A phase 3 randomized open label study of durvalumab with or without tremilumimab versus standard of care (SoC) chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE)

Study Design: 
DANUBE is a randomized, phase 3 trial to evaluate durvalumab, with or without tremelimumab, vs platinum-based chemotherapy as a first-line treatment for metastatic UC. Patients were randomized 1:1:1 to Durvalumab 1500 mg q4w alone until progression (n=346) or Durvalumab plus Tremelimumab 75 mg q4w for up to 4 doses (n=342) or SoC chemotherapy (gemcitabine + cisplatin or carboplatin, up to 6 cycles) (n=344.)
Platinum-based chemotherapy is the standard of care (SoC) for first-line treatment of metastatic UC. While chemotherapy regimens yield high response rates, survival outcomes are poor. Durvalumab (anti-PD-L1) is FDA approved for the treatment of platinum-refractory, metastatic UC. Tremelimumab (anti-CTLA-4) and the combination of durvalumab plus tremelimumab have shown activity in platinum-refractory, metastatic UC regardless of PD-L1 expression.
The co-primary endpoints were OS comparing durvalumab monotherapy vs. chemotherapy groups among patients whose tumors had high PD-L1 expression and overall survival comparing durvalumab + tremelimumab vs. chemotherapy groups in the intention-to-treat (ITT) population.
The primary endpoints in his study were not met. With a median follow-up for survival of 41.2 months, this study has the longest follow-up to date for a randomized trial of an immunotherapy in previously untreated, metastatic UC. Further investigation of the combination in the context of checkpoint inhibitors may be warranted.
The DANUBE trial did not meet either of the co-primary endpoints of overall survival. However, secondary analyses suggested that the combination of durvalumab + tremelimumab has activity, which is enhanced in patients with tumours that have high PD-L1 expression. This trial was a negative trial but it does suggest that a biomarker-based strategy should be tested in patients whose tumors are PD-L1 positive and may benefit from the combination of durvalumab + tremelimumab.