Background: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need. Methods: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites. Results: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS – mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups. Conclusion: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations.

Androgen Receptor-Targeted Agents (ARTA) have dramatically changed the therapeutic landscape of metastatic Castration-Resistant Prostate Cancer (mCRPC), but 20–40% of these patients progress early after start of ARTA treatment. The present study investigated the potential utility of plasma cell-free microRNAs (cfmiRNAs) as prognostic markers by analyzing a prospective cohort of 31 mCRCP patients treated with abiraterone (N = 10) or enzalutamide (N = 21). Additional potential prognostic factors were extracted from clinical records and outcome was evaluated as overall survival (OS) and progression-free survival (PFS). cfmiRNAs were measured in plasma samples using quantitative real-time RT-PCR. Linear correlation among clinical factors and cfmiRNAs was assessed using the Spearman's rank correlation coefficient. The association with survival was studied using univariate and multivariate Cox proportional hazards models. Continuous variables were dichotomized with the cut points corresponding to the most significant relation with the outcome. Univariate analysis indicated that plasma levels of miR-21-5p, miR-141-3p and miR-223-3p, time to development of castration-resistance (tCRPC), and blood hemoglobin (Hb) levels strongly correlated with both PFS and OS. Multivariate analysis revealed that low plasma levels of miR-21, shorter tCRPC, and lower Hb values were independent factors predicting reduced PFS and OS. These findings suggest that the integrated analysis of cfmiRNAs, tCRPC, and Hb may provide a promising, non-invasive tool for the prognostic stratification of mCRPC patients treated with ARTA.

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442 Background: Niraparib is an oral inhibitor of poly ADP-ribose polymerase (PARP) enzymes. Based on the association of mutations in homologous recombination repair (HRR) genes with platinum sensitivity, aim of this phase II trial was to compare maintenance treatment with niraparib plus BSC vs. BSC alone in pts with advanced UC who obtain objective response (OR) or stable disease (SD) with first-line PBCT. Methods: Meet-URO12 is a randomized phase II multicentre trial enrolling pts with advanced transitional cell UC, without evidence of progression after 4-6 cycles of first-line PBCT (cisplatin or carboplatin). Pts were randomized (2:1) to experimental arm A (niraparib 300 or 200 mg daily according to body weight and baseline platelets, plus BSC) or control arm B (BSC alone). Primary endpoint was progression-free survival (PFS). 77 pts were planned and 65 PFS events were needed to detect Hazard Ratio 0.57, with 80% power and one-tailed alpha 0.1. Accrual was prematurely stopped due to availability of avelumab in the same setting, and protocol was amended to perform analysis with ≥ 40 PFS events. Molecular characteristics, including alteration of HRR genes, were assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay. Results: Between Aug 2019 and Mar 2021, 58 pts were randomized in 14 Italian centers (39 assigned to arm A and 19 to arm B); 1 pt assigned to arm A did never start niraparib. Median age was 69y (44-84); ECOG PS0 65.5%/ PS1 34.5%; best response with PBCT OR 55.2%/ SD 44.8%. As of Aug 2021, after a median follow-up of 8.5 mos, 47 PFS events were recorded. Median PFS was 2.1 mos in arm A and 2.4 mos in arm B (HR 0.92; 95%CI 0.49 – 1.75, p=0.81). 6-months progression-free rate was 28.2% and 26.3%, respectively. Time to treatment failure for pts who started niraparib was 2.4 mos. Out of 47 pts with molecular info, 21 (44.7%) had HRR alterations: 6 (12.8%) known pathogenic mutations and 15 (31.9%) variants of unknown significance. In pts with pathogenic mutations, median PFS was 2.0 mos in arm A and 1.9 mos in arm B. In pts with any HRR mutation, median PFS was 2.0 mos in arm A and 2.0 mos in arm B. Any grade≥3 treatment-emergent adverse event (AE) was reported in 25/38 pts (65.8%) in arm A and in 3/19 pts (15.8%) in arm B. 18/38 pts (47.4%) needed dose reduction of niraparib. Most common AEs with niraparib were anemia (50.0%, G3 10.5%), thrombocytopenia (36.8%, G3-4 15.8%), neutropenia (21.1%, G3 5.3%), fatigue (31.6%, G3 15.8%), constipation (31.6%, G3 2.6%), mucositis (13.2%, G3 2.6%), nausea (13.2%, G3 2.6%). Conclusions: Maintenance niraparib plus BSC did not prolong PFS, as compared with BSC alone, among pts with urothelial cancer without progression after first-line PBCT. Clinicaltrials.gov Identifier. NCT03945084. Clinical trial information: NCT03945084.

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