An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer

Powles, T. et al. (2021) An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer. Nature Medicine, 27(5), pp. 793-801. (doi: 10.1038/s41591-021-01317-6) (PMID:33941921)

Abstract

Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer (AUC)1. AUC is characterized by several recurrent targetable genomic alterations2,3,4,5. This study (NCT02546661, BISCAY) combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory AUC populations including: (1) fibroblast growth factor receptor (FGFR) inhibitors in tumors with FGFR DNA alterations (FGFRm); (2) pharmacological inhibitor of the enzyme poly-ADP ribose polymerase (PARP) in tumors with and without DNA homologous recombination repair deficiency (HRRm); and (3) TORC1/2 inhibitors in tumors with DNA alteration to the mTOR/PI3K pathway3,4,5.This trial adopted a new, biomarker-driven, multiarm adaptive design. Safety, efficacy and relevant biomarkers were evaluated. Overall, 391 patients were screened of whom 135 were allocated to one of six study arms. Response rates (RRs) ranged 9–36% across the study arms, which did not meet efficacy criteria for further development. Overall survival (OS) and progression-free survival (PFS) were similar in the combination arms and durvalumab monotherapy arm. Biomarker analysis showed a correlation between circulating plasma-based DNA (ctDNA) and tissue for FGFRm. Sequential circulating tumor DNA analysis showed that changes to FGFRm correlated with clinical outcome. Our data support the clinical activity of FGFR inhibition and durvalumab monotherapy but do not show increased activity for any of the combinations. These findings question the targeted/immune therapy approach in AUC.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jones, Professor Robert
• Authors: Powles, T., Carroll, D., Chowdhury, S., Gravis, G., Joly, F., Carles, J., Fléchon, A., Maroto, P., Petrylak, D., Rolland, F., Cook, N., Balar, A. V., Sridhar, S. S., Galsky, M. D., Grivas, P., Ravaud, A., Jones, R., Cosaert, J., Hodgson, D., Kozarewa, I., Mather, R., McEwen, R., Mercier, F., and Landers, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Medicine
• Publisher: Nature Research
• ISSN: 1078-8956
• ISSN (Online): 1546-170X
• Published Online: 03 May 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Medicine 27(5): 793-801
• Publisher Policy: Reproduced in accordance with the publisher copyright policy