Patient Characteristics to Consider for Doublet, Triplet Therapy in mHSPC and mCRPC

In the second segment of this roundtable discussion, David Morris, MD, FACS; John Phillips, MD; Jeremy McDuffie, MD; Katy Beckermann, MD, PhD; and Alan Tan, MD, discuss key considerations for patient selection in doublet and triplet therapies for metastatic hormone-sensitive and castration-resistant prostate cancer. The panel examines pivotal factors such as disease volume, comorbidities, treatment tolerability, and the impact of chemotherapy on future treatment options. Other topics include practical approaches to tailoring care for diverse patient populations, including those in rural settings, and balancing efficacy and quality of life in advanced prostate cancer management.

Watch the third segment of this roundtable series: Treatment Considerations After New Data: ARASENS, ARANOTE, and PEACE-3

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Dr. Morris:
I guess the opposite end of the lower volume grayer area, someone clearly, you mentioned really elevated PSAs, PSAs in the hundred range with multiple bony lesions, God forbid a visceral liver lesion. We’re then left with this conundrum of how aggressively to treat that patient. And kind of walk me through your guys’ decision about, you mentioned doublet therapies and triplet therapies. What’s kind of your line in the sand for someone you might encourage to consider triplet therapy versus doublet therapy? Is there, I’m checking these few boxes to say you fit enough of them that I would encourage that. What are those for you?

Dr. Tan:
Yeah, I think with abiraterone and docetaxel, really the benefit was mostly for high lung disease. So at that point it was more important to look at conventional imaging and see who is in that category. We don’t want to over-treat patients, but then the ARASENS trial actually showed significantly benefit in high-volume and low-volume. So I think that really changed the game for me as far as not having to look at high-volume and low-volume with darolutamide. So hazard ratios were very similar. When you look at high-volume and low-volume, I think both populations benefit really well.

Dr. Beckermann:
Yeah, I think it’s been interesting. I tend to also agree that I find the benefit to be in both high-volume and low volume. Both PEACE trial and ARASENS really have confirmed this.

It’s interesting in my practice I’ve offered it a lot, but I don’t find the uptake to be quite as high as I thought it would be. I mean, I really emphasize the overall survival benefit and the PSA90 reduction that we just saw presented at ESMO this last year correlating with almost doubling of people who got to PSA-undetectable by adding on chemotherapy.

But a lot of patients, understandably, they just don’t want it. They have their own reasons or that’s just not… It’s too much of a shock maybe in that initial discussion.

So I would say, I don’t know what everybody else thinks, but probably only about 50% of my patients after thorough conversation decide that they would want triple A therapy.

Dr. Morris:
And I would point out those are the patients that have already made their way to a medical oncology practice. There are many others that for whatever reason, throw up roadblocks that just that’s not something that they’re open to early.

And Dr. McDuffie, you practice in a more rural area than downtown urban Nashville, similar to myself further out in the community. What’s your experience? Is there a distinction there in terms of availability, socioeconomic or travel distances? What have you seen?

Dr. McDuffie:
I think that one of the major barriers is the patient population. We serve a older population with probably more medical comorbidities, and one of the biggest things that’s attractive to my patients is not being on something indefinitely, whether the side effects are the same. Once they tease out the data, they’re typically not interested in length of life or overall survival. They tend to be more interested in, “Doc, what’s my quality of life going to be? How often am I coming to the office?”

And what I find is if the uptick in these practices are 50% respectively, we’re probably much lower than that, probably a quarter, because most of my patients want to take chemotherapy, six rounds up front, get their benefit, their LHRH agonist therapy, and they’re not really interested in oral drugs in the upfront setting. So I actually find that when I try to bring in that novel anti-androgen, they’re pretty resistant to that.

Dr. Morris:
So you bring up a great point in terms of comorbidity and individual patient management, are there other specific factors for you from a patient side that you can just look at someone, docetaxel tends to be fairly mild as a monotherapy, even from a urologist perspective, we recognize that it has real benefits. I often feel like I’m treating chemo like it’s a four-letter word and trying to back people out of their preconceived notions.

But are there things that you would look at and say maybe not an ideal person for docetaxel on the front end besides frailty, or what would be those factors where you would look at somebody maybe I’m not going to encourage this as much versus I would?

Dr. Tan:
Right. Yeah, if they’re very frail in a wheelchair, I think doing a lead-in of a doublet and then having in the back of my mind that maybe was psycho… These patients have PSA90 reductions really quickly a lot of the times and they’re really impressed with, “My PSA came from 300 down to 10 and just what, six weeks?” And it actually happens and it’s very predictable. So that happens more times than not.

And then by the time they’re at six or eight weeks later, they’re probably in a better shape to do chemo. I’ve actually done that with a recent eighty-year-old gentleman and you don’t have to give them 75 milligrams per meter squared of docetaxel. You may try 50 megs per meter squared and they might derive some benefit as well.

And why would I push an eighty-year-old to get that? So maybe I did have the luxury of having some biomarkers available.

I did have a TP-53 and RB1 loss, so I told them the long game was to try to delay the chance that you’re going to have castrate resistance. And he saw that as a valuable, him along with his daughters and his family, they thought, “Hey, if I could get another five years, I’d be really happy and if that would help me get there at a higher likelihood, I’m in for it.” So he’s still doing well, dose reduced docetaxel.

Dr. Morris:
Right. Dr. Beckermann, any specific patient characteristics push you to or away from?

Dr. Beckermann:
Yeah, I think what you all have both said is it’s more of a kind of performance status of multiple medical comorbidities. Often it’s an aged population, so it is a lot of my patients don’t come in fit enough maybe to get that triplet or I’m attempting kind of a lead-in maybe starting with docetaxel and then seeing how my PSA response is doing, recognizing that’s not how the trial was done.

Dr. Morris:
So it’s great… The time to CRPC is, it’s a newer metric that we’re seeing in some of the trials at least reporting, it’s a quality of life measure that it’s extending quality of life before you get to a disease state where things get more real.

Having chemotherapy given in the front line, does that change your next available options? Does it bring up something that opens the door for you later that you would not have if you had not already used chemotherapy? And I may be leading the discussion here, but does that play a role in your decision to potentially say this will let offer something else next that I might have a difficulty giving you if you’ve not already had chemotherapy? Does that ever come up with a patient to kind of at least mention it?

Dr. Tan:
Yeah, obviously I think knowing what you’re getting at, you could get radioligand therapy with lutetium and PSMA-617 as your next line of therapy. But ultimately if you have a fit patient that chemological, one way to discuss it with them is, “You’re probably going to get chemotherapy at some point in your sequencing. When you’re more fit, when you’re younger is probably a better time to get it. Then maybe when you’re in third, fourth line, maybe your bone marrow’s not going to tolerate that anymore.” And so I think once they hear it from that angle… But of course there’s some people that just are just refusing. You hear of somebody that had a friend that died from breast cancer treatment and it is hard to tell them the spectrum.

When I try to explain to patients, I say there’s a scale of chemotoxicity. Here is adriamycin and ifosfamide or something like that. And then docetaxel, so it’s kind of like a three or four in my opinion. There’s a single agent.

Dr. McDuffie:
Yeah. I think one thing to just kind of piggyback is something that was hit on earlier. We tend to see a very rural, very farm-oriented population. A lot of people play instruments and so one of the big drivers is neuropathy, neuropathy, neuropathy. And I actually have a similar conversation. You’ll never be as young as you are today to receive chemo.

And one of the things that I tend to do in my practice a lot is an old TAX 327 trial that looks at the different dosing schedules of docetaxel. So it’s 75 milligrams per meter squared versus 50 versus 25. And a lot of my frail older eighty-plus year old patients will settle on 25 milligrams per meter squared weekly.

Dr. McDuffie:
Yeah, so certainly because we’re dealing with a much more rural population, a lot of people play instruments. One of the number one factors is the side effect of neuropathy. And like was said earlier, the patient will never be as young as they are that day. So one of the conversations we have is the different dosing schedule from an old TAX 327 study of 75 milligrams per meter squared versus 50 milligrams per meter squared versus 25. And I find that in a lot of my octogenarians we settle on 25 milligrams per meter squared because we do reduce that neuropathy and they do quite well with that regimen.