@article{3120446,
    title = "Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial",
    author = "Powles, T. and van der Heijden, M.S. and Castellano, D. and Galsky, M.D. and Loriot, Y. and Petrylak, D.P. and Ogawa, O. and Park, S.H. and Lee, J.-L. and De Giorgi, U. and Bögemann, M. and Bamias, A. and Eigl, B.J. and Gurney, H. and Mukherjee, S.D. and Fradet, Y. and Skoneczna, I. and Tsiatas, M. and Novikov, A. and Suárez, C. and Fay, A.P. and Duran, I. and Necchi, A. and Wildsmith, S. and He, P. and Angra, N. and Gupta, A.K. and Levin, W. and Bellmunt, J. and van der Heijden, M.S. and Lee, J.L. and Eigl, B.J. and Mukherjee, S.D. and Suarez, C. and Westgeest, H. and Flechon, A. and Ou, Y.-C. and Park, I. and Matveev, V. and Pérez-Valderrama, B. and Cheng, S. and Frank, S. and Anido, U. and Hamzaj, A. and Retz, M. and Sridhar, S. and Scagliotti, G.V. and Voortman, J. and Alekseev, B. and Alyasova, A. and Komyakov, B. and Dumez, H. and Pavic, M. and Kimura, G. and Mizokami, A. and Osanto, S. and Arranz, J.A. and Piersma, D. and Shin, S.J. and Karyakin, O. and Delgado, I. and Gonzalez, J.L. and Pang, S.-T. and Tran, A. and Lipatov, O. and Su, W.-P. and Flaig, T. and Alva, A. and Park Kyong, H. and Kopyltsov, E. and Almagro, E. and Domenech, M. and Chang, Y.-H. and Sautois, B. and Ravaux, A. and Aravantinos, G. and Georgoulias, V. and Mulder, S. and Kim, Y.J. and Kater, F. and Chevreau, C. and Tagawa, S. and Zalewski, P. and Joly, F. and Hatiboglu, G. and Gianni, L. and Morelli, F. and Tambaro, R. and Hashimoto, Y. and Nosov, A. and Font, A. and Rodriguez-Vida, A.M. and Jones, R. and Vasudev, N. and Srinivas, S. and Zhang, J. and Gil, T. and Finch, D. and Grimm, M.-O. and Su, Y.-L. and Chowdhury, S. and Hocking, C. and Plas, E. and North, S. and Jensen, N.V. and Theodore, C. and Imkamp, F. and Peer, A. and Kobayashi, T. and Sakai, H. and Sassa, N. and Yoshimura, K. and Aarts, M. and Ferreira Castro, A. and Topuzov, M. and Rodriguez, J.F. and Vazquez, F.J. and Tsai, Y.-C. and Crabb, S. and Hussain, S. and Bendell, J. and Gross-Goupil, M. and Gwenaelle, G. and Berger, R. and Statsenko, G. and Evans, L. and Drakaki, A. and Somer, B. and Davis, I. and Lynam, J. and Borges, G. and Dettino, A. and Fay, A.P. and Martins, G. and Zucca, L.E. and Agerbaek, M. and Kalofonos, H. and Rosenbaum, E. and Enokida, H. and Kikukawa, H. and Nishimura, K. and Tamada, S. and Uemura, M. and Lopez, Y. and Gietema, J. and Slojewski, M. and Fernandes, I. and Smolin, A. and Mazhar, D. and Kalebasty, A.R. and Carthon, B. and Loidl, W. and Franke, F. and Girotto, G. and Alimohamed, N. and Macfarlane, R. and Pappot, H. and Niegisch, G. and Mavroudis, D. and Sella, A. and Porta, C. and Ebara, S. and Nakamura, M. and Obara, W. and Okuno, N. and Shinohara, N. and Sugimoto, M. and Suzuki, A. and Tokuda, N. and Uemura, H. and Yamaguchi, A. and Ramirez, F. and Rozanowski, P. and Wiechno, P. and Keam, B. and Kislov, N. and Plaksin, D. and Cicin, I. and Kumar, S. and Galsky, M.D. and Petrylak, D.P. and Rosales, J. and Vaishampayan, U. and Culine, S. and Papandreou, C. and Nara, T. and Erman, M. and Kreiger, L. and Janoski, J. and Rosa, D. and Siqueira, M. and Canil, C. and Sengelov, L. and Tourani, J.-M. and Arai, G. and Hashine, K. and Kawakita, M. and Nakaigawa, N. and Nomi, H. and Shiina, H. and Suzuki, H. and Yonese, J. and Kuri, R. and Macedo, E. and Rivera, S. and Villalobos Prieto, A. and Polakiewicz-Gilowska, A. and Zaucha, R. and Lopes, F. and Ponomarev, R. and Pomerantz, M. and Shariat, S. and Luk, C. and Lesniewski-Kmak, K.",
    journal = "The lancet oncology",
    year = "2020",
    volume = "21",
    number = "12",
    pages = "1574-1588",
    publisher = "The Lancet Publishing Group",
    doi = "10.1016/S1470-2045(20)30541-6",
    keywords = "amylase;  carboplatin;  cisplatin;  corticosteroid;  durvalumab;  gemcitabine;  programmed death 1 ligand 1;  ticilimumab;  triacylglycerol lipase;  antineoplastic agent;  durvalumab;  immunological antineoplastic agent;  monoclonal antibody;  ticilimumab, acute kidney failure;  acute liver failure;  adjuvant chemotherapy;  adult;  aged;  alopecia;  anemia;  Article;  asthenia;  cancer chemotherapy;  cholestatic hepatitis;  constipation;  controlled study;  decreased appetite;  diarrhea;  drug dose reduction;  drug efficacy;  drug safety;  drug withdrawal;  fatigue;  female;  human;  human tissue;  intention to treat analysis;  leukocyte count;  leukopenia;  liver metastasis;  lung metastasis;  lymph node metastasis;  major clinical study;  male;  monotherapy;  multicenter study;  multiple cycle treatment;  nausea;  neoadjuvant chemotherapy;  neutropenia;  neutrophil count;  open study;  overall survival;  phase 3 clinical trial;  platelet count;  pneumonia;  priority journal;  progression free survival;  pruritus;  randomized controlled trial;  rash;  septic shock;  side effect;  thrombocytopenia;  transitional cell carcinoma;  treatment duration;  treatment response time;  tumor regression;  visceral metastasis;  vomiting;  administration and dosage;  adverse event;  carcinoma;  clinical trial;  comparative study;  drug effect;  middle aged;  mortality;  pathology;  time factor;  treatment outcome;  urinary tract tumor;  urothelium, Aged;  Antibodies, Monoclonal;  Antibodies, Monoclonal, Humanized;  Antineoplastic Agents, Immunological;  Antineoplastic Combined Chemotherapy Protocols;  Carcinoma;  Female;  Humans;  Immune Checkpoint Inhibitors;  Male;  Middle Aged;  Time Factors;  Treatment Outcome;  Urologic Neoplasms;  Urothelium",
    abstract = "Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma. Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24. Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury). Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted. Funding: AstraZeneca. © 2020 Elsevier Ltd"
}