Triplet Therapy vs. ADT: Choosing the Right Approach for Metastatic Prostate Cancer

In part four of this roundtable series, Dr. Appleman leads a panel discussion with Drs. Mehta, Kelly, Chablani, and Wong on the latest strategies for managing hormone-sensitive metastatic prostate cancer. The panel begins by exploring treatment options for de novo metastatic cases, delving into the nuances of selecting therapies based on patient factors such as disease volume, comorbidities, and genetic markers. They compare the effectiveness of ADT with triplet therapy (ADT + ARSI + docetaxel) and discuss practical considerations in balancing aggressive treatments with quality of life. The group also shares insights on PSA response as an indicator for treatment adjustment and when to consider chemotherapy.

Watch the fifth part of this series: Insights From ARANOTE and PEACE 3 Trials: Optimizing Prostate Cancer Treatment

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Dr. Appleman:
The next topic we’re going to talk about is systemic therapy for hormone-sensitive metastatic prostate cancer. And maybe we’ll start with the most aggressive form, the de novo metastatic hormone-sensitive disease. How do you all approach those cases in terms of selecting therapy?

Dr. Mehta:
Yes. So always I struggle in community when we are seeing variety, but whenever I see a de novo metastatic prostate cancer coming… I just saw a patient a week ago had a PSA-100, had a bony lesions, we get the PSMA PET, we get a visceral met. The way I can make a decision in community is high volume, low volume. And if it’s a high-volume disease, I tend to go more triplet therapy. And if it’s a low volume, then we still have to have a discussion with the patients. At that time, I’d look at the patient’s performance status, age and the clear understanding of the goals of treatment, but that’s how I start. But I’m very curious to know with all this data and pretty much every AR agonist, how you use this data to your patients.

Dr. Kelly:
Yeah. So we do something similar. I do something similar in my practice looking at high volume, looking at low-volume disease, the ARASENS data, the PS1 data, adding triplet therapy to ADT and ARSI, and adding Docetaxel to those patients. And those who are a low-volume disease really picking between the two. And similarly with regards to the ARASENS and PEACE, abiraterone, if they’re low volume, how are you picking between enzalutamide, apolutamide, abiraterone? Really then it’s talking to the patient side effect profile. Do you have a history of falls, seizures? I’m less likely to choose something like Enzalutamide.

I know we’re going to talk about some new data with hormone-sensitive and darolutamide and ADT, but really side effect profiles and discussions with the patients. Technically, ADT by itself is sometimes a consideration if you have someone with a lot of comorbidities. So I think it’s very, very, it’s about treating the patient in front of you is how I see it.

Dr. Appleman:
If we can just go around the room. What percentage of your patients with charted high-volume disease do you end up treating with Docetaxel in this setting?

Dr. Chablani:
I would say 30 to 40% I would treat with the triplet. The other patients I offer ADT plus ARSI alone because of age, comorbidities, they don’t want chemotherapy. They’d like to avoid it at all costs because of what they’ve heard about chemotherapy. And also we know from ARASENS, right, that it was ADT plus Darolutamde plus Docetaxel versus ADT plus Docetaxel. And there was an overall survival benefit with the triplet compared to ADT plus Docetaxel.

But we don’t have that trial of the triplet ADT plus ARSI plus Docetaxel compared to ADT plus ARSI. So we don’t know if the OS benefit is being driven by the ARSI alone. It’s very possible that it is or that the triplet is. There’s some sort of synergy there. But I think without a head-to-head trial of the triplet versus ADT plus ARSI, it’s hard for me to tell patients that you have to go for the triplet.

And if they’re young, if they’re in their 50s and they have metastatic de novo prostate cancer, and I’m worried and I really want to do everything I can to expand their overall survival if they have metastatic disease, but a low PSA that’s like, is there some bad tumor features here going on? Then I’ll add the triplet, high-volume disease, visceral mets, specifically liver mets, and then I also look at tumor NGS. So if they have two out of three mutations in tumor suppressor genes P-10, RB-1, TP-53, then I am suggesting, let’s go for the dose of this is maybe not bread and butter, prostate cancer, this is looking a little bit more aggressive. The biology is more scary.

Dr. Wong:
Yeah, I think I agree with the maybe 30 to 50% estimate, and I think part of that is driven by me and part of that is driven by the patient. As you said, a lot of patients don’t want to get chemotherapy. And there’s also a wide range, I think within high-volume disease, right? There’s patients who have visceral disease and then to have, what is it four or more bone lesions with one outside the axial skeleton. I think it’s very different for someone to have four lesions that fit that criteria versus a super scan on the bone scan. So I think within high-volume disease there is that degree of variation, too.

Dr. Appleman:
Yeah, I agree. It seems to perform very well. I was looking back this morning at the meta-analysis of STAMPEDE, CHAARTED, and GETUG, and they all showed that, but it’s still a pretty… that four metastasis with one outside the axial skeleton, It’s not like BRCA2, you have it or not. It’s a mechanistic black-and-white difference. We know that it’s a rough estimate that we’re aging and there’s going to be people who are going to perform differently than the cutoff.

And I agree that the people who are on the borderline that you might treat with chemotherapy or exactly what you mentioned, the young people with unfavorable factors that I might… even a few low volume people, technically low volume. For example, people with bulky lymphadenopathy, they weren’t really studied directly in those three studies as a separate group, but technically they’re low volume, but they have a lot of cancer in their body and maybe even though they’re going to probably do well with lymph node only, it seems like there’s a lot of cancer there to treat.

Dr. Chablani:
Yeah, and in the ARASENS trial, there was an OS benefit, even in the low volume subset. There was in the entire population, they looked at high volume, low volume, and there was an overall survival benefit. So it’s not wrong to do it, but yeah, you could potentially spare Docetaxel and we still know that ADT plus Aeroside backbone works very, very well for many patients.

Dr. Mehta:
And in terms of triple-A therapy, as I recall, there are data for two agents, as you know, RBPRED with Docetaxel and now Darolutamide. Because as we know Docetaxel can affect liver function tests, so do you tend to add there’s an agent by second cycle how we are using in the practice? Granted, we do have sometimes takes the time for payer to cover it and so forth. But all those things aside, are you try to add by second cycle, third cycle how you are approaching in your practice?

Dr. Kelly:
At least for me, when I meet them, I’m sending off authorizations for kind of everything. We have certain pharmacies that we work with that can get folks drug quickly. And then the decision between Abireta and Nubeqa or Darolutamide oftentimes is, do I trust you to come every two weeks for LFT checks for the first three months? Is that something that I think you’re going to do? It comes down to blood pressure, the mild leukeminias, a little bit of GI-upset and talking through them.

And it’s a lot of patient-centric decision-making. But oftentimes we are able to procure these drugs pretty quickly. I’ve gotten Abireta on Prednisone within a few days with a certain pharmacy and even Darolutamide we’re getting quite quickly. Similarly, with ADT, even if we’re going with something like Orgovix, Lupron, we can get quickly, Docetaxel, we can get quickly. But even Orgovix now we can procure pretty quickly. So I kind of get everything in tandem.

Dr. Appleman:
There’s some people where I will see how they do if they’re a little bit marginal in terms of their functional status. I may see how they do on enhanced ADT for… and I think in CHAARTED, they had up to 12 weeks to register. So I’ll see how they do the first couple months. And if I’m really worried about chemotherapy, I might even as to what Dr. Wong said about the SWOG studies with the PSA, I might, there’s not really data directly for this, but see if at three months their PSA is undetectable already, I may feel less of a need to add the Docetaxel in a marginal patient than if their PSA is only down by 50% at that point.

Dr. Chablani:
Yeah, I agree with that sort of an adaptive approach where you’re starting with the… in the majority of cases, if we’re making the commitment to go with triplet therapy like Dr. Kelly, just order it all and get started with whatever I can as soon as possible. But if they’re kind of on fence about the Docetaxel component, I can start with the ADT plus ARSI backbone. And I like to look at PSA, and again, the PSA of less than 0.2 at six months has been actually in all the registrational trials, ARCHES and TITAN and ARASENs and P-1 was shown to be associated with overall survival benefit.

So if they’re kind of, their PSA is going down a little sluggishly and they’re not getting to that 0.2 in three to six months, I think it’s reasonable if the patient is still motivated to think about adding the Docetaxel. So it can be done all at once or sort of a more adaptive approach, I think.