NIAGARA is a big randomised Phase III study. It explores neoadjuvant chemotherapy and cystectomy with the addition of perioperative durvalumab that’s given in the neoadjuvant and the adjuvant setting. The trial is a big randomised Phase III. It was positive; it resulted in a reduction in the risk of events, it has an overall survival benefit, and it also has an increase in pathCR. It was safe from a surgical perspective, and the adverse events were somewhat predictable.

We then looked at ctDNA within the context of this trial. ctDNA is something which I’ve been interested in for a long time, and many other people have too. We’ve done quite a lot of work with ctDNA in the adjuvant setting. In the adjuvant setting it looks to be quite strongly prognostic. There is some suggestion it may predictive of response to immune therapy, although there’s a study called IMvigor011 which is really testing that properly.

We haven’t looked at it too much in the neoadjuvant setting; we have a little bit, but not too much. This is a 1000 patient study; about half of them had serial ctDNA performed at baseline, before neoadjuvant chemotherapy, after neoadjuvant chemotherapy and before surgery, and then post-surgery. What we showed using the Signatera assay is about 60% of patients were positive at baseline. That drops to about 25% of patients pre-surgery and then only 10% post-surgery. So actually only 10% of patients are positive post-surgery, 60% before we start, which shows how effective therapy is.

We showed it was strongly prognostic, so no matter where you were, if you were ctDNA positive, it was associated with a bad outcome. We showed that many patients who were positive were able to clear their ctDNA with the intervention of chemotherapy and the addition of durvalumab resulted in increased ctDNA clearance by 13%. That underpins the principle of a positive trial, a higher pathCR rate, overall survival, higher ctDNA clearance supporting durvalumab in this space.

We looked at the adjuvant setting, and we looked at the accuracy of ctDNA there. What we showed is it was strongly prognostic, but even a proportion of the negative patients still relapsed, and in that group of negative patients, the addition of durvalumab was associated with better outcomes. So it’s not possible using ctDNA analysis to say whether or not we should be giving that adjuvant period, in fact we need a third arm in these trials to test that.

In summary, durvalumab added to neoadjuvant chemotherapy and cystectomy is a standard of care now in the neoadjuvant setting in muscle-invasive bladder cancer. We’ve shown a survival benefit, we’ve shown it’s pretty safe. We’ve also shown higher pathCR rates, and now we’re showing ctDNA from a prognostic perspective is really important, but also it gives some clues to durvalumab maybe working a bit better with that bounce of 13% increase in ctDNA clearance.

Is there anything else you would like to add?

I think this is a field that’s moving very quickly. I think muscle-invasive bladder cancer is becoming a really exciting area to maybe cure patients in the future. I think NIAGARA is a big positive study with an overall survival advantage but I don’t think it’s going to be the last big positive study with an overall survival advantage in this field. I think the antibody drug conjugates, the immune checkpoint inhibitors, which are very effective later in the disease will be effective here as well, and I think they will also have an overall survival advantage.

I can see us moving to a field where we’re using techniques like ctDNA to determine whether or not patients need to have, dare I say it, cystectomy, and whether or not we’re actually curing these patients with MRI scans, with cystoscopies, with ctDNA. I think ctDNA is probably more accurate than pathological complete response. We haven’t had great biomarkers of bladder cancer before; we’re beginning to get those now.