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Alicia Morgans: Hi. I'm thrilled to have here with me today Dr. Kala Sridhar, who is an Associate Professor of Medicine at The Princess Margaret Hospital, The University of Toronto, and a GU Medical Oncologist. So delightful to have you here with me today.

Kala Sridhar: Thank you for having me.

Alicia Morgans: Of course. We have talked a lot, and you've actually talked at GU ASCO this year about challenges and opportunities, I would say, in the treatment of localized prostate cancer. And I'd love to hear your thoughts on where do we stand, and where can we go, and how can we really take some steps to move the field forward in that area?

Kala Sridhar: Right, for sure. I mean I did speak about localized high-risk prostate cancer, which is an area that as medical oncologists, we have not traditionally been in, because we tend to treat patients, as you know when they're much further along in the course of their disease.

But with many of the new treatments that we have available, we're now starting to see those move into the earlier settings. In large part, because despite local therapy, the radiation therapy with hormonal therapy or surgery by way of radical prostatectomy. Despite those treatments, the cancer can still find its way back.

We know in more advanced disease that the systemic treatments and new systemic treatments that we have are effective so the thought is, if we can move those treatments earlier, maybe we'll be able to cure more of our patients. And so, in that regard, I think that we as medical oncologists are being brought more into the earlier stages of this disease as we have the experience in administering these drugs. And I think it's a good thing because I think it builds up multidisciplinary collaboration which we know really helps the field to grow and move forward.

Alicia Morgans: Absolutely. And so what are some of the approaches for optimizing systemic therapy in localized disease. I'm just thinking about the STAMPEDE approach, the RTOG 521 approach, there are different ways that this has been done and I would say we're probably still waiting on some data to solidify our knowledge of systemic therapies in this area but what are some of the approaches that you really focus on?

Kala Sridhar: Yeah, I mean I think that some of the things that are particularly interesting are when we look at moving the new hormonal agents, things like ARN-509, the abiraterone and enzalutamide perhaps not so new anymore, but looking at bringing those agents earlier, they of course have the benefit of not impacting so significantly on quality of life as far as perhaps chemotherapy might do.

That being said based on CHARRTED and STAMPEDE where we've seen the movement of chemotherapy from very advanced stages, earlier showing a benefit, the question being, will it show even bigger benefit when it's given in the context of surgery or in and around the context of radiation therapy. I think we don't yet understand how the biology is going to be impacted by the different treatments that we're using so does radiation and chemotherapy is there some synergy there, that type of thing.

I think it's still early days, but there are a number of trials that we're waiting to report out and I think those trials will help us move forward. I think one of the things we really have to think about though, especially in localized diseases, unlike in the advanced setting where patients often will live a short period of time comparatively speaking patients who have localized, high-risk prostate cancer may live a decade or even longer.

Alicia Morgans: Absolutely.

Kala Sridhar: So, if we're gonna do a trial we have to wait a decade or longer to get our endpoint of overall survival. And so, I think it's really critical to have earlier endpoints, earlier surrogates, and validated surrogates, we know about the ICECaP initiative that's really worked hard to find those earlier surrogates and metastasis-free survival is one of those earlier validated surrogate endpoints. And I think incorporating that into trials is important and then the other thing that I'm particularly interested in is harmonizing eligibility criteria and really taking a really close look at what are the criteria that we are outlining for patients to get on trials.

Okay, cause there's two reasons. One is, we have a fairly high screen failure rate so we published data on this saying about 30% of patients screen fail and I think we really have to look into the reasons for that. We really have to ask if the patients that we're getting on trial are truly representative of the patients that are out there, cause we may have this very highly selective group of patients on trial whose outcomes don't mirror what you see in the general population.

So, there are efforts ongoing to harmonize the eligibility criteria as well so when we look across treatments, across states of the disease, perhaps we will be better informed.

Alicia Morgans: Absolutely and I think the point you make about whether these patients reflect those patients we see in daily practice is really important one.

I think historically we've had eligibility criteria that have been devised to try to maintain safety and to make sure that things are going to go well and that really the effects that we see are related to the drugs themselves and not in an incredibly vulnerable population that will be particularly sensitive to toxicities, but regardless of the way that those eligibility criteria are defined, we find ourselves in clinical practice having to extrapolate to the patients that we actually see and those are the patients who are getting the treatments.

So, having those patients actually included in the eligibility for these trials and making sure that the eligibility criteria are loosened where they can be to maintain safety, but also to reflect the patients that we see on a day-to-day basis. It's a really critical part I think-

Kala Sridhar: Right. Right.

Alicia Morgans: Of moving the bar in this high-risk localized disease setting.

Kala Sridhar: Yeah, yeah.

Alicia Morgans: The other that I wanted to just touch on is that I completely agree with the importance of things like the ICECaP initiative and those intermediate endpoints because as you said, if patients are living for 10 years, we must have something before that or we'll never finish any of these trials.

Kala Sridhar: Right. Right.

Alicia Morgans: So, besides MFS, are there endpoints that you're thinking about what you think might be of interest whether that's MFS has defined by novel imaging perhaps or other approaches. What are your thoughts on that?

Kala Sridhar: I mean I think it's an area of active study. I don't think we know yet what they are, I think we have to look through everything that we have and, in some diseases, like for example, prostate cancer you may have markers like PSA that you can look for metastases with conventional or new imaging, but I think we can also look to other cancers like bladder cancer.

Are there earlier things we can look at to help tell us, yet maybe not as significant in bladder cancer, especially advanced disease cause the life expectancy is shorter, but certainly kidney with a lot of the new treatments that we have ongoing. We may start to need those endpoints to help us to know what's gonna happen long term, so I think it's an area of active study right now.

Alicia Morgans: Absolutely, both in high-risk localized disease as well as in bladder and kidney in many cases.

Kala Sridhar: Yeah.

Alicia Morgans: And thank you also for mentioning the multidisciplinary approach because I think that that benefits our patients including medical oncologists, radiation oncologists, surgeons, urologists of course.

Kala Sridhar: Right.

Alicia Morgans: And then the other supportive services that we know help to keep our patients well as they go through these treatments.

So, thank you so much for sharing your insights on this.

Kala Sridhar: You're welcome, thank you for having me.