CARD Trial TE Articles

Articles

  • ASCO 2020: CARD: Overall Survival Analysis of Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel versus Abiraterone

    (UroToday.com) The CARD trial, initially presented at ESMO 2019 and subsequently published, addressed the question of appropriate third line therapy in mCRPC for patients who had previously received docetaxel and also progressed on an anti-androgen therapy (either abiraterone or enzalutamide) within 12 months. Patients meeting these criteria were randomized to cabazitaxel (25 mg/m2 every 3 weeks) or the alternative anti-androgen therapy. This study showed a statistically significant improvement in radiographic progression-free survival and overall survival in the cabazitaxel treated group.

    Published May 29, 2020
  • ASCO 2020: Efficacy and Safety in Older Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel versus Abiraterone or Enzalutamide in the CARD Study

    (UroToday.com) Prostate cancer is the 2nd and 3rd leading cause of cancer death in the USA and in Europe, respectively,1,2 with most deaths occurring in men over the age of 75. In men with metastatic castrate-resistant prostate cancer (mCRPC), there are multiple treatment options available today, but the most appropriate treatment sequence and its impact on elderly patients are still unknown.
    Published May 29, 2020
  • ASCO GU 2020: Pain Response and Health-Related Quality of Life Analysis in Patients with Metastatic Castration-Resistant Prostate Cancer (CARD)

    San Francisco, California (UroToday.com) The survival outcomes of the CARD trial, a practice-informing study of men with pre-treated metastatic castration-resistant prostate cancer (mCRPC), have previously been reported. However, there were a number of pre-planned quality of life (QoL) outcomes that importantly influence the clinician’s and the patient’s decision regarding choosing chemotherapy versus potent hormonal therapy, that are closely awaited. In his rapid abstract talk, Prof Karim Fizazi presented QoL outcomes of the study and importantly, elaborated on the importance of these findings to the clinical care of men with mCRPC.

    Published February 14, 2020
  • AUA 2020: Effect of Cabazitaxel vs. Abiraterone or Enzalutamide on Patient-Reported Outcomes in Metastatic Castration-Resistant Prostate Cancer: A Pre-Planned EQ-5D-5L Analysis of the CARD Study

    (UroToday.com) The CARDstudy (Figure 1) was a multicenter, randomized, open-label study enrolling patients with metastatic castrate-resistant prostate cancer who progressed in less than 12 months on prior androgen receptor-targeted agent1 (before or after docetaxel therapy).
    Published June 30, 2020
  • Cabazitaxel Demonstrates Improved Overall Survival when Compared to an Alternative AR-targeted Agent (CARD) - Cora Sternberg

    Cora Sternberg, MD, FACP, shares her experiences from the CARD study, which was the first trial to evaluate the sequencing of the androgen-signaling–targeted inhibitor (abiraterone or enzalutamide) compared to cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC) who had been previously treated with docetaxel and the alternative androgen-signaling–targeted agent (abiraterone or enzalutamide). In this conversation with Alicia Morgans, MD, MPH, Dr. Sternberg describes the overall survival data where cabazitaxel was consistently superior to a second pathway inhibitor.  Cabazitaxel was also shown to double radiologic progression-free survival with a similar hazard ratio for patients both above and below 70 years. Dr. Sternberg outlines the clinical relevance of these data in the geriatric population. 

    Biographies:

    Cora Sternberg MD, FACP Professor Medicine and Clinical Director of the Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York.

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


    Read the Full Video Transcript

    Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago, Illinois. I'm so excited to have here with me today, a colleague and friend, a Full Professor of Medicine at Weill Cornell Medicine, as well as a GU medical oncologist, Dr. Cora Sternberg, who is also the Clinical Director of the Englander Institute for Precision Medicine, as well as being one of the Primary Investigators on the CARD trial. She's talked to us about it several times before. We always appreciate hearing her insights. Thank you so much for being here with us today, Dr. Sternberg.

    Cora Sternberg: Thank you very much. It's always a pleasure to be here with you and with UroToday. The CARD study was the first study to look at the sequencing of novel therapies for patients with metastatic CRPC. And what we did was we took patients with metastatic CRPC, metastatic castration-resistant prostate cancer, who had all received docetaxel and had received one novel AR targeting agent, which was either abiraterone or enzalutamide and who had failed that AR targeting agent within 12 months of receiving the agent. They were then randomized on a one-to-one basis to receive either cabazitaxel 25 milligrams per meter squared, plus GCSF and prednisone, or to receive the alternative AR targeted agents, either abiraterone and prednisone or enzalutamide, depending what they had received before. Now, the dose of cabazitaxel at the time that this study was done in Europe is the dose of 25 milligrams per meter squared, but GCSF was given and subsequently known that perhaps the dose of 20 milligrams per meter squared gives very similar results.

    At any rate, the primary endpoint was radiologic progression-free survival and secondary endpoints included overall survival. And what was reported already in the New England Journal of Medicine was the primary endpoint of radiologic progression-free survival with a hazard ratio of 0.54. We can say that cabazitaxel as compared to abiraterone or enzalutamide doubled the radiologic progression-free survival. Doubled it. And in terms of overall survival, the hazard ratio was 0.64, which corresponded to a decrease in death of 36%.

    And these data have not been updated recently. Those were the data published in the New England Journal of Medicine. This study was run between 2015 and 2018. Run primarily in Europe. And really showing the cabazitaxel chemotherapy was better, more efficacious than an AR targeted agent if patients had already failed another AR targeted agent. And it was a selected population because the patients actually had not done very well on an AR targeted agent. They'd responded for less than 12 months.

    What was done in the two abstracts presented at ASCO, the first one was a deeper dive, let's say, into the univariate and multivariate analysis of overall survival. And looking first at a univariate analysis, they looked at many of the things that had prognostic value in the past in patients with metastatic CRPC such as PSA, alkaline phosphatase, LDH, age, visceral disease,  many things. And all of these did have prognostic value in univariate analysis, but when looked at in multivariate analysis, the most important items for overall survival were a high NLR, nuclear lymphocyte ratio, a decreased hemoglobin, or an increase in PSA. These all portended a worse overall survival in the multivariate analysis model.

    And in all of the factors, both univariate and multivariate that were looked at, cabazitaxel was superior to adding a second pathway inhibitor in all. The overall survival for the various endpoints we'e looked at and no matter what was looked at, also in terms of when we started treatment, if overall survival was the time for metastatic disease and metastatic CRPC diagnosis or overall survival from metastatic CRPC diagnosis or overall survival from the first life-extending treatment or overall survival from the second life-extending treatment, all of these factors all showed an improvement with cabazitaxel as compared to the alternative AR inhibitor.

    And this is I think, a very important thing to know in terms of sequencing, because many people like to use one AR inhibitor after the other, thinking that perhaps they're less toxic or whatever they're doing. And I think that probably we've shown that it's less efficacious to do that, particularly in patients who didn't respond for more than 12 months. And the results support the use of cabazitaxel over abiraterone or enzalutamide as a standard of care in patients previously treated with both docetaxel and the alternative AR targeted agent.

    Now, the other abstract looked at age and we know according to the SIOG, the Society of Geriatric Medicine guidelines, we should look at a senior adult population as those over 70 as compared to those less than 70. And that's why we chose that cutoff. I don't know how relevant that still is, but the truth is that in CARD, the median age for patients on cabazitaxel was 70 years of age. And there was quite more than a third of the population was more than 75 years of age, actually.

    We looked at the cutoff between greater than 70 and less than 70. And here we found that cabazitaxel doubled the radiologic progression-free survival with a hazard ratio of 0.58 in patients that were 70 years or older and 0.47 in those less than 70 years. What we see again, a recapitulation, the fact is that about 50% of the patients in CARD were older than 70 and that the hazard ratio really was pretty much the same in terms of radiologic progression-free survival and overall survival, irrespective of age.

    And regarding the safety, which is really important when people are worried about age, I think that if you look at it, what we showed was that the grade more than 3 adverse events in patients greater than 70 versus less than 70, we saw that there was a slightly higher frequency in those older than 70. Grade 3 ischemia, diarrhea and febrile neutropenia occurred more frequently in patients more than 70 of age who received, cabazitaxel and grade more than 3 cardiac events, infection, kidney adverse events more frequently in those greater than 70 receiving abiraterone or enzalutamide. So in many of our patients with comorbidities such as cardiovascular disease, it may not be so gentle to give abiraterone or enzalutamide. It may be a better option to give chemotherapy with cabazitaxel and GCSF as was done in this particular trial. I think this trial supported the use of cabazitaxel over abiraterone or enzalutamide as a standard of care, irrespective of age in patients previously treated with docetaxel and the alternative androgen receptor-targeted agent.

    Now, I would like to say that these results were a third-line study. The patients were highly selected. The patients received an androgen receptor-targeted agent and they didn't respond for more than 12 months. But honestly, if I look deeper into the data and I don't even know if this is published, the patients who received in the hormone-sensitive prostate cancer setting, were 40% and the patients who received an alternative abiraterone or enzalutamide in the castration-resistant setting after docetaxel were 60%. This is because these drugs were not approved as early as they were in the United States in Europe. And the study was primarily conducted in Europe.

    If you compare these results to the TheraP trial that was presented at ASCO by Hofman et al. from Australia was a very interesting trial that compared to lutetium PSMA treatment to cabazitaxel. They showed looking at the PSA 50 that lutetium PSMA-50 was perhaps better than cabazitaxel. The response rate in terms of PSA was very similar 37 and 38%. But if you look at this closely, the PSMA-50 is really not a surrogate, as far as we know for overall survival. And the other thing is that the patients on that trial were highly selected patients who had a PSMA positive scan and another PET scan that showed active disease. And they also had a PSA of over 20. There's a different kind of selection here. And some 30% of patients were not admitted into that trial who did not fit those strict criteria of expressing PSMA.

    Now we know well that PSMA and PSA may not be the best way to look at these patients, and in the CARD trial that we selected patients for not responding to the alternative therapy, we didn't select patients based on having a high PSA. And not selecting patients on a high PSA means we treated all-comers that were not treated on the other trial. In terms of sequencing, I think there's still a lot of work to be done in terms of cabazitaxel and PSMA. And I think that their study is an excellent study, but we need further follow-up. We probably need to do other sequencing studies in the future, both to understand and put it in perspective, both CARD and the PSMA TheraP trial.

    Alicia Morgans: Thank you so much for putting that all in perspective. And I did fail to mention, but wanted to make sure it was clear, you were actually on the Steering Committee of the CARD trial and we so appreciate hearing your insights both in terms of the deeper dive on the overall survival, but also certainly in the geriatric analysis and in the context of the TheraP trial. I think we so appreciate this, especially because you have such an interest in real-world applications for the data. And as you said, particularly things like the geriatric analysis are quite reassuring when we're thinking about using a treatment in this third-line setting and many people feel that perhaps this is too toxic of a drug.

    What your study really brought out, and I just want to emphasize this for the listeners is that, although there are some side effects that may be more common in this geriatric or over 70 population, there are certainly some side effects that are more common when using another AR targeted agent. And of course, if that agent is also not controlling the prostate cancer but causing these comorbidities in terms of cardiac events, for example, that's really not doing patient any service by any stretch. Can you let me know, how do you use the data that you just talked about, the data, particularly the geriatric data, in your day to day clinical practice?

    Cora Sternberg: Well, I think that that data is really important. I think that what we have shown and we know this from other studies, these splice variants, et cetera, that patients who have had an AR targeting agent and not done well on it, particularly if that was the last treatment that they just received, they are not the patients who will do very well in another AR targeted agent. And we may think that when we have an elderly patient that we're doing them a huge favor by giving them another AR targeted agent, but perhaps it would be better and more gentler to give them chemotherapy with cabazitaxel. In this case, it was done with 25 per meter squared and GCSF, but we know from the PROSELICA study that you can give 20 per meter squared.

    And in my own practice, if I have a really elderly patient, I will give 20 per meter squared and GCSF and try to be as gentle as possible in elderly patients. And I think that if you control their disease, we've seen quality of life data from the last GU ASCO, that controlling their disease as you've said, is the most important thing that we can do. And we think we're being gentle by giving them a pill instead of chemotherapy, but perhaps that's not the most gentle way of going about it.

    Alicia Morgans: I completely agree. Well, as we wrap up this tour de force through the recently reported CARD data, the TheraP data, all of this data really reflecting our understanding of cabazitaxel as it is still quite a relevant and useful tool in our armamentarium against prostate cancer, what would your closing thought be, or your message to the audience?

    Cora Sternberg: Well, I think that cabazitaxel is really a very good drug after failing docetaxel. We know this from several studies. Cabazitaxel will become generic in Europe very shortly in the next year and I'm not sure when it will be in the United States and we're still waiting for PSMA scanning to be FDA approved in the United States and lutetium to be approved as a therapy. I think it's a very promising, interesting therapy and there probably will be a place for all of these agents, both cabazitaxel and lutetium therapy. But I think we need to understand the right sequence of these treatments. When is the best time to give which one? I think both of these trials are looking in third-line treatment. And I think that it's always very difficult to compare among trials when they use completely different selection criteria.

    And I think that that's important and one should use what they're familiar with and feel most comfortable with what they think will be best for their patients. But again, the cost will be a problem as well and we need to consider cost efficacy. Cabazitaxel works against AR dependent and AR independent cells and we know that when many people are in the third -ine, that many of the cells are AR independent. That's an advantage of using chemotherapy as opposed to an AR targeted therapy, such as lutetium PSMA. I think we need to have more data from the TheraP trial. We need to do probably more sequencing in the future to understand better the place of PSMA lutetium, eventually actinium, and also chemotherapy.

    Alicia Morgans: Well, I could not agree more and I appreciate your continued efforts to help us as a field, understand how to best use all of these options in a way that makes sense in selecting the treatment for an individual patient that will hopefully work and will be safe and will be the right choice. Thank you so much for your time and your expertise today, Dr. Sternberg.

    Cora Sternberg: My pleasure.

    Published June 21, 2020
  • Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Castration-Resistant Prostate Cancer - Karim Fizazi

    In the CARD study, cabazitaxel significantly improved radiographic progression-free survival and overall survival versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen signaling-targeted inhibitor. Here, we report the quality-of-life outcomes from the CARD study.

    In the quality-of-life analysis from the CARD study reported in The Lancet Oncology, Karim Fizazi, MD discusses these findings that cabazitaxel improved pain response, time to pain progression, time to symptomatic skeletal events, and EQ-5D-5L utility index, clinicians and patients with metastatic castration-resistant prostate cancer can be reassured that cabazitaxel will not reduce the quality of life when compared with treatment with a second androgen signaling-targeted inhibitor.

    Biographies:

    Karim Fizazi, MD, Ph.D., Head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France and Professor of Oncology at the University of Paris

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


    Read the Full Video Transcript

    Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the United States. I'm so excited to have here with me today Dr. Karim Fizazi, who is a Professor of Oncology and a GU medical oncologist at Gustave Roussy, in Paris, France. Thank you so much for being here.

    Karim Fizazi: It's always a pleasure, Alicia. Thank you for inviting me.

    Alicia Morgans: Wonderful. Well, I wanted to speak with you a little bit about the quality of life data that was recently published on the Phase IV CARDtrial, and you did both a presentation, and you're the lead author in the paper that came out just a few weeks ago, actually. Can you tell us a little bit about what the CARD trial was, and then we can get into what the data was in terms of quality of life.

    Karim Fizazi: Sure. So CARD was basically a very pragmatic Phase IV trial trying to look at a very simple question that we're facing very frequently in the last decade or so in men with advanced metastatic prostate cancer who had failed castration, obviously, but also one AR-axis agent, such as abiraterone or enzalutamide, and one taxane, namely docetaxel. And the question in these men was really what's next while they're progressing. Of course, sometimes you and I would have a nice clinical trial with a fancy new drug and a new concept to propose to these men, but for the large majority of men, especially at this time, this was not the case, and the discussion was really, "Should you use a second AR agent or should you use a second taxane?". 

    And of course, in countries where all these drugs are available, it was probably tempting for many, many oncologists to just use the AR drug just because it's easier, just a simple prescription on a piece of paper. The side effects, at least the immediate side effects, are quite limited. And so it's an easy conversation, and you don't need to enter into a hard discussion with the patient about side effects, about his disease being advanced, and all of these things.

    So I know that many of us were actually doing that, prescribing abiraterone after enzalutamide or vice versa, in this setting. But actually, we realized from a retrospective study, and it's a large way of course, it's almost everywhere on the planet... that actually using abiraterone after enzalutamide was very rarely associated with efficacy, and even enzalutamide post abiraterone had minimal efficacy, with approximately 20% response rate by PSA, and probably less convincing effect on stronger endpoint symptoms, etc., so time to symptoms, these things. While on the other hand, the experience with cabazitaxel in these men was perhaps more convincing, again both in terms of PSA control and symptoms control. So this is why we embarked on a randomized Phase III trial, testing the two options, again the second AR, whatever that was, enza or abi, with second taxane, cabazitaxel.

    A year ago at ESMO, Dr. de Wit reported the first finding of a trial in terms of a primary endpoint, which was radiographic progression-free survival, and also the secondary major endpoint which was overall survival, and both were actually met, which, when I think about it, is not something happening so often in oncology. This is pretty much a third-line or even a fourth-line treatment... we should take into account castration... and seeing overall survival improvement in this setting is really scarce, unfortunately. And that is the case with cabazitaxel, and it was really clear cut. It's not, you know, curves not separating, and you always wonder whether it's meaningful or not. It was very clear.

    So what we did also in the trial is that we looked at secondary endpoints of quality of life, symptoms control, burn problems, all these things, and all those seem also to favor cabazitaxel. For example, time to pain deterioration, and it's mostly, of course, bone pain deterioration, was significantly improved with cabazitaxel, as compared to the second AR drug. Also, skeletal-related events were improved, and quality of life... often with quality of life, and you are an expert, Alicia, you see that it's mostly maintained across the board, but when you're looking at various domains, it's actually slightly better, favoring cabazitaxel.

    And this is also a very important message because many of our medical oncologist colleagues might think that using chemotherapy will be associated with impaired quality of life due to the side effect of the chemo, but actually, I think we should change our mind and more think that... our main goal is to target the cancer hard in the way that... using the best treatment that we have at a given time, and here it's not an easy situation for men who have already developed resistance to many things. And if truly we are improving patients' outcomes from the cancer standpoint, very likely the rest of their life will be also improved. Because the cancer is so important at this point of time to them in terms of consequences to their life that even if you have adverse side effects, it's actually minimal as compared to the benefit you are deriving from the anticancer efficacy. And actually, the side effects were pretty much the ones we knew from cabazitaxel, mostly some hematotoxicity, which can be prevented GCSF, and some diarrhea, which doesn't happen very often.

    For example, the treatment-related deaths were not more frequent with cabazitaxel as compared to abiraterone or enzalutamide in this trial, which is also very reassuring. So, again, I guess in other good news, I mean, to me, this is a new standard of care. To be honest, it already was based on the retrospective data we had. Most often, I was proposing cabazitaxel to my patients in this setting when I hadn't a clinical trial to propose, but I guess this is level I evidence, and it's more convincing and helping colleagues who are not dealing with prostate cancer on a daily basis and also payers, all those things, so I think it's very important to have this trial available.

    Alicia Morgans: I completely agree, and what I think is so important is that, not only did you very clearly demonstrate the efficacy, through this quality of life data, you demonstrated tolerability, also improvement in multiple symptoms, and as compared to, say, the nonmetastatic CRPC patient population, in which the cancer is actually really causing a lot of pain or other burdensome side effects, in this setting, in the mCRPC setting, the cancer is the driver of poor quality of life, and so when you control the cancer, it's interesting that the quality of life actually stabilizes or improves in that population, and you can see that decline in the population with an ineffective cancer-directed therapy. So as you said, it has been really our standard of care, but because of practice patterns not necessarily being consistent, it's so important to have this kind of data, I think.

    So what would your thought be also on the fact that, in this trial, the cabazitaxel was dosed at 25 mg/m2, which I believe is common in Europe and actually has been the initial label, but in the US, many physicians actually reduce that dose to 20 mg/m2. Despite that higher dose, still, the quality of life was maintained or improved. What would your thought be there?

    Karim Fizazi: Well, to be honest with this regard, I guess I'm a US citizen. I'm also using 20 mg and perhaps [inaudible 00:09:07] to be honest, but you know, 20 mg is actually my standard. I'm using it routinely. I haven't been using 25 for years now. I think the data are very convincing. We have two Phase III trials, basically with 20 and 25 mg face-to-face. At the end of the day, we see that 20 mg, the efficacy remains, and the safety is much better, so I'm indeed using 20 mg in my practice. I think we probably should also, in countries were GCSF is available and when it's not unavailable but also it's available front line because I know in some other countries you have to wait for first neutropenic fever to be allowed to use it, but in countries where that's not the case and you can freely use it, I think we should use it, and actually, this is what I'm doing also in my practice with this drug. Which is easy to handle, to be honest. With 20 mg and GCSF, patients are happy.

    Alicia Morgans: I understand. I do exactly the same. And there's definitely conversation about, "Well, maybe you don't need the GCSF if you're having that 20 mg/m2 dose," but I have access to it, I use it, and I think it keeps patients out of the hospital. So I agree.

    And what's also interesting is the quality of life data from those comparisons of 20 mg versus the 25 versus actually docetaxel suggests that that 20 mg may be even better tolerated than docetaxel in some senses, the fatigue, the nail issues-

    Karim Fizazi: Absolutely.

    Alicia Morgans: So I have also found that it's been quite tolerable. So as you think about this data and the way that it integrates into practice, what would your final message be to the listeners?

    Karim Fizazi: Well, I think that cabazitaxel was nice progress for the field, but unfortunately, that's a drug that came probably too late in the history. It is as it is. And because of that and because when it was basically launched people were already thinking about next-generation drugs, tyrosine kinase inhibitors, new targets, etc., etc., people perhaps didn't pay enough attention to this molecule, which, at the end of the day, is not a good thing for patients. Because we now have very clear evidence that it is an important drug in the armamentarium. It's also soon going to be a generic drug in many countries, so the price and the cost issues might not be one anymore, so I think we should really revisit the way we are integrating this drug in our current armamentarium for patients and we are not forgetting using it. Because it's really helping tremendously many patients, and I think it's a very important message for the future.

    Alicia Morgans: I agree. And really we need to recognize and remember that sequencing AR-targeted agents after AR-targeted agents is really not the way to go anymore. This is very clear evidence that you can get both efficacy and disease control, as well as quality of life stabilization and improvement with this agent. Cabazitaxel works, and patients benefit. So thank you so much for your efforts, and thank you so much for your time today.

    Karim Fizazi
    A pleasure. Thank you, Alicia.

    Published October 26, 2020
  • Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer

    The efficacy and safety of cabazitaxel, as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear.

    Published October 1, 2019
  • Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer - Beyond the Abstract

    The robust outcome of CARD with a hazard ratio (HR) for radiographic progression-free survival (rPFS) 0.54 in favor of cabazitaxel allows meaningful subgroup analyses. Preplanned subgroups of particular interest and that, importantly, retained statistical significance including the time to failure on the first androgen receptor targeted agents (ARTA) (0-6 months, 6-12 months) and the docetaxel- first ARTA sequence.

    Published October 7, 2019
  • ESMO 2019: CARD: Randomized, Open-label Study of Cabazitaxel vs Abiraterone or Enzalutamide in Metastatic Castration-resistant Prostate Cancer

    Barcelona, Spain (UroToday.com) Multiple therapeutic options have been approved for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC), including the second-generation anti-androgens abiraterone and enzalutamide, and chemotherapy with docetaxel or cabazitaxel. However, the appropriate order in which to stagger these therapies is not uniformly clear. With regards to anti-androgens, there is the suggestion that enzalutamide may be effective after progression on abiraterone and less suggestion that abiraterone is effective after enzalutamide. Additionally, while many patients do respond to newer anti-androgen therapies, a subset of patients progress within a year or less, representing a more aggressive disease phenotype that may benefit from chemotherapy rather than another anti-androgen.

    Published October 1, 2019
  • ESMO 2019: Invited Discussant (LBA13) - The CARD Trial, A Randomized, Open-Label Study of Cabazitaxel vs Abiraterone or Enzalutamide in mCRPC

    Barcelona, Spain (UroToday.com) Dr. De Wit’s presentation of the positive CARD trial, Dr. Silke Gillessen provided an invited discussion regarding the implications and practice-changing measures that result from these findings. Dr. Gillessen notes that currently, we have several agents for metastatic castration-resistant prostate cancer (mCRPC) patients with overall survival (OS) benefit, including: abiraterone, cabazitaxel, docetaxel, enzalutamide, radium-223, and sipuleucel-T. As follows is a general timeline of drugs approved in this space and their corresponding line of therapy.
    Published October 2, 2019
  • ESMO Virtual Congress 2020: Cabazitaxel Activity in Men with Metastatic Castration Resistant Prostate Cancer with and without DNA Damage Repair Defects

    (UroToday.com) Up to 30% of metastatic castration-resistant prostate cancer (mCRPC) men harbor DNA damage repair defects and may benefit from poly-ADP ribose polymerase (PARP) inhibitors after abiraterone/enzalutamide and docetaxel failure. Cabazitaxel was recently shown to improve overall survival in this population,1 though benefit by DNA damage repair status is unknown. At the prostate cancer session during the European Society of Medical Oncology – 2020 Virtual Congress (ESMO), Dr. Mihaela Aldea and colleagues reported outcomes of their assessment of cabazitaxel activity in men with mCRPC according to their DNA damage repair status.

    Published September 18, 2020
  • ESMO Virtual Congress 2020: Neutrophil-Lymphocyte Ratio as a Prognostic and Predictive Biomarker in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Cabazitaxel vs. Abiraterone or Enzalutamide in the CARD Study

    (UroToday.com) It is well known that inflammation is a hallmark of cancer, harboring a critical role in tumor development and metastatic progression in many cancers, including prostate cancer.1 It has been shown that baseline neutrophil-to-lymphocyte ratio (NLR), calculated by dividing the absolute peripheral neutrophil count by the absolute lymphocyte count, is an accessible and inexpensive marker of cancer inflammation.When this ratio is high at baseline, data shows its associated with poor overall survival (OS) in many tumor types, including metastatic castration-resistant prostate cancer (mCRPC).2
    Published September 19, 2020
  • ESMO Virtual Congress 2020: Real-World Evidence For Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Cabazitaxel: Comparison with the Randomized Clinical Study CARD

    (UroToday.com) Taxanes (docetaxel, cabazitaxel) and androgen-signaling-targeted inhibitors (abiraterone, enzalutamide) have shown survival benefits in metastatic castration resistant  prostate cancer (mCRPC), however until recently the optimal sequence of these treatments was unclear. In clinical practice, many patients with prostate cancer often receive sequential androgen-signaling-targeted inhibitors. Patients who have progressed on an androgen-signaling-targeted inhibitor may not respond to a second alternative androgen-signaling-targeted inhibitor, possibly due to shared resistance mechanisms.

    Published September 19, 2020
  • ESMO Virtual Congress 2020: Treatment in CARD Eligible Metastatic Castration Resistant Prostate Cancer Patients According to the Status of Germline HRR Mutations: Cabazitaxel vs Enzalutamide/Abiraterone

    (UroToday.com) The CARD trial was a randomized open-label study of cabazitaxel versus the alternative anti-androgen therapy in patients with metastatic castration resistant prostate cancer (mCRPC) who had progressed on docetaxel and also progressed on either enzalutamide or abiraterone within 12 months of therapy initiation. This study showed a statistically significant improvement in radiographic progression free survival and overall survival with cabazitaxel. The PROfound trial, a study of olaparib therapy in men with mCRPC who progressed on at least one anti-androgen therapy and whose tumors possessed certain mutations in homologous recombination repair (HRR) genes, has demonstrated superior radiographic progression free survival and overall survival2 with Olaparib therapy. The authors of this poster hypothesized that the presence of HRR alterations may impact response to cabazitaxel chemotherapy in mCRPC.
    Published September 23, 2020
  • Journal Club: Discussing Quality of Life in Patients with Metastatic Prostate Cancer Following Treatment with Cabazitaxel Versus Abiraterone or Enzalutamide - Christopher Wallis & Zachary Klaassen

    Christopher Wallis, MD, PhD, and Zachary Klaassen, MD, MSc, discuss the recently published data (Lancet  Oncology) from the CARD trial "Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide." Previously reported from the CARD Study in the NEJM cabazitaxel significantly improved radiographic progression-free survival and overall survival versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer who had previously been treated with docetaxel and the alternative androgen signaling-targeted inhibitor. The current Journal Club discusses findings since cabazitaxel improved pain response, time to pain progression, time to symptomatic skeletal events, and EQ-5D-5L utility index, patients with metastatic castration-resistant prostate cancer (mCRPC) can be reassured that cabazitaxel will not reduce the quality of life when compared with treatment with a second androgen signaling-targeted inhibitor.

    Biographies:

    Christopher J.D. Wallis, MD, Ph.D., Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee

    Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

    Read the Full Video Transcript

    Chris Wallis:  Hello, and thank you for joining us for this UroToday Journal Club. Today we're discussing a recent publication from the CARD trial entitled "Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide". This was a randomized multicenter open-label phase 4 trial. I'm Chris Wallis, a fellow in urologic oncology at Vanderbilt. And with me today is Zach Klaassen, an assistant professor in the division of urology at the Medical College of Georgia. This here is the citation we are discussing recently published in The Lancet Oncology. And so just for a little bit of background, you can see this recent figure from a publication with UroToday highlighting recent FDA approvals in metastatic castrate-resistant prostate cancer.

    And as you can tell, there's been a whole variety of changes in the last 15 years with a preponderance in the last 10 years. And so all these changes and new approvals mean that we have a plethora of treatment options and we're now in the position, which is somewhat fortunate, of having to choose how to combine treatment options and how to sequence them for maximum benefit. And that's one of the questions addressed in the CARD trial. And so relevant background comes from the work from Kim Chi and others looking at switching between androgen-access targeting agents. And so as you can see in the figure on the right, PSA responses are relatively poor when switching from abiraterone to enzalutamide or enzalutamide to abiraterone. Somewhat worse, as you can see on the far right among those who started with enzalutamide and switched to abiraterone.

    So the CARD trial, which was published, the primary analysis in The New England Journal looked at patients with metastatic CRPC, who had progressive disease and had received docetaxel as well as a prior androgen-axis targeting agent, and that could be either before or after receiving docetaxel. And at the time of progression, patients were randomized to receive cabazitaxel or a switch to the other androgen-axis inhibitor. And so as was previously reported, the use of cabazitaxel as opposed to an androgen-axis inhibitor switch was associated with improved imaging-based progression-free survival as well as overall survival. However, there are other important endpoints. Overall survival obviously is one of the primary endpoints for our registration trial, so the quality of life is very important for patients during the time that they are alive. And so this was a secondary endpoint of this trial. And so to look in a little more detail of the methodology for this study, we are talking about a randomized multi-center, open-label trial conducted among 62 centers in 13 European countries.

    Men are included if they had metastatic CRPC with castrate levels of testosterone. Progressive disease for the prostate cancer working group criteria had received prior docetaxel at least three cycles and had progression within the first year of being on an androgen-signaling inhibitor, so abiraterone or enzalutamide. Those patients were then randomized in a one-to-one fashion to either cabazitaxel or switched to the other, abiraterone or enzalutamide. This was an open-label design and keeping with the phase 4 methodology with patients and investigators unmasked, but study personnel masked to allocation. And randomization was stratified by ECOG Performance Status. Time to progression on androgen-signaling inhibitors and timing of androgen-signaling inhibitors either before or after the receipt of docetaxel.

    And so the treatment approach is relatively standard, but in short, cabazitaxel co-administered with prophylactic G-CSF as well as prednisone and dose reductions of both chemotherapy and oral agents were allowed before treatment discontinuation. And follow-up was fairly standard with imaging laboratory investigations and adverse event monitoring. Notably for this analysis patient-reported outcomes and pain was assessed at baseline every three weeks before the initiation of treatment, during treatment, and then at the end of each treatment, and then every 12 weeks following the completion of treatment until a disease progression.

    And these assessments were made using the FACT-P questionnaire, EQ-5D-5L, BPI-SF, and the WHO analgesic ladder. And so the prior publications are focused on oncologic endpoints, including the primary outcome of radiographic progression-free survival and secondary endpoints, including overall survival, PFS, PSA-response, and objective response rate. In this study, we focused on the quality of life metrics, including pain scores. And so in this study, pain response was defined as a greater than 30% decrease in pain intensity from baseline repeated on at least two consecutive measures, and pain progression, conversely, was a 30% or more increase in pain intensity from baseline, again, repeated on two measures. Symptomatic skeletal events were consequently defined as the use of external beam radiotherapy, new symptomatic pathologic fractures, new spinal cord compression, or tumor-related orthopedic interventions. And the decline in health-related quality of life was defined as a 10 point change or more in the FACT-P total score.

    This shows you the inclusion criteria and allocation of these patients over time. 303 patients assessed for eligibility, and of those 48 were excluded, leaving 255 randomly-assigned relatively equally between the two arms. And we have reporting data on the vast majority. So in terms of statistical analysis, the study was powered on the basis of radiographic progression-free survival and not on the basis of any of these secondary endpoints. However, pain response and patient-reported outcomes were assessed in the intention-to-treat population among those who do perform baseline surveys and at least one other survey during followup. And as Dr. Klaassen will highlight, time to event endpoints were analyzed with the survival analysis, and patient-reported outcome changes for baseline were analyzed using mixed ANCOVA linear repeated measures models.

    Zach Klaassen:  Thanks, Chris. So in terms of discussing the results, this study was from November 17th, 2015 to November 28th, 2018. And as mentioned, 255 patients were randomized. You can see table one on the left. These are well-balanced populations between the cabazitaxel group and the abiraterone or enzalutamide group. Looking at this analysis, the data cutoff was on March 27th, 2019 with a median follow-up of 9.2 months. And pain response was evaluable in 86% of the randomized patients, so the majority of the patients were included in this trial.

    This is just a continuation of the table one baseline characteristics. You can see that in terms of the number of patients that had baseline FACT-P scores that are revival was 84% in the cabazitaxel group and 90% in the abiraterone or enzalutamide group. And you can see just by comparing the mean and the standard deviations that, at the entrance to this trial, these patients had a similar quality of life.

    So this is the table looking at the results in terms of time to deterioration. You can see that I've- it's a bit of a busy table. I've put a box around the hazard ratio here in the middle, and you can see that the metrics with an asterisks were the ones that were statistically significant. So time to deterioration overall survival was 13.6 median months for cabazitaxel, 11.0 months for abiraterone or enzalutamide with a significant hazard ratio of 0.64 and a 95% confidence interval of 0.46 to 0.9. Similarly, we see a strong hazard ratio, favoring cabazitaxel in terms of pain progression and the brief pain inventory score, not reached in the cabazitaxel group and median of 8.5 months in the abiraterone or enzalutamide. Another important metric that was positive, and we'll see this again in the graphs, is that emotional wellbeing significantly favored cabazitaxel with the hazard ratio of 0.46. The median time to deterioration was not evaluable in the cabazitaxel group and was 13.7 months in the abiraterone or enzalutamide group.

    Looking at this table of symptomatic skeletal events, you can see here on the top row that 19% of patients in the cabazitaxel group had an SSE, compared to 28% in the abiraterone or enzalutamide group. And this was actually achieved despite lower use of denosumab or bisphosphonate in patients treated with cabazitaxel, which was 21% versus abiraterone or enzalutamide at 37%. In terms of the median time to symptomatic skeletal event was not reached for the cabazitaxel group compared to 16.7 months for the abiraterone-enzalutamide group with a hazard ratio of 0.59. It's close to the statistically significant hazard ratio, a 95% confidence interval of 0.35 to 1.01.

    In these next two graphs, we'll look at the percent of patients with improvement based on each cycle. And so this table here is for FACT-P. And just to sort of summarize what this is showing, is that this green box shows improve FACT-P score by cycle, and you can see here on the left is cabazitaxel, and on the right is the abiraterone for each cycle. And you can see that the green box continues to improve, deteriorates a little bit at cycle six, and then improves again at cycle seven. And if you compare these side by side, each cycle has improvement in FACT-P with the cabazitaxel group compared to the abiraterone group. And this is quite similar as well in the EQ-5D-5L tool as well. As you can see once again, improvement for cabazitaxel on the left versus abiraterone on the right all the way through cycle 8.

    In terms of the change from baseline in health-related quality of life scores, there are several figures over the subsequent slides, which I'll walk you through. In general, all of these six figures, there was no difference between cabazitaxel and abiraterone or enzalutamide. You can see cabazitaxel is highlighted in blue and abiraterone or enzalutamide, in red. So there is no difference in terms of FACT-P score, Fact-P general, trial outcome index, emotional wellbeing, social or family wellbeing, as well as physical wellbeing. The median time to FACT-P total score deterioration was 14.8 months for cabazitaxel compared to 8.9 months with abiraterone-enzalutamide with a hazard ratio of 0.72, 95% confidence interval of 0.44 to 1.2.

    This is a continuation of this figure, and we can see that once again, functional wellbeing, prostate-specific concerns wellbeing, and the EuroQol-5D visual analog score were not significant. However, this EuroQol-5D dimensions, five-level utility score index did favor cabazitaxel as did the pain-related subscale wellbeing.

    The next three sides will show the time to deterioration in FACT-P as subscales. You can see here that, once again, cabazitaxel is in blue, abiraterone is in red. There was no difference in these three metrics in terms of FACT-P, FACT-G, as well as trial outcome index. Subsequently once again, no difference between physical wellbeing and social or family wellbeing, but as we showed previously in the table, emotional wellbeing significantly improved with cabazitaxel compared to abiraterone-enzalutamide with the stratified hazard ratio of 0.46. And you can see a pretty early split in these curves here right from the beginning in terms of emotional wellbeing.

    And finally, once again, no difference between functional wellbeing prostate-specific concerns and pain-related subscale between these two groups.

    So this is an important secondary paper from the CARD study. It does bring up several important discussion points. And what we saw in this study was that cabazitaxel significantly improved pain responses and prolonged time to pain progression versus abiraterone or enzalutamide. What was also encouraging was the cabazitaxel over the reduced probability of SSEs, despite the lower use of denosumab or bisphosphonates. What the ERA223 trial showed us was that there was a high level of abiraterone radium-223 patients that had symptomatic skeletal events and very low use of BPAs. And so subsequently in the ongoing EORTC-1333/PEACE III trial, which is randomizing radium-223 plus enzalutamide versus enzalutamide alone, the bone protective agents are now mandated. So I think this is important as we've shown that the fracture rate can be high without BPAs and the cabazitaxel group actually had reduced SSEs, despite lower use of these agents.

    And finally, cabazitaxel had no deleterious effects on patient-reported outcomes compared with second androgen-signaling targeted inhibitors. And so this is important as chemotherapy often gets a rap that quality of life may decrease. This study of the CARD trial PORs shows that there was no difference between cabazitaxel and the ARIs. So in conclusion, in medical oncology, effective interventions are often not the best choice for patients' perspective secondary adverse events that affect health-related quality of life. Cabazitaxel was not associated with a detrimental effect on the quality of life in these patients with metastatic castration-resistant prostate cancer. And so ultimately, favorable quality of life data plus the previously published OS benefit in the CARD trial should assure patients and treating physicians that these patients can tolerate and benefit from chemotherapy, and also highlight the importance in the context of back-to-back ARIs are not durable in the second-line setting and should be the platform for cabazitaxel. Thanks so much for your attention to this year's UroToday Journal Club. We appreciate it. Thank you.

     

    Published October 16, 2020
  • Making Quality Inferences from GU ASCO Quality of Life Data: How I Interpret the Evidence

    As medical oncologists, urologists, radiation oncologists, and other clinicians, we find ourselves feeling very comfortable understanding Kaplan Meier survival curves and forest plots describing subgroups in the setting of different treatments. We review CTCAE adverse event data, drilling down on the 10% of adverse effects that happen most commonly, and nearly always arrive at the conclusion that “such and such treatment is relatively well tolerated”.
    Published April 20, 2020
  • Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study.

    In the CARD study, cabazitaxel significantly improved radiographic progression-free survival and overall survival versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen signalling-targeted inhibitor.

    Published September 16, 2020
  • The Clinical Implications of The Efficacy and Safety in Older Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel versus Abiraterone or Enzalutamide In The CARD Trial - William Oh and Stephen Freedland

    William Oh and Stephen Freedland join Alicia Morgans to discuss the efficacy and safety in older patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel versus abiraterone or enzalutamide an analysis of the CARD Trial.  Prostate cancer is the 2nd and 3rd leading cause of cancer death in the USA and in Europe, respectively, with most deaths occurring in men over the age of 75. In men with metastatic castrate-resistant prostate cancer (mCRPC), there are multiple treatment options available today, but the most appropriate treatment sequence and its impact on elderly patients are still unknown. This data presented at ASCO 2020 was a subgroup analysis stratified by age, over 70 versus under 70. The top-line result was that there was no difference in the progression-free survival (PFS), radiographic progression-free survival (rPFS), or overall survival (OS) benefit based on an older or younger age. Drs. Oh and Freedland discusses patient selection for chemotherapy, treatment sequencing when using cabazitaxel, and the right treatment landscape for this drug in patients with metastatic castration-resistant prostate cancer (mCRPC) regardless of age. Importantly, 

    Biographies:

    William Oh, MD Chief of Division of Hematology and Medical Oncology, Deputy Director of The Tisch Cancer Institute, Professor of Medicine and Urology at Icahn School of Medicine at Mount Sinai in New York

    Stephen J. Freedland, MD, Director, Center for Integrated Research in Cancer and Lifestyle, Co-Director, Cancer Genetics, and Prevention Program, Associate Director, Faculty Development Samuel Oschin Comprehensive Cancer Institute, Professor of Surgery, Cedars-Sinai, Los Angeles, California

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


    Read the Full Video Transcript

    Alicia Morgans: Hi, this is Alicia Morgans GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, Dr. Stephen Freedland, who is a Professor of Urology at Cedar Sinai in Los Angeles and Dr. William Oh, who is the Chief of the Division of Hematology and Oncology at Mount Sinai in New York. Thank you so much for being here with me today, both of you.

    Stephen Freedland: Hi, Alicia.

    William Oh: Great to be here, thanks.

    Alicia Morgans: Wonderful. So I wanted to talk with you guys a little bit about one of the presentations at ASCO 2020, the virtual meeting, there was an analysis of the CARD data, the cabazitaxel data in metastatic CRPC patients in the third-line, that was really looking a little bit more closely at the differences that may exist or may not exist between elderly patients and patients who were less than elderly. The cutoff in this particular analysis was greater than or less than 70 years of age. And I'm wondering if you could tell me a little bit about this analysis, Dr. Oh, and what your thoughts were top level.

    William Oh: Sure. So obviously chemotherapy has been and remains a very important treatment for metastatic CRPC patients. And the CARD study was a randomized trial looking at men who received docetaxel with mCRPC and also received first-line AR targeted therapy, either abi or enza. They were randomly assigned to receive cabazitaxel or the opposite AR targeted therapy. So this is third-line treatment, and many of these patients actually remained quite intact. They were randomly assigned to one or the other, and it was significant survival and PFS benefit in the men who received cabazitaxel compared to the opposite AR targeted therapy. And we saw this data last year, and it was published in the New England Journal of Medicine because it was such an impactful and important study.

    So the data in this abstract and presentation at ASCO in 2020 is really to look at older patients, patients older or younger than the age of 70. And one of the reasons to look at this subset is that we all know that men with prostate cancer are older, and we know that older men are at greater risk for side effects, particularly of drugs like chemotherapy. And I think in my career, and I think for you, and for all of us in this field, there's always been a concern that men who are older will not tolerate chemotherapy. And this is an important question. This was a subgroup analysis based stratified by age, over 70 versus under 70. And basically the top-line result was that there was no difference in the PFS, the rPFS, or the OS benefit based on an older or younger age.

    Alicia Morgans: Great, thank you. And these are really important conversations. As you mentioned. There's definitely some thought in the field that these drugs, like cabazitaxel, taxane chemotherapies may be more challenging to give in an older population. Importantly and interestingly, the benefit seems similar. And also importantly and interestingly I think, the CARD data was done using a dose of cabazitaxel that's actually a little higher than the one that we typically use here in the U.S. In that study, they use 25 milligrams per meter squared whereas we usually use 20 milligrams per meter squared. And then most of us still are many of us still use Neulasta®. It was definitely used in the CARD trial. And so when you're thinking about these kinds of decisions, Steve, I know as a urologist, you may be more peripherally involved in these kinds of decisions. What do you think about data like this, looking at differences in populations if they exist or not as we're using that and the way that we use that information to make treatment choices?

    Stephen Freedland: I think these are very important data for sure. And I think there's this perception out there that, a novel hormonal agent abi or enza, it's easier, it's kindlier, gentler and response rates when you failed one going on to another aren't zero. And so, therefore, "Look, let's just give it a try. It's not that toxic. Let's just see what happens." So then I think these are important data that when you're sitting with the patients, "Yeah, no" as a urologist not giving chemo, but we are having those conversations in terms of what the patients to say, "Look, I'm older. I don't really want it. I've been through chemo once and I'm not excited about going through it again" and, "Oh, let's just do the other one." I think it's important to remind people that first off when you look at the toxicity profile in the AEs, you're right. This is a higher dose of cabazitaxel than typically given.

    They weren't dramatically different between the two. So it's not like cabazitaxel had all of these toxicities and other hormonal agents had zero. The numbers actually aren't that dissimilar. And you actually, particularly in older men, saw an increased risk of cardiac disease with the novel hormonal agents in the older patients. So something that, yes, we tend to think older, frailer, maybe not great for chemo, but they have cardiac issues and the alternatives are not great for cardiac reasons. So I think a lot of it comes down to fitness comorbidities, overall things, and not necessarily age as a strict number, which we know intuitively in earlier stage disease, but we often tend to forget and go by age. So it's really looking at the patient. Not just a single number.

    Alicia Morgans: I completely agree. And thank you so much for highlighting the AE issues. So it was really interesting I thought that the incidents of febrile neutropenia as we would expect was higher with cabazitaxel as was diarrhea, but cardiovascular AEs were actually higher in AR targeted agents than in the chemotherapy arm. William, does this affect your treatment conversations with patients having this piece of information for them?

    William Oh: Well, I think it's very important to customize your treatment plan for each patient. We've appreciated recently that there are important toxicities related to AR targeted therapies. They're terrific drugs, but for example, we do understand that there's more cardiovascular risk with drugs, for example, like abiraterone with prednisone. And you see, outside in this randomized trial as Steve the pointed out, these were grade 3/4 toxicities, not just small and inconsequential rises in blood pressure. These were serious AEs.

    That said, obviously, there are people for example, who are not great candidates for chemotherapy, and you pointed out something really important in this study, which is the dosing issue. Most oncologists would not use 25 milligrams per meter squared, which is what was used in this randomized trial. At the time it was the labeled indication. But we realized from subsequent studies afterward that 20 milligrams per meter squared would be perfectly reasonable and as efficacious as 25. So that's what most oncologists in the United States are using. That's what I use. There are times when if I think that a patient might be frail because of his age, I might start at a slightly lower dose, but in most patients, I found that they tolerate 20 milligrams per meter squared quite well. And I think that customization to the situation at hand is really, really important, but the most important thing about this study and the most important take-home messages, giving drugs, because they're easier, or you think they're easier that don't work is not a good strategy.

    Bad drugs don't help patients and these are great drugs when you use first-line. But we know from many, many other studies that when you use them that... Even if you flip over to the other drug from abi to enza and enza to abi second-line, certainly third-line fourth-line in mCRPC, these drugs do not have activity that justifies their continued use and study after study keeps showing that this study clearly shows that second-line chemo is much more valuable than second-line AR targeted therapy, at least in the confines of this trial.

    Alicia Morgans: Yeah, just to emphasize that again... An active treatment, particularly one that's tolerable, and this seemed to be tolerable even at this higher dose is going to be more effective for your patient than a drug that the patient probably already has a resistance mechanism against. So AR followed by AR, even if you have a docetaxel treatment in the middle and you think, "Oh, this sandwich approach is going to be better and restore sensitivity," it's not an effective strategy. And I think it's interesting too, that we saw this, not just in CARD. We actually saw this in PROfound as well. So these were patients who had AR targeted therapy, docetaxel, they may have actually even had cabazitaxel, and when we randomize them to an agent that had happened to be quite effective, a PARP inhibitor, versus the second AR targeted agent, we actually saw very similar control arm as we did in the CARD trial. And that population wasn't even restricted to a population that had to have disease progression on an AR targeted therapy within 12 months.

    So I don't think that this story is unique to this group of patients who progressed within 12 months. It's probably that as you develop resistance to an AR targeted approach, you have developed resistance and another drug with the similar mechanism of action's not going to work. And so I really appreciate you bringing that out. You know, Steve, when you're seeing patients, you actually work at a veteran's hospital, and certainly nothing you say in terms of treatment conversations would be a recommendation from the VA. But just to comment, as you're treating patients in that facility, I can imagine particularly if they have many comorbid illnesses that it would be maybe not uncommon as for any practice that includes patients with many comorbidities to say, "Well, I'll give them the easy way out." As we just discussed, that does not seem like the way that we'd want to go with the CARD data come into your conversations, if you were having them with patients in your practice, particularly this geriatric data.

    Stephen Freedland: Yeah, I know. Absolutely. Again, this is third-line therapy we're talking here. And so the number one threat in that stage to quality of life is the cancer. It's not the treatment. It's progressing cancer. These patients, even with good therapy, don't have forever to live. They're worried about pain from the cancer and those issues. And so even if you have an agent that is a little bit higher risk of AEs, and we see that a little bit higher risk, but it's modest risk, but we saw data from GU ASCO, for example, in February that actually showed cabazitaxel had a better quality of life. And so to me, the primary thing is we got to get good cancer control. We're beyond the stage of subtle differences in AEs.

    You've got to get to an active agent and these novel hormonal agents, second novel hormonal agents just are not active enough. And age, again, says here is a number to be thought of. And it does impact counseling in terms of AEs and things to think about. But patients did really well. And it was actually over half the patients and an entire study were over the age of 70.

    So it was over 50% of these patients and they tolerated it well. Now, these are ECOG 0/1. So if you had an ECOG, 3 or 4 patients who are 75 and 80, harder to know, but for that healthy kind of chemo fit patient, just because they're over 70 shouldn't matter.

    Alicia Morgans: Great. Well, as we wrap up, Dr. Oh, what are your closing thoughts and messages to the listeners?

    William Oh: I think the most important thing is, think of what's best for your patient. And don't use age cutoffs as a reason not to use or to use a certain treatment. I've given chemotherapy to men in their 90s. If they're fit and you're able to manage the side effect risk and you individualize it, there's really no upper age limit for how chemotherapy can help if you're able to really be an experienced oncologist and deliver the therapy effectively. And as Steve said, and as we all agree, you have to be able to give your patients the best shot at controlling the cancer. Cause in the end you know mCRPC is still lethal.

    Alicia Morgans: Absolutely. And any closing thoughts, you've given us lots to chew on, Dr. Freedland, any closing thoughts from you?

    Stephen Freedland: Yeah, no. I mean, I think William said a very nice thing. I think to have that conversation with the patients and to let them know we have treatment options that can keep the cancer under better control, prolong survival, prevent pain, improve quality of life, and to present them with the options and not deny them life-prolonging therapies just because they happen to be a particular age.

    Alicia Morgans: Absolutely. Well, thank you both for your review of this information. We of course thank the CARD investigators for doing this analysis so that we understand best how these treatments may affect our older patients. And I appreciate your time today, both of you.

    William Oh: Thank you.

    Stephen Freedland: Thanks for having us.

    Published June 7, 2020