Abstract 800TiP
Background
Niraparib is an oral inhibitor of poly ADP-ribose polymerase (PARP) enzymes. PARP inhibitors induce synthetic lethality in cells with aberrations in BRCA1, BRCA2 or other genes impairing homologous recombination (HR). HR deficiency (HRD) is also implicated in the sensitivity to platinum-based chemotherapy, the backbone of perioperative and first-line treatment of UC patients. In preclinical models, a reduced capacity for HR repair is associated with increased sensitivity to PARP inhibitors, and the combination of PARP inhibitor and cisplatin causes a significant increase in DNA damage compared to cisplatin alone. The prevalence of somatic mutations in HR genes in UC and their association with platinum sensitivity represent a good rationale to test PARP inhibition in UC pts. Aim of this trial is to compare maintenance treatment with niraparib plus BSC vs. BSC alone in pts with locally advanced or metastatic UC obtaining objective response or stable disease with first-line platinum-based chemotherapy.
Trial design
Meet-URO 12 is a randomized phase II multicentre trial enrolling pts with locally advanced or metastatic transitional cell UC (either pure or mixed histology), who have received 4-6 cycles of first-line platinum-based chemotherapy without evidence of progression. Primary endpoint is progression-free survival (PFS). 77 pts will be randomized (2:1 ratio) to experimental arm (niraparib 300 or 200 mg daily according to body weight and baseline platelets, plus BSC) or control arm (BSC alone). Treatment will be continued until disease progression, or unacceptable toxicity. 65 PFS events are needed to detect Hazard Ratio 0.57 (median PFS increase from 4 to 7 months), with 80% power and one-tailed alpha 0.1. Secondary endpoints are 6-month PFS rate, objective response rate, duration of response, overall survival, safety and tolerability, patient reported outcomes. Exploratory endpoints are BRCA mutation and HRD test. The study is open, with 16 patients enrolled as of May 20, 2020. Clinical trial information: NCT03945084.
Clinical trial identification
NCT03945084 EudraCT: 2018-004147-24.
Editorial acknowledgement
Legal entity responsible for the study
Department of Oncology, University of Turin.
Funding
Tesaro GSK.
Disclosure
U. Basso: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Janssen; Honoraria (self), Advisory/Consultancy: Incyte; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol Myers Squibb; Honoraria (self), Advisory/Consultancy: MSD; Research grant/Funding (institution): Ipsen; Honoraria (self), Speaker Bureau/Expert testimony: Pfizer; Honoraria (self), Speaker Bureau/Expert testimony: Sanofi Aventis; Honoraria (self), Speaker Bureau/Expert testimony: Novartis. M. Di Maio: Research grant/Funding (institution): Tesaro GSK; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Janssen; Honoraria (self), Advisory/Consultancy: Astellas; Honoraria (self), Advisory/Consultancy: Eisai. All other authors have declared no conflicts of interest.