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

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 alterations2-5. 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 pathway3-5. 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.

Thomas Powles1, Danielle Carroll 2, Simon Chowdhury 3, Gwenaelle Gravis 4, Florence Joly 5, Joan Carles 6, Aude Fléchon 7, Pablo Maroto 8, Daniel Petrylak 9, Frédéric Rolland 10, Natalie Cook 11, Arjun V Balar 12, Srikala S Sridhar 13, Matthew D Galsky 14, Petros Grivas 15, Alain Ravaud 16, Robert Jones 17, Jan Cosaert 18, Darren Hodgson 2, Iwanka Kozarewa 2, Richard Mather 18, Robert McEwen 2, Florence Mercier 18, Dónal Landers 1

  1. Barts Cancer Institute, QMUL, Barts Cancer Centre, London, UK. .
  2. AstraZeneca IMED Biotech Unit, Cambridge, UK.
  3. Guys and St Thomas' Hospital, London, UK.
  4. Institute Paoli-Calmettes, Marseille, France.
  5. UNICANCER, Centre Léon Bérard, Lyons, France.
  6. Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
  7. Centre Léon Bérard, Lyon, France.
  8. Hospital de la Santa Creu i San Pau, Barcelona, Spain.
  9. Yale School of Medicine, New Haven, CT, USA.
  10. Institut de Cancerologie de l'Ouest, Saint-Herblain, France.
  11. The Christie NHS Foundation Trust and The University of Manchester, Manchester, UK.
  12. Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
  13. Princess Margaret Hospital, Toronto, Ontario, Canada.
  14. Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  15. University of Washington, Seattle, WA, USA.
  16. Bordeaux University Hospital, Bordeaux, France.
  17. University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.
  18. AstraZeneca Oncology R&D, Research and Early Development, Cambridge, UK.
  19. CRUK Manchester Institute Cancer Biomarker Centre, Manchester, UK.

Powles T, Carroll D, Chowdhury S et al. "An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer," Nat Med. 2021 May;27(5):793-801. doi: 10.1038/s41591-021-01317-6.