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.
Original language | English |
---|---|
Pages (from-to) | 1574-1588 |
Number of pages | 15 |
Journal | The Lancet Oncology |
Volume | 21 |
Issue number | 12 |
DOIs | |
Publication status | Published - 2020 Dec |
All Science Journal Classification (ASJC) codes
- Oncology
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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. / Powles, Thomas; van der Heijden, Michiel S.; Castellano, Daniel et al.
In: The Lancet Oncology, Vol. 21, No. 12, 12.2020, p. 1574-1588.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE)
T2 - a randomised, open-label, multicentre, phase 3 trial
AU - Powles, Thomas
AU - van der Heijden, Michiel S.
AU - Castellano, Daniel
AU - Galsky, Matthew D.
AU - Loriot, Yohann
AU - Petrylak, Daniel P.
AU - Ogawa, Osamu
AU - Park, Se Hoon
AU - Lee, Jae Lyun
AU - De Giorgi, Ugo
AU - Bögemann, Martin
AU - Bamias, Aristotelis
AU - Eigl, Bernhard J.
AU - Gurney, Howard
AU - Mukherjee, Som D.
AU - Fradet, Yves
AU - Skoneczna, Iwona
AU - Tsiatas, Marinos
AU - Novikov, Andrey
AU - Suárez, Cristina
AU - Fay, André P.
AU - Duran, Ignacio
AU - Necchi, Andrea
AU - Wildsmith, Sophie
AU - He, Philip
AU - Angra, Natasha
AU - Gupta, Ashok K.
AU - Levin, Wendy
AU - Bellmunt, Joaquim
AU - van der Heijden, Michiel S.
AU - Lee, Jae Lyun
AU - Eigl, Bernhard J.
AU - Mukherjee, Som D.
AU - Suarez, Cristina
AU - Westgeest, Hans
AU - Flechon, Aude
AU - Ou, Yen Chuan
AU - Park, Inkeun
AU - Matveev, Vsevolod
AU - Pérez-Valderrama, Begoña
AU - Cheng, Susanna
AU - Frank, Stephen
AU - Anido, Urbano
AU - Hamzaj, Alketa
AU - Retz, Margitta
AU - Sridhar, Srikala
AU - Scagliotti, Giorgio Vittorio
AU - Voortman, Jens
AU - Alekseev, Boris
AU - Alyasova, Anna
AU - Komyakov, Boris
AU - Dumez, Herlinde
AU - Pavic, Michel
AU - Kimura, Go
AU - Mizokami, Atsushi
AU - Osanto, Susanne
AU - Arranz, Jose Angel
AU - Piersma, Djura
AU - Shin, Sang Joon
AU - Karyakin, Oleg
AU - Delgado, Ignacio
AU - Gonzalez, Jose Luis
AU - Pang, See Tong
AU - Tran, Anna
AU - Lipatov, Oleg
AU - Su, Wen Pin
AU - Flaig, Thomas
AU - Alva, Ajjai
AU - Park Kyong, Hwa
AU - Kopyltsov, Evgeny
AU - Almagro, Elena
AU - Domenech, Monserrat
AU - Chang, Yen Hwa
AU - Sautois, Brieuc
AU - Ravaux, Andre
AU - Aravantinos, Gerasimos
AU - Georgoulias, Vasileios
AU - Mulder, Sasja
AU - Kim, Yu Jung
AU - Kater, Fabio
AU - Chevreau, Christine
AU - Tagawa, Scott
AU - Zalewski, Pawel
AU - Joly, Florence
AU - Hatiboglu, Gencay
AU - Gianni, Luca
AU - Morelli, Franco
AU - Tambaro, Rosa
AU - Hashimoto, Yasuhiro
AU - Nosov, Alexander
AU - Font, Albert
AU - Rodriguez-Vida, Alejo M.
AU - Jones, Robert
AU - Vasudev, Naveen
AU - Srinivas, Sandhya
AU - Zhang, Jingsong
AU - Gil, Thierry
AU - Finch, Daygen
AU - Grimm, Marc Oliver
AU - Su, Yu Li
AU - Chowdhury, Simon
AU - Hocking, Christopher
AU - Plas, Eugen
AU - North, Scott
AU - Jensen, Niels Viggo
AU - Theodore, Christine
AU - Imkamp, Florian
AU - Peer, Avivit
AU - Kobayashi, Takashi
AU - Sakai, Hideki
AU - Sassa, Naoto
AU - Yoshimura, Kazuhiro
AU - Aarts, Maureen
AU - Ferreira Castro, Ana
AU - Topuzov, Marlen
AU - Rodriguez, Juan Francisco
AU - Vazquez, Federico Jose
AU - Tsai, Yu Chieh
AU - Crabb, Simon
AU - Hussain, Syed
AU - Bendell, Johanna
AU - Gross-Goupil, Marine
AU - Gwenaelle, Gravis
AU - Berger, Raanan
AU - Statsenko, Galina
AU - Evans, Linda
AU - Drakaki, Alexandra
AU - Somer, Bradley
AU - Davis, Ian
AU - Lynam, James
AU - Borges, Giuliano
AU - Dettino, Aldo
AU - Fay, André P.
AU - Martins, Graziella
AU - Zucca, Luis Eduardo
AU - Agerbaek, Mads
AU - Kalofonos, Haralambos
AU - Rosenbaum, Eli
AU - Enokida, Hideki
AU - Kikukawa, Hiroaki
AU - Nishimura, Kazuo
AU - Tamada, Satoshi
AU - Uemura, Motohide
AU - Lopez, Yamil
AU - Gietema, Jourik
AU - Slojewski, Marcin
AU - Fernandes, Isabel
AU - Smolin, Alexey
AU - Mazhar, Danish
AU - Kalebasty, Arash Rezazadeh
AU - Carthon, Bradley
AU - Loidl, Wolfgang
AU - Franke, Fabio
AU - Girotto, Gustavo
AU - Alimohamed, Nimira
AU - Macfarlane, Robyn
AU - Pappot, Helle
AU - Niegisch, Guenter
AU - Mavroudis, Dimitrios
AU - Sella, Avishay
AU - Porta, Camillo
AU - Ebara, Shin
AU - Nakamura, Motonobu
AU - Obara, Wataru
AU - Okuno, Norihiko
AU - Shinohara, Nobuo
AU - Sugimoto, Mikio
AU - Suzuki, Akitaka
AU - Tokuda, Noriaki
AU - Uemura, Hiroji
AU - Yamaguchi, Akito
AU - Ramirez, Francisco
AU - Rozanowski, Pawel
AU - Wiechno, Pawel
AU - Keam, Bhumsuk
AU - Kislov, Nikolay
AU - Plaksin, Denis
AU - Cicin, Irfan
AU - Kumar, Satish
AU - Galsky, Matthew D.
AU - Petrylak, Daniel P.
AU - Rosales, Joseph
AU - Vaishampayan, Ulka
AU - Culine, Stephane
AU - Papandreou, Christos
AU - Nara, Taketoshi
AU - Erman, Mustafa
AU - Kreiger, Laurence
AU - Janoski, Juliana
AU - Rosa, Diogo
AU - Siqueira, Mariana
AU - Canil, Christina
AU - Sengelov, Lisa
AU - Tourani, Jean Marc
AU - Arai, Gaku
AU - Hashine, Katsuyoshi
AU - Kawakita, Mutsushi
AU - Nakaigawa, Noboru
AU - Nomi, Hayahito
AU - Shiina, Hiroaki
AU - Suzuki, Hiroyoshi
AU - Yonese, Junji
AU - Kuri, Roberto
AU - Macedo, Eleazar
AU - Rivera, Samuel
AU - Villalobos Prieto, Alberto
AU - Polakiewicz-Gilowska, Anna
AU - Zaucha, Renata
AU - Lopes, Fabio
AU - Ponomarev, Roman
AU - Pomerantz, Mark
AU - Shariat, Shahrokh
AU - Luk, Cynthia
AU - Lesniewski-Kmak, Krzysztof
N1 - Funding Information: This study was sponsored by AstraZeneca (Gaithersburg, MD, USA). We thank the patients who volunteered to participate in this study and their families; all the investigators and study site personnel; the members of the independent data monitoring committee; Feng (Mike) Xiao (AstraZeneca) for his contributions to statistical analyses; and Ward A Pedersen (Parexel, Hackensack, NJ, USA) for medical writing and editorial assistance, which was funded by AstraZeneca. Funding Information: TP has received honoraria from AstraZeneca, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Pfizer, and Roche/Genentech; has served as a consultant or adviser for AstraZeneca, BMS, Genentech/Roche, Incyte, Ipsen, MSD, Novartis, Pfizer, and Seattle Genetics; has received research funding from AstraZeneca/MedImmune and Roche/Genentech; and has received travel expenses from AstraZeneca, BMS, MSD, Novartis/Ipsen, Pfizer, and Roche/Genentech. MSvdH has served as a consultant or adviser for Astellas Pharma, AstraZeneca/MedImmune, BMS, MSD Oncology, Roche/Genentech, and Seattle Genetics; has received research funding from Astellas Pharma, BMS, and Roche; and has received travel expenses from Astellas Pharma, MSD Oncology, Novartis, and Roche. DC has served as a consultant or adviser for Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Ipsen, Janssen Oncology, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Sanofi; has received research funding from Janssen Oncology; and has received travel expenses from AstraZeneca Spain, BMS, Pfizer, and Roche. MDG has stock and other ownership interests in Rappta Therapeutics; has served as a consultant or adviser for Aileron Therapeutics, Astellas Pharma, AstraZeneca, BioMotiv, BMS, Dendreon, Dracen, EMD Serono, Genentech, GlaxoSmithKline, Incyte, Inovio Pharmaceuticals, Janssen, Lilly, MSD, Novartis, NuMab, Pfizer, and Seattle Genetics; has received research funding from AstraZeneca, BMS, Dendreon, Genentech/Roche, Janssen Oncology, MSD, and Novartis; and holds a patent (application number 20120322792): Methods and Compositions for Treating Cancer and Related Methods (Mount Sinai School of Medicine, July, 2012). YL has received honoraria from Pfizer and Sanofi; has served as a consultant or adviser for Astellas Pharma, AstraZeneca, BMS, Clovis Oncology, Incyte, Janssen, MSD Oncology, Roche, and Seattle Genetics; has received research funding from AstraZeneca, Boehringer Ingelheim, Clovis Oncology, CureVac, Exelixis, Incyte, Janssen Oncology, Medivation, MSD Oncology, Oncogenex, Pfizer, and Sanofi; has received research funding from AstraZeneca, Boehringer Ingelheim, Clovis Oncology, CureVac, Exelixis, Incyte, Janssen Oncology, Medivation, MSD Oncology, Oncogenex, Pfizer, and Sanofi; and has received travel expenses from Astellas Pharma, AstraZeneca, Janssen Oncology, MSD Oncology, and Roche. DPP has stock and other ownership interests in Bellicum Pharmaceuticals and Tyme; has served as a consultant or adviser for Astellas Pharma, AstraZeneca, Bayer, Bellicum Pharmaceuticals, Dendreon, Exelixis, Ferring, Johnson & Johnson, Lilly, Medivation, Millennium, Pfizer, Roche, Sanofi, and Tyme; has received research funding from Agensys, Astellas Medivation, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Endocyte, Genentech, Innocrin Pharma, Johnson & Johnson, Lilly, MedImmune, MSD, Millennium, Novartis, Pfizer, Progenics, Roche, Sanofi, Seattle Genetics, and Sotio; and has provided expert testimony for Celgene and Sanofi. SHP has served as a consultant or adviser for Lilly. J-LL has received honoraria from Amgen Korea, Astellas Pharma, and BMS; has served as a consultant or adviser for BMS Korea, Eisai, Pfizer Korea, and Sanofi Aventis Korea; and has received research funding from AstraZeneca/MedImmune, BMS, Janssen, MSD, Novartis, Pfizer, and Roche/Genentech. UDG has served as a consultant or adviser for Astellas Pharma, Bayer, BMS, Ipsen, Janssen, Pfizer, and Sanofi. MB has received honoraria from Amgen, AstraZeneca, Bayer, BMS, Eisai, EUSA Pharma, Ipsen, Janssen, MSD, Novartis, and Roche; has served as a consultant or adviser for Advanced Biochemical Compounds, Amgen, AstraZeneca, Bayer, BMS, Eisai, EUSA Pharma, Ipsen, Janssen, MSD, Novartis, and Roche; has received research funding from Janssen; and has received travel expenses from Amgen, Bayer, BMS, Janssen, and Novartis. AB has received honoraria from BMS and Novartis; has served as a consultant or adviser for AstraZeneca, BMS, MSD, Pfizer, and Pierre Fabre; has participated in speakers’ bureaus for AstraZeneca, BMS, Novartis, and Pfizer; has received research funding from AstraZeneca, BMS, Novartis, Pfizer, Roche, and Sanofi; and has received travel expenses from Novartis and Pfizer. BJE has received honoraria from AstraZeneca, Bayer, Janssen, MSD, Roche Canada, and Pfizer; has served as a consultant or adviser for AstraZeneca, Janssen, Merck, and Roche Canada; and has received travel expenses from Janssen. HG has served as a consultant or adviser for Astellas, AstraZeneca, BMS, Ipsen, MSD, Pfizer, and Roche. SDM has served as a consultant or adviser for AstraZeneca, MSD, Roche, and Novartis. YF has served as a consultant or adviser for AstraZeneca, MSD, Sanofi, and TerSera Therapeutics; has received research funding from Astellas, IMV, Janssen, MSD, and TerSera Therapeutics; and has received travel expenses from Sanofi and TerSera Therapeutics. IS has received honoraria from Astellas, AstraZeneca, Bayer, Eli Lilly, GlaxoSmithKline, Ipsen, Janssen, and Sanofi; has served as a consultant or adviser for Eli Lilly; and has received travel expenses from Eli Lilly. MT has received honoraria from AstraZeneca, BMS, Ipsen, Janssen, MSD, and Roche; and has served as a consultant or adviser for AbbVie, BMS, Ipsen, and Janssen. CS has received research funding from Ipsen; has served as a consultant or adviser for Astellas, Bayer, BMS, Ipsen, MSD, Pfizer, Roche, and Sanofi; has received honoraria from Astellas, BMS, Ipsen, and Pfizer; and has received travel expenses from BMS, Pfizer, and Roche. APF has received honoraria from AstraZeneca, BMS, Novartis, Pfizer, and Roche; and has served as a consultant or adviser for AstraZeneca, MSD, Novartis, Pfizer, and Roche. ID has received honoraria from Astellas Pharma, BMS, Ipsen, Janssen Oncology, MSD Oncology, and Roche/Genentech; has served as a consultant or adviser for Bayer, BMS, Janssen Oncology, MSD Oncology, Novartis, Pharmacyclics, Roche/Genentech, and Seattle Genetics; has received research funding from Astellas Pharma, AstraZeneca Spain, Janssen Oncology, and Roche/Genentech; and has received travel expenses from AstraZeneca Spain and Roche/Genentech. ANe reports employment, stock, and other ownership interests with Bayer; has received honoraria from AstraZeneca, Foundation Medicine, Janssen, MSD, and Roche; has served as a consultant or adviser for AstraZeneca, Bayer, BMS, Clovis Oncology, Incyte, Janssen, MSD, Rainier Therapeutics, Roche, and Seattle Genetics/Astellas; has received research funding from AstraZeneca and MSD; and has received travel expenses from AstraZeneca, Janssen, MSD, and Roche. SW, NA, and WL are current employees of AstraZeneca. PH reports employment with AstraZeneca, Celldex, and Sanofi; stock and other ownership interests in Celldex and Sanofi; and has received travel expenses from AstraZeneca and Celldex. AKG is a current employee of AstraZeneca and has stock and other ownership interests in AstraZeneca and BMS; has served as a consultant or adviser for AstraZeneca; and has patents, royalties, or other intellectual property with BMS. JB has received honoraria from UpToDate; has served as a consultant or adviser for Astellas Pharma, AstraZeneca/MedImmune, BMS, Genentech, MSD, Novartis, Pfizer, and Pierre Fabre; has received research funding from Millennium and Sanofi; and has received travel expenses from MSD Oncology and Pfizer. OO and ANo declare no competing interests. Publisher Copyright: © 2020 Elsevier Ltd
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85091519786&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091519786&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(20)30541-6
DO - 10.1016/S1470-2045(20)30541-6
M3 - Article
C2 - 32971005
AN - SCOPUS:85091519786
VL - 21
SP - 1574
EP - 1588
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 12
ER -