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Alicia Morgans: Hi, I'm so excited to be here today with Professor Neha Vapiwala of the University of Pennsylvania. Thank you so much for being here with me today.

Neha Vapiwala: Thank you for having me.

Alicia Morgans: Wonderful. Well, I'm excited to talk with you about the INDICATE trial, which is a really exciting phase three trial that is being run through the ECOG-ACRIN Group, but is actually endorsed by and supported by all of our NCI designated cooperative group partners. Tell me a little bit about this trial.

Neha Vapiwala: I would love to, and thank you for your excitement. It does mean a lot to us that all of the cooperative groups have really come together to support this study. So to take a step back, it's for patients with biochemical recurrence after prostatectomy who specifically are getting baseline PET scans. Now, as you're well aware, PET scans have become really revolutionary in terms of our ability to restage patients in that setting and make treatment decisions based on the findings. But what isn't clearer and what remains unknown is if we're improving outcomes when we make decisions based on what we see on PET scans alone for findings that we're not seeing on conventional imaging scans. So bone scan, CAT scan, MRI. And one of the things this study really is trying to do is help us as clinicians, but also help patients to know what benefit they may derive from additional treatment that's recommended based on findings on PET.

So we take these patients with post prostatectomy, biochemical recurrence who get baseline PET scans, and we determine one of two paths for them. One is if their PET is negative for cancer outside the pelvis, then they're randomized to standard of care radiation and six months of hormone therapy, which is considered the typical treatment in the setting of biochemical recurrence with or without six months of a medication known as apalutamide, which is really trying to say, let's intensify the systemic treatment in these patients where there isn't evidence of cancer already outside the pelvis because we know that the standard of care treatment alone still leads to more biochemical recurrence than we would like. There's still a significant number of patients who go on to recur again. So we know there's room for improvement, and could we perhaps capitalize on these new agents, these new drugs, to really hit the cancer hard for a short period of time, the six months to achieve benefit?

The other pathway is for those patients who do have cancer outside the pelvis, so their PET shows cancer outside, and the question becomes, if it's not seen on conventional imaging, do we need to treat it and do we need to treat it as real? Well, everyone's on a different place on the map on that and literally and figuratively on the map because we have countries that have long used PET and directed their treatments based on that. We have many countries and within the United States where PET is not as commonly used unless conventional imaging also corroborates the findings. So we're saying for that group, for that population, everyone can get standard of care certainly, radiation and the six months of hormone therapy, everyone will get the six months of apalutamide. But now the study question is, does metastasis directed radiation to those lesions seen on PET improve outcomes?

Because currently we're in this hodgepodge where some patients get the metastases treated with focal radiation and nothing done to the pelvis. Some get all of the above. Some get sequential treatment and people try to follow in between. So it's really because of this very unclear clinical picture, we felt this study, it was really trying to address a series of questions that we think are very clinically relevant and hopefully really will help patients in the end so that when they're getting a PET scan, they know there's actual value to this and that I'm not just having a reaction to what I'm seeing that doesn't actually change my outcome and that providers can feel confident that they're not just throwing treatments at a patient without knowing that the benefits warrant the side effects.

Alicia Morgans: It is such an important thing, especially as PET scans have come into the fore with the PSMA tracers that we're using. It's really changed a lot of our decision-making and we don't always know if we're making the right choices, and this will certainly help to figure that out. Now I wonder how are patients followed over time? This is something that I'm sure was a topic of hot debate as the study was being designed.

Neha Vapiwala: For sure. So I think for any investigators who have been at the inception of a study concept and seen it through, how it evolves over time is very important. One of the things we've tried to do, even though this is a phase three randomized trial, and so there's a lot of necessary strictness around the way it's conducted, one of the things we've still tried to do in that context is be adaptable and be pragmatic. And one of the major changes that's happened in our most recent amendments is allowing for PET scan to be used as part of the follow-up and not only for that very first baseline PET. Believe it or not, when this study first came online as a new concept, the National Cancer Institute based on the standards at the time, only allowed us to use conventional imaging for the follow-up period.

Absolutely they had their reasons scientifically, but you and I both know that practice has since evolved to patients getting PET scans and being followed with that on a regular basis. So we decided it didn't compromise the integrity of the science, but it did allow for more inclusivity of sites that chose to continue to follow their patients with PET. So whatever the imaging tool of choice may be, as long as patients get some consistency in whatever is chosen, that's all we ask for so that we can compare over time the same types of scans. And that is really the only requirement that we have now, recognizing that we want the eventual results to be very applicable and to make sense to people and not be so curated that by the time the results came out, they're just so restrictive in who they apply to. So we're hopeful that by allowing for PET as well as conventional imaging and follow-up that we've done that.

Alicia Morgans: Wonderful. So let's go through quickly just some of the basic eligibility. These are patients who have had a prostatectomy in the past, now have a rising PSA. What else do they need?

Neha Vapiwala: Absolutely. So the idea is that they're basically candidates for standard of care, pelvic radiation, and six months of hormone therapy. So to be a candidate in many places, that simply means you've had your prostatectomy and at some point in time you present with a measurable, and in many cases, measurable and rising PSA. Whether or not you have findings on your PET is not necessarily relevant to that standard of care piece. What we've done, however, is for the purposes of the study, require that the PSA be of a certain minimum value because we're trying to enrich for patients who are at slightly higher risk, who could justify being on apalutamide for six months and who may actually have PET findings of cancer outside the pelvis. So if you take only patients with very, very low PSAs, you're not going to see that.

So our minimum requirement is 0.2 for anyone who's had their prostatectomy within the past year, and for anyone who's had their prostatectomy more than a year ago, it is 0.5, which is for many patients and for many doctors, an uncomfortably high number in some cases. But we are seeing these patients and they do need this study question answered. And what I would say is we've added more recently a waiving of any minimum PSA as long as your PET is positive somewhere in the body. So if you have a PET that lights up, even if it's just where the prostate used to be known as the prostate bed, then it doesn't matter what your PSA minimum is because you've met the spirit of the minimum, which is that there's something that can be seen on PET. So that's allowed for some patients who didn't quite meet the minimum of 0.5 to enroll.

Outside of that, we just ask that you not have had prior pelvic external beam radiation because that's a critical part that all four arms involve. There are some criteria specifically to apalutamide in terms of safety issues to make sure that the drug would be as well tolerated as possible, and then certainly no other active cancers that would interfere with the treatment. But if you have a history of another cancer that doesn't directly interfere, we've also allowed for those patients to be included because the NCI really has said in recent years that they are wanting investigators to be more inclusive rather than restrictive in who they allow. And that was always a criterion that didn't need to directly impede. So those are some of the key ones. And then as long as you've had a baseline PET, whatever the finding may be, we have a study arm for you. So hopefully patients can be referred for the study.

Alicia Morgans: That's wonderful. So what should people do if they're interested, if a study is available near them?

Neha Vapiwala: Absolutely. So if it's not available and they find it on clinicaltrials.gov or through the ECOG-ACRIN website or any other resource or through UroToday and they want to ask about nearby centers that offer it, hopefully we'll have that information available in terms of centers that have it. And the best thing to do, of course, is to ask your providers about the study because we currently have a growing number of sites that are able to offer the study that have it open or that are thinking about having it open. So we'd love to continue to grow that number. And EA8191, which is the ECOG-ACRIN 8191 is the formal name of the study, if you look up that email alias, it's a great way to ask all your questions and it's available as well on the clinicaltrial.gov site. So if you have any questions as a study patient or as a study investigator, we're always available. Happy to answer those at any time.

Alicia Morgans: Wonderful. So if you had to sum up, what's your final message to listeners?

Neha Vapiwala: So my final message, whether you're a patient or a provider, a loved one, anyone that really wants to answer the most important clinically pressing questions of the day, we believe in science. We believe in doing high level, high quality studies. We also want to be adaptive and recognize that things are changing as we speak, and we have to use our resources. And that means patience, patience, time, their energy, and all of the resources that go into conducting a trial. We want to use them wisely. So the reason I would say that this study, and I really hope everyone does consider it, is trying to answer all of those questions as efficiently, hopefully as possible in one trial so that we can celebrate the technology, technology like PET and radiotracers.

We can celebrate how much they teach us and show us, but do so in a way that's responsible and do so in a way that's not just, oh, we're excited because now there's something new, but we're excited because there's something new and we know how to use it. And I have to say, unfortunately, I do feel in many cases the cart's been put before the horse where we're so thrilled of having the ability to see more, but we don't actually know if we're seeing better. And until someone proves to us that we're seeing better, we don't know that we're doing better by our patients. And that's why this study's so important, and we hope patients and their doctors will strongly consider it when they see an eligible patient.

Alicia Morgans: Well, I am certain that they will after your wonderful-

Neha Vapiwala: Thank you.

Alicia Morgans: Conversation about it. And certainly we will also make sure that we try to connect with the clinicaltrials.gov website that does list a bunch of contacts in different places where the study is open. But certainly for clinicians, if it's not open and you're interested and you're a member of ECOG-ACRIN or actually one of the other cooperative groups, it has been endorsed and so it is an opportunity to potentially open a clinical trial at your site. So thank you so much for taking the time today.

Neha Vapiwala: Thank you so much for having me. Really appreciate it.