Alicia Morgans: Hi, I'm so excited to be here with Dr. Neha Vapiwala, who's a professor of radiation oncology at the University of Pennsylvania. Thank you so much for being here with me today.

Neha Vapiwala: Thank you for having me, Dr. Morgans.

Alicia Morgans: Wonderful. So, Neha, I'd love to hear a little bit more about a trial that you have been organizing and running through ECOG. It's ECOG 8191 or better known as INDICATE. It's a really exciting study that offers an opportunity to patients that may not appear to be cured at the time of identification, but we'll see. Maybe we can really change the trajectory of their disease using radiation and some advanced imaging. Can you tell me a little bit about it?

Neha Vapiwala: I would love to, thank you for having me here to speak to the audience about it. So, as with many large randomized trials, it is a project in which many of us at pour our heart and soul, and it means a lot to us. So I'm really, I think in particular hopeful that we will get some answers for this patient population. So, to just refresh or inform everybody, it is for post prostatectomy patients with biochemical recurrence who are candidates for standard salvage therapy, which we're defining as essentially pelvic node and prostate bed radiation and six months of standard androgen deprivation therapy. So, based on multiple clinical trials that have established this combination as the standard of care in this population. And the idea here is that patients... I say our candidates for this because if one was to do conventional imaging, so CT or MR bone scan, any of those scans, there's no evidence of metastatic disease and therefore the goal is a second chance at cure.

We know however, that obviously now with the advent of greater availability of advanced molecular imaging, specifically PET imaging and of course PSMA PET more recently FDA approved and growing number of tracers in that space. We recognize that more and more patients are undergoing PET scans as part of their staging before they proceed to standard of care treatment. And we also know that findings based on PET scan alone, not seen on conventional imaging are sometimes guiding treatment decisions that are no longer now offering that original intended standard of care treatment. So, in some cases a metastasis seen outside of the pelvis for example, is now leading providers to say, "Okay, well we're not going to treat your pelvis like we intended to." We're calling this metastatic disease and we're going to do long-term, for example, long-term systemic therapy or conversely, we're going to not do systemic therapy.

We're just going to try to give some focal radiation to the spot and see how you do. So, there's a lot of... As you can imagine, permutations on this, so many variables and so much variability in how these patients are managed. So, our thought was why don't we test two hypotheses based on what the PET is telling us? And so, the PET directed piece in our title comes from the fact that all eligible patients who are candidates, as I said for standard care radiation and hormone therapy, conventional imaging negative get a PET. And if their PET is negative for metastases outside the pelvis, great, they proceed with standard-of-care or the standard-of-care plus six months of apalutamide. And the idea here is that systemic therapy intensification plays a role in these patients because we already know that if all they get a standard-of-care, there's still about 30% to 40% of patients who go on to have yet another biochemical recurrence even though they had nothing outside their pelvis, they should have been cured after salvage radiation.

We're not doing as well as we could. So, the question is... For that population, we're really just trying to improve on what we know current standard-of-care doesn't fully accomplish. Then, for the population where the PET is positive for one or more lesions outside of the pelvis there all patients will receive standard-of-care, salvage radiation and six months of androgen deprivation therapy plus six months of apalutamide because we won't want to treat them with anything less than what patients in the other randomization half of them are getting. Now, the question becomes what is the role of focal therapy intensification and specifically with stereotactic body radiation therapy or other forms of modern radiation therapy directed at metastases seen on PET. And so, that randomization plus or minus met-directed radiation is trying to test the hypothesis that the addition of focal met-directed radiation enhances outcomes and improves progression-free survival.

And so again, this is a question that I don't think at this point has been answered in a level one evidence setting, even though it's being done in various ways and forms all across the world. I will say a couple of important things. The primary endpoint for all forearms for both randomizations is progression-free survival. And that progression-free survival includes a component of radiographic progression. So, that's really important and we're evolving that definition to now include PET. We actually have an amendment we're working on as we speak to try to keep this study relevant. Because as the times adapt and as the guidelines adapt, we don't want our study designed a couple years ago to not be as relevant as it possibly can be, while staying true to the science. So, progression-free survival is radiographic progressions, progression-free survival, development of symptomatic disease or death. And so, that's the end point.

And then, the other key point I want to make is that for that randomization to plus or minus met-directed radiation, we do not set an upper bar of five lesions. Many studies out there are focused on the oligometastatic population, which is obviously very important. This study encompasses oligometastatic disease but also includes patients who may for whatever reason have six or seven lesions because at the end of the day we don't know if the upper limit of oligo in the PET era, if we really know what that threshold should be. It's based on conventional imaging. So, we're trying to keep it open.

Alicia Morgans: Great. Well, I think it's really exciting and it sounds like it's really responsive to many of the things that we're doing in clinical practice and really designed, I think in a way that hopefully is really going to help people find it easy to enroll their patients. Are you finding this study that is working well with your practice? Are you finding these patients?

Neha Vapiwala: I am. Thank you. I think that there are primarily patients who, again, love the idea of using that PET scan and trying to learn from it and having some approach that is incorporating the PET findings and also potentially allowing them access to a medication that they wouldn't have otherwise had for treatment intensification. The part where we can sometimes run into difficulty, and I think this is the case for anyone trying to do a randomized trial when the practice in the world has already sort of gone ahead of the evidence, the cart before the horse kind of situation, it's occasionally trying to convince folks that the plus minus met-directed radiation therapy piece is still reasonable because we're not undertreating you, we're still giving you systemic therapy, which is the appropriate treatment. Sometimes that can be difficult for patients to understand because there are folks willing to give the met-directed radiation therapy off protocol.

The other key factor is the baseline PSA threshold for eligibility. The NCI did ask us to keep it at 0.5, so that we would have enough patients enriched for potential findings on PET. As you know, Alicia, the PSA is too low. The chances of the PET showing anything are incredibly limited. And so, that would skew our population more towards that first randomization. But we have been able to work with the PSA threshold where it is, and we also have a threshold of 0.2 for anyone whose PSA starts going up within a year. So, that way we're still capturing some of those high risk patients and not having to necessarily wait till 0.5, which is the current eligibility threshold for everyone else.

Alicia Morgans: That's great. And really, I think quite practical in terms of trying to meet the sponsors in the middle in terms of ensuring that you have PET that are positive, but also being really responsive to what we're kind of seeing in practice and how early we're thinking about getting this imaging. So, that's really good. So, if there are docs out there, if there are patients who are looking to get involved or looking to enroll and indicate how would they do that?

Neha Vapiwala: Yes. So, of course, they are more than welcome to contact me directly, but we also have our study email, , so feel free to reach out. We are also our protocols listed on the clinical trials website. It's of course listed in clinicaltrials.gov for patient facing interest and we have lots of materials and resources available. And I just want to also mention that we have wonderful NRG and SWOG and Alliance Study Champions as well. So, if you're more engaged in one of those cooperative groups, you can still absolutely contribute to the study and support all of the cooperative groups.

Alicia Morgans: Absolutely. And very easy to open and hopefully to enroll. And if you can't open at your own center, there are going to be centers and there are centers open across the country. So, please think about sending your patients and patients think about finding a center that might work for you. Well, thank you so much for your time, for your expertise, and for sharing all of this information about INDICATE with us today.

Neha Vapiwala: Well, thank you for having me and really appreciate the support. Thanks everyone.