitors could be incorporated in this setting. Durvalumab is a PD-L1 blocking antibody active in advanced urothelial carcinoma pretreated with platinum-containing chemotherapy and currently under evaluation in first-line, both as monotherapy and in combination with tremelimumab. Olaparib is a PARP inhibitor especially important in tumors with deficiencies in DNA repair mechanisms. Preliminary results from combination trials suggest that these drugs could have synergistic effect dependent on an immunogenic modulation related with STING pathway, and an increase of neoantigens. Unexpected toxicities have not been described. Methods: Design: Open label phase II single arm clinical trial. Primary Objective: To assess the impact of neoadjuvant treatment with durvalumab plus olaparib in the molecular profile of MIBC. Secondary Objectives: Efficacy (Radiological and pathological responses); Safety. Exploratory objective: To identify predictive and prognostic biomarkers. Key correlative studies: Independent central pathologist for histological review and assessment of immunohistochemistry for PD1, PD-L1 and PD-L2; Genomic characterization (WES) and Expression assessment (RNAseq) of the tumors pre and post treatment; Assessment of soluble biomarkers and their evolution during the treatment: flow cytometry for immune cells; immunoassays for cytokines; HLA genotyping. Treatment: Durvalumab 1500 mg iv Q4W & Olaparib 150 mg bid orally during 6 to a maximum of 8 weeks pre-cystectomy. Recruitment: 29 patients. Collaborating institutions: 10 (members of Spanish Oncology Genitourinary Group). Key Inclusion Criteria: Subjects with histological confirmation of T2-T4a MIBC aimed for cystectomy without neoadjuvant chemotherapy; Available samples for correlative studies; Adequate medullary, renal and hepatic function. Key Exclusion Criteria: Use of immunosuppressive medication; Documented autoimmune disorders. Clinical trial information: NCT03534492.

e16061 Background: Markers of the systemic inflammatory response have prognostic value in ccRCC prior to starting treatment. Dynamic changes during therapy and their role in predicting prognosis are not well characterised. Methods: A retrospective analysis was conducted of a randomised, double-blind phase II study evaluating cediranib vs cediranib and saracatinib in patients with relapsed metastatic ccRCC (COSAK). Haemoglobin (Hb), neutrophil count (N0) platelet count (Plt), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were recorded at randomisation, 8-weeks and progression (PD). Change in mean values at each time point were compared. Baseline prognostic values for overall survival (OS) were assessed using Cox regression. Absolute changes in parameters were calculated at 8 weeks and PD, patients were grouped around the upper or lower quartile. Prognostic value of dynamic changes was assessed at 8 weeks and PD using the Kaplan-Meier method. Results: 138 patients were assessed; median OS was 12.0 months (IQR 8.1-15.6 months). Outcomes in the combination arm were similar to single agent arm (HR 1.28 (1.00–1.63)). On multivariate analysis at baseline, MSKCC score (0/1-2/≥3) (HR 2.52 (1.60 -3.96)), CRP ( < 10/≥10mg/L) (HR 1.72 (1.04 – 2.86)) and N0 ( < 7.5/≥7.5x109) (HR 2.38 (1.43 – 3.96)) were independent predictors of OS. Mean CRP was significantly different at baseline, 8 weeks and PD (64.9, 42.3 and 85.7 mg/L respectively, p < 0.001). Mean N0 count at baseline was 5.3 x109/L and was significantly higher 6.3x 109/L at PD (p < 0.001). Mean Hb at baseline, 8 weeks and PD was 11.5, 13.0 and 12.9g/L respectively (P < 0.001). A rise in CRP or N0 at 8 weeks was predictive of poor outcome ((HR 1.62 (1.10-2.56) and (HR 1.77 (1.19-2.61) respectively). A fall in Hb was predictive of poor outcome at 8 weeks (HR 1.75 (1.18-2.60)) and PD (HR 1.80 (1.20-2.76)). Conclusions: Dynamic changes occur in prognostic markers in patients receiving VEGF-targeted therapy in ccRCC and may predict OS.

1579 Background: Cervical cancer is still the main cause of death from cancer in indigenous population and rural communities in Mexico. We have evaluated both screen-and-treat colposcopy and oncoge...

5059 Background: The natural history of prostate cancer is highly variable and difficult to predict accurately. Better markers are needed to guide management and avoid unnecessary treatment. To val...

184 Background: Prostate cancer shows a wide variation in the clinical incidence and mortality rates of different geographical regions. While it is the most common male cancer in Western countries, it is much less frequent in Asian countries. We investigated genomic changes in prostate cancers from UK and China using microarrays to determine the genetic similarities and differences as well as the underlying mechanisms. Methods: We determined genome-wide genomic alterations using Affymetrix SNP array 6.0, and evaluated data using fluorescence in situ hybridisation (FISH) and immunohistochemistry. In addition, we assess androgen induced TMPRSS2 and ERG co-localization and fusion. Microsatellite analysis was used for AR CAG repeat polymorphism in UK and Chinese population. Results: Genome-wide analysis of 32 UK and 39 Chinese samples revealed that losses of 21q22 (leading to TMPRSS2:ERG fusion) and 10q23.3 (PTEN) were at much higher frequency in Western than Chinese prostate cancers. Using FISH analysis of 160 UK and 143 Chinese samples, we showed that PTEN deletion and ERG rearrangements were at a significantly higher frequency in samples from UK than China (p Conclusions: We revealed genomic differences in prostate cancer comparing the high-risk (Western) and low-risk (Chinese) populations. We further demonstrated that TMPRSS2:ERG fusion can be induced by androgen. The difference of CAG repeat length between the two populations are potentially associated with TMPRSS2:ERG fusion positive prostate cancers.