Ashish Kamat: Hello everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, urologic oncologist in Houston, Texas, and it's a distinct pleasure to welcome to our forum, Professor Maria De Santis. Maria really needs no introduction. She's done a lot of work in GU oncology over the years. And this year, really, she presented the groundbreaking trial, the POTOMAC Study at ESMO, which is a randomized open-label phase 3 study that all of us have really been awaiting the results for, for several years now really, because it was truly going to be something that would answer the question, "Can we do better than BCG?" So Maria, thank you so much for joining us and the stage is yours.

Maria De Santis: Well, thank you very much, Ashish. It is a great pleasure talking about POTOMAC with you in the first place. It's really great. So, I'm Maria De Santis. I'm a medical GU oncologist and based in Berlin in Germany. And ESMO this year was also in Berlin, so it was a great event for me and for POTOMAC. So thank you very much. POTOMAC, as we heard, is a randomized open-label phase 3 global study, and we presented the final analysis at this ESMO meeting. We actually set out to improve BCG treatment. So here is the study rationale. The standard of care treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of the bladder tumor followed by Bacillus Calmette-Guérin, so BCG, induction and maintenance therapy. Combining durvalumab with BCG may improve long-term outcomes for patients with BCG-naive high-risk NMIBC.

The background is that BCG stimulates the immune system by initiating and/or expanding antitumor T-cells, while we know that durvalumab extends the activity of cytotoxic T-cells for a more durable response. So, this was the first slide at the ESMO meeting, and we presented the final analysis of this randomized phase 3 trial. Here, we have the study, design of the study of the POTOMAC. We included adult patients with BCG-naive non-muscle-invasive bladder cancer. High-risk tumor was defined as any of the following: T1 high-grade, or Tis carcinoma in situ, and multiple and recurrent and large tumors of three centimeters and above. We randomized 1,018 patients to receive durvalumab plus BCG induction and maintenance therapy, durvalumab plus BCG induction only, and BCG induction and maintenance therapy as the control arm. Durvalumab was given intravenously every 4 weeks for 13 cycles, so 1 year of treatment, and BCG induction 6 weeks as standard, and BCG maintenance was of 2 years. Stratification factors were high-risk papillary disease and carcinoma in situ.

The primary endpoint was disease-free survival of durvalumab plus BCG induction and maintenance versus the control arm. POTOMAC met its primary endpoint of disease-free survival. And at the median follow-up of 60.7 months, the addition of durvalumab to BCG induction and maintenance led to a 32% risk reduction of a DFS event. The hazard ratio is 0.68 and the P value 0.0154. The curves separate early before four months. Overall survival was no primary endpoint, so it was not powered for overall survival, but the descriptive analysis showed an overall survival hazard ratio of 0.8, demonstrating no detriment to overall survival with the addition of durvalumab. Currently, we have a 14% maturity for overall survival. The safety shows that we did not see any unexpected adverse events, but of course we saw immune-mediated adverse events of any grade, which was 27%, and the maximum grade 3 or 4 immune-mediated adverse events were 8%. We did not see any grade 5 immune-mediated adverse events, and we did not see any treatment-related adverse events that led to death. So in summary, POTOMAC supports one year of durvalumab in combination with BCG induction and maintenance therapy as a potential new treatment for patients with BCG-naive, high-risk, non-muscle-invasive bladder cancer. Thank you very much.

Ashish Kamat: Thank you very much, Maria, for presenting that succinct summary of the entire presentation at ESMO. I think one of the things we all were expecting was this to have read out maybe last year or the year before. And I think it's because the trials such as POTOMAC and even CREST and ALBAN were powered for the older data with BCG, that of course we had to wait for more events to occur. But once the events occurred, it was remarkable to see the hazard ratio of 0.68 by the addition of one year of durva in this study. And the hazard ratio was very similar to the CREST, right? So there clearly is activity of adding an immune-checkpoint inhibitor to BCG. Could you share with me a little bit your insight into the definition of disease-free survival, because it was a composite endpoint, right? Included recurrence, included some progression. What was the breakdown of the different events that led to the disease-free survival endpoint?

Maria De Santis: Yeah, so the disease-free survival endpoint in POTOMAC was defined very similar to the CREST. It was only named the event-free survival, and it was high-risk, non-muscle-invasive bladder cancer that included T1, Tis, or carcinoma in situ, or Ta high-grade, but of course also progression to muscle-invasive bladder cancer or metastatic disease.

Ashish Kamat: And do you recall offhand how many patients on each arm had progression events? Because of course, when we're sitting with a patient, one of the questions that they have is, "Can you help me save my bladder, and of course, my life?" And the progression is the critical event. Do you recall offhand the progression numbers?

Maria De Santis: The progression numbers were very low. I don't recall the exact number here, but the progression was very, very low. Also, we had a very long follow-up of more than five years.

Ashish Kamat: Yeah, absolutely. So Maria, when we're sitting and talking to patients and we're trying to counsel them, one of the things now we have to tell them, of course, is that there is a treatment combination that can improve the results with BCG over what BCG has alone when it comes to mainly recurrence rates, right? But then there's a trade-off of toxicity. So you have this 5 to 7% improvement in recurrence-free survival, and then you have a trade-off in toxicity. Could you share with us a little bit some of the data or your insights into toxicity? How many patients had high-dose steroid requirement, for example?

Maria De Santis: The high-dose corticosteroids, we published that in The Lancet, it was around 40%, but only those that had immune-mediated adverse events. Most of them were recovered, and long-term sequelae, very rare. Most of them were hypothyroidism with then substitution with L-thyroxine.

Ashish Kamat: Okay. And again, I know we always say we should not be doing subgroup analysis, but we always say, "Did you do subgroup analysis?" In fact, I know you did because it was published and I saw you present it, but any insights from your standpoint as to signals, which patient would you say benefited the most from the addition of durva?

Maria De Santis: So in our study, yeah, as you said, the issue with the subgroup analysis is that they're not powered, et cetera, but most of our patients had papillary disease only and the carcinoma in situ population was much lower. Carcinoma in situ-only was very low, particularly. Most of the patients that benefited had papillary disease, and we saw a carcinoma in situ subgroup with a hazard ratio of one, but with a very broad confidence interval that included the ITT population, ITT confidence interval. So, I think we can't draw firm conclusions. The ITT population, the ITT result was the positive result. However, as you already said, the subgroup analysis hinted more towards the papillary disease group to have the benefit from durvalumab, but we saw also the benefit in the combination of papillary disease plus carcinoma in situ. Yes, with all the caveats about the subgroup analysis, in total, I think with the small subgroups, we run into trouble and we should not draw too early conclusions, I think.

Ashish Kamat: Exactly, exactly. Because again, if people start looking at the CREST data and they see that there's more of a benefit in CIS patients, then you look at the durva and it seems like the papillary patients are helped. And then at EMUC, there was a presentation where the very high-risk group of patients, according to the EAU classifications, seemed to derive more benefit when it came to addition of IO agents. So, I think what's good about the subgroup analyses is at least there's a hint or a signal that the patients that are more at risk are potentially deriving more benefit. At least that's good, because it supports our desire to do better for our patients. Maria, congratulations to you and the entire team. This was really groundbreaking. And again, hats off to you, the entire team, and thank you for taking the time and spending with us.

Maria De Santis: Well, thank you very much for discussing POTOMAC with me, and it is a pleasure, Ashish. Thank you very much.