John Fortin: Welcome to today's coverage of the 12th International Symposium on Focal Therapy and Imaging in Prostate and Kidney Cancer. I am excited to introduce Dr. Art Rastinehad. Art, your broad experience, including your NIH training in radiology as a urologist and as a focal therapy principal investigator, I look forward to hearing your thoughts on today's topic, a clinician's perspective evaluating a new device for focal therapy. As you know, there's been considerable debate for over a decade as to if focal therapy makes sense. Where are we in this debate?

Art Rastinehad: I think we're at a really exciting point in the treatment of prostate cancer and diagnosing prostate cancer. Initially, we had difficulties with overtreatment and overdiagnosis. With the advances in imaging and other technologies, we really shifted how we identify patients. In that shift, we really help identify patients that should be on active surveillance with low-grade, low-risk disease, but there are patients that need some type of treatment. The challenges are what are those patients need? Traditionally, they would recommend to have surgery and/or radiation. That falls in the category of whole gland treatments and that is associated with the issues that men find unappealing about these treatments, which is urinary incontinence and erectile dysfunction. For the last 13 years, we've been having meetings on the topic of focal therapy and how can we move this field forward and develop the science behind it to support our ideas of just treating a part of the prostate, hopefully helping men avoid the unnecessary side effects of whole gland therapy.

John Fortin: Okay. We understand why there was so much interest. The challenge is, how do we do rigorous research that is needed to bring focal therapies to the market? We have a complex regulatory and provider environment in the United States. The FDA regulates drugs and devices for treatment, various associations such as the NCCN and provider guidelines, the AMA authorizes procedure codes, CMS and the insurance carriers controlled reimbursement. At a high level, could you help us understand navigating this environment for focal devices?

Art Rastinehad: That is an incredible question and a challenge that we face every day as clinicians. First, looking at what the FDA gives us as guidance is what they need to approve a device and what is the device being approved for? First, is prostate ablation. A lot of companies are trying to go to that hurdle first because it's a little easier to overcome, and then prostate cancer would be next. Recently, the FDA gave a response and turned down a focal therapy company for indication for prostate cancer. I think that's a challenge in the marketplace, as well as the medical practice of this is that we have to identify the best patients. I think it's difficult in some of these trials to identify the best patients because after you run a trial for five years and have follow-up, maybe our views on prostate cancer have changed, therefore, it's not really applicable, the data that was created.

So when we do this, we do this in a few phases. The first one is a pilot, where a short small group of patients to see if it's actually safe. Then the pivotal is our expansion, which is typically up to a hundred patients to see if it's effective. How does it impact the man's quality of life? As going through this process as an investigator, it's really important to have some foresight and where the field is going so you can design a trial that still would be applicable when you seek an indication from the FDA to qualify your device for prostate cancer or prostate ablation.

John Fortin: Traditionally, whole gland studies attempt to measure overall survival, cancer-free survival, and other longterm primary endpoints. In your opinion, what endpoints may be appropriate for focal therapy device trials?

Art Rastinehad: First, let's look at when traditional therapies looked at overall survival, cancer-free survival, and other longterm primary endpoints. It's difficult for them to even prove the utility of, say, a prostatectomy. Now, given the current data on the outcomes, because their patient selection was so poor, a lot of patients with low-grade disease never needed to be treated and high-grade disease patients showed some benefit, but it was difficult to take this data and push forward to really justify even these treatments we're putting patients currently through. For a focal device, the current endpoint for the lowest hurdle as I described before was ablation of prostate tissue. Can you say you're going to ablate something and then you biopsy and prove that the tissue is there or you treat and resect? That is the first step usually in these trials.

A second endpoint can be treatment-free survival. How many patients that should have had a prostatectomy or radiation therapy to have intermediate-risk prostate cancer can avoid therapy? We can look at five and 10-year data on this. Finally, which is probably the hardest thing to obtain, is metastatic-free survival. That takes too long to develop these types of progression of disease. So looking at patients that avoided therapy and can we adequately ablate what we say we're going to ablate, are the two ways currently we're trying to measure the to these devices and qualify their success.

Another important fact that I think is important for patients and clinicians to understand when they counsel patients is oncologic control. We're looking at focal therapy as a cancer control, not a cure. I think this is an interesting thing that the focal therapists have developed to use as talking points when confronted by people that perform prostatectomy. Because people have claimed that a prostatectomy, there's no recurrence in the prostatectomy site because it's been removed. So you can't have cancer pop up in a new place, but if you'll leave the prostate in place, there's a possibility for a recurrence and they're implying that's a failure. I think people should understand that if we treat intermediate-risk prostate cancer, there's 25% of patients that have surgery will have a biochemical recurrence of their PSA and they're not exactly curing their patients. They're trying to control their cancer. I think the big difference for focal therapy, we are trying to obtain oncologic control while maintaining a man's quality of life.

Importantly, as I talk about counseling patients and clinicians and adopting these therapies, it's important that patients support these research trials by clinicians. We wouldn't be here today and I certainly wouldn't be here speaking today in this interview if I didn't have the support of my patients who have trusted me and enrolled in my trials to help me move this field forward. This is a hurdle that all clinicians face, but developing the trust and taking the correct steps in a fashion that does not just go to the end and say, "This is a cancer cure," but we can critically evaluate this inside a clinical trial is very important.

John Fortin: In terms of designing a clinical trial, at what point do you get input from the FDA and CMS? Is that before the trial even begins or is that more after the fact when you're delivering the results?

Art Rastinehad: I would say it happens at a few different stages. First, we have an expert opinion on how trials should be designed because the FDA does sit down with us and have joint meetings to discuss these specific topics. But in the end, the FDA takes the information provided to them and then comes out with a statement or suggestions that are going to be followed by investigators to be able to paint approval for the current indications. Right now with focal therapy devices in our conversations with the FDA, you must have tissue as an endpoint for ablation. I mentioned that earlier in the interview that we want to say we ablate and then prove that that's actually ablated is the first hurdle to overcome in developing these new technologies. With respect to different arms, they have not asked for randomized trials specifically with respect to ablation because that's a very simple equation. You ablate and then you biopsy.

They do recommend the biopsy to occur between six and 12 months after treatment to allow time for the lesion to contract and healing to occur so you have a space that can be sampled. Having multiple arms and trials is extremely difficult because patients if they don't need to be treated like active surveillance, why would they undergo a therapy? And some possibly, maybe due to the fact that patients on active surveillance may require therapy in the future, if they can decrease that, that shows a value that I think that's very difficult to prove. Recently, a company was turned down for an indication by the FDA for just that scenario as an alternative to active surveillance, to ablate visible lesions to hopefully help men avoid coming off active surveillance.

With respect to looking at the other group as a whole gland therapy, to have a patient enroll for focal versus whole-gland is extremely difficult. They're already informed, they've already sought out your counsel. Showing up it's difficult to say you're going to be randomized to a prostatectomy versus just an ablation, which you could always have a prostatectomy later or whole gland treatment later without all the side effects. So I think that's sometimes challenging to get patients to enroll in the trials. Some people have postulated we could do a placebo trial. I find that kind of unethical and difficult to do in this scenario. We could have a sham procedure, but you are dealing with prostate cancer and one of the challenges in prostate cancer is that we still have difficulty staging the lesion and the patient while the entire prostate is inside because the biopsy has some limitations, MRI has improved that and Dr. Pinto's recent paper in the New England Journal of Medicine reinforces that, but we still aren't there yet. So I think that would be a real challenge with us trying to perform a sham procedure.

I think a key component of staging patients for focal therapy is imaging. I think fusion biopsy and imaging today is our current standard to enroll patients in the trials. They must have standard biopsies, as well as targeted biopsies so they at least meet the standard of care. I think there's going to be many more patients involved in focal therapy because AUA recently recommended that patients at risk for prostate cancer with a suspicion of prostate cancer prior to biopsy should have an MRI. Therefore, that would lend itself to the pathway of a fusion biopsy, and I'm very excited about that. We've been fighting that battle for almost a decade now and it feels like we're really moving forward. Almost every major organization in the world has supported imaging prior to biopsy.

John Fortin: So as I understand it, a randomized controlled trial is problematic if your compared arm or surveillance groups, Gleason 6, very low risk, why even do the trial? Because presumably, a very low risk patient doesn't need treatment, and yet if you had a compared arm of someone who needed the whole gland treatment, how would you enroll someone into that? At least in this country, it'd be very difficult to find a patient who'd be willing to enroll and how many patients would want to stay enrolled for a variety of reasons for many years? Would they even be willing to go into a blinded trial? Would they be willing to have annual TRUS biopsies for many years when we think about the harms from antibiotics, the risk of infection, ED? I don't know how we even can do annual TRUS biopsies for many years. I don't know if that's an issue, Art.

Art Rastinehad: The followup after focal therapy is in flux, but we have some guidelines from expert opinion that in the first year, you should have at least a restaging biopsy at one year. And that's what the FDA recommends by one year, have a restaging biopsy, which would be a standard biopsy and a targeted biopsy of the lesion that was treated and any additional lesions that have arisen in that time that has elapsed since the treatment. That's your first biopsy point.

Dr. Emerton, myself and others feel after this point, the patient falls into a cancer control paradigm. There's no reason to rebiopsy the patient if there's no imaging changes or other suspicion that disease has progressed like their PSA remains stable, their MRI at one year, there were no lesions. We maybe can obtain an MRI in one to two years to get an imaging endpoint and then continue to use imaging as needed, maybe once at five years. So we're really trying to eliminate the biopsy for the exact reasons you said having the risk of infection, which most people are moving to transparent needle only to decrease infection rates. At Northwell Health, we no longer do TRUS biopsies, it's transperineal only. Europeans have already moved to transperineal. So these are all exciting things and we're trying to decrease the number of biopsies, as well as maybe use other genomic markers to screen patients for progression of disease.

John Fortin: So really, we have a complex environment. We have standards of care that are evolving over time. We have greater acceptance of TRUS biopsies as a secondary role to targeted biopsies. And who knows, maybe the TRUS biopsies at some point may not be needed. That's in flux right now. But we also have a complex regulatory environment with FDA and CMS and others wrapping their heads around what are appropriate protocols. I understand a number of trials that are really measuring the decrease in PSA or they're measuring novel endpoints. How many years does it take to be free from radical treatment? So these kinds of different endpoints really muddy the waters, at least from a patient's perspective in terms of understanding what's been approved and really what focal therapy may be most appropriate.

Art Rastinehad: I think those trials that use PSA only as an endpoint, there's a fallacy, right? Because as you're saying, all the PSA is our metric we're going to use. That's not an oncologic outcome except that the entire prostate wasn't present in the patient. Then the percent decrease in PSA some people have postulated could be a surrogate. That doesn't make any sense because the more prostate tissue ablates, the more the PSA would decrease. We all understand that prostate cancer does produce more PSA or allow more PSA to leak into the bloodstream; however, I do not think that's a great approach for an endpoint in a trial. The regulatory issues are numerous. That's why the FDA is giving guidance about the tissue of endpoint. Dr. Emerton, honestly, he and I discussed this often. He feels like imaging should be the endpoint because if you don't see anything, that probability of having high-risk disease progressing is extremely low and they have a lot of data to support that from UCL.

I don't think we're there yet in the US. The regulatory environment in Europe is much different for focal therapy. They are reimbursed for it and their reimbursement structure is different than the US. The goal of the focal therapy society is to foster the development of trials, scientific data and help with the regulatory hurdles to get everyone under one umbrella to work towards a common good. Even the Europeans at some of this stuff, is not that applicable to with respect to the regulatory issues are supporting their American colleagues in trial design, so data can be used in both areas to support moving focal therapy forward.

Right now I think the biggest thing is getting the news out about the society, talking about how we're working together, and trying to develop more scientific evidence to push the field of focal therapy forward. We've covered the regulatory from the FDA, which has given most of the guidance on this with respect to the tissue as a primary endpoint for ablation. Prostate cancers made an extremely difficult challenge for an indication to be obtained by a company. Most companies aren't even attempting that at this point. They've decided that they have their ablation indication, they're moving towards obtaining a code and just kind of continue on. I think that's a challenge too because once the industry has their code, the amount of support or further research, I guess, decreases because they're able now to have a commercial environment for their product.

John Fortin: And the real danger is the patient has no clue as to what's been studied, has no clue what the indication means when it says it's been approved for treating the prostate, the patient assumes blessed as an oncologic therapy. When we hear just, "Prostate has been approved," we have no clue what that means, they say it for BPH, they say it for cancer. So you, as a clinician, know the difference, but the patient assumes it's just as blessed if not more blessed because anything to do with the prostate, it's been blessed. So I think that's where this is going to have a lot of complications as these things get approved and reimbursed.

Art, thanks again for sharing your insights. I've learned that focal devices have a different process than the drug side and take a different approach. I've learned that the focal side has a different situation than definitive treatment. While focal therapy may be very appealing to patients, it is a new paradigm and we need to understand what is appropriate for this new paradigm. But for over a decade, clinicians, researchers, and regulators have tried to wrap their heads around MRIs, targeted biopsies, and the need for focal therapies. Now, we're seeing a variety of trials with different endpoints, monitoring, and levels of evidence. Your insights are valuable as we all try to understand results from trials. And thanks to our audience for listening.