Alicia Morgans: Hi, I'm so excited to be at ASCO 2022, where I'm speaking with Dr. Channing Paller about her work and her considerations in the timing and intensity of ADT in biochemical recurrence. Thank you so much for talking with me today.

Channing Paller: Thank you so much for inviting me to be here today. This is so fun. This is my favorite time of year when we come to ASCO and get to learn what all my colleagues are doing in this space. So I was thrilled and honored for the opportunity to present on the timing and intensity. My talk explored first, the definition and what we do and how we define it, and how it's a very heterogeneous population. So we used to think of it as anyone who had received radiation and/or surgery, and they had the Phoenix definition for after radiation greater than two.

And the question is really is that outdated now in this new era? And they also said, okay, well, after a PSA of .2, after a radical prostatectomy, that's when you defined biochemical recurrence post-surgery. And so first we defined it in the talk and then we went forward and said, okay, well, how do we decide about timing and intensity and what data do we have?

Alicia Morgans: Well, I think this is such an important question. And to your first points about the definitions of recurrence after surgery and after radiation, I think those are questions that we've been asking in the field. Did you conclude, did you say that especially the Phoenix criteria … I feel is something that we often act before someone meets the definition of recurrence in the post-radiation setting. What are your thoughts there?

Channing Paller: Absolutely. I think those data are old in the new era with new scanning techniques, such as PSMA. So first we talked about the TOAD trial when to initiate hormone therapy. And this was a trial that looked at patients with biochemically recurrent prostate cancer. And it said, should we initiate it immediately within eight weeks or delay two years until patients have either a doubling time of six months or metastases or clinical symptoms? And what they found was that there was no benefit to initiating hormone therapy earlier.

The other thing that we talked about is, although this is not definitive, they are prognostic factors to look at both the doubling time and the Gleason score. There was a study by Antona Rockus that looked at 400 men, 135 of which had metastases. And he looked at all the clinical factors that seemed to be important and what really stood out was a PSA doubling time of less than nine months. It was clinically significant for metastasis-free survival, as well as a Gleason score over eight. So these are some more variables that we have to take into consideration when we talk to our patients.

And I always remind my patients that the whole patient matters. So they may have a very slow doubling time and they may not die of prostate cancer, and they may not need initiation of hormone therapy.

Alicia Morgans: So how do you have that conversation? Because that's one of the things that can be so tricky when people come into the clinic and they are anxious, they say my PSA after prostatectomy has gone from .1 to .2. This patient said prostatectomy and radiation say to the salvage radiation to the pelvis. And now it's .2 and last time we saw this happen, you radiated me and now it's happening again. What am I supposed to do? Why shouldn't I start on treatment?

Channing Paller: Yeah. So this is a very interesting area. So we have to get data to start with. So I always ask my patients, how do you feel? Are you having any symptoms anywhere? That's the most important thing for quality of life. The second question is we need to figure out what their doubling time is, how fast is their doubling time? Is this something that's going to rise very slowly over time or not? And we also need to know that their testosterone has recovered. Is this just their testosterone recovering? And then the third is if either they're not feeling well or their PSA is rapidly rising, I'm going to get imaging.

And in this patient population, if I defer hormonal therapy, I do check their PSA every three months and scans annually. And what's really nice with the new PSMA scan, it's a two-for-one scan. So they get their bone scan and their CT scan at the same time and it's more sensitive and specific. And, so, then that leads to a whole other question. So, I have these patients that come in with .2 or .7 PSAs, their doubling time is two years and they have 10 little spots all over their lymph nodes of two millimeters and they say, oh no, Dr. Paller, I need to start hormone therapy right away.

I'm 80 years old. I have heart disease and high blood pressure and I really just want to go to Florida. And I said, guess what, I have great news for you. You can go to Florida. You are not going to die of prostate cancer right now and you do not need hormone therapy. It will not increase your overall survival and it may actually inhibit your quality of life.

Alicia Morgans: I think that's such a nice way to phrase it. I try to do the same. It's actually a good thing to not need treatment for your prostate cancer. You can feel as well as you currently feel and we will not interfere with that in any way. And so that's such a compelling message, I think, from a patient perspective. So what else should we be thinking about?

Channing Paller: Right. So I also have the sort of other end of the spectrum where PSMA PET makes a huge difference for PET-directed therapy. So when the PSA's low is when we're likely to find oligometastatic disease. And yes, in the olden days we would've just started hormone therapy, but now they might have less than three to five spots that our radiation oncology colleagues can isolate and radiate and give them improved progression-free survival. They offer a cure, but I call that five-year delayed progression-free survival, because I do think that it tends to come back.

Alicia Morgans: And for many of these people, we don't know because we certainly just don't have the follow-up. So it's hard to claim something when we really can't establish it, so I'm with you on that. So in that setting, and this wasn't necessarily included in your talk, are you in clinic combining hormonal therapy with that SBRT or are you really using that data in the spirit in which it was intended, which was to delay the time to systemic therapy?

Channing Paller: That was a great question that was actually asked by David Nanus because I think the practice differs throughout the country and even differs with when my own institution at Hopkins by radiation oncologists, what they also prefer. I would say there are patients with slow doubling times that I only use radiation therapy on and I think sort of the goal is to delay. But they're patients with really rapid doubling times that I have a sense where I also have a clue from the PSMA scan that they have micrometastatic disease elsewhere or one questionable lesion where I will add hormone therapy to the radiation, just to give it that extra boost.

What do you do in your practice?

Alicia Morgans: I do the exact same thing. And I think that this is where it really comes down to the art of understanding the clinical features, understanding the patient in front of you, too, and how intense do we need to be and trying to find that perfect fit. I do think that we will have some data in this space at some point, and I'm excited for that data because right now we are really making these choices on a patient-by-patient basis. But once we have the data, we'll still make the decisions on a patient-by-patient basis, but they'll at least be a little bit better informed with some data, so exciting days to come.

And at least between the two of us, we have a pretty consistent approach, which is helpful to hear as well.

Channing Paller: Absolutely.

Alicia Morgans: So, what else do we need to know as you're thinking about really timing these treatments and biochemical recurrence? What else is on your mind?

Channing Paller: I think it's just to remind everybody the CRUK data. We asked the question, should we do intermittent or continuous and it was found out that the continuous arm had 9.1 years median overall survival and the intermittent arm had 8.8 years median overall survival with no significant difference. And so really we recommend intermittent in this space. But again, that's changing because all of these men are now going to have metastatic disease based on PSMA scan. And so I think the take on point here is although we all wish we could do a placebo-controlled trial of head-to-head PSMA versus CTM bone scan, it's not going to happen.

It would take 10 to 20 years to read out, to figure out the overall survival. And in that time period, our technology would drastically improve and it would be a whole different question. And so this is where we are, this is the reality and so we need to work with it and really understand the whole patient. I also think we should start including other biomarkers. I think there are a lot of other tumor types, colorectal cancer is one of them that uses ctDNA and really starting to incorporate ctDNA, CTCs into our clinical trials with PSMA scans will help us better understand this disease state.

Alicia Morgans: I could not agree with you more. I think that PSA is what we've been using and the purpose is very much the same. If the PSA is detectable, clearly, there's something there. But if we have this evidence of minimal residual disease by some other blood-based biomarker, I think we would be able to make at least more informed decisions than we currently do and it would be much more sensitive than PSA. So I'm with you all the way. So as you kind of wrap this up, what's your final message in biochemical recurrence for the practitioners who are trying to do their best each day in clinic?

Channing Paller: I think this is an exciting new phase where we have PSMA scans and to use them and think about the whole patient and not just react too quickly to metastatic disease and really think is it oligometastatic and what are the other clinical factors associated with the patient before you move forward.

Alicia Morgans: Well, thank you so much. It is a time when things are changing so rapidly in an area where our technology is outpacing our knowledge, but you have really helped us put everything into context. And I think it'll make Monday a lot easier in clinic next week. Thank you for your time.

Channing Paller: Thank you so much.