NIAGARA is a large randomised phase III study in which we tested perioperative durvalumab when added to neoadjuvant chemotherapy in muscle-invasive bladder cancer in patients who were going to have surgery for their disease. The study previously showed that adding durvalumab improved on event free survival, overall survival and pathological response rates.

In a previous study we had already looked at circulating tumour DNA in the plasma and found that ctDNA was prognostic for outcome at various points during treatment, so at baseline, pre-cystectomy and also after cystectomy.  Whereas it was clearly correlated with outcome, the association with pathological response was not as great. So whereas patients who were still positive for ctDNA had a very high chance of not having a pathCR, the reverse was not true. So patients who cleared their ctDNA as a result of neoadjuvant therapy had only a pathCR in half of the patients. So clearly something to improve upon, especially since we are now looking more and more at bladder preservation therapies and to study this further in the current study we looked at urinary tumour DNA. So this is DNA that comes from the urine and, of course, the bladder tumour is in the urine, so to say, it could perhaps be a more sensitive assay to predict pathological complete response.

What was the study design?

In this study we looked already at ctDNA previously but we also collected urine to look at urinary tumour DNA. We did that at baseline and through neoadjuvant therapy with the main second timepoint being the pre-cystectomy timepoint, which is the timepoint after neoadjuvant therapy but before patients would have their cystectomy.

An assay was done using a Signatera personalised assay, both for circulating tumour DNA and urinary tumour DNA.

What were the key findings?

With urinary tumour DNA we found that the majority of patients, 85%, had urinary tumour DNA detectable at baseline. We found that clearance of urinary tumour DNA was associated with a better prognosis, as we had seen with circulating tumour DNA, and we also found that patients who received durvalumab had a higher chance of clearing their urinary tumour DNA.

The more interesting bit was about the pathological response because we found there, and it’s different from circulating tumour DNA, that the absence of urinary tumour DNA was actually associated with a pathological complete response. So it was still not perfect, it was about 72% of patients who had absence of urinary tumour DNA who had a pathCR but that’s better than what we’ve observed with plasma ctDNA.

When we looked further into the pathological response and analysed that together with circulating tumour DNA, we found something which I think is very interesting, especially when continuing with bladder preservation therapies, is that circulating tumour DNA, so in the blood, seems to correlate mainly with either invasive disease or micrometastases or nodal metastases, so more systemic disease, whereas urinary tumour DNA seems to correlate mostly with the local primary tumour, so whether there is residual disease after neoadjuvant therapy. So in patients who are double negative, so who have no urinary tumour DNA and no circulating tumour DNA detectable, the rate of pathCR was highest. Those patients who were negative for circulating tumour DNA but positive for urinary tumour DNA tended to have local disease, whether muscle-invasive or non-invasive. Those patients who were ctDNA positive, regardless of the presence of urinary tumour DNA, generally did not have a pathCR and also did worse in their outcomes.

So the final bit which I think is also of interest is that ctDNA was already shown to be prognostic but especially if you are ctDNA negative, urinary tumour DNA seems to add another layer of prognostic information. So patients who were double negative did better than patients who were ctDNA negative but urinary tumour DNA positive.

What could be the clinical implications of these results?

In this era where we find more and more active systemic therapies, now with the NIAGARA regimen and also, of course, the enfortumab vedotin plus pembrolizumab regimen, we see higher pathCRs and, for obvious reasons, patients are asking whether they still should undergo surgery. Now at this point this is still the standard of care that was tested in these trials, however, in future trials we can find ways to offer bladder preservation, especially if we can find those patients who have a pathCR, which, for example in enfortumab vedotin plus pembrolizumab, was in patients who had surgery about 60% of patients.

So where ctDNA is very helpful in prognostic information and, to some extent, in pathological response, I think urinary tumour DNA, while not perfect, can help to identify those patients who have a pathCR.

It’s at this point, and I think that’s important to emphasise, this is the first data in a large prospective randomised study to look at urinary tumour DNA and this type of analysis still needs to involve more. So remember that for circulating tumour DNA there’s a lot of tumour types where this can be measured and there’s a lot of data already to support this and several large series have been done in bladder cancer but for urinary tumour DNA we are still at the beginning of this journey and there are still improvements to be made. Also looking at perhaps the quantity of urinary tumour DNA, the number of variants, all those things, we need to still discover a bit more and get more information.

In the end, these types of assays together with clinical assessment can really help to pinpoint those patients who have a very high likelihood of a complete pathological response and perhaps don’t even need any consolidation therapy at all or could go for de-escalated consolidation therapy of the bladder.