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
  • ASCO GU 2021: Cabazitaxel Multiple Rechallenge in Metastatic Castration-Resistant Prostate Cancer: A Therapeutic Option to Increase Overall Survival?

    (UroToday.com) The field of advanced prostate cancer has rapidly progressed over the past 15 years. Prior to the publication of TAX-327, there were no proven life-prolonging therapies for patients with metastatic castration-resistant prostate cancer (mCRPC). Since that time, there have been many new agents that have proven survival benefits including taxane-based chemotherapy, agents targeting the androgen axis, and bone-targeting agents. However, many patients will exhaust efficacious treatment options. Cabazitaxel is typically used in the second-line chemotherapy setting. In a plenary abstract presentation in the Poster Highlights Session: Prostate Cancer session at the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), Dr. Pobel and colleagues assess the feasibility and efficacy of cabazitaxel multiple rechallenges in patients with mCRPC.
    Published February 11, 2021
  • ASCO GU 2021: CTC Counts as a Biomarker of Prognosis and Response in Metastatic Castration-Resistant Prostate Cancer (mCRPC) from the CARD Trial

    (UroToday.com) There have been many advances in the field of systemic therapy for advanced prostate cancer in the past 15 years. While, prior to the publication of TAX-327, there were no available treatments with proven life-prolonging benefits, we now have many treatments available with demonstrable improvements in overall survival. Thus, we now face the question of how to sequence these agents. In the prospective CARD trial (NCT02485691), cabazitaxel treatment demonstrated significantly improved progression-free survival (rPFS) and overall survival (OS) compared to abiraterone acetate or enzalutamide among patients with metastatic castration resistant prostate cancer (mCRPC) who had previously received docetaxel and progressed within 12 months of starting the alternative androgen-axis inhibitor.
    Published March 8, 2021
  • 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
  • Baseline neutrophil-to-lymphocyte ratio as a predictive and prognostic biomarker in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel versus abiraterone or enzalutamide in the CARD study.

    There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691),

    Published August 31, 2021
  • Cabazitaxel activity in men with metastatic castration-resistant prostate cancer with and without DNA damage repair defects.

    Cabazitaxel was shown to improve overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after abiraterone/enzalutamine and docetaxel failure, though benefit by the presence of DNA damage repair (DDR) defects is unknown.

    Published November 9, 2021
  • 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 is Active in Men with mCRPC with DDR Alterations - Karim Fizazi and Mihaela Aldea

    The presence of mutations in DNA damage repair (DDR) genes has been found in up to 30% of men with metastatic castration-resistant prostate cancer (mCRPC). The CARD trial (Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer) where cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling–targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling–targeted agent (abiraterone or enzalutamide). In this conversation, Drs. Karim Fizazi and Mihaela Aldea join Alicia Morgans, MD, MPH highlighting a retrospective multicenter study examining the activity of cabazitaxel in patients with or without defects in DDR genes. Patients with mCRPC, who received cabazitaxel as monotherapy irrespective of their prior lines were included from 15 centers from France and Spain. This study supports the efficacy of cabazitaxel regardless of DDR gene status.

    Biographies:

    Karim Fizazi, MD, Ph.D., is a medical oncologist at Gustave Roussy, and a full professor in Oncology at the University of Paris-Saclay in Villejuif, France.

    Mihaela Aldea, MD, PhD, is a medical oncologist, Institut Gustave Roussy, University of Paris Saclay, Villejuif, France.

    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, and I am a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, Dr. Karim Fizazi, who is a Professor of Medicine and a GU medical oncologist at Gustave Roussy in Paris, France, as well as his colleague Mihaela Aldea, who is a medical oncologist at Gustave Roussy also. Thank you both so much for being here with me today.

    Karim Fizazi: Always a pleasure, Alicia. Thank you for having us with you today.

    Alicia Morgans: Wonderful.

    Mihaela Aldea: Thank you, Alicia.

    Alicia Morgans: Thank you. So I wanted to talk with you both about a presentation that you made at ESMO 2020. It was a really interesting presentation thinking about the use of cabazitaxel in patients who have DNA repair defect alterations. And Before we really dig into that specific work and your presentation, maybe Karim, you wouldn't mind just reviewing for us what the role is of cabazitaxel in the metastatic castration-resistant prostate cancer setting.

    Karim Fizazi: Sure. So cabazitaxel is a well-known drug in prostate cancer. It was developed in the 2000s, and actually, we've been using it quite broadly in the last decade based on Phase 4 evidence that overall survival is improved even in men who have failed castration, but also docetaxel chemotherapy.

    Having said that, during this decade, and because also we had so many other drugs to play with, there was debate as to whether the role of cabazitaxel was still important. And this is why the CARD Phase 4 data was conducted. And versus a Phase 4 arm looking at men who have failed castration, one AR drug which is abiraterone or enzalutamide. One taxane, docetaxel. And what [inaudible] was whether we should use a second taxane or second AR drug. And data came out also at ESMO some two years ago, plus or minus and actually, it was very clear that not only cabazitaxel improves the primary endpoint over radiographic progression-free survival, but also, overall survival when compared versus the second AR drug.

    And actually, it was really fun because I was sitting in the room at this time when the data was presented and just side by side, the CARD data was presented. And then right before, or right after, I can't remember, the PROFOUND data looking at olaparib in pretty much the same population of men with DDR alterations was also shown, establishing the role of olaparib, a PARP inhibitor in a vast population of men. And when we get out of the room at ESMO, everybody was happy, of course, because we had two active Phase 3 trials, and everybody was asking the question, but should we really test patients for DDR alterations and go for a olaparib? Or should we just use cabazitaxel in all comers? And this is why we felt that it was worth it, trying to better understand the role of cabazitaxel in men with DDR alterations.

    Alicia Morgans: Well, thank you for that summary and for that nice memory, I also was sitting in that audience and it was so powerful because these were the presidential symposia, the main presentations, or the most exciting presentations of ESMO and you are right. I think that we saw firmly, or clearly that cabazitaxel, so firmly has this established role, particularly when compared with the second AR targeted agent, and it really improved quality of life outcomes as well. I mean, all of that was so powerful, but the question remained, how should we think about patients, this smaller population of patients who have DDR alterations and Mihaela, are you able to tell us just how did you put this study together in order to try to answer that question?

    Mihaela Aldea: Yes. Thank you, Alicia. So actually we wanted to investigate if cabazitaxel is active in mCRPC patients with, and without DDR defects, and we performed a retrospective multicenter study. We included 15 centers from France and Spain. We included the patients with mCRPC, who received cabazitaxel as monotherapy irrespective of their prior lines. We included those patients who already had an available DDR molecular profile. And actually, we performed two groups, patients with DDR positive tumors and patients where no DDR alterations were found in their tissue analyses. These patients were matched in a one-to-one ratio for the same molecular test and within the same institution in order to reduce the flows of retrospective studies. And in order to make the two populations more comparable.  We assessed the PSA decline in this population, radiographic progression, free survival, and overall survival. And, actually, in the end, we had 190 patients that were included, 95 patients with the DDR alterations and 95 patients without. In the NGS panel, there were various NGS panels, but we choose those patients in which the NGS panel evaluated, at least BRCA, CDK12 ATM, CHEK2, FANCM, PALB2, Ret51, and reaper alterations.

    Alicia Morgans: So that is such powerful work to do, and to really make sure that the DNA repair alterations that you were assessing were actually going to be similar across all of the sites that you included, including several sites in France and in Spain as well, that in itself is a task to really be proud of undertaking. And so I love that you were able to do that, that you were able to make sure that this was a consistent assessment of these DNR repair alterations. And then, you compared actually, before we even get into the results of PSA and radiographic progression you were able to compare your populations. Then as you chose this DNA, these patients who had the alterations and those who did not, and it was interesting, I think, how these two populations really compared to each other across these sites, what did you find?

    Mihaela Aldea: So actually there was a difference in terms of the median age of patients.  We found the younger patients in the DDR positive group as compared to the DDR negative group, actually, DDR positive group had the median age of 66 years and as compared to 69 in the DDR negative group. So suggesting that these patients might have more aggressive disease, but there was no difference in terms of the presence of visceral metastases between the groups or in terms of the performance status, the median PSA, or the Gleason score at the diagnosis. And also these populations are comparable in terms of prior treatments, both groups had a number two median prior lines, but in the DDR positive group, of course, these patients received a significant proportion of cases, PARP inhibitors, and carboplatin. Actually, we had nearly 45% of patients who were treated with PARP inhibitors and 38% who received carboplatin anytime in their disease evolution. Actually, in the DDR positive group, the most predominant alteration were BRCA alterations followed by ATM and CDK12. We did not have the germline status for all the patients, but for those patients where the germline analysis was available, nearly 50% of cases had germline alterations.

    Alicia Morgans: Wow. You know, that's, that's so impressive. The amount of data you were able to collect on those patients. And also very impressive to me that, so many of the patients with DNA repair alterations across these sites actually had been treated with PARP inhibitors or with carboplatin. So very interesting that there was such exposure.  As we think about the results Karim, can you tell us, did cabazitaxel work in these patients who had these DNA repair alterations,

    Karim Fizazi: Right. It indeed seems to be the case. Of course, this is a retrospective analysis. We need to be cautious with the data.  But again, given the methodology we used, just really find the patients who are screened in clinical trials and match them with DDR negative patients. I think we were quite comfortable with the results and indeed the degree of efficacy, as far as we could tell by PSA decline, clinical responses, and time to progression indicates that indeed cabazitaxel seems to be an active drug in men with DDR alterations and mCRPC, which I guess is very reassuring to us because not everybody on earth has access to a PARP inhibitor. For example, carboplatin is cheaper and broadly of a label, but that's not necessarily the case for PARP inhibitor due to approval or cost or whatever reason. So knowing that cabazitaxel remains active in a vast population of men, of course, is very important.

    Now, the question, I guess, we haven't completely addressed due to the methodology, but also to the number of patients we had is what actually is the activity of cabazitaxel in patients who have failed a PARP inhibitor and actually visa versa. We waited on the data, Mihaela can comment a bit more, but from the data we have, it seems that there is at least a degree of cross-resistance, whether it's true cross-resistance or just the fact that the cancer that has already progressed on one drug is more difficult to treat in general oncology. We don't know, but it seems to be the case. Again, this requires clearly more data and hopefully, we'll be able to generate more, but again, Mihaela may comment more on the efficacy data.

    Mihaela Aldea: We need perspective data in order to respond to this question. The limit of this analysis was that the subgroup was very small. We evaluated only 18 patients in the post-PARP setting. So we cannot draw clear conclusions, but it was interesting to note that in the BRCA population, there were 10 patients in the post-PARP setting and neither of these patients obtained a 50% PSA decline in the post-PARP setting. But maybe because they were already in a more advanced stage after significant benefit on the PARP inhibitors, we don't know, we need more data.

    Alicia Morgans: Yes. And just for the viewers who don't have a copy of the poster to really clarify this, I think it was so interesting that the responses to cabazitaxel in terms of PSA and radiographic progression actually seem to be similar among patients who had these DNA repair alterations when compared to patients who did not, but what Karim and Mihaela are really digging into is that the cabazitaxel response rates and progression time seemed to be longer in patients who had the DNA repair alterations prior to their treatment with a PARP rather than after when compared to after. But as Mihaela said, the numbers get so small that it is really difficult to draw any conclusions, but it certainly is hypothesis-generating and why this could be, maybe the diseases, as Karim said is simply more advanced, is more resistant.

    Maybe there is some cross-resistance who knows, but we do know that the drug seems to work and for all of our patients or my patients, my goal is always to get as many lines of therapy into a patient as possible, because, with each line that is effective, that is more time that the patient has as long as the treatments are treating them okay. And we know that these drugs can be tolerable for patients. So very, very interesting, and important to see that the responses are strong, that they are consistent despite these DNA repair defects and more work to be done, for sure. So Karim, is there more work? Is this something of interest that you or others you think will be exploring in terms of sequencing or understanding this more thoroughly and in patients with these alterations?

    Karim Fizazi: Right. I think, and this is a general thing, that we should do more and more. I mean, if I'm comparing this to the current situation and the soon situation, as compared to the situations we were living say, five years ago, we will currently, or we will soon have PARP inhibitors, likely PSMA targeting. cabazitaxel remains there. And we need to better understand whether patients can still benefit from a given treatment when we have exhausted one of them either, because in the PARP inhibitors story because they have DDR defects or say for PSMA targeting because the cancer is expressing PSMA. And I think that taxane may remain active in at least a minority of these men. But again, we need prospective data on that. And that is true for PARP inhibitor, as it will soon be hopefully with PSMA targeting. Those are the data we need to generate again because I'm like you, Alicia, I mean, this is a chronic disease. And when you have exhausted one treatment, you still want your patients to benefit from another one. So we need to try to figure out what is the best treatment to propose in those particular settings. Hopefully, we will generate these trials prospectively.

    Alicia Morgans: Absolutely. Well, to both of you, then just a final question. If you had to summarize Mihaela the results of your study and give a message to the viewers, what would your message be?

    Mihaela Aldea: So my message would be that cabazitaxel is definitely active in mCRPC patients irrespective of their DDR status.  Maybe the overall survival of these patients, maybe of patients with DDR alterations, maybe longer than patients with DDR negative profiles, because these patients are also treated with PARP inhibitors and carboplatin or carboplatin. We don't know if the efficacy of cabazitaxel is lower in men, previously treated with a PARP inhibitor, but this requires validation in a prospective study.

    Alicia Morgans: Well, that is a great summary. We will see, what is left for Karim to put things into context for us.

    Karim Fizazi: She really said everything. Maybe I may just start on a financial thing, which is that I mean, first, it is good news for the patients. We all know that BRCA2 patients, for example, have quite aggressive cancers very often. And having one more line of therapy is obviously good news. Of course, it's not a Phase 3, but the data I think is robust. And as Mihaela said, it very clearly suggests that cabazitaxel is active in these men with DDR positive cancers. And financially speaking, cabazitaxel will soon become a generic drug, which means that the costs will significantly decrease. And again, this will hopefully let much more patients worldwide get access to this agent as it is already the case for carboplatin, for example, for DDR positive cancers. And I think worldwide, this is also very good news.

    Alicia Morgans: I completely agree. Well, thank you both so much for your time, for doing the work that you do, and for sharing your expertise today. I sincerely appreciate it.

    Karim Fizazi: Thank you very much. Have a great day, Alicia.

    Mihaela Aldea: Thank you.
    Published April 11, 2021
  • 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 castration-resistant prostate cancer: post hoc analysis of the CARD study excluding chemohormonal therapy for castrate-naive disease.

    In the CARD study (NCT02485691), cabazitaxel significantly improved clinical outcomes versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen-signalling-targeted inhibitor.

    Published March 22, 2021
  • 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
  • Cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2 trial.

    Treatment for poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting.

    Published April 12, 2021
  • Efficacy and Safety of Cabazitaxel Versus Abiraterone or Enzalutamide in Older Patients With Metastatic Castration-Resistant Prostate Cancer in the CARD Study – Beyond the Abstract

    Despite treatment advances in prostate cancer, it is associated with approximately 79,000 deaths in Europe and 34,000 deaths in the USA each year, presenting a clear unmet need.1,2 Most patients with metastatic castration-resistant prostate cancer (mCRPC) are ≥ 70 years of age and the median age of those who die from the disease is 80 years.3,4

    Published October 25, 2021
  • Efficacy and Safety of Cabazitaxel Versus Abiraterone or Enzalutamide in Older Patients with Metastatic Castration-resistant Prostate Cancer in the CARD Study.

    In the CARD study (NCT02485691), cabazitaxel significantly improved median radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone/enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel and progressed ≤12 mo on the alternative agent (abiraterone/enzalutamide).

    Published July 27, 2021
  • ESMO 2019: The CARD Trial, A Randomized, Open-Label Study of Cabazitaxel vs Abiraterone or Enzalutamide in mCRPC, Discussion

    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 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 2021: Circulating Tumor Cell Morphologic Sub-Types Present Prior to Treatment in the CARD Trial Identify Therapy Resistance

    (UroToday.com) The European Society of Medical Oncology (ESMO) 2021 virtual annual meeting’s prostate cancer session included a presentation by Dr. Johann de Bono presenting data assessing the impact of circulating tumor cell (CTC) morphologic sub-types prior to treatment in the CARD trial.1 In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer who had received docetaxel and progressed ≤ 12 months with the alternative androgen receptor-targeted agent. There is a current unmet need to identify superior monitoring tools of treatment efficacy so that patients do not remain on ineffective therapies when they no longer clinically benefit from them. CTC counts are a validated pretreatment prognostic measure, as well as a validated tool for response monitoring. The objective of this pre-planned CARD EPIC biomarker study was to analyze the morphology of CTC subtypes in a liquid biopsy.

    Published September 18, 2021
  • ESMO 2021: Clinical and Cost Impact of Cabazitaxel vs a Second Androgen Receptor Targeted Agent for Patients With mCRPC Previously Treated With Docetaxel and the Alternative ARTA (Abiraterone or Enzalutamide)

    (UroToday.com) In the on-demand poster session of the European Society for Medical Oncology (ESMO) Annual Congress, Dr. Alicia Morgans discussed a modeling analysis of cabazitaxel compared to repeat treatment with an androgen receptor targeting agent (ARTA) among patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and the alternative ARTA.

    Published September 16, 2021
  • 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
  • Evaluating Circulating Tumor Cells in Patients on the CARD Trial - Eleni Efstathiou

    In the PHASE 4 CARD trial, cabazitaxel significantly improved radiographic progression-free survival (rPFS) and overall survival versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer who had received docetaxel and progressed within 12 months with the alternative androgen-signaling-targeted inhibitor.  

    In this conversation, Alicia Morgans, MD, MPH, and Eleni Efstathiou, MD, Ph.D. highlight a preplanned biomarker analysis of circulating tumor cells in patients on the CARD trial. This was work that the CARD investigators conducted in collaboration with Epic using their technology.  Overall the investigators had 237 evaluable screening samples, 213 samples at enrollment to day 1, and 166 samples at the end of treatment.  As Professor de Bono stated in his ASCO GU 2021 presentation, this CTC count is highly prognostic for overall survival, but not for rPFS. The baseline CTC is prognostic but does not predict the duration of response to the drugs given in this trial, i.e. cabazitaxel or a second of abiraterone after enzalutamide or enzalutamide after abiraterone.


    Clinical Trial Information: NCT02485691

    Biographies:

    Eleni Efstathiou, MD, Ph.D., Associate Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

    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, and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to talk today with Dr. Eleni Efstathiou, who is an Associate Professor of Medicine and a GU Medical Oncologist at MD Anderson. Thank you so much for being here with me today, Eleni.

    Eleni Efstathiou: Thank you so much for having me, and it's always wonderful to be in the presence of a wonderful host and a colleague I really look up to.
    Alicia Morgans: Oh, well, thank you. Well, the feeling is certainly mutual, and I really look forward to you teaching us a little bit more about the CARD study, which continues to give us insights, as we think about the treatment of men with advanced metastatic CRPC. Your team presented some really fascinating information about CTCs among patients in the CARD trial and thinking about responses at GU ASCO 2021. Can you tell us a little bit about that?

    Eleni Efstathiou: Thank you for this opportunity, and really, the CARD trial is a trial that succeeded against a lot, because there wasn't a lot of excitement at first and accruing. As we have discussed previously, physicians were like, most of us in the academia never really wanted to sequence androgen-signal inhibitors, but we had to prove our point and that has been proven. It's a New England paper. But then, the trial becomes a trial that keeps giving, and that was the reason why I participated from the translational biomarker standpoint.

    Now, if we take a little bit of a step back, we should all agree that the circulating tumor cell story, starting a while back, is something that, it's been exciting academically, there's been a lot of beautiful papers. Very consistent. People like Johann de Bono, Howard Scher, have worked for years on all the platforms to prove these points, but it has not caught on, even though we do have one platform available in some centers. For multiple reasons.

    I want to point out that in the case of the CARD study, the one that was used was the Epic Biosciences platform, which I find very fascinating, because it reminds you a little bit of a transition from a tissue to a liquid biopsy. Because what you do is you put those circulating tumor cells, essentially, on the slide. It's like a good old school psychology. And then you've got the ability, not just to count them, but to also assess them with molecular characteristics. And that's going to be a big part of what we're hoping to give out moving forward. So we already had some very nice data from the past, from this platform, suggesting that a conversion to 0, if you can detect them with baseline with any of the treatments available, is the best bet for good solid response and overall survival benefit. Howard Scher was extremely convincing presenting that.

    So, we took that, and it was a predefined analysis, this is not a post-hoc, which becomes super important as well. So it's not just a fishing expedition, is what I'm trying to say. We collected samples at baseline screening, and at least cycle two, and if we could, and we could in a lot of cases, at the end of treatment. This time, we presented the changes from baseline to cycle two, which is an early event, it's just after one cycle, essentially, of treatment and also the association of baseline with outcomes.

    Let's start with the association of baseline with outcomes. Obviously, detectable and high CTC count as a continuous variable associated with a poor outcome in general. When you've got detectable CTCs, we know to tell our patients, "Okay, we've got a big fight ahead of us. This is not a good start." But what becomes important is to look at the conversions again, and we see clearly that a conversion that happens even after one cycle, from a detectable to an undetectable, or even to a lower, is a very favorable readout, and associates wonderfully well with overall survival. Even though it does associate with other biomarkers, such as LDH, PSA, it stands out also, though, as independent in the multivariate analysis. And that becomes important.

    But the new thing that we also looked at, is specifically at those circulating tumor cells that are high cytokeratin-expressing, and the clearance of those CTCs was double in the active arm, which was cabazitaxel, versus the enhanced androgen-signaling inhibition, which also becomes important. It points to the fact that we need to look at specific CTCs. So hopefully ASCO, or another meeting, ESMO, we're going to be reporting more on specific biomarkers within those CTCs.

    Alicia Morgans: That's really fascinating and so important, and as you said, I think it's interesting that it's the Epic Biosciences platform. I think I've heard them describe it as 'no cell left behind'. They truly are able to evaluate the morphology, they're able to really, obviously, count the cells. But to dig more deeply, I'd love to hear your thoughts on what do you think is happening with these cytokeratin-positive cells? You mentioned that these may be the ones that we need to watch for. What do you think the biology is there?

    Eleni Efstathiou: It's been something that I've looked back in the literature for the past 10 years, several investigators have been looking at high cytokeratin across solid tumors, and the data is very conflicting. What I can tell you is that what we need to look at, and it could be an epiphenomenon that's more speaking to multiple genomic events within those specific cells. We don't know. We have to look at it more carefully, because if you look at older studies with different technologies, and as we know, assay is very, very important, they do not really speak to our finding. Which again, I say, it's a predetermined perspective, we can call it ambispective because we went back and looked at results. It's the first of its kind, so a lot more to come.

    And I think, again, if somebody is really interested, I would recommend, go look at the poster, go listen to Johann, present it and speaks to that, 'no cell left behind'. And remember, the good thing about this platform is you can store those slides in your freezer, and when the time comes or you've got a new biomarker, go check them, exactly like you do with paraffin-embedded formalin-fixed tissue.
    So with that in mind, I wanted to bring up another point that's close to what we were saying about new, interesting things. Remember, we were talking earlier about the importance of sequencing of treatments before we started this discussion, and essentially, for years, all of us have been fighting to get enhanced androgen-signal inhibition early, early, early on. Now, if you look at the table of the results here, you'll see that interestingly, tumors that had been treated first with docetaxel and then with an enhanced androgen-signal inhibitor, actually had a higher percentage of circulating tumor cells detectable. 62% of the tumors had detectable CTCs. Whereas if you have tumors that had first been targeted with abiraterone and enzalutamide then with docetaxel, only 30% of these tumors had CTCs.

    Does that speak also to the biology and the need to have the right sequence to avoid further events of resistance? I would say, yes, it has to be proven in a similar fashion like what we're seeing with high of cytokeratin.

    Alicia Morgans: Again, that is fascinating, and thank you for your point about the way that we can store these slides and come back later, because I do think this is something that you and the team are really, of course, whetting our appetite, because now, hopefully we'll be able to go back, do some multi-variable models looking at cytokeratin and the sequence of therapy. You may be able to provide even more insights over time as we continue to struggle to sort out what the best sequence is, which may vary on some clinical characteristics or some patients characteristics, but may also be informed by CTCs and other molecular markers that we are still developing.

    So, I love that you're able to continue to analyze the CARD data in this way, and hopefully inform more than just a single treatment period in time, but perhaps the sequence of treatments that patients have received preceding the addition of cabazitaxel. It's really fascinating. As you think about just sort of summarizing this particular analysis, your findings and where they actually fit in the treatment landscape, what would you say?

    Eleni Efstathiou: I would say that, first of all, this clinical experiment actually confirms the efforts that started years ago by people like Howard Scher. He was the first to work with them and to be very enthusiastic, and we have to give that to him. He was fully dedicated to it. And being linear and committed pays off, even though it's so hard. So we're cashing in now and we're seeing that, actually, if you used such a liquid form of biopsy, you might be able, beyond just prognosticating it if your patient is in trouble, you might be able to, early on, tell the patient, where you can't tell the PSA, that, "We're good. You're responding." Remember, 30% of patients who are treated with taxane will have this flare phenomenon. You can't tell, you just need to keep on going.

    And inversely, within this trial, we saw that also those who had a rise in their circulating tumor cell count early on, they did not perform well. So we can put you on the alert to monitor that patient more carefully. We might be able to bring on having a good biomarker to trace when PSA is not helpful, the responsiveness and the early responsiveness of treatment. Furthermore, as you suggested, clearly, this is the opportunity to use CTCs to actually characterize a tumor and sequence accordingly.

    Alicia Morgans: I think that's fascinating, and I so appreciate your insights. As we continue to do work in prostate cancer, I think we continue to recognize that cancers and the people in whom they dwell are all biologic systems. We just keep peeling back these layers of biology, and hopefully, at one point, we'll be able to read the book more clearly. So, thank you so much for your time, for your efforts, for your explanations. We really, really appreciate you.

    Eleni Efstathiou: Thank you. Thank you for having me. Always a pleasure.
    Published March 6, 2021
  • 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
  • Real-World Evidence of Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Cabazitaxel: Comparison with the Randomized Clinical Study CARD - Beyond the Abstract

    The CARD study results were reported at the 2019 ESMO meeting and simultaneously published in the NEJM. CARD investigated the efficacy and safety of cabazitaxel as compared with an androgen-receptor-signaling inhibitor ( ARSI; abiraterone or enzalutamide), in patients with mCRPC who were previously treated with docetaxel and had progressed within 12 months while receiving the alternative inhibitor (abi or enza).
    Published February 1, 2022
  • Real-world evidence of patients with metastatic castration-resistant prostate cancer treated with cabazitaxel: comparison with the randomized clinical study CARD.

    The CARD study demonstrated superiority of cabazitaxel over abiraterone/enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who received prior docetaxel and progressed ≤12 months on the alternative androgen-receptor-targeted agent (ARTA).

    Published January 20, 2022
  • 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 K. Oh, MD, Chief Medical Officer (CMO), of the Prostate Cancer Foundation (PCF).

    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