Tanya Dorff: My pleasure. Good to be here.
Zachary Klaassen: So let's start off with just those initial discussions. You meet the family, you meet the patient, they've got a PSA, let's say it's 50 to 80. They're coming in, there's a lot to discuss. When do you start to instill those discussions of PSA response, how long it takes to get to those response, the depth of response? This is what patients can see. How do you address this in those first initial visits?
Tanya Dorff: Yeah, it's such a critical part of our everyday decision-making. And there's two ways I approach it. One is I talk about the importance of it and how it is our quickest, easiest way to gauge whether the cancer is growing or whether it's being controlled. I try to make sure they understand it's not like a one-to-one. This much PSA doesn't correspond to this much disease. It's imperfect and there can be fluctuations and things can go up before they go down.
But generally speaking, of course, it is a very valuable tool and I'm sure we'll get to some of the redundant data in mHSPC or APMN in the new terminology. Newly diagnosed patients, that PSA decline has been shown to be extremely prognostic. But at the same time, I do tell them that I'm always going to look at three things in my decision-making, the PSA, the patient, and the scans. That PSA, because it has its imperfections, can't be the only tool. It's an important tool, but it's just one of three pieces that we put together when we're trying to understand how a patient's doing on treatment.
Zachary Klaassen: Yeah, that's great background for our discussion. And I think too, I let off with the patients and see it. They can see these numbers when they log into their MyChart. They may not understand an image, they may not understand the nuances of quality of life and balancing that, but they can see their PSA. So I guess my next question may lead into how frequently are you checking it usually every three months in my practice, is there situations where you may check it more frequently? How are you starting off these patients?
Tanya Dorff: I definitely check PSA more frequently at the very beginning because patients are starting to experience treatment side effects. They've just been handed this diagnosis that is totally life altering. And as you said, they see that PSA. And so, early on, I think checking it at four to six weeks when we probably want to be checking how people are tolerating treatment and making adjustments to try to ensure that their body is receiving our treatment well.
So at that time, that drop in PSA can really also be helpful to close the circle. Okay, I got this diagnosis, I started on treatment. Treatment is working, I'm having side effects, but then that can all get put together into the patient's sense of where they are. So with certain drugs like abiraterone, you're bringing people in any way to monitor electrolytes, LFTs. So probably we're getting PSAs a little more frequently in that scenario as well. But certainly just in that first three month period, I'll see people at least once, sometimes twice, and check a PSA. And I think it's really helpful in just getting them comfortable and seeing that there is life after this diagnosis that the treatment can work. And then yeah, we go to usually the every 12-week schedule unless we're concerned about something.
Zachary Klaassen: Yeah, no, great background for that. I think you mentioned that deep PSA and foreshadow that depending on the study and there's been multiple post-hoc analyses 0.2, 0.02 and even some situations over a period, let's say 9 to 12 months, or some people have looked at anytime PSA deep responses, what situations are you looking at trying to drive their PSA down to that? Is there situations when it's not going down quick enough that you're getting concerned, maybe think about next lines of therapy?
Tanya Dorff: That's a great question. I mean, the data are what they are. They tell us that achieving that deep nadir is associated with better prognosis, but we don't really yet have any sort of prospective data to suggest that if we do something different in the guys who don't hit that target nadir by a certain time point that we improve things. And so, just now there are clinical trials in that space and I think those will be really critical. So for an example, TRIPLE-SWITCH, which is co-led by CCTG, the Canadian Clinical Trials Group and SWOG is looking at men who've started on doublet therapy and after 6 to 12 months, PSA nadir is not less than 0.2. So we know prognosis is inferior in that setting and then randomly assigning to start six doses of docetaxel or just continue because just continuing is what we would do now.
I mean, I think we all have those guys in our practice who don't get all the way down at 6 months, maybe by 12 months. And I think there's more for us to understand about what that means. But what's remarkable is the consistency across every major clinical trial in this disease setting, LATITUDE, STAMPEDE, TITAN, all of those ARASENS and all of them, that PSA nadir less than 0.2 and then even corroborated in real-world data sets, that Nadir marker is so profound. And you're right, people have looked at different cutoffs and different time points, but it gives us some framework. So helpful when the patient reaches that and you can say, look, we know that now you're on the better side of the survival curve, a little bit more troubling when it doesn't reach that. And yet I'm not super comfortable switching treatment yet. I think we need a little more data, especially I think surrounding what does a PET scan look like and can that really inform whether a change in treatment is needed?
Zachary Klaassen: Yeah, no, I'm glad you mentioned TRIPLE-SWITCH. It's one of my favorite trials that it's ongoing because I think it's going to inform that treatment intensification aspect and knowing from that post-hoc analysis you just mentioned nicely about that getting to that point too, and if you don't get there, is there a time where we can intensify? And along that same line is there may be patients that are exceptional responders or maybe thinking about de-escalating therapy trials in that space ongoing as well. How are you handling those patients within 6 months they do greater or even 3 months they get down to 0.2, how are you handling those patients currently and what trials are you looking for in that space?
Tanya Dorff: Yeah, I've always felt that six months is just not enough treatment. I really base it on a lot of what we learned in the perioperative, those neoadjuvant trials where you see that it takes quite a while to eliminate cancer even in the prostate primary and maybe you could argue we do better in the metastases than in the primary. So I'm happy with a quick drop in PSA if nadir's below 0.2 by three months, maybe that's great, but I'm not ready to think about treatment holiday or de-intensification by any means that early on. I think the question is an open one as to when we might be comfortable. We all recognize the limitations of SWOG-9346, which is the intermittent versus continuous study for metastatic prostate cancer that found that stopping and starting was not non-inferior to continuous. But obviously, we recognized that was in an age where we didn't have doublet, we didn't radiate the primary, many things we were doing differently. And so, the question deserves to be revisited.
So in my own practice, I do have patients who are on treatment holiday. I go through an extensive discussion about what we know, what we don't know. And the A-DREAM data that were presented at ASCO recently, I think, were very helpful. It's a small cohort, only 70, 75 patients, but what we saw from those data were you can take someone who's in a good remission, who's really struggling with quality of life because that is the reason to do a treatment holiday right now. There's no biologic cancer control reason. It's only about balancing cancer control and quality of life, but you can take those gentlemen and you can stop treatment. Many of them do recover testosterone, which was helpful to see because if you're having a holiday, you really want to reverse side effects and you're not going to reverse your side effects by and large without recovering testosterone.
And some of them were able to stay off treatment for at the early look, a year, two years. We need longer-term follow-up. We don't know what the impact is on cancer control over the long-term. And so, we always have to talk about those caveats, but it was nice to finally see some prospective, rigorously collected data showing that potentially someone in a good remission we can start to think about it. But I would really emphasize that it is for quality of life purposes. If you have those patients like I do some in my clinic who are just living their best life on doublet in a good remission, I don't see a compelling reason to offer those patients a treatment holiday.
Zachary Klaassen: Yeah, well said. And I think the A-DREAM, like you said, it gives us at least some inkling of that, okay, there's some potential rationale. And you're right, we have the patients that are just trying to get through it each treatment and they hit that point and we can maybe say, okay, treatment holiday potentially, but those guys are four years out, they're doing great. You just keep patting them on the back and saying, "Hey, this is working great. We're going to keep rolling with it." The last question I'd like to ask you is even when PSA is low, let's take those really good responders, how often are you still doing imaging in the excellent responders?
Tanya Dorff: That's a tough question. I'm curious what you're doing. I mean, prostate cancer working group initially laid out imaging every 12 weeks, but now that we have data with doublets where we know that median time to progression is close to three years, it feels like a lot of imaging to be doing it every 12 weeks during that honeymoon period. So my approach typically is to image at four to six months in, and then if everything's looking good on PSA at least once a year, sometimes twice a year, depending on how aggressive the cancer presentation was or the genomics or something else, that makes me a little more concerned, but at least once a year. And I have patients who are seven or eight years on their first-line doublet still in remission. Sometimes even that annual check-in becomes a challenge and yet we see these data that maybe 5%, maybe 10% of patients can have progression without PSA, but you see it on imaging.
And that actually happened recently with a patient of mine where it was really the prostate primary. He was eight or nine years on treatment, so we weren't radiating prostate primaries for metastatic patients back then and that's where the progression occurred and it was without PSA, which is really unusual. So I would also say if you're seeing progression without PSA, probably want a biopsy. But I'm curious from your perspective how often you think imaging should be done in this scenario.
Zachary Klaassen: I'm with you. I think once we get to that two to three-year point, they're doing well. I think annual, it's almost like the patients that I have in the kidney cancer realm where you've taken out their kidney and you're still doing annual imaging five or six years out. I say, "Hey, you had aggressive cancer, you still have metastatic prostate cancer that's responded very well." I'm in that same camp. I think once a year is always reasonable. I think we're aligned on that. I think it's a very interesting question because this is the real-world practice of taking care of advanced prostate cancer. It's not always going to be guideline specific and we're dealing with patients' travel schedules and their anxiety level high or low. And I think it's on us to be judicious, but also work with them too.
Tanya Dorff: I mean, anxiety level-wise, this new era where all of the scan reports are instantly released to patients and I do have patients who come in terrified about something they read in their scan report that they didn't understand thinking they have another kind of cancer or some major problem. So I do think we have to consider both the harms of the imaging potentially as well as the benefits and really be proactive about talking to our patients about what we expect to see, what the language of the scan might look like and all of that.
Zachary Klaassen: No, absolutely. Tanya, fantastic conversation. Anything we haven't hit on regarding PSA guiding therapy? Any take-home messages for our listeners?
Tanya Dorff: The one thing we didn't talk about is when it's rising and patients get really concerned and want to switch therapy. And I think most of us experienced clinicians have had that conversation a hundred times. Little rise in PSA doesn't necessarily mean the cancer's out of control and we need to jump to next line therapy. And really, all of our registrational trials for abiraterone for enzalutamide a decade ago, they kept patients on drug as long as imaging looked good if there was a little PSA rising.
So I think these days we have many different things we can do and we have PET scans, but I think that's just the other piece is we always want to see a trend. PSA can go up and then next time we check it could be back down. We see sometimes fluctuating patterns. So just talking patients through that, but really as clinicians reminding ourselves too that we don't need to race and change treatment every time PSA goes up, that we really need to establish a trend. We need to look at imaging, look at how the patient's doing it and make a fully informed decision.
Zachary Klaassen: Yeah, fantastic take-home point. Tanya, thanks so much as always for joining us on UroToday.
Tanya Dorff: My pleasure. Have a good evening.
Zachary Klaassen: Thank you.