Reflections on the rapidly evolving treatment landscape for bladder cancer

Over the last years, a continuous stream of practice changing studies has gradually reshaped the treatment landscape for patients with urothelial cancer. With the presentation of the NIAGARA data at ESMO 2024 a new chapter was added to this therapeutic revolution. In this video, Prof Dr Christof Vulsteke from the Integrated Cancer Center in Ghent and Dr Tom Van den Mooter, medical oncologist in the Ziekenhuis aan de Stroom (ZAS) in Antwerp discuss the results of this practice-changing study evaluating the combination of perioperative durvalumab with neoadjuvant chemotherapy in patients with cisplatin-eligible muscle invasive bladder cancer (MIBC). 

In this trial, perioperative durvalumab added to neoadjuvant chemotherapy proved to be associated with a significant improvement in both event-free (EFS) and overall survival (OS). At the 2-year landmark, 67.8% of patients in the durvalumab arm were event-free as compared to 59.8% in the control arm (i.e., neoadjuvant gemcitabine–cisplatin followed by radical cystectomy alone) (HR[95%CI]: 0.68[0.56-0.82]; p< 0.001). Corresponding rates of OS were reported at 82.2% and 75.2%, respectively, corresponding to a significant 25% lower death risk for patients treated with perioperative durvalumab (HR[95%CI]: 0.75[0.59-0.93]; p< 0.01).1 

NIAGARA is only the first of several studies evaluating an immune checkpoint inhibitor (ICI) in the perioperative treatment for bladder cancer patients. In this respect, Prof Vulsteke is especially looking forward to the results of KEYNOTE 866 (perioperative pembrolizumab) and KEYNOTE 905 (perioperative pembrolizumab + enfortumab vedotin), two clinical trials in which he is actively participating. The success of chemo-immunotherapy in the neoadjuvant treatment of patients with MIBC also bears the question whether this could become an alternative for trimodality treatment as a bladder preserving  option for these patients.

For Prof Vulsteke and Dr Van den Mooter, one of the more important challenges for the future is the identification of reliable predictive biomarkers for a response to ICI-based therapy. From previous analyses it became clear that PD-L1 and tumor mutational burden carry little to no predictive information. During ESMO 2024, a biomarker analysis of the phase III EV-302 study also demonstrated a benefit of first line pembrolizumab and enfortumab vedotin irrespective of the nectin-4 level in patients with metastatic urothelial cancer.2 Perhaps circulating tumor DNA will prove to be more valuable as a predictive biomarker in the years to come.