CHAARTED 2 Study Shows PFS Benefit with Cabazitaxel in Metastatic Prostate Cancer in Phase 2 - Christos Kyriakopoulos

June 11, 2024

Alicia Morgans sits down with Christos Kyriakopoulos to discuss the findings from the CHAARTED 2 trial. This study builds on the success of the original CHAARTED trial, focusing on combining standard therapies with second-line chemotherapy to improve outcomes for patients with metastatic castration-resistant prostate cancer. Initiated in 2018 and completed amid the challenges of the COVID-19 pandemic, CHAARTED 2 investigates the addition of Cabazitaxel to the standard treatment of Abiraterone and Prednisone. The trial shows a significant improvement in progression-free survival for patients receiving the combination therapy, despite no observed benefit in overall survival. Dr. Kyriakopoulos highlights that Cabazitaxel is particularly effective in patients who rapidly progress after androgen deprivation therapy, emphasizing the need for tailored treatment strategies. Future analyses will explore molecular and imaging biomarkers to deepen understanding and optimize treatment.


Christos Kyriakopoulos, MD, Oncologist, Division of Hematology, Medical Oncology and Palliative Care, University of Wisconsin, WI

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA

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Alicia Morgans: Hi, I'm so excited to be here today with Dr. Christos Kyriakopoulos, who is joining me from the University of Wisconsin-Madison, as well as ASCO 2024, where he presented the CHAARTED 2 data, which is very exciting. Thank you so much for being here with me today.

Christos Kyriakopoulos: Thank you very much, Dr. Morgans, for the invitation. I'm really excited to be here.

Alicia Morgans: Well, I am always excited to talk to you, Christos. And I'm really excited to talk about the CHAARTED 2 study, which has been a labor of love, a work in progress for so many years. Right? Can you tell us the impetus to design this trial? And then what was the design?

Christos Kyriakopoulos: Yeah, thank you first of all for giving me the opportunity to talk about CHAARTED 2. That's like a trial that I have been working on for a very long time.

Reflecting back to how we came up with that idea, I remember I was a first-year faculty when we started designing the study and when we first talked to ECOG about that concept.

So CHAARTED 2, basically we picked a name as a direct reference to the original CHAARTED. So everybody was excited about the CHAARTED results back in 2014, 2015. It was like a groundbreaking study that showed for the first time a significant improvement in the overall survival of patients with metastatic castration-sensitive disease.

Of course, a lot of things have happened since then, and the treatment landscape has changed dramatically, I would say. So we know that these are the bad players, meaning the patients with the worst prognosis in a way.

So the question was early use of those attacks, how does that change subsequent lines of therapy?

And of course at the time when we designed CHAARTED 2, the available treatments probably like most of the people post-CHAARTED, were using either Abiraterone or Enzalutamide. These were the two second generation androgen receptor inhibitors that were available. So the question was can we do any better? And that's how the CHAARTED 2 idea came up and the idea was to combine what was considered standard of care, which is either Abiraterone or Enzalutamide with a second line chemotherapy, which is Cabazitaxel.

Of course, at the time of the design of the study, we only had safety data for the combination of Cabazitaxel with Abiraterone. So that's why we designed it that way in a way. Of course there were some clinical data that support the idea that maybe lowering the antigen levels may have a synergistic effect with taxanes. That was another reason to consider combining Cabazitaxel with Abiraterone.

The concept first time presented to the ECOG- ACRIN group in 2015. Eventually the study was activated in February of 2018. First patient study May of 2018, and last patient study April of 2021. Something important is that, as we all know, February March, 2020, we were hit by pandemic and this is a study that includes chemotherapy treatment with chemotherapy. About 80 to 90% of patients were enrolled during the pandemic, but still we were able to finish the study on time, actually one month earlier compared to what we included in the protocol. In the protocol, we said 36 months. We finished the study in 35 months.

Alicia Morgans: Congratulations.

Christos Kyriakopoulos: Thank you.

Alicia Morgans: Congratulations. Let's just reiterate, all patients had ADT Docetaxel, and what were the arms to which they were randomized?

Christos Kyriakopoulos: So it was a requirement for all patients to have received at least three cycles of Docetaxel for castration-sensitive disease. The design was pretty straightforward, so patients in our May received Cabazitaxel at 25 milligram per meter squared for up to six cycles, plus standard dose Abiraterone and Prednisone, and the control arm was just like a standard dose like Abiraterone and Prednisone.

A question that came up was about the dose of Cabazitaxel, and I know that most of us are using the lower dose, but the idea was that we wanted to eliminate as many resistant clones as possible and based on the PROCELICA, we know that the higher dose, some of the parameters in the study like PSA response actually was better with a 25 milligram dose. Eventually, we decided to do the 25 milligram dose. Even though of course for patients who could not tolerate the higher dose, dose modification was permitted.

The primary endpoint of the study was progression-free survival, either radiographic or defined by clinical progression, and of course, we continue to follow the patients for overall survival. Some other important secondary points were like PSA response, time to PSA progression, of course, safety and tolerability of Cabazitaxel and Abiraterone.

Alicia Morgans: Wonderful. Well, I want to just take a moment and reflect back what you said a minute ago. The way that this was enrolled and the way that patients were followed during the pandemic, congratulations to you and to the patients, particularly with that Cabazitaxel dose being 25 milligrams per meter squared. Neulasta was permitted and included in this study.

Christos Kyriakopoulos: Correct. So basically our recommendation was for the investigators to follow their institutional guidelines. We didn't mandate the use of growth factors, but I'm pretty sure that people used them as needed.

Alicia Morgans: Okay, and what did you find?

Christos Kyriakopoulos: As I said, the primary endpoint of the study was progression-free survival. So the study was positive for the primary outcome. There was a statistically significant difference of five months in favor of the patients who received Cabazitaxel, which to my mind is also clinically relevant and important.

Of course, we also saw a better PSA response. These patients had a lower PSA nadir, which is a prognostic-like feature for patients with metastatic prostate cancer. Time to PSA progression was also longer for the patients who received Cabazitaxel.

However, there was no overall survival benefit. The patients did exactly the same. So for RNA, it was 25 months versus 26.9 months, and actually looking at the Kaplan-Meier curves, they run in parallel. Again, there are a lot of reasons for that and again, maybe the regimen is not prolonging survival, but also we need to take into consideration that this is a small study and also patients had access to other life-prolonging therapies upon progression of the Abiraterone.

So Cabazitaxel is available for those patients and most likely the patients upon this progression did receive additional therapies. I suspect even though we don't have that data, I suspect that some of these patients also have received treatment with lutetium because lutetium became available in the US sometime around probably 20, 21, 22. So I suspect that patients did and also all these patients were in academic centers, so probably they also participated in clinical studies.

Alicia Morgans: Despite not finding the difference in overall survival, I think that the study is clearly important for multiple reasons. One of them being demonstrating again, the difficulty in demonstrating an overall survival benefit when we have an earlier-line intervention, this being first-line metastatic CRPC, and we do have all of these other therapies as well as clinical trials available to patients as they continue to progress.

And to your point, patients involved in an academic clinical trial like this are, I think, more likely to get engaged with ongoing clinical trials and potentially have access to things that aren't even out yet per standard of care, things like Lutetium PSMA 617.

The other thing that I think is so important is that we, or I see at least from community colleagues and from others, the consideration of adding chemotherapy to an Abiraterone backbone in some situations perhaps after progression on Docetaxel.

I've seen these intensified strategies used in situations outside of the metastatic hormone-sensitive setting where we know that piece one demonstrated a benefit. I think this study demonstrates that although there might be a PFS benefit and perhaps if that's the goal, if the goal is quick control and that burst of disease control and need for management, there may be some value there. But when it comes to the end of the line with all of the therapies that may come after this, it may not be the most effective strategy.

In any event, from my perspective and my cursory review, we're still waiting of course for the manuscript. I still think this is such an important study, negative or positive from a survival standpoint, it continues to teach us a lot.

Christos Kyriakopoulos: Correct. Correct. So that Cabazitaxel is active. Also, an important take-home point is that actually what we saw is that Cabazitaxel was more effective in patients, for example, who had quick progression on androgen deprivation after treatment with Docetaxel. Also, as I said, we saw a better PSA response with Cabazitaxel. We know that that's a prognostic factor, so maybe not everybody needs treatment intensification. So maybe somehow we can select patients based on PSA or other parameters, and then pick the patients that we know that are not going to do well and then offer them a more, so to speak, aggressive treatment.

Alicia Morgans: Absolutely. So will there be ongoing work within CHAARTED 2 looking at molecular factors? Are there clinical factors for further analyses that we can continue to learn from this really rich amount of data?

Christos Kyriakopoulos: Absolutely. Absolutely. So as part of the study, we did include two correlative studies. One is circulating tumor cell analysis for splice variant seven. We didn't see that, actually we don't have that data yet. So this is work in progress. We collected CTCs at three time points, baseline, week 12, and time of disease progression.

So we are going to learn more about the mechanism of resistance and of course for patients who are already resistant to second to Abiraterone in this case to see whether the addition of Cabazitaxel could potentially change the molecular profile of these patients in a way like restoring sensitivity to Abiraterone. The second correlative is like disease assessment using sodium fluoride. So that was like a sub-study of CHAARTED 2. We only initially, like our plan was to enroll about 50 patients with bone-only disease.

Eventually for different reasons we ended up enrolling less, but still, it's a fair number of PET scans that we have already started analyzing and hopefully we will have those results for a future meeting. Maybe like GU-ASCO next year or we'll see as part of the study. We also collected plasma again at three time points, baseline, week 12, and time of disease progression. So we also have some ideas and we have already started sending some proposals and hopefully, we're going to like secure funding to do this additional work.

Alicia Morgans: Fantastic. Well, we will not hold you to the timelines you mentioned, though I may tease you off-camera about them and make sure that we get those in. But I would say there's a lot of rich data that will come, whether that is a blood-based correlative, whether it's an imaging biomarker standard, we will be able to learn so much. I think it is really wonderful and such a testament to the work that the team was able to enroll a chemotherapy-based trial that actually included a higher dose of Cabazitaxel than many of us use in clinical practice during a pandemic, complete enrollment, complete follow-up, and present. This is of course why you were given that oral presentation and fantastic work. Thank you so much to you and your colleagues.

Christos Kyriakopoulos: Thank you, Alicia. Thank you very much.