Goals: Pevonedistat, the first small-molecule inhibitor of the NEDD8-activating enzyme, disrupts proteasomal degradation of select proteins and has shown encouraging clinical activity in combination with azacitidine in acute myelogenous leukemia (AML). This phase 2, randomized, open-label trial evaluated the efficacy and safety of pevonedistat+azacitidine vs azacitidine in patients with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) or low-blast (LB) AML. Materials and methods: Patients with higher-risk MDS/CMML (Revised International Prognostic Scoring System risk >3, including intermediate [≥5% blasts], high, or very high risk) or LB-AML who were naïve to hypomethylating agents were randomized 1:1 to receive pevonedistat intravenously (IV) (20 mg/m2 days 1, 3, 5) + azacitidine IV/subcutaneous (75 mg/m2 days 1–5, 8, 9) (n = 58), or azacitidine alone (n = 62), in 28-day cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The study was powered on an endpoint of event-free survival (EFS; time from randomization to death/transformation to AML). Overall survival (OS), overall response rate (ORR; complete remission [CR] + partial remission [PR] + hematologic improvement [HI] in higher-risk MDS/CMML, or CR + CR with incomplete blood count recovery [CRi] + PR in LB-AML) and safety also were assessed. Patient-reported health-related quality of life (HRQoL) was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30. Mutational profiling was performed on screening bone marrow aspirate samples. Results/Discussion: In the intent-to-treat (ITT) population (n = 120), EFS trended longer with pevonedistat+azacitidine vs azacitidine (median 21.0 vs 16.6 months; hazard ratio [HR] 0.67; 95% confidence interval [CI], 0.42–1.05; P =.076) and was longer in higher-risk MDS (median 20.2 vs 14.8 months; HR 0.54; 95% CI, 0.29–1.00; P =.045). Median OS was 21.8 vs 19.0 months (HR 0.80; 95% CI, 0.51–1.26; P =.334) in the ITT population, 23.9 vs 19.1 months (HR 0.70; 95% CI, 0.39–1.27; P =.240) in higher-risk MDS (n = 67), and 23.6 vs 16.0 months (HR 0.49; 95% CI, 0.22–1.11; P =.081) in LB-AML (n = 36) with pevonedistat+azacitidine vs azacitidine, respectively. In response-evaluable patients (n = 108), ORR with pevonedistat+azacitidine vs azacitidine was 71% vs 60%; in higher-risk MDS (n = 59), ORR was 79% vs 57%, and CR rate was 52% vs 27%. Median azacitidine dose intensity was 97% (pevonedistat+azacitidine) vs 98% (azacitidine). Grade ≥3 adverse events occurred in 90% (pevonedistat+azacitidine) vs 87% (azacitidine) of patients (most common: neutropenia [33% vs 27%], febrile neutropenia [26% vs 29%], anemia [19% vs 27%], thrombocytopenia [19% vs 23%]). No difference was observed in patient-reported HRQoL between arms, with similar mean scores maintained from study entry to end of treatment. Clinical activity was observed in patients with higher-risk MDS or LB-AML harboring poor prognostic mutations. Conclusions: Pevonedistat+azacitidine led to longer EFS vs azacitidine in higher-risk MDS, had a comparable safety profile to azacitidine alone, and azacitidine dose intensity was maintained. A randomized phase 3 trial (NCT03268954) is ongoing to evaluate further.