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; Heijden, Michiel S. van der; Castellano, Daniel; Galsky, Matthew D.; Loriot, Yohann; Petrylak, Daniel P.; Ogawa, Osamu; Park, Se Hoon; Giorgi, Ugo De; Bögemann, Martin; Bamias, Aristotelis; Eigl, Bernhard J.; Gurney, Howard; Mukherjee, Som D.; Fradet, Yves; Skoneczna, Iwona; Tsiatas, Marinos; Новиков, А И; Suárez, Cristina; Fay, André P.; Durán, Ignacio; Necchi, Andrea; Wildsmith, Sophie; He, Philip; Angra, Natasha; Gupta, Ashok; Levin, Wendy J.; Bellmunt, Joaquim; Lee, Jae‐Lyun; Westgeest, Hans M.; Fléchon, Aude; Ou, Yen‐Chuan; Park, Inkeun; Matveev, Vsevolod; Pérez-Valderrama, Begoña; Cheng, Susanna; Frank, Stephen Jay; Anido, Urbano; Hamzaj, Alketa; Retz, Margitta; Sridhar, Srikala S.; Scagliotti, Giorgio Vittorio; Voortman, Jens; Alekseev, Boris; Alyasova, Anna; Komyakov, B K; Dumez, Herlinde; Pavic, Michel; Kimura, Go; Mizokami, Atsushi; Osanto, Susanne; Arranz, José Ángel; Piersma, Djura; Shin, Sang Joon; Karyakin, Oleg; Delgado, Ignacio; González, José Luís; Pang, See‐Tong; Tran, Anna; Lipatov, Oleg; Su, Wen-Pin; Flaig, Thomas W.; Alva, Ajjai; Kyong, Hwa Park; Kopyltsov, Evgeny; Almagro, Elena; Domenech, Monserrat; Chang, Yen‐Hwa; Sautois, Brieuc; Ravaux, Andre; Aravantinos, Gerasimos; Georgoulias, V; Mulder, Sasja F.; Kim, Yu Jung; Kater, Fabio; Chevreau, Christine; Tagawa, Scott T.; Zalewski, Paweł; Joly, Florence; Hatiboglu, Gencay; Gianni, Luca; Morelli, Franco; Tambaro, Rosa; Hashimoto, Yasuhiro; Носов, А. К.; Font, Albert; Rodríguez‐Vida, Alejo; Jones, Robert J.; Vasudev, Naveen S.; Srinivas, Sandhya; Zhang, Jingsong; Gil, Thierry; Finch, Daygen L.; Grimm, Marc-Oliver; Su, Yu‐Li; Chowdhury, Simon; Hocking, Christopher; Plas, Eugen; North, Scott; Jensen, Niels Viggo; Théodore, C; Imkamp, Florian; Peer, Avivit; Kobayashi, Takashi; Sakai, Hideki; Sassa, Naoto; Yoshimura, Kazuhiro; Aarts, Maureen J.B.; Castro, A; Topuzov, Marlen; Rodrı́guez, Juan F.; Vázquez, Federico; Tsai, Yu‐Chieh; Crabb, Simon J.; Hussain, Syed A.; Bendell, Johanna C.; Gross‐Goupil, Marine; Gravis, Gwénaëlle; Berger, Raanan; Statsenko, Galina; Evans, Linda; Drakaki, Alexandra; Somer, Bradley G.; Davis, Ian D.; Lynam, James; Borges, Giuliano Santos; Dettino, Aldo Lourenço Abbade; Martins, Graziella; Zucca, Luis Eduardo Rosa; Agerbæk, Mads; Kalofonos, H. P.; Rosenbaum, Eli; Enokida, Hideki; Kikukawa, Hiroaki; Nishimura, Kazuo; Tamada, Satoshi; Uemura, Mamoru; López, Y.; Gietema, Jourik A.; Słojewski, Marcin; Fernandes, Isabel; Smolin, Alexey; Mazhar, Danish; Kalebasty, Arash Rezazadeh; Carthon, Bradley Curtis; Loidl, Wolfgang; Franke, Fábio; Girotto, Gustavo; Alimohamed, Nimira; Macfarlane, Robyn Jane; Pappot, Helle; Niegisch, Guenter; Mavroudis, Dimitriοs; Sella, Avishay; Porta, Camillo; Ebara, Shin; Nakamura, Motonobu; Obara, Wataru; Okuno, Norihiko; Shinohara, Nobuo; Sugimoto, Mikio; Suzuki, Akitaka; Tokuda, Noriaki; Uemura, Hiroji; Yamaguchi, Akito; Ramirez, Francisco; Różanowski, Paweł; Wiechno, Paweł; Keam, Bhumsuk; Kislov, Nikolay; Plaksin, Denis; Çiçin, İrfan; Kumar, Satish; Rosales, Joseph; Vaishampayan, Ulka N.; Culine, Stéphane; Papandreou, Christos N.; Nara, Taketoshi; Erman, Mustafa; Kreiger, Laurence; Janoski, Juliana; Rosa, Diogo Augusto Rodrigues da; Siqueira, Mariana Bruno; Canil, Christina; Sengeløv, Lisa; Tourani, Jean-Marc; Arai, Gaku; Hashine, Katsuyoshi; Kawakita, Mutsushi; Nakaigawa, Noboru; Nomi, Hayahito; Shiina, Hìroaki; Suzuki, Hiroyoshi; Yonese, Junji; Kuri, Roberto; Macedo, Eleazar Omar; Rivera, Samuel; Prieto, Alberto Villalobos; Polakiewicz-Gilowska, Anna; Zaucha, Renata; Lopes, Fábio; Ponomarev, Roman; Pomerantz, Mark; Shariat, Shahrokh F.; Luk, Cynthia T.; Leśniewski-Kmak, Krzysztof

doi:10.1016/s1470-2045(20)30541-6

Cited by 389 publications

(308 citation statements)

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“…Indeed, multiple studies tried to challenge the standard gemcitabine/cis- or carboplatin chemotherapy by chemoimmunotherapy (adding a PD-1 or PD-L1 ICI induction), 5 but without success. Pembrolizumab (KEYNOTE-361 trial 6 ) atezolizumab (IMvigor130 7 ) and durvalumab (DANUBE 8 ) association with standard of care chemotherapy did not improve OS when compared to chemotherapy alone. The important results of another recent study, not included in this review, need to be discussed: the INDUCOMAIN trial (NCT03390595).…”

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confidence: 97%

Re: Updates in the management and future landscape of urothelial carcinoma

Sarkis

Assaf

2020

J Oncol Pharm Pract

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Immunotherapy is gradually revolutionizing bladder cancer treatment. In this extensive review published by Hanna et al. in your journal, the authors presented recent studies that are trying to challenge the standard platinum-based chemotherapy as first-line treatment of metastatic bladder cancer by chemoimmunotherapy. However, upfront pembrolizumab, atezolizumab and durvalumab association with standard of care chemotherapy did not improve overall survival when compared to chemotherapy alone. We hereby highlight a study that was not included in this review, the INDUCOMAIN trial, by discussing its results and its future implications on immunotherapy for metastatic bladder cancer.

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Re: Updates in the management and future landscape of urothelial carcinoma

Sarkis

Assaf

2020

J Oncol Pharm Pract

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“…The role of immune checkpoint inhibitors (ICIs) in urothelial cancer (UC) remains in flux. However, three recent randomised trials in the first-line setting have clarified many of the outstanding issues and are discussed here [1][2][3].…”

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“…There was a lack of public data to support the change, which thus increased uncertainty around optimal treatment. Results have now been reported for a series of large randomised phase 3 studies in front-line UC therapy that addressed these issues [1][2][3].…”

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confidence: 99%

“…It is worth noting that the atezolizumab study [1] had a high proportion of patients receiving carboplatin-based therapy in the control arm. The durvalumab trial [2] excluded patients with a performance status of 2. The control arm of the pembrolizumab trial [3] had the highest exposure to subsequent immune therapy (48%).…”

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Immune Checkpoint Inhibitors in Front-line Therapy for Urothelial Cancer

Szabados

Prendergast

Jackson-Spence

et al. 2021

European Urology Oncology

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The role of immune checkpoint inhibitors (ICIs) in urothelial cancer (UC) remains in flux. However, three recent randomised trials in the first-line setting have clarified many of the outstanding issues and are discussed here [1][2][3].To date, PD-1 and PD-L1 inhibitors are established as second-line therapy after first-line platinum-containing chemotherapy (CT) [4,5]. This strategy was based on a positive phase 3 randomised trial investigating pembrolizumab versus CT [4]. Debate around the role of the biomarker and the efficacy of other agents, such as atezolizumab, in this setting is ongoing [6]. It is apparent that all five ICIs approved by the US Food and Drug Administration (FDA) in this setting have more similarities

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Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors

Maiorano,

Di Maio,

Cerbone

et al. 2024

JAMA Netw Open

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ImportanceImmune checkpoint inhibitors (ICIs) have broadened the metastatic urothelial carcinoma (mUC) therapeutic scenario. The association of programmed death ligand 1 (PD-L1) with response and survival in patients treated with ICIs is still controversial.ObjectivesTo evaluate the association of PD-L1 with response rate and overall survival among patients with mUC treated with ICIs.Data SourcesPubMed, Embase, American Society of Clinical Oncology and European Society for Medical Oncology Meeting Libraries, and Web of Science were searched up to December 10, 2023.Study SelectionTwo authors independently screened the studies. Included studies were randomized and nonrandomized clinical trials enrolling patients with mUC receiving ICIs with available overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) data, separated between patients with PD-L1–positive and –negative tumors.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Two reviewers independently extracted data. Fixed- or random-effects models were used depending on the heterogeneity among the studies.Main Outcomes and MeasuresPrimary outcomes were odds ratios (ORs) for ORR and hazard ratios (HRs) for OS, comparing patients with PD-L1–positive tumors and patients with PD-L1–negative tumors. Secondary outcomes were the PFS HR between patients with PD-L1–positive and –negative tumors and OS HR between ICI arms and non-ICI arms of only randomized clinical trials.ResultsA total of 14 studies were selected, comprising 5271 patients treated with ICIs (2625 patients had PD-L1–positive tumors). The ORR was 13.8% to 78.6% in patients with PD-L1–positive tumors and 5.1% to 63.2% in patients with PD-L1–negative tumors, with an association between PD-L1 status and ORR favoring patients with PD-L1–positive tumors (OR, 1.94; 95% CI, 1.47-2.56; P &lt; .001). Median OS ranged from 8.4 to 24.1 months in patients with PD-L1–positive tumors and from 6.0 to 19.1 months in patients with PD-L1–negative tumors. The pooled HR showed a significant reduction for patients with PD-L1–positive tumors compared with those with PD-L1–negative tumors in the risk of death (HR, 0.71; 95% CI, 0.57-0.89; P = .003) and risk of progression (HR, 0.55; 95% CI, 0.44-0.69; P &lt; .001) when ICIs were administered. PD-L1 is not likely to be a predictive biomarker of ICI response.Conclusions and RelevanceThis systematic review and meta-analysis suggests that PD-L1 expression is associated with improved ORR, OS, and PFS for patients with mUC who receive ICIs, but it is unlikely to be useful as a predictive biomarker. Developing predictive biomarkers is essential to select patients most likely to benefit from ICIs and avoid toxic effects and financial burden with these agents.

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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

Cited by 389 publications

References 24 publications

Re: Updates in the management and future landscape of urothelial carcinoma

Re: Updates in the management and future landscape of urothelial carcinoma

Immune Checkpoint Inhibitors in Front-line Therapy for Urothelial Cancer

Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors

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