Alicia Morgans: Hi, I'm excited to be here today at APCCC 2019, to discuss with Dr. Maha Hussain and Dr. Tia Higano, some considerations regarding nonmetastatic CRPC. Dr. Hussain is a Professor of Medicine at Northwestern University and Dr. Higano is a Professor of Medicine at University of Washington. Thanks so much for being here with me today guys.

Maha Hussain: Our pleasure.

Alicia Morgans: Wonderful. So you both just gave a really exciting talk on pros and cons of treatment in the nonmetastatic CRPC setting. I think this is something that as we were just discussing, really comes down to a shared decision between patients and physicians. I'd love to hear your thoughts on how we can work together to make that choice, maybe starting from the clinician's perspective and going to the patient perspective and kind of going back and forth. But what are some of the things that you think about when seeing patients with nonmetastatic CRPC, Dr. Hussain?

Maha Hussain: I think that are multiple factors. You don't look at PSA alone and not look at the patient because at the end of the day, the objective is to do no harm and do hopefully, lots of good. The critical point is going to be balancing risk and benefit and understanding what the patient's wishes are, but also guide your decision by evidence. One of the things that I tell my patients, they can be emotional, their family can be emotional, I have to stay objective for their sake to ensure I'm giving them the right advice.

I would say, like anything else, there are the extreme ends. There are patients who literally we have whose PSA literally monthly, doubles. That's one extreme end. There is also the other extreme end where patients you see and you see lots of fluctuations, but at the end of the day, the spectrum is not a rapid rise. And this is where the patients, I tell them, "This is not a matter of if, but rather than when, and at this moment, you have an option to wait because I can't tell you that I'm going to make you live longer if I treat you today versus treat you in three months." These are the different factors that we consider.

Alicia Morgans: Absolutely. And what do you think about Dr. Higano, also thinking about reasons why we wouldn't necessarily want to start treatment now, like Dr. Hussein said, and what makes you want to start that treatment?

Celestia Higano: Well, I mean I think the first thing is important to acknowledge that this is the first time we've had drugs that can actually make a difference clinically for patients in terms of metastasis-free survival. And when they hear this difference of two years versus a few months, I mean, that's a big-

Alicia Morgans: ... It's compelling.

Celestia Higano: ... gain for them. On the other hand, we also have a better appreciation based on these trials about some of the side effects. That's where we really have to start talking to patients because the benefit looks really good, but you have to balance the side effects now. Now, if I had a patient who was 85-years-old and a little frail getting around, I might not want to give that patient one of these new drugs. The other thing about the new drugs is, we don't know if one is actually less toxic. I mean the most recent drug, darolutamide, appears to have perhaps some less toxicity than apalutamide, or enzalutamide, but there's no head-to-head studies. So I think it is important to inform the patients. But the other thing I say is, "You know what? You can start this and if it's not agreeing with you, we'll stop it and do something else."

Alicia Morgans: Yeah. And it's nice to have that option. And I also want to emphasize, actually something that you mentioned to me when we talked about this at some point, maybe six months ago, that it's important to actually select patients on the front end in whom you'd actually want to start ADT at all. Right?

Celestia Higano: Right.

Alicia Morgans: We don't want to start ADT, or at least I don't always start ADT all the time in biochemical recurrence when the PSA doubling time is very long, and patients, certainly, if they're older and frail with a very long doubling time, I'm probably not going to start it in the first place. So limiting toxicities from that point even, I think is really important. What do patients tell you when they're on these treatments, Maha? Do they generally seem to tolerate them well? And you've probably used all of these agents at some time or another.

Maha Hussain: Yeah. I think there are patients, just to highlight, there are patients who clearly do not want to be treated.

Alicia Morgans: Yes.

Maha Hussain: That is one group of men that we would continue to monitor and obviously at some point they may change their mind or especially if I feel this is a critical time point for them, I'm going to strongly recommend treatment potentially. But overall, I would say patients tend to tolerate treatment. Again, you have to be careful. You do not just give it to anybody walking through your door because the potential for harm is real. And so definitely, as I was mentioning earlier in my presentation, you get somebody who has congestive heart failure coming to your office in a wheelchair, that's one thing. Now the average patient is not necessarily that way, but I do think that clearly patients who are on treatment, they tend to tolerate it reasonably well.

The one advice I give to all of your audience, I think in the US this is a fact, but I don't know if it's uniform, it is very critical to actually go through specialty pharmacy to actually make sure there are no drug interactions, because as we go through this process, and again, I don't know, this is available, let's say in rural areas, smaller cities and things of that sort, because there is a real drug interaction. And all of these men are on blood pressure medication, diabetes medication, clotting medications and things of that sort and the safety has to happen first.

The other good news is this, no one with this situation is going to die tomorrow, so there's no urgency in starting the treatment this month until you go, let's say through the process of screening, making sure that all the checkmarks are checked, that it's okay and safe to provide to the patients.

Alicia Morgans: Absolutely. And do you think about similar things I would imagine, or what other considerations do you have?

Celestia Higano: Yeah. The same things, the comorbidities that we have to consider before we go in that direction. But I do think although in the trial data, these drugs seem to be pretty well tolerated. I think we've all had the experience where we've treated a patient who came back three months after starting and refused to take the drug anymore.

Alicia Morgans: Yeah.

Celestia Higano: And that was one of the things I was trying to allude to in my discussion, which is it would be ideal if there were some pharmacogenomics markers, perhaps a drug metabolism that we could understand who that patient is. Because anecdotally, some of our colleagues will tell us they have the same experience and some of the patients who experienced that level of toxicity, don't necessarily regain their former selves after stopping the drug. I just think we're at a point where we still have a lot to learn.

Alicia Morgans: I agree. And I think one of the learning points that we actually did not touch on today is, how do you monitor these patients in terms of imaging? Actually, that was alluded to in some other talks. I think William Oh did a really nice talk in the metastatic setting, thinking about there's really not clear guidance. What is your practice for imaging these patients, because if you do start them on this therapy, typically they are going to have a PSA that goes down. What is your thought? Do you think about it the way that you think about metastatic disease for example, or how do you approach it? What do you think Maha?

Maha Hussain: I think I am mindful of not increasing cost to patients.

Alicia Morgans: Yeah.

Maha Hussain: And the only time where I would consider imaging is if I begin to be concerned about something going on. I think that the PSA is a flag, but it's not the only flag. You evaluate a patient and you think there's something not right going on, I think that would be one indication to make sure that it's not the cancer that's causing the problem. Clearly, if the PSA goes up. One of the issues, I think it depends on what kind of imaging is available.

Part of it would be for patients who, let's say, have very low PSA levels, the odds of conventional imaging showing something is very low. This is where we would consider doing, for example, the Axumin PET for these patients. The flip side would be, you get a major shift in the number and I would want to caution the audience also, do not react to one PSA value.

Alicia Morgans: Yeah, agree.

Maha Hussain: I think it's very critical to confirm that in fact, whatever is occurring is verified, and I don't think waiting a month to repeat the PSA to see that the trend is real, before you act on it. Again, you have to use your sort of clinical judgment as to what would be appropriate from there. But the other thing in terms of monitoring, I wanted to highlight that it isn't just about imaging, it's about the totality of the individual. Generally, I usually when I start, just about everybody, I bring them back in a month, just to see how they're tolerating things. Are there any collateral issues occurring? Is the blood pressure going... Usually they're hypertensive, I tell them to monitor their blood pressures, at least two or three values a day, and bring those with them to the clinic so I can see it and see what's going on and things of that sort, just to make sure that there is some safety boundary that you're abiding by, and then space out the visits accordingly afterwards.

Alicia Morgans: Absolutely. What do you think about... And then the other thing I wanted to know from you Dr. Higano, because I imagine, that's very similar to my practice, if not exactly mirroring it. And I bet yours is very similar.

Celestia Higano: Yes.

Alicia Morgans: Yes, that's true, of course. But the question I have for you, Tia, is more around diagnosis. And so sometimes... I think it's less than in the US, but certainly internationally, people will have negative conventional imaging and a positive PSMA or Axumin PET. What is your thought about that disease setting and I think we recognize, and I'm sure patients must recognize that this is a continuum, but in terms of the indication and using these drugs, what do you think about that situation, negative conventional imaging, positive molecular imaging?

Celestia Higano: Well, I would say first of all, in the setting of negative conventional imaging in patients who usually had prior therapy, treated with ADT and now are in this setting, I mean, honestly, we know that most of those people have metastatic disease, even though it didn't show up in the conventional imaging. I mean, so yes, it's nice that these molecular imaging techniques, I mean Axumin or PSMA PET, may be able to identify little areas that we couldn't see on conventional imaging. But, it's not surprising when we find something. It's probably the surprise when we don't find something, in a way, I do think that going forward, we will hopefully have some clinical trials with molecular imaging that will help us figure out, "Well, maybe this guy, we wouldn't need to add these drugs right now. Maybe we can, so call, salvage them with directed therapies. It may be SBRT, or who knows what, surgery. I mean there's all kinds of things that could come into play.

There are times when I consider doing those imaging studies, in addition to traditional imaging because I do them together. That's a little bit maybe different from some of our colleagues where PSMA PET is so available outside the US. The reason I do it is because I know from many years of practice, how I interpret a negative imaging. But if I just see the PSMA PET results in the absence of that imaging, I mean you can get kind of freaked out and, "Oh my God, look at all these." But the thing is, if you know that's in the context of negative traditional imaging, you can balance that and interpret it and react to that in a lot more sensible way.

I worry that the absence of conventional imaging to balance the PSMA PET results could be problematic. But I think the paper that we talked about in this meeting quite a bit, that's about ready to be published, that was a multi-institutional PET imaging study in nonmetastatic disease. I mean, I think that they're suggesting that we'll learn a lot going forward by doing some of these trials, but it probably is going to require pairing conventional imaging with PSMA PET, in nonmetastatic disease.

Alicia Morgans: I agree. I don't think you can do that. You can answer the questions without the traditional imaging-

Celestia Higano: Yeah, exactly.

Alicia Morgans: ... with all the trials based on traditional imaging. You have to benchmark against something.

Celestia Higano: Well, and that's the other thing that people keep forgetting. I mean we have all of these Phase III trials have been done with regulation bone scan and CAT scans, and we still got these great results, right?

Alicia Morgans: That's why actually, if I have negative traditional imaging, if the patient's actually already had salvage radiation and we're assuming that that's actually happened-

Celestia Higano: Yeah, exactly. 

Alicia Morgans: ... in a prostatectomy patient, I don't necessarily need Axumin scan at that point.

Celestia Higano: Oh, no, no.

Alicia Morgans: I would say that that patient is negative by traditional imaging, if I want to treat. But sometimes they can be very helpful, just like you said, if you are able to target a certain lymph node.

Celestia Higano: Right. But I mean, I would say in that case, if the PSA doubling time is rapid, in that high-risk group, I mean, what's a PET Axumin scan going to tell you?

Alicia Morgans: What is it adding? Yeah.

Celestia Higano: I mean, you want to treat those people right now, I would think.

Alicia Morgans: Yes.

Celestia Higano: Where it's the slow PSA doubling time guys, I think where-

Alicia Morgans: Yeah, right. It might be useful.

Celestia Higano: ... the molecular imaging might be useful and maybe delay the need for using these other drugs.

Alicia Morgans: It's the same here.

Maha Hussain: This is actually what I do, is these people who have a slow doubling time because then, if you identify something, I usually, I don't feel agnostic about... I'm not a believer. I feel like it's our obligation to prove what it is that we're dealing with, because you don't want to subject people to toxicities. And there are times where we actually see something on Axumin PET where I isolate the lesion. I actually try to biopsy it partly because maybe, just maybe, if you kind of nail it with some radiation, you can leave the patient without treatment for a period of time. At the end of the day, they may need treatment, but this provides them what I call a honeymoon period, where they don't have to be treated, aside from their hormone treatment.

Alicia Morgans: Absolutely. Well, I really appreciate your time.

Celestia Higano: Well, you're welcome.

Alicia Morgans: Thank you so much for coming and chatting with me today.

Maha Hussain: Thank you.

Celestia Higano: My pleasure.

Maha Hussain: Thank you. It was a pleasure.