Alicia Morgans: Hi, I'm so excited to be here with Dr. Mohamad Allaf, who is visiting us from Johns Hopkins University. Thank you so much for talking with me today.

Mohamad Allaf: Thank you. It's great to be with you today.

Alicia Morgans: Well, wonderful to talk to you and really exciting to talk to you about the PROSPER Study, which I think is teaching us a lot, even if its primary endpoint was not positive. Just to remind everyone, PROSPER is an ECOG study that was looking at a neoadjuvant perioperative approach to treating patients with kidney cancer. So, can you set it up by just telling us, really, what was the schema? How did we approach this study? What was the PROSPER study?

Mohamad Allaf: Yeah. Obviously, we start with the rationale, and the rationale is that some patients who have high-risk kidney cancer, that seemingly is cured by surgery, aren't cured, and a good proportion 20-30%, maybe even 40% in some risk groups, recur. And so there's been multiple approaches to try to decrease the recurrence of these patients. We hypothesized that a perioperative approach of a single dose of nivolumab pre-surgery followed by 9 monthly adjuvant doses compared to the standard of care would decrease recurrence-free survival. And so that's the premise of the study. The study population is patients with high-risk kidney cancer, those are with a 7 centimeter or larger tumor, or those with any size but nodal metastasis. We did include M1 patients as long as they were deemed disease-free within 12 weeks. So treated surgically, et cetera. It was two arms, open-label, randomized, standard of care, not placebo in the control arm, and the treatment arm as I described earlier.

Alicia Morgans: I think we were all very excited. One thing I want to comment on before we get into the results is how challenging the study was, even as we were thinking about it, really relying on a close collaboration between the surgeons that often saw these patients and the medical oncologists who would be brought in to support and to give the medical therapy for those patients on the treatment arm. Can you tell me a little bit about how that worked and what we showed even, again, despite some negative results for the study overall?

Mohamad Allaf: Yeah. I would say one of the big take-home messages of the trial is the win of a team based approach into sort of accrual into this trial. The standard pathway, which we had to fight, is patients are seen by a urologist, they have the scary kidney tumor, and they've been told by many that the next step is surgery and you got to get to surgery. Traditionally, the adjuvant trials were run mainly by medical oncology because surgeries happened. And so this required a lot of close collaboration between medical oncologists and urologists, and there were a lot of skeptics out there thinking we would not accrue to such a trial. I think we showed the skeptics wrong, and it's thanks to the strong community. The SWOG, for example, rallied around this trial and really showed that we could work together. I would hope that this is a model for future neoadjuvant approaches in kidney, but in other GU tumors.

Alicia Morgans: Absolutely. So, we've waited long enough. Tell us, what were the findings on the trial?

Mohamad Allaf: Yeah, unfortunately a futility analysis was run and the trial did not meet its endpoint, and the primary endpoint was recurrence free survival benefit. And so the single dose of nivolumab prior to surgery followed by 9 adjuvant doses did not seem to improve recurrence-free survival in this trial.

Alicia Morgans: Okay. Well, that is a pretty clear message. However, work is still being done in the PROSPER trial. Can you tell us a little bit about what we're planning and what other analyses we might see in the future?

Mohamad Allaf: Yeah. Unique to this trial was the mandatory biopsy in the treatment arm. So we randomized the patients, and if you're randomized to the nivolumab arm, you were mandated to get a biopsy. And the biopsy either showed cancer or it was nondiagnostic and considered a good faith effort. But the idea is you don't want to give patients who don't have cancer a potentially toxic drug. So we have a lot of tissue prior to surgery, prior to treatment, after treatment, and we have radiology and all sorts of rich biological repository, I'd say, of data, and so there's all sorts of correlatives that are going to come out of this trial that I think are going to be incredibly informative.

Alicia Morgans: I could not agree more. And I think sometimes some of the most information that we get comes out of these analyses looking at biomarkers and their association with response and just trying to help us craft the next trial, even if this one was not going to be a positive one. Of course, even a negative trial can teach us something. So, what would your final words and message be about the PROSPER trial?

Mohamad Allaf: Yeah, I think that we're just starting to unravel the data in PROSPER. So yes, we reported the primary outcome here, but when you look at the trial, there's always going to be subsets and details in terms of, did everyone get the neoadjuvant dose? Were there biases in terms of who enrolled on the trial? Things like that, that we're going to answer. And I think this is going to be critical in light of the adjuvant trial, KEYNOTE-564 being a positive trial for RFS. Of course, there's now been another trial using Atezo that was negative, similar to PROSPER, and that was also just an adjuvant trial.

So I think a lot of confusion in this space at this point in time. But I would say we're going to get a lot more granularity and clarity. So stay tuned, and if you see PROSPER in the literature, hopefully we're going to learn a lot from it as we move forward.

Alicia Morgans: Well, thank you, and I'm sure that we absolutely will. I can commend you and the investigators and certainly thank all the patients for participating. Wonderful, wonderful effort and really a wonderful demonstration of what a community can do when we work together to answer these big questions, so thank you for your time and your expertise.

Mohamad Allaf: You're very welcome. You said it beautifully there. Thank you.