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Zachary Klaassen: Hello, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center. I'm delighted to be joined on your show today by Dr. Amanda Myers, who is a urologic oncology fellow at MD Anderson Cancer Center. Today, we'll be discussing a presentation by Amanda at the South Central AUA meeting, discussing elucidating the response rates to additional BCG and the implications for clinical trial design. Amanda, thanks so much for joining us on your show today.

Amanda Myers: Thanks so much for having me. Excited to talk about our study today that we conducted at our institution. As with the continued investigation of BCG alternatives, establishing a benchmark for the response rate to BCG is essential to be used as a comparator so that we can actually direct our resources towards the best candidate treatments and perform appropriate sample size calculations. Otherwise, we just risk underpowered trials or accepting subpar treatments into practice.

However, a critical limitation of interpreting previous research stems from the considerable variability in outcome definitions in patient populations. Thus, we decided to report the response rates of patients with high-risk non-muscle invasive bladder cancer to additional BCG using the current definitions of BCG exposed and BCG unresponsive to inform clinical trial design. We conducted a single institution study from January 2000 to September 2021. We looked at high-grade recurrences after BCG in patients who received additional BCG as primary therapy. Recurrences greater than two years after BCG were treated as new index cases, and we used the Kaplan-Meier method to estimate survival outcomes.

We defined BCG unresponsive using the FDA criteria, and we defined BCG exposed opposed using the IBC criteria, which is a high-grade recurrence within two years of BCG, not meeting BCG unresponsive criteria. So at our institution, we had 857 patients who received BCG, 213 of these had a high-grade recurrence. We excluded 25 patients with upper tract urothelial carcinoma, as these patients are typically excluded from clinical trials. Eighty-eight patients received additional BCG and were included. This included 52 patients who were BCG exposed, 20 with CIS and 32 with papillary only. For BCG unresponsive, it was 17 with CIS and 19 with papillary only.

When we look just first at the BCG exposed group, about 70% had Ta and a very small percent had T1. Twenty-five percent had CIS only and 12% had concomitant CIS. Additional BCG was given in either the form of repeat induction BCG in 46% or maintenance BCG in 54%. Of all 52 patients, 79% had no disease after receiving this additional BCG, and we saw a median duration of response calculated out to 169 months. Importantly, 95% of patients who responded received ongoing maintenance BCG.

When we then take a look at our BCG unresponsive cohort, 36 patients, we see a much higher rate of patients with T1, 56%, and about a similar amount of CIS only, 25%, and 15% had concomitant CIS. Additional BCG again was given as either repeat induction BCG or maintenance BCG with just three additional doses. In this subset of patients, we found 75%, 27 of the 36, had no disease after receiving their additional BCG treatment, and the median duration of response calculated to 83 months. Ninety-six percent received ongoing maintenance BCG of those who responded.

Now, when we look at some of our outcomes, we looked at high-grade, disease-free survival for those in the BCG exposed group. The two-year disease-free survival was 63%. And then in the BCG unresponsive group, the two-year disease-free survival was 63%, on the right. When we look at the progression-free survival, we can see that BCG exposed on the left, two-year progression-free survival of 90%. And for the BCG unresponsive, two-year progression-free survival was 86%.

Our cystectomy-free rates were, for the BCG exposed on the left, the two-year cystectomy rate was 82%, and on the right, the BCG unresponsive, the two-year rate was 79%. Some of the limitations are important to point out, as these results reflect select patients receiving care at a high-volume, single institution. And we're really unable to discern any association of stage or presence of CIS to outcomes. Patients with LVI, variant histology, and hydronephrosis were not considered for additional BCG in our series.

What we can conclude from our data is that we have reference data for response rates to additional BCG using contemporary information, which can serve as a comparator for non-randomized studies and inform power calculations for randomized studies. This study is the first to our knowledge to report outcomes using the BCG exposed definition, and given the high response rates to additional BCG in the BCG exposed groups, it is essential that clinical trials in this population compare to BCG as a control arm. Thank you.

Zachary Klaassen: That was great. I mean, I think there's so much good information here. And I think this is the beauty of having an institution like MD Anderson where we can look at long-term outcomes and have a cohort of patients that have additional treatment but also great follow-up as well. So in your opinion, if we're looking at all these options, we have cystectomy, multiple approved therapies after BCG, who's the person we should really be considering additional BCG, and just from a very clinical perspective?

Amanda Myers: So the patient is that patient who received induction BCG, and at three months you have high-grade Ta or CIS. That patient should be getting rechallenged with BCG. So that's that patient that really we should be focusing it on. We have the resources at that point. We shouldn't throw BCG out with the bathwater yet.

Zachary Klaassen: Exactly. And you kind of highlighted it in your conclusion a bit. But this really does have some clinical trial implications and how we interpret these FDA-approved single-arm non-randomized studies. Just highlight again, for our listeners, how we should be interpreting this data for the future in our trial design, but also how we think about those results from additional trials?

Amanda Myers: So there's been a lot of studies in the BCG unresponsive space, and we're moving to see more trials now underway in the BCG exposed space. And given the observed success rates, it's really essential that we're comparing in these randomized trials to BCG as a comparator. Additional BCG is the standard of care. Both the EU and AUA guidelines recommend giving a repeat course of BCG for these patients.

And something to point out is that the BCG shortage is often cited as a reason for not using BCG as a control arm. We do expect there to be a manufacturing increase in the next few years that may exceed global demand and really should not be a reason not to use BCG as a control.

Zachary Klaassen: Yeah, great answer. I think that's awesome.

Amanda Myers: So for the BCG unresponsive patients, we actually see that some patients, while selected, did really well. And we know that single-arm trials have really served their role in the BCG unresponsive space to catalyze drug development. But there is significant heterogeneity in the disease course and selection bias with single-arm studies. And at this point, we should really move towards avoiding cross-trial comparison of agents and moving towards randomized studies to truly understand the value of a single treatment.

Zachary Klaassen: Yeah, absolutely. Amanda, always a great conversation. And thank you for sharing your time and your study today. Maybe just a couple take-home messages for our listeners today.

Amanda Myers: So some take-home points would be at the time of first recurrence after BCG, rechallenge has high success rates and allows you to truly exhaust one therapy before moving on to another. Patient selection relies heavily on clinical staging. High-quality TUR is critical. And lastly, but importantly, knowing when not to offer BCG. And that simply puts patients at risk for understaging. So patients with LVI, variant histology, hydronephrosis I mentioned, were not considered for additional BCG in our series. We excluded patients with extravesical disease. And that's really important to think about when you're deciding who to give BCG to.

Zachary Klaassen: Excellent summary. Amanda, thanks, as always, for joining us on UroToday. Appreciate it.

Amanda Myers: Thanks, Zach.