The combination of immunotherapy and targeted therapies does not improve outcomes in previously treated advanced urothelial cancer

  • A study in which the VHIO has participated would seem to show that the combination of durvalumab, an anti-PD-L1 monoclonal antibody, associated with targeted therapies against different molecular alterations does not improve the results of immunotherapy
  • Despite this negative result, the study is highly relevant since it avoids the conduct of combination studies in which a large number of patients would be exposed to ineffective treatments
  • The journal Nature Medicine has just published these results, which have also served to demonstrate the usefulness of designing new multi-arm study formats which, with a small number of patients, allow us to test the usefulness of new treatment combinations

Barcelona, May 4, 2021– Personalised medicine is the great hope for cancer treatment. Advances in recent years have made it possible to gain a deeper understanding of the different types of tumours and thus discover potential therapeutic targets based on the molecular characteristics of cancer cells. In some types of cancer, the combination of immunotherapy, the other great hope in cancer treatment, with these targeted therapies is beginning to show results. However, it would seem that this combination has failed to improve the efficacy of immunotherapy as monotherapy in advanced urothelial cancer.

This is what seems to emerge from a recent study that has just been published in the journal Nature Medicine, in which Dr Joan Carles, head of the Genito-urinary, CNS and Sarcoma Tumours Programme at the Vall d’Hebron Institute of Oncology (VHIO), part of the Vall d’Hebron Campus, has participated. A ground breaking trial aimed to ascertain whether the combination of durvalumab, an anti-PD-L1 monoclonal antibody, with different therapies targeting the different genomic alterations found in the tumour could improve the outcome of patients with advanced urothelial cancer.

‘Previous studies had already demonstrated the efficacy of durvalumab in patients who had developed resistance to chemotherapy, achieving long-lasting remissions in a subset of these patients. Knowing that urothelial cancer is characterised by several recurrent genomic alterations, it was thought that combining this antibody with drugs targeting the molecular alteration found in the tumour could offer benefits for these patients who were progressing after an initial treatment’, explains Dr Joan Carles.

It was therefore proposed to see to what extent combination with three different types of inhibitors could be useful. These were inhibitors of fibroblast growth factor, inhibitors of the enzyme poly (ADP ribose) polymerase (better known by the acronym PARP), and inhibitors of TORC1/2. ‘There were grounds for testing these three combinations, although only fibroblast growth factor inhibition had previously been tested with positive outcomes in urothelial cancer.,’ adds Dr Joan Carles.

A novel design
In order to take this forward, and before embarking on a larger, more costly patient study, the possibility of using a new adaptive, biomarker-driven, multi-arm design was considered in order to determine whether these combinations, and potentially others, were useful. With this in mind, a total of 391 patients were enrolled, 135 of whom were assigned to one of six study arms, including a durvalumab monotherapy arm to test whether the addition of any of the inhibitors offered improved outcomes.

Response rates ranged from 9% to 36%, but did not exceed the 40% response rate observed with durvalumab monotherapy. Overall survival and progression-free survival were similar in the combination arms and in the monotherapy arm with the monoclonal antibody. The data obtained were only positive for fibroblast growth factor inhibitor monotherapy, but not for the combination thereof with durvalumab. Biomarker results in the other arms were less consistent and coincided with clinical activity.

‘What we have been able to see is that combined targeted therapy and immunotherapy did not improve activity, despite careful patient selection. This would seem to indicate that, at least in urothelial cancer, this approach is not the best option for patients, and new treatments must be investigated for them’, adds Dr Joan Carles.

Liquid biopsy validation
Despite its negative outcome, the study was also used to test whether the analysis of free circulating tumour DNA in plasma was in any way related to the tumour DNA extracted from the tissue samples.

‘The biomarker analysis showed a strong correlation between free circulating tumour DNA and tissue for tumours with alterations in fibroblast growth factor DNA, which increases the chances of replacing tumour biopsy with blood analysis for the determination of this molecular alteration.’, stated Dr Joan Carles, whilst also pointing out that both the baseline circulating tumour DNA and that obtained during treatment showed a strong correlation with the clinical result, identifying the alterations that occurred in the traced DNA.


Thomas Powles, Danielle Carroll, Simon Chowdhury, Gwenaelle Gravis, Florence Joly, Joan Carles, Aude Flechon, Pablo Maroto, Daniel Petrylak, Frédéric Rolland, Natalie Cook, Arjun Balar, Srikala S. Sridhar, Matthew Galsky, Petros Grivas, Alain Ravaud, Robert Jones, Jan Cosaert, Darren Hodgson, Iwanka Kozarewa, Richard Mather, Robert McEwen, Florence Mercier, Dónal Landers. An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced/metastatic urothelial cancer. Nature Medicine. D.O.I. https://dx.doi.org/10.1038/s41591-021-01317-6