Background: Urothelial cancer (UC) is the ninth most common cancer worldwide, this tumour has a poor prognosis when in advanced stage. Cisplatin-based chemotherapy is considered the most effective treatment but more than 50% of patients are considered not eligible (cis-unfit) for this regimen and have a median survival of only 6-9 months. In the past years, the most used chemotherapy regimen for cis-unfit patients was the combination of carboplatin and gemcitabine. Two single arm studies tested the anti-PD-L1/PD1 monoclonal antibodies atezolizumab and pembrolizumab and reported a response rate of 25% with good safety profile in an unselected population for PD-L1 expression. Recently, atezolizumab alone showed longer OS compared to carboplatin-gemcitabine regimen. Avelumab is another fully human anti-PD-L1 IgG1 antibody already tested in urothelial and in other cancers with a promising safety and efficacy profile. Methods: The single arm, phase II ARIES trial (NCT03891238), aims to evaluate the activity and efficacy of avelumab in patients with metastatic or locally advanced UC considered cis-unfit with PD-L1 expression ≥5%. Overall survival is the primary endpoint. Cis-unfit definition includes at least one of the following characteristics (i) ECOG-Performance status=2; (ii) creatinine clearance <60 ml/min; (iii) grade ≥2 peripheral neuropathy or hearing loss; (iv) disease progression within six months after a previous adjuvant/neoadjuvant treatment with cisplatin-based therapy. Avelumab will be administered at standard dose of 10 mg/kg in 1-hour intravenous infusion every 2 weeks (Q2W). Sixty-seven patients will be enrolled, and supportive care is allowed during the study. Avelumab may be continued after radiological progression of disease at physician’s discretion if an improvement of symptoms or not new symptoms will be reported. The study is currently ongoing in twenty centres in Italy. Clinical trial information: NCT03891238