Purpose In patients with newly diagnosed glioblastoma that harbors a nonmethylated O6-methylguanine- DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. Patients and Methods In this phase II, unblinded trial 182 patients in 22 centerswere randomly assigned 2:1 to BEV (10mg/kg every 2 weeks) during radiotherapy (RT) followed bymaintenance BEV (10mg/kg every 2 weeks) plus IRI(125 mg/m2 every 2 weeks) or to daily TMZ (75 mg/m2) during RT followed by six courses of TMZ (150-200 mg/m2/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). Results In themodified intention-to-treat (ITT) population, PFS-6 was increased from42.6%with TMZ(95%CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P ,.001). PFS was prolonged from amedian of 5.99months (95%CI, 2.7 to 7.3months) to 9.7months (95%CI, 8.7 to 10.8months; P, .001). At progression, crossover BEV therapy was given to 81.8%of all patientswho received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: The median OSwas 16.6months (95%CI, 15.4 to 18.4months)with BEV+IRI andwas 17.5months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) -C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms. Conclusion BEV+IRI resulted in a superior PFS-6 rate andmedian PFS comparedwith TMZ. However, BEV+IRI did not improveOS, potentially because of the high crossover rate.BEV+IRI did not alterQOLcompared with TMZ.