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Charles Ryan: Hello from EAU 2019. I'm sitting here with Tom Powles from Barts Hospital in London, and we're going to talk about the perioperative space for bladder cancer. Should we use immunotherapy, chemotherapy? Who should we test, and what do the tests mean? Tom, thank you for joining me. 

This is perhaps the area where we can make the most difference in essentially helping people to not experience relapse after surgery, or to perhaps improve surgical outcomes. So what is the status of immunotherapy in the perioperative space at this point? 

Thomas Powles: The status is, I would say, perhaps the most exciting piece. If you said to me three years ago when your original question was, has it fulfilled its promise, I'd have said three years ago, I'm most excited about immune combinations. I'm no longer as excited about that. I'm hopeful, but the data we've seen with CTLA-4, PD-L1 and other immune combinations, bladder cancer has not been as fantastic as we'd like, speaking frankly. We've not cured bladder cancer with immune combinations. Three years ago there was discussion about that, so that's not really worked that well.

We hope that's going to change, and there are some new drugs coming through. Some of those drugs aren't classic immune therapies but the thing which actually has been more promising is, when we use the drug earlier in the disease setting, the response rate seems to be going up. So two cycles of atezolizumab in the ABACUS trial, or three cycles of pembrolizumab in the PURE-01 trial are associated with path CR rates of between 30 and 40%, and the patient populations are between 50 and 100 patients. So it's not spectacularly robust.

Charles Ryan: And just by way of comparison with neoadjuvant gemcitabine, cisplatin or CMV, pathologic CR rates where the five to 10% range if on a good day. I mean, it was, they were ...

Thomas Powles: It depends on which study you read. They're different studies. Again, it comes back to the issue around have we as a group of investigators, have we done robust studies in bladder cancer? Some of the answer to that is perhaps not as robust as in breast cancer and colorectal cancer, but the path CR rates for chemotherapy, you can get up to 35%, 40%, and if you give accelerated MVAC, you can perhaps even nudge a bit higher than that in single-arm trials. The point you're making is neoadjuvant chemotherapy four cycles doesn't look a lot higher than that.

And so these results of between 30 and 40% are for ... with only a short period of therapy are pretty exciting. Some of the work that we've done is, we've looked at the biology, so we've done immunohistochemistry, RNA sequencing, and we've done mutational analysis of those samples. What we can see, which is different from the metastatic patients, the metastatic samples, we can see more inflamed tumors. They're more PD-L1 positive. They have a higher immune phenotype of the three immune phenotypes inflamed and deserts and excluded immune. They're more inflamed and excluded-

Charles Ryan: These are the biopsy samples of patients who went on to have complete responses?

Thomas Powles: Yeah. Oh, yeah, but also if you look at the population as a whole, they're more primed. In my opinion, and I don't know this yet, but the biology work is ongoing. In my opinion, this earlier setting is slightly different from the metastatic setting.

I think the stromal influences which are negative and inhibitory are less prominent. There are more accelerators and less breaks. One of the reasons why in the metastatic setting perhaps we haven't seen the fantastic results we hoped as yet ... I think we will. There are front-line trials coming out, but I hope that will change. Chemotherapy combinations, for example, might be positive, but it may be the biology later in the disease is more complex. An earlier PD, PD-L-1 access is more crucial, and therefore these more prime tumors, if you just remove one of the major blocks, you actually get more activity early on. Later the disease, it's too complex to get in control.

And so what I'm seeing at the moment and the way I'm feeling is the way these drugs may end, not this week or next week, not even perhaps this year, but over the next two or three years, what I suspect what we're going to be doing is we're going to be giving periods of perioperative therapy, looking at the biology of the disease, and then either giving immune combinations, chemotherapy immune combinations, chemotherapy by itself.

And what we'll have in bladder cancer, in my opinion, in over the next decade, is the drugs moving from the metastatic space earlier in the disease and curing more patients. And so this is, for me, is the most ... from an investigator, the most exciting thing. But what do we do today and tomorrow? 

Check out the current time. Where do I sit with this space? Currently neoadjuvant chemotherapy prior to cystectomy is the standard of care. It remains the standard of care. It's not used enough, and that needs to be pursued. These new data I described should not supersede that or detract from that. The survival benefit is there, but I think there are going to be adjuvant immune therapy studies coming out in the near future. My feeling is, and if my hypothesis that they're more active in this earlier space, they should be positive.

I think if those trials are positive, I think that will change the mindset, which will then move to neoadjuvant chemotherapy, cystectomy, adjuvant immunotherapy. And then, we're changing the perioperative space and curing more patients because if this story ends up where all we did was have a series of second-line drugs which helped a small group of patients, I think that conclusion will be we weren't successful.

Charles Ryan: It will be a little bit disappointing.

Thomas Powles: Yeah, it will.

Charles Ryan: Right. Well, thank you for your thoughts. As always, brilliant to hear what's going on in the field and in your mind and in your clinics. So always a pleasure to talk to you, Tom, and thank you for joining us here at EAU 2019.