Alicia Morgans: Hi, I'm so excited to be here at APCCC, 2022 in Lugano, Switzerland, where I am talking now with Dr. Kosj Yamoah, who is the Chair of the Department of Radiation Oncology at Moffitt Cancer Center. Thank you so much for being here.

Kosj Yamoah: Thank you for having me.

Alicia Morgans: Wonderful. Well, you gave a fantastic talk today, really, about a topic that has been in such evolution over the last few years and an exciting gray area for us to discuss at APCCC. You were talking to us about adjuvant versus salvage radiation in the biochemical recurrent or adjuvant setting and help to guide us on our thoughts there. Can you give us a little recap? What should we be thinking about for these high-risk patients?

Kosj Yamoah: Thank you for the question. This meeting has been phenomenal so far, and with this specific topic of adjuvant versus salvage, the reason why the field continues to undergo an evolution is because most of the time, when we look at prostate cancer with the tools we have, we are oftentimes looking at a snapshot of what's really going on. Is this an indolent disease, or is this an aggressive kind? And is this a late stage presentation? Or is this something that is so aggressive that we are catching that disease process at a time where something needs to be done immediately?

Right after the surgery, we don't really know that. Of course, in the last decade or so, there's more genomic testing and things that are coming in to inform some of that, but still, we are having to define how we use that in the field. And so that has also impacted patients who get adjuvant radiotherapy versus those that you may want to wait until salvage. And because, if everyone were to get adjuvant radiotherapy just because they have risk factors for recurrence, about half of men treated with radiotherapy would just buy themselves side effects with no real benefit. But that brings the next question, is, how do you determine who gets it and who doesn't get it? Or, should everybody get early salvage, because that way, at least where the disease is going?

And so, over the last decade or more, the field has gone through a reevaluation of adjuvant radiotherapy, where we've looked at studies that said, yes, adjuvant radiotherapy is great and meta-analysis will give you the data that you do improve biochemical control with adjuvant radiotherapy. In fact, in a meta-analysis, you also improve metastasis, meaning decreased metastasis in adjuvant radiotherapy. However, you get more side effects, and frankly, with the exception of one study, you don't really get overall survival when you put all the studies together. So, it will behoove us to begin to understand the patients that can actually benefit from adjuvant, or at least adapt an early salvage approach.

More recently, there has been three studies, randomized trials, which is the RADICALS, the RAVES, and the GETUG looking at the timing for radiation delivery for these patients. And the clear winner seems to favor an early salvage approach, because those patients are actually able to, again, have less side effects and you're actually tailoring the treatments to those that need it the most.

However, what we don't know is, are there still patient subsets that can still benefit from adjuvant radiotherapy? To answer that question that is emerging evidence suggesting that we may need to look a bit away from an entirely PSA-based approach in determining patients that should get adjuvant therapy to more of a combination of clinical and genomic risk factors that culminates in treatment recommendation. A couple of factors that emerged from different presentations that we've held today has been patients that have pathologic T3b/T4 disease, involvement, also if they have a surgical margins from their R1 resection, and if they have a high genomic decipher score, which is basically the 22-gene panel that is supposed to predict developing five years metastasis for patients. Almost like a biomarker for aggressive disease. When you have these factors, regardless of the PSA, that these patients might be the subset of patients that will benefit from adjuvant radiotherapy. And so I think that, by and large, the field is adapting an early salvage approach, and yes, still, there are sub population of patients that may be considered to have adjuvant radiotherapy in select patients.

Alicia Morgans: I think that's so important. And just to clarify for everyone watching, what is your definition of early salvage, the one that was used in these trials?

Kosj Yamoah: Right. By way of definition, we would consider adjuvant radiotherapy by and large be given when patients do have certain adverse pathologic features, extraprostatic static extension, [inaudible 00:04:55], positive surgical margins, or higher Gleason 8s, 9s, 10s. Those patients, potentially, will be eligible for an adjuvant radiotherapy approach in the absence of the PSA recurrence. Now, early salvage definition has been a bit broad, but oftentimes we range from a PSA of 0.1 to about 0.5, depending on the studies you look at. Some studies actually constricted to 0.1 to the classic definition of salvage, which is 0.2 and above 0.2. But in some studies, the gap was a little bit wider, all the way up to 0.5.

Alicia Morgans: Okay.

Kosj Yamoah: But, by and large, that early PSA detection that triggers radiotherapy post-operatively will be considered an early salvage approach.

Alicia Morgans: Absolutely. So, question then a little bit about that, and those features that you mentioned, which are phenomenal, mostly clinical features, but maybe bringing in Decipher. So, do we have evidence to say that population will only benefit from adjuvant and will less so benefit from early salvage? Or is the data really that these are the highest risk patients who may consider adjuvant and we don't know yet whether they may benefit in the same way from early salvage?

Kosj Yamoah: That's a very, very important comment and observation there. I'll say the latter is more so. What the data that most of this is based off is actually a smaller study set, where they looked at the benefit of salvage, true salvage radiotherapy in the context of low genomic risk versus intimidated to high genomic risk. And the data says that, if you had a low genomic risk of metastatic disease, which could imply this disease is more indolent than not, then, whether you did adjuvant radiotherapy or salvage really didn't matter. The benefit was the same. So, that makes sense.

Now, what is less clear, and to your point, is that salvage group, the observation was that if you added radiation therapy later when they actually developed the medical criteria for salvage, then the benefit of radiation was a little bit more blunted than if you had done it earlier.

But that doesn't answer the question. It's just a question of early salvage still as beneficial as, and that needs more studies to really answer that specific question. But I think what's more clear is that if a patient has a low genomic risk of metastasis or has indolent disease, there's no need to rush with adjuvant, or even early salvage for that matter. However, obviously the PSA keeps rising, then we have to treat. And if that's requires giving radiation only to the post-oped, that has been shown to be decreased disease recurrence. There's a whole discussion on whether to add systemic therapy or not.

Alicia Morgans: Yes.

Kosj Yamoah: And they're probably outside the scope of this timeframe. But again, that also goes to the fact that if a patient has aggressive disease, then localized radiotherapy alone, even in the context of high genomics, may not even be their only option that a patient should be having, and perhaps we may need to layer on systemic treatments, whether ADT or ADT and something else, depending on the risk factors and the PSA density and things like that.

One thing that I also wanted to mention is to pay attention to the PSA doubling time, PSA DT, which means that if you do have surgery and patients are doubling their PSA, either less than 12 months, or in some cases, less than 18 months, it's almost a signal. That biomarker is a strong signal for aggressive disease. And that should trigger a different type of strategy that may involve an early salvage approach than if it's a 10 year PSA rise from an indolent cancer. And then we need to also peel back and factor in important things like the age of the patient, the comorbidities, their life expectancy, and all those things, and also the patient's wishes to make sure that whatever we do, if we are not going to change overall survival, that we make sure that we mitigate side effects, and between that, give our patients the best quality of life as possible whilst we treat the disease.

Alicia Morgans: I completely agree, and I so appreciate you walking us through this incredibly complex, but so important landscape. I wonder if you could comment on one other thing that's so critical and really affecting our decision making here, and that is PSMA or other PET imaging techniques. So, what are your thoughts there?

Kosj Yamoah: It is more important to use PSMA imaging as a tool to layer over our known proving through clinical trials approach that we use to treat patients, rather than just treat based on what the PSA signal is telling us. The reason why I think that's so important is, once you've you've done an imaging modality, say, in the context of our conversation now, this is going to be post-surgery and you are having a suspicion of a PSA rise and you do PSMA PET image imaging. Once you have this PSMA imaging done and you recognize that there is signal in the post-oped or in the pelvic lymph nodes or even extrapelvic regions, that gives you information into where the disease might be recurring, and that's very valuable.

However, that information should augment what you'd have done without the PSMA PET testing. So what we need to do now then is to look at that image and be able to let it inform how we treat the patients with that imaging modality to augment that therapy, rather than change entirely what the guidelines is recommending by treating signal. For example, if you have a past PSMA PET test in the pelvic node, and your CAT scan correlates that the CT portion of it does not show any signal, versus a scenario where the PSMA PET corresponds to a CT signal.

Those two imaging observations are quite different, because in one instance, you do know that there is a CT evaluable area of recurrence that needs action. And in the other case, you might need to understand that this might be an early sign of recurrence, but may not be actionable yet. Our field needs to define that clearly. And also, we shouldn't forget patient anxiety, and in instances where we don't even know we're going to change overall survival. And by having signals show up all up in these places without being able to change the patient's ultimate outcome, could eventually become a source of stress and anxiety for patients that we don't know what to do with yet.

And so, as we learn these things, I think we know that PSMA PET is being widely used, and so that's a great thing, but we have to be very rigorous in our prospective evaluation of how the data is and see if this is informing and changing patient outcomes before we make that mainstream. But in any event, I think PSMA PET testing is here to stay, and we just have to learn how to use it correctly.

Alicia Morgans: And I love your message about ensuring that the patient gets the standard of care and using the PSMA pet to add on to that standard of care, because especially as things are evolving, if we do have a chance to potentially cure a patient through standard of care management, we wouldn't want to, in most cases, I think, remove that option for cure, unless there was something very clear and obviously suggesting that was going to be ineffective.

Kosj Yamoah: Absolutely.

Alicia Morgans: I really appreciate that message. So, thank you for walking us through such a complex topic that is so clinically important for our patients and an area of many questions for our field. I sincerely appreciate your time.

Kosj Yamoah: Thank you for having me, and I'm looking forward to doing more of this.