Therapy Resistance Identified in Circulating Tumor Cell Morphologic Sub-Types Present Prior to Treatment in the CARD Trial - Cora Sternberg

October 15, 2021

Alicia Morgans and Cora Sternberg discuss the ESMO 2021 presentation on the impact of circulating tumor cell (CTC) morphologic sub-types in blood samples prior to treatment in the CARD trial. The objective of this pre-planned CARD Trial, EPIC biomarker study was to analyze the morphology of CTC subtypes in a liquid biopsy looking at chromosomal instability. Dr. Sternberg highlights the findings from this study Dr. Sternberg considers this as a future option we could potentially use as a screening tool to decide who should receive cabazitaxel and who should not.


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, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston. I'm so excited to have here with me today, a good friend and colleague, Dr. Cora Sternberg, who is a Professor of Medicine and the Clinical Director of the Englander Institute for Precision Medicine at Weill Cornell Medical College, and Cornell University in New York City. Thank you so much for being here with me today, Dr. Sternberg.

Cora Sternberg: It's a pleasure to be here with you, Alicia.

Alicia Morgans: It is always my pleasure and it's always exciting to have you, especially to talk about some of the big trials you've been involved in. Today, we are going to talk about some work that you and your team have done looking at CTCs within the CARD study, which is, of course, information that you and the team presented at ESMO 2021. Before we dig into what you presented, can you remind all of us, briefly, what was the CARD study?

Cora Sternberg: Basically, the CARD study was looking at the sequencing of therapy in metastatic CRPC, and patients had already received either abiraterone or enzalutamide, and they were patients who actually did not respond for more than 12 months and they had also received docetaxel. They were randomized between cabazitaxel and then the other novel androgen receptor therapy. What was seen in that study was the patients who received cabazitaxel did much better than the patients who received enzalutamide or abiraterone. There was a difference in radiological progression-free survival and in overall survival. And this has been presented many, many times.

What was presented now at ESMO was looking at the circulating tumor cells in blood samples that were collected first at screening, and then during therapy, in a subset of the patients. What we saw was that we sent these CTCs to Epic Sciences for analysis. We looked at chromosomal instability, which was defined as having at least three CTCs with chromosome instability, and we also looked at patients having abnormalities that were associated with and looked more like neuroendocrine prostate cancer.

What we found in this study was that if patients had chromosomal instability, and if they either got worse or it didn't change, those patients on cabazitaxel did not benefit from cabazitaxel. The patients who were on hormonal therapy, no matter what they had, just did poorly anyway, whether or not they had chromosome instability or not. But it was very clear that the patients on cabazitaxel who had that chromosome instability did not do very well. Likewise, patients who had a neuroendocrine phenotype also did not benefit from cabazitaxel at all, not really very much. Patients really benefited who had CTCs that were without the chromosome instability and without a neuroendocrine phenotype. So this was an interesting study, it's retrospective, looking at the CTCs, and perhaps in the future, we could use this at screening to decide who should receive cabazitaxel and who should not.

Alicia Morgans: That is really fascinating, and I have to say, I'm a little surprised that the patients with chromosomal instability wouldn't necessarily be affected by chemotherapy. But it is what it is. And it's interesting because I think of these neuroendocrine, in particular, as being on a spectrum towards small-cell. There is a phase two study that is going on right now called CASCARA that is looking at the combination of cabazitaxel and carboplatin to see if that combination, then followed by abiraterone, may be a good way to capture more patients who have progression on chemotherapy. It seems like this might suggest that is potentially where we could go, although of course, neuroendocrine is not small-cell cancer, we know small-cell, again, on the spectrum can be affected by platinum.

Cora Sternberg: I'm not really sure what this means, because this is the neuroendocrine phenotype in the CTCs. And as you know from the work by Ana Aparicio at MD Anderson, cabazitaxel and carboplatin are a good combination, it's a combination that we use in patients with neuroendocrine prostate cancer. So I'm not really sure what to make of this. I guess we're just selecting out a poor part of the patient group. These were patients with adenocarcinoma who had cells that showed this neuroendocrine phenotype, and the cabazitaxel alone in those patients had lower response rates and just didn't do as well as those who didn't have it. So I think we're probably just selecting out a poor phenotype. Not to say that other trials will not work.

Alicia Morgans: Absolutely. I really appreciate that and I just think it's interesting that we learn more and more from the analyses we do in the trials that we run, and I really love that you are doing this biomarker work to help us pull all that we can from this data and really inform patient decisions. If you had to sum it up and give a message to listeners, what would that be?

Cora Sternberg: Well, I think the phenotypic diversity that you can find in circulating tumor cells just shows that there are many different mechanisms of resistance to therapies, to chemotherapy, and even to endocrine therapy, and I think that we should look more into that and look at those mechanisms of resistance, and perhaps CTCs is one way of doing that.

Alicia Morgans: I could not agree more. I appreciate your continued devotion to enlightening the field, and of course, the work that you do, and all the patients that you help. We appreciate, of course, your expertise as well tonight, so thank you so much for your time.

Cora Sternberg: Thank you, Alicia.
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