Interpreting Data From the CARD Trial in Metastatic CRPC

Tanya Dorff, MD, and Elisabeth Heath, MD, FACP, review data from the CARD trial and discuss the nuanced selection and sequencing of treatment in metastatic CRPC.


Elisabeth Heath, MD, FACP: Earlier, you mentioned the CARD trial [NCT02485691], and where dosing is. Do you want to just describe what that study was and what your thoughts are on that?

Tanya Dorff, MD: It dovetails very nicely on our discussion. One of the things that jumped out at me most in the CARD trial was the number of patients who entered the trial with pain progression. So, this was an aggressive population of metastatic castration-resistant prostate cancer [mCRPC]. This was with patients who had prior docetaxel. They had to have had at least 3 cycles of docetaxel to enter. They also had to have been exposed to abiraterone or enzalutamide. But most studies have multiple inclusion criteria for progression to qualify. You can enter just because your PSA [prostate-specific antigen] is going up. You can enter if you have 2 new spots on your bone scan. But two-thirds of these patients entered with worsening pain. I think this just speaks to a population where we saw greater efficacy with cabazitaxel. The primary end point was radiographic progression-free survival. That’s commonly used in studies in this setting. And that was positive. It was double. It was 8 months vs 3.7 months for a second androgen receptor [AR]-targeted agent: abiraterone, if you had enzalutamide before; enzalutamide, if you had abiraterone before. But really, what was striking was the pain relief: 45% with the cabazitaxel vs 19% for a second [AR]-targeted agent. So, all the parameters really aligned in CARD. This really did influence my thinking and changed my practice when I saw this particular study. We had already started hearing a little bit about [how] going from abi [abiraterone] to enza [enzalutamide], or vice versa, is not the most effective strategy. This was one of the studies that really outlines that in a big way for me. If we want to think about objective responses, if we’re watching tumors grow sometimes down in the pelvis, having the response rate 37% vs 12% for the second hormonal agent, I think these can all be meaningful in different clinical scenarios. I think once physicians get comfortable with the safety profile, then they can point to data like you mentioned [in] FIRSTANA and just the tolerability. And then, there [are] even specific quality-of-life data that I think can be very helpful at telling someone who maybe isn’t ready to do more chemotherapy [that] that’s going to be their best choice at that moment. Did the CARD data impact your practice?

Elisabeth Heath, MD, FACP: I think [they] did. A lot helped with our communication with other providers in the community. Sometimes, because these are metastatic patients, and there’s so much expertise our urology colleagues are definitely still involved. Maybe they’re not the ones giving the chemotherapy, but a lot of these [patients] still have a lot of frequency or nocturia. We still have an active management plan with neurology. Before this trial happened, it was like…we gave a round of chemotherapy, OK, how would you like to send the person back and think about putting another oral agent on board? And this was a way to say, look at this data set and it’s not just all about responses where it really did help patients feel better. And I think being able to show that to not just [medical oncologists] but to the urology groups has really helped me explain why we’re doing what we’re doing. And then they say, “OK, that makes sense.” I think the study measured pain but they did pack quality-of-life measures, and really made that a focus, which I think was really helpful. In a way, our urology colleagues are very good at that because they look at things like they weigh score and whatever it is that relates to how patients are doing. They do, I think, appreciate that intentional “here’s the study, here are the numbers” approach. So, I think, in that sense, it’s been helpful.

Tanya Dorff, MD: It’s strange. You and I both seem aligned that these data were impactful. But there’s a real-world study presented at ASCO [American Society of Clinical Oncology] this year using the big database of health records. And it showed that treatment patterns didn’t change and that still the most common sequence of treatment is to go from one [AR] agent to another. I think it’s really remarkable how you’ve been able to engage with your urology colleagues who are really data-driven and care about how the patients are doing. I don’t know where else the gap is and why other people didn’t have more uptake on this. Maybe age? I don’t know. Some people really worry about elderly [patients] and frailty. That’s not necessarily exempted in a treatment with a drug like enzalutamide. Where you can see things like loss of muscle strength and falls.

Elisabeth Heath, MD, FACP: [Yes.]

Tanya Dorff, MD: Chemotherapy, we know, can be tough on patients. Cora Sternberg, MD, [NewYork-Presbyterian Weill Cornell Medical Center, New York, New York]did a very nice analysis of patients over 70 [years] vs under 70 [years]. I think maybe if these kinds of data get broader publicity, it can be helpful in overcoming a physician who’s saying, “I know I shouldn’t use abi after enza or vice versa.” But this guy’s 75 or 80 [years], he’s just not going to tolerate treatment with cabazitaxel. But the study really showed not only that the benefits that we’re seeing in these clinical trials were maintained in terms of response and survival, but that the toxicity was no greater. I think that can be a surprising piece of information for some folks.

Elisabeth Heath, MD, FACP: Don’t you think patients, though, have a say? They are weighing in more than ever. And they may just want to say, “I see what you’re saying and this has happened to me a few times.” It’s like, “I see what you’re saying. But I [have] got to go with the pill.” So, I think it’s a patient issue in terms of what he wants or just flexibility, and that they’re just tired of coming down to see us, whatever it is. It’s hard to factor that decision-making in with any of these studies.

Tanya Dorff, MD: That’s true.

Elisabeth Heath, MD, FACP: But I think it’s true. I think that’s what’s happening or is similar to what we’re seeing with all these great level 1 data in metastatic hormone-sensitive disease. And it was like the real world, big data set after big data set including one that we just did where the prescribing pattern was quite different between neurology and oncology. But a lot of it is just you wonder why, are we educating, like what’s going on? But we don’t take into account what the patient wants because there’s no little checkbox that was discussed and was declined; we don’t have that.

Tanya Dorff, MD: Absolutely, you’re right. I can think of patients whom I can talk [to] until I’m blue in the face and they’re like, “Nope, I’m just going to pass on that.” And that has to be OK, right? There’s patient autonomy, as long as we’ve done the job of educating and recommending. Don’t you wish we had a better way of selecting now that we do have more than 1 treatment choice? When a patient looks at me after I’ve talked about some of the options, and they say, “What’s going to work best for me?” I don’t really have a good answer. Hopefully, lots of people are working on this; it’s been a tough nut to crack. But there are some data that suggest the neutrophil-to-lymphocyte ratio can really predict someone who’s just not going to do well with a hormone agent like abiraterone or enzalutamide. I don’t know [whether] that’s something that you look at or [whether] there are any other biomarkers that you used, but let’s say that person wants to do the second [AR-targeted agent]. What would [you] tell them? That it’s really not going to work, and push them for the chemotherapy?

Elisabeth Heath, MD, FACP: I think it was Dewitt, was it last year, [who] said what you just said: sometimes-just AR-V7s [androgen receptor splice variant 7]. I know we haven’t talked about that for a while. That’s actually a test that a lot of patients bring up and I think that’s in the mainstream of a lot of the discussion groups that are out there online as a tool to say- what about this? So sometimes if they bring it up, they’re looking for something, I will check the V7 stems. I think depending on where you sequence or whether that’s a one-off, then you get just that test. It’s at least something to help guide them. I do think, though, once they made up their mind that they really don’t want to receive the chemotherapy, it’s really hard to get them out of that line of thinking.

Tanya Dorff, MD: Right. And they’ll know pretty quickly if you start on the AR- targeted drug.

Elisabeth Heath, MD, FACP: [Yes.]

Tanya Dorff, MD: And maybe they just need that breathing space and to feel heard, that you’ve taken their preferences and thought process into account.

Transcript edited for clarity.

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Michael A. Carducci, MD, professor of oncology, AEGON Professor of Prostate Cancer Research, Johns Hopkins Medicine
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Jeremie Calais, MD, MSc, assistant professor of nuclear medicine and theranostics, David Geffen School of Medicine, University of California, Los Angeles (UCLA), UCLA Health,
Tanya Dorff, MD, medical oncologist, associate clinical professor, Department of Medical Oncology & Therapeutics Research, City of Hope
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