NCCN Guidelines Updated for Prostate Cancer M1 Systemic Therapy Based Upon The CARD Trial - Tanya Dorff

January 18, 2021

Tanya Dorff joins Alicia Morgans discussing recent updates to the NCCN guidelines for systemic therapies in the treatment of M1 prostate cancer.  The CARD trial was a multicenter, randomized, open-label study that enrolled men with metastatic castration-resistant prostate cancer (mCRPC) between 2015 and 2018. Patients were eligible if they had evidence of symptomatic progressive disease within 12 months of prior androgen receptor-targeted agent (ARTA), before or after prior docetaxel. Dr. Dorff notes that the majority of patients receiving cabazitaxel experienced pain palliation at a deeper level and for a longer time than the patients experienced on their second line of AR-targeted therapy.  
Both physicians emphasized a key takeaway from the CARD trial, also demonstrated in the PROfound Study, that back to back AR-targeted therapy, even if separated by docetaxel lacks a durable response.    In terms of the CARD trial, Drs. Dorff and Morgans review the survival advantage and the quality of life benefits in as real-world implications in clinical practice impact on elderly, comorbid men who benefit from cabazitaxel as it is both well-tolerated and improved pain progression.   


Tanya Barauskas Dorff, MD., is an associate clinical professor in the Department of Medical Oncology & Therapeutics Research and serves as head of the genitourinary cancers program at City of Hope. She is an internationally recognized leader in prostate cancer and is renowned for her work in other genitourinary tumor types, including kidney, bladder, and penile cancer. City of Hope Comprehensive Cancer Center, Duarte, CA

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi. My name is Alicia Morgans, and I am a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today, a friend and colleague, Dr. Tanya Dorff, who is the GU Division Chief at City of Hope and an Associate Professor of Medicine. Thank you so much for being here to talk with me today, Dr. Dorff.

Tanya Dorff: Great to see you.

Alicia Morgans: Wonderful. So I wanted to speak with you a little bit about the NCCN guidelines and relatively recent updates in those guidelines related to the use of cabazitaxel in a third-line setting per the CARD trial. And you certainly are a member of the NCCN Guideline Committee, and I would love to hear your thoughts on that. Can you tell us a little bit about the CARD trial and how it was designed, and what it ultimately showed?

Tanya Dorff: Sure. The CARD trial was examining the role of cabazitaxel in men with metastatic castrate-resistant prostate cancer who had already been treated with docetaxel and abiraterone or enzalutamide. So it was a randomized trial. Patients were randomized to receive either cabazitaxel at the standard, FDA-approved dose of 25 mg per meter squared dose every three weeks or the other AR-targeted agent that they hadn't yet received.

So, this showed a very strong survival advantage for cabazitaxel, which kind of fits with PROfound data as well, showing that a second AR-targeted therapy after one has already become resistant to the other, tends to just not be very successful.

There were some unique aspects of the CARD trial that I think go under-recognized. One was that this wasn't your everyday prostate cancer population. The majority of patients coming onto the trial had progressed with symptomatic, progressive disease. And, so, they were able to look at pain palliation, in part, because of that. But I think we have a whole slew of different kinds of prostate cancer patients. And it's important to take that piece in context when you're looking at the patient in front of you.

Alicia Morgans: Absolutely. But I think, to your point, it's really important for us to recognize as a field, as the NCCN guidelines recognize too, that this back-to-back AR-targeted approach, even if separated, perhaps by chemotherapy, between lines of AR-targeted agents, does not seem to be effective. And it was really interesting, I thought, in the CARD trial, as you said, also in the PROfound trial, that these active agents would be superior, actually, in both of those settings, to that second AR-targeted agent.

In the case of the CARD trial, it was cabazitaxel, importantly at the 25 mg/m2 dose, with these patients all getting Neulasta®, having that radiographic progression-free and overall survival benefit, as compared to that AR-targeted agent.

So, one of the things that I do in clinical practice is, of course, you look at the literature as it is, look at those studies as they are, and, of course, think about the NCCN guidelines, and then try to implement them in practice. And, in some cases, actually in cabazitaxel's case, similar to the guidelines, I think about using either a 25 mg/m2 dose or a 20 mg/m2 dose. In my case, I actually tend to use both of those with Neulasta®.

But I'm wondering what your thoughts are on that because the CARD data did use a 25 mg/m2 dose. It seemed to be quite tolerable for those patients, but I generally tend to actually to use the 20 mg/m2 dose. What are your thoughts?

Tanya Dorff: Yeah, I think it's a real challenge. When the cabazitaxel TROPIC data were first presented, I think a number of us were struck by the very high rates of diarrhea and febrile neutropenia. And, so, when PROSELICA came out, showing similar effectiveness of 20 mg/m2, many of us adopted that, and there was a hope that we wouldn't need growth factor support.

But, like you, I worry many of my patients have had extensive radiation. They're older with comorbidities. And now with the era of COVID too, just wanting to protect the immune system. So, that particular cost-benefit maybe hasn't panned out as much. I think a lot of us still use G-CSF with the 20/m2.

But I think it's important to see that the 25/m2 dose is actually well-tolerated. Once we started using it in practice after the initial TROPIC presentation, I think many of us were pleasantly surprised that the numbers on the screen didn't match necessarily what we saw in practice and that patients actually tolerate it quite well. We've had some patients who can stay on it for a year-and-a-half or two years continuously, which really speaks to some tolerability.

So, to see the CARD data with the 25/m2 dose, we know that that induces a higher rate of PSA responses from PROSELICA, and to see it well-tolerated and showing a survival advantage maybe is going to shift more of us back to trying to use that dose, in the more robust patients where we think they can tolerate it.

Alicia Morgans: I agree. And certainly for younger patients and in patients that I start at 20 who tolerate well, I'll often go back up to the 25 mg/m2 dose, but I do think it was encouraging, at least, in the CARD trial, that patients did not seem to discontinue treatment at very high rates, did seem to tolerate it, and seemed to benefit, at least as compared to the other arm that second AR-targeted agent.

One of the other things, and you alluded to this, that I always think about in terms of the real-world implications of the use any of the drugs we have for prostate cancer, is how these drugs are going to be used or useful in certain populations, particularly patients who are elderly, who have comorbidities. Has your experience been generally that those patients could tolerate cabazitaxel, or what are your thoughts on that?

Tanya Dorff: I think we always have to have that gut instinct and that art of medicine when we look at a patient. But, in general, I would say that even my more elderly and comorbid patients have tolerated it fairly well, and I've been impressed by the sorts of responses that we get. So I think definitely one has to look at bone marrow reserve, both in terms of what are the CBC numbers at present and how much radiation has the marrow received over time? But I think we might be a little more cautious than we need to be, perhaps. And I like your strategy of, if you start at 20, and they're sailing through, then consider that bump up, since there might be just slightly greater efficacy.

Alicia Morgans: Absolutely. And one more thing before we get your general sense or your final thoughts on this. I'm just curious. You mentioned that pain progression outcome or pain control outcome that was assessed in the CARD trial, which, I agree, is actually, I think, such an important endpoint and a really important endpoint if you're a patient who's entering the clinic with pain to begin with. And, like you said, a fair number of those patients actually met inclusion criteria because their progression of disease was pain progression, which indicates, of course, patients who are really suffering from their prostate cancer and, in many cases, a very aggressive prostate cancer.

So, can you comment at all on that endpoint, that pain progression endpoint, that seemed to be better for patients treated with cabazitaxel then the second AR-targeted agent?

Tanya Dorff: Yes. I mean, there was clear superiority. I think the majority had some pain palliation with cabazitaxel. I don't remember the number off-hand. It wasn't zero for the other AR-targeted agent, which I also found very interesting. However, it was undoubtedly much shorter-lived. So, it's not that we get zero responses with the second AR-targeted agent. We get some, but they just tend to be not as deep and not as lasting. So I think the pain palliation from the cabazitaxel in the CARD trial really is impressive and speaks to that dual goal that we have for our advanced prostate cancer patients of not only helping them live longer but being able to tell them that we think you'll live better, your quality of life may be improved by palliating the pain in a way that doesn't only involve pain medication. So I think it's a meaningful thing to talk to patients about. Sometimes they look at the survival numbers and say, "Oh, you know, they only gained a couple of months. What does that mean?" But there's that second impact of maybe alleviating the pain, which is very significant.

Alicia Morgans: I agree. And I think also really pertinent when you're thinking about that cost-benefit ratio, and people do have sometimes some fears of chemotherapy. By the time people get to cabazitaxel, they often have already been, or should have already been exposed to docetaxel, so have some sense. But cabazitaxel seems to be actually, in some cases, better tolerated even than docetaxel. And then there also is this potential for pain palliation. So, I think usually in the patients that I talk to, certainly worth that risk-benefit, in favor of taking the cabazitaxel.

So, as you think about this in your general practice, and you continue to advise on the NCCN panel, of course, what are your final thoughts on the CARD data, thinking about cabazitaxel in that third-line setting, for metastatic CRPC?

Tanya Dorff: So, it's been funny over my career to watch the waxing and waning of chemotherapy in prostate cancer. There had long been this thinking out there somewhere that chemotherapy didn't work for prostate cancer, even after docetaxel got approved in 2004. And then I think CHAARTED really brought back to mind how powerful chemotherapy could be in this disease.

And now the CARD data, again, really speak to the importance of chemotherapy. As the cancer becomes more resistant, it becomes maybe more amenable to the benefits of chemotherapy. And, so, using it in that third-line space, while patients can tolerate it, while their marrow still has reserve, and while we know there'll be not only survival prolongation but also pain palliation, is a really important thing for us to be thinking about. We do have a lot of tools, but these are really strong level one evidence data that suggests that this is a very, very good tool and one that's tolerable to patients.

Alicia Morgans: Great. Well, thank you for sharing your expertise and for lending some of your clinical experience. I think that all of us can use this once in a while, getting together with colleagues and friends, just to think through the data and how we would best implement that in our practice. I appreciate your time.

Tanya Dorff: Thanks so much.