Effect of cabazitaxel vs abiraterone or enzalutamide on patient-reported outcomes in mCRPC: A pre-planned EQ-5D-5L analysis of the CARD study - Neal Shore

Neal Shore, MD, FACS joins Alicia Morgans, MD, MPH to discuss the outcomes of the CARD trial, Cabazitaxel Versus the Switch to Alternative AR-targeted Agent (Enzalutamide or Abiraterone) in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients Previously Treated With Docetaxel and Who Rapidly Failed a Prior AR-targeted Agent (CARD) in a recent analysis presented at the AUA 2020 Virtual meeting. A phase IV trial that randomized patients with evidence of progressive disease within 12 months of prior androgen receptor-targeted therapy, before or after prior docetaxel, to cabazitaxel versus abiraterone or enzalutamide with a primary endpoint of radiographic progression-free survival (rPFS).  CARD met its primary objective; cabazitaxel more than doubled rPFS vs abiraterone or enzalutamide.  Further, cabazitaxel reduced the risk of death by 36% vs abiraterone or enzalutamide.  Cabazitaxel also improved pain, time to pain progression, time to SSEs.  The safety profile of cabazitaxel was manageable, with 3% of patients developing febrile neutropenia. Also, changes in VAS and utility score of EQ-5D-5L numerically favored cabazitaxel and the results support the use of cabazitaxel over abiraterone or enzalutamide as a standard of care in patients previously treated with docetaxel who progressed within 12 months with the alternative ARi. In their consideration of patients' response to the treatment, Dr. Morgans and Dr. Shore also highlight the positive outcomes of patients who received cabazitaxel outside of the CARD trial, referencing forthcoming real-world data from multiple international centers.


Neal Shore, MD, FACS, is the Medical Director of the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina

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, I'm 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. Neal Shore, who is the Director of the Carolina Urologic Research Center in South Carolina. Thank you so much for being here with me today, Dr. Shore.

Neal Shore: Great. Thank you, Alicia. Great to be with you.

Alicia Morgans: Wonderful. So, I wanted to talk with you a little bit about the CARD trial, which was a recently reported Phase IV trial looking at cabazitaxel in the third-line setting as compared to patients who were treated with a second AR targeted therapy after being treated with both docetaxel chemotherapy in the past as well as an AR targeted therapy in the past, and really to sort of dig into the quality of life data that has been recently reported. Can you talk to us a little bit about the CARD trial and what your thoughts are on some of the quality of life implications?

Neal Shore: Yeah. No, I'd love to. I've been prescribing taxane-based therapy for over 10 years, starting with docetaxel and then with the approval of cabazitaxel for docetaxel progressors, I think it was 2012, the TROPIC trial. And so, that's really been a standard of care for docetaxel progressors, as certainly a very appropriate option whether it's second- or third-line. The New England article, first author, Ron [inaudible 00:01:25] in 255 patients, and you've summarized it, how they were randomized to basically cabazitaxel or either abi or enza. All of the patients in the study had received one NHA or androgen receptor drug therapy being primarily abi or enza, as well as having received docetaxel. What was really, in a 255 patient study, the data clearly demonstrated statistical significance in radiographic progression-free survival benefit for those who got cabazi versus abi or enza up approximately four months, and also survival benefit.

And so, some folks may say, "Well, I'm sequencing, it's an oral, let me just go to another oral," but here are the rPFS data, the overall survival data, is statistically significant and that's why it was a New England Journal article with just 255 patients. So, hats off to all of those investigators who did a really great job in doing that. What you're alluding to today, which is really some very nice work that was published by Gero Kramer and others in the CARD study, was presented at ASCO and at AUA. And essentially showed that there was, looking at the EQ-5D-5L questionnaire and the visual analog scale, that not only did patients have really marked improvement in delay to pain and pain progression. But when you look at the EQ-5D-5L parameters, which are levels of wellbeing and functional wellbeing and anxiety, it was all markedly in favor of the patients who received cabazi versus sequencing abi to enza or enza to abi.

Additionally, there was a delay in symptomatic skeletal events for these patients. There were no new safety signals, in fact, there were a little bit more adverse events in the androgen receptor antagonist arm in terms of cardiovascular events. As you'd expect, there's a little bit more on the neutropenia side for cabazi. Of note, the patients in the study all got the highest dose of cabazi, the 25 milligrams per meter square. Many of us based upon our earlier data, we are comfortable using the 20 milligrams per meter square, and you see a better safety tolerability profile, so I really command Gero Kramer and others who were part of it, Doctors Fizazi, [inaudible 00:04:09], a lot of folks who were a part of this study.

And so I think it's important, and if I could summarize your question and I thank you for asking me, is this whole sequencing thing of abi/enza, enza/abi, this trial and as well as other work, nice work done by Kim Chi and the PLATO trial recent work and the PROfound trial, clearly tells me that, yes, we can talk about anecdotal examples of someone benefiting from the sequencing of oral, and we all have had that experience, it's anecdotal but the real data speaks for itself. And I think again, I really commend the folks who did the CARD trial, and now this follow-up demonstration of safety and tolerability benefit.

Alicia Morgans: I agree. And one of the things I thought was most compelling was that, and this was actually, some of this data was reported at GU ASCO 2020, was that the time to pain progression was also prolonged with treatment with cabazitaxel. And just to emphasize the importance of the EQ-5D, this assessment or analysis can actually be converted into something called QALYs, Quality-Adjusted Life Years, and that helps us understand what the value of that benefit is. Because we do have a conversion for QALS into dollar amounts, whether they're in the UK or whether they're in the U.S., you can convert these into dollar amounts and then really understand what the financial implications of this are. But what was so interesting is that at every time point, really the QALYs were better with patients treated with cabazitaxel.

And as you mentioned, this was cabazitaxel at a higher dose than we often use in the U.S., a dose that may have higher complication rates, and may have more symptomatic rates if we talk to a patient. But at the lower dose, we see similar effects in terms of ensuring the survival benefit at least. And if the patient is tolerating it better, it actually may be a bigger bang for your buck, for your actual buck as measured by QALYs, which is really, really interesting. So I'm wondering, in your practice, does this come into conversation? Does this come into play when you're making treatment decisions that patients actually say that their quality of life is better, even though when you're having that conversation with a patient, the patient may say, "Well, it's chemotherapy, there's no way that could be better?"

Neal Shore: So yeah, I think that is a pivotal conversation, and I love the way you also, getting back to this issue of how you can do that conversion of the safety tolerability of prospective data to the QALYs. And that really translates to economic benefit, because if you have a diminution in pain progression, time to pain, other complications that lead to emergency department visits and hospitalization, that is what we now call under the umbrella of health economic outcome reporting. And so, I'm very aware of that, and we as providers in all specialties of cancer care should be thinking about this. As it relates to patients, you're spot on in that I do talk to my patients and I say, "Look, this may be a second- or third-line treatment for you now, the diseases progressing." We all have this conversation, we know it's inevitable. And then you bring up this word chemotherapy, and a lot of folks bristle. They bristle because of other things that they may have heard or other disease states and friends or relatives who've had bad experiences.

And what's really kind of remarkable to me, and now that we have this data, that I'm able to say to them, "But no, I'm going to tell you that, yes, it's chemotherapy and yes, it's going to be an intravenous administration, but I can tell you that I'm going to delay your onset of pain, I'm going to delay the time to pain progression, symptomatic skeletal events, and this is going to really improve the quality of your life under that general rubric."

And so, I also tell patients if they've had prior docetaxel and now they're getting cabazitaxel, there's less alopecia, there's less risk of neuropathy. And it really comes, I think for clinicians, whether it's medical oncologists, urologists, radiation oncologist, to be really very forthright and have this patient-physician shared discussion and say, "Yeah, it may seem easier to just take a pill, but we've got data now, prospectively acquired in this really well and nicely designed study." And now the follow-up information that's been presented to say, "No, you'll actually do better." And so, that's, that's the conversation that I have with my patients and I think patients really respect that actually and they see that there's a benefit for them.

Alicia Morgans: I agree. And I think for folks who want to dig deeper into this analysis, it was presented at the AUA Virtual Meeting this year. And interestingly and importantly, there was also a recent publication of patients treated in the real world. And I think that's so important to you and to me, as we take care of people who don't necessarily fit the absolute inclusion or exclusion criteria on a clinical trial. These patients treated in the real world also had an improvement in the quality of life and also had an improvement in terms of their pain, which when I talk to patients, one of the things that they are most afraid of is actually the pain that they'll have to endure when they think about advanced or progressive prostate cancer. So this real-world analysis that also demonstrated those benefits, I think is really powerful in those conversations with patients. What is your thought?

Neal Shore: Yeah, no, I think that's a very nice paper that you're referencing. I believe it's currently or about to be published in the Clinical Genitourinary Cancer, or CGU, as I tend to call it, Joe Lee is the first author and Nicholas Moore is the senior author on it. And you're right. It's a very nice real-world prospective look at patients in multiple centers in France and how they responded to the use of cabazitaxel in quality of life metrics and pain, and it really recapitulates what Gero Kramer presented recently now at AUA. So, I think those are always important papers and studies when there's some correlation with real-world data.

And that gets back to the question you asked me, and that's why I feel very comfortable in explaining that to patients. And then when you see those results and, and, and you see them have not only a diminution of any existing pain or prevention of pain, but also that you see other things too, when the tumor burden comes down, the PSA comes down, their energy level oftentimes can be improved, and their inanition and cachexia. I mean, I don't want to completely minimize it, but I mean all of our mCRPC drugs have side effects and things that we need to be cognizant of. But I think for now, and the basis of all of your questions is, we really want to optimize the sequencing and I think this data really speaks very nicely to it.

Alicia Morgans: I agree. So, as I talk patients, I always emphasize that this is not a contract, you're not buying into 10 cycles in the mCRPC setting of cabazitaxel, you are buying into cycle by cycle, and you tell me if you feel better. And actually I've had very, very few patients tell me that they think that it's better to stop the chemotherapy. And a majority of patients have actually told me, "I'm surprised, doc, but I actually feel better."

And when I see the PSA is going down and I see that things seem to be at least stable, if not shrinking on CTs, and improvements on bone scans or at least stable bone scans, I really do see the benefit. And I'm grateful for the CARD data for demonstrating that in a population in this Phase IV setting, as well as the real-world quality of life data and the data presented at the AUA as well as GU ASCO, that say that patients actually report not just in my clinic, but they report more broadly that they do feel better. So, if you were going to sum this up, Dr. Shore, what would you say your final message would be on cabazitaxel in this setting in terms of the quality of life implications?

Neal Shore: So, thank you, Alicia. I would say that this is a very effective therapy. It was approved on the basis of docetaxel progression and now we see that it clearly has benefit, not just for simply docetaxel progression, but also docetaxel plus one of the oral androgen receptor access drugs. And it's really beneficial to then place this in that sequencing paradigm as opposed to just going to another oral androgen receptor antagonist therapy that might seem simpler, pills, capsules daily, but on a systemic basis, this clearly has value and benefit. It's overall, the quality of life metrics as we've talked about today are enhanced as opposed to sequencing to another oral, that there's a delay in pain progression, delay in pain. The overall quality of life is achieved. Oh, and not to mention rPFS and OS, [inaudible 00:14:13] important components. So clearly, this is the discussion that I have, I think that it's now been recapitulated in real-world data, you and I have had this same experience as many of our other colleagues. The same goal is to optimize patient care, and that's where I think it's really important that our colleagues understand this.

Alicia Morgans: I completely agree. And I think that better disease control most likely results in a better quality of life. And when we use drugs that are less effective, or perhaps are not effective when we use them in a follow-up setting, we will find that they are not going to improve quality of life, which is what we would actually expect. And this has measured it and has proven it, I think at least in these settings. So thank you so much for your time and your expertise, I really appreciate it. 

Neal Shore: My pleasure. Thank you.