Randomized phase II study of niraparib plus best supportive care (BSC) versus BSC alone as maintenance treatment in patients with advanced urothelial carcinoma (UC) whose disease did not progress after first-line platinum-based chemotherapy (PBCT): The Meet-URO12 trial.
Authors: Vignani Francesca , Tambaro Rosa , De Giorgi Ugo , Giannatempo Patrizia , Bimbatti Davide , Carella Claudia , Stellato Marco , Atzori Francesco , Aieta Michele , Masini Cristina , Hamzaj Alketa , Ermacora Paola , Veccia Antonello , Pignata Sandro , Lolli Cristian , Procopio Giuseppe , Pierantoni Francesco , Zonno Antonia , Santini Daniele , Di Maio Massimo ,   Meet-URO12 Investigators
Published: February 2022

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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.