Ep. 13: Avoiding Repeat Lines of AR-Targeted Therapy in mCRPC



Neal Shore, MD, FACS: Alicia, can we move to the CARD trial? What’s the implication? It goes back to our comments about switching therapy and perhaps the pervasiveness that we oftentimes see switching 1 oral AR [androgen receptor]—targeted agent for another. Tell us about the CARD trial, which was very important at ESMO [European Society for Medical Oncology Congress] 2019.

Alicia K. Morgans, MD, MPH: The CARD trial included patients with metastatic CRPC [castration-resistant prostate cancer] who had previously received docetaxel chemotherapy and 1 of the AR-targeted agents and had continued to progress. It’s interesting: they could have progression by PSA [prostate-specific antigen], by pain or clinical features, by radiographic progression, or by any combination of those. It wasn’t necessarily just radiographic progression. Patients had to have not been treated with an AR-targeted agent for longer than 12 months. It was a specific population that seemed to have a more aggressive phenotype, or at least a phenotype that was not as sensitive to AR-targeted therapies.

They were randomized to treatment with cabazitaxel at the standard dose from the initial label, 25 mg/m2—they were given Neulasta [pegfilgrastim] as well—versus the other AR-targeted agent that they had not previously received. They were followed for radiographic progression and overall survival.

What is really interesting is that it was very clear that cabazitaxel had a very demonstrable benefit in terms of radiographic progression-free survival, as well as overall survival, in this trial as compared with that second AR-targeted agent. The second AR-targeted agent showed radiographic progression sometime around 2½ months, which suggests that it was essentially at the first scan that at least 50% of the patients were progressing. We heard quality of life seemed to be better in the patients treated with cabazitaxel, perhaps because the disease was better controlled. There was also better pain response in those patients.

The other thing I found to be interesting is that there were more grade 5 adverse events in patients treated with the AR-targeted agents than with cabazitaxel. We think a lot about the toxicity of cabazitaxel in the United States. The label is actually 20 mg/m2 for most patients, and certainly we can start with that and increase the dose if we want to. Most patients, at least in my clinic, start at 20 mg/m2 rather than 25 mg/m2. But even at 25 mg/m2, there were more grade 5 events with the AR-targeted agents.

This suggested to me—and really is 1 of the reasons for my comments on switching mechanism of action—that AR-targeted agents back-to-back are not going to be so effective. At the same ESMO 2019 meeting—I don’t know if it was just before the CARD data or just after—we saw Maha Hussain present the PROfound study, a phase III trial. It was selective for patients with DNA-repair defects.

These patients had mCRPC [metastatic CRPC], and they had progressed on at least 1 chemotherapy and at least 1 AR-targeted agent. They were randomized for treatment with olaparib versus the second AR-targeted agent. We saw in those patients a very similar radiographic progression-free survival for the AR-targeted agents, which might have been around 3½ months. These were not patients who were selected to have more rapid progression on an AR-targeted agent. There was no requirement regarding 12 months on a previous AR-targeted agent. To me, this just drives home the message that AR-targeted therapy after AR-targeted therapy, which is what we use at this point, is just not the right thing to do.

Neal Shore, MD, FACS: That’s a very profound point. Pedro, do you have any thoughts about that? I also want to remember to throw it back to Nancy, who can talk about PARPs in a second.

Pedro C. Barata, MD, MSc: I fully agree, and it’s not a coincidence that we saw the CARD data published in 1 of the major journals used by all of us, because it’s really practice changing. All of us used to have patients who progressed on abiraterone and got enzalutamide or vice versa. I should mention the study by Kim Chi that asked the question prospectively, is 1 sequence better? Does sequence matter? The study showed it does not impact second-line rPFS [radiographic progression-free survival], meaning if you start abiraterone followed by enzalutamide or if you start enzalutamide followed by abiraterone, in terms of disease on the scans with the second agent, there was no difference found. It’s a small phase II trial, but it’s a good concept that was put on paper. We conducted a study that was a consequence of what we were all doing in real life.

Going back to CARD, it’s a European study. It was good for them because they were able to do it. The reason I mention that is we were just talking earlier today about what is really a third-line CRPC study in the sense that less than 20% of patients received docetaxel in the castration-sensitive setting, which means that the majority of the patients had received docetaxel and abiraterone or enzalutamide in the castration-resistant setting. These were patients who were perhaps treated pre-CHAARTED and pre-STAMPEDE. To me, that’s relevant because—in our discussion with colleagues in the different places that we work—I do see treating physicians shifting the way they see this disease and using cabazitaxel sooner rather than later after the data were presented. Those were very important data, and I’m glad the study was done in that way.

Nancy Ann Dawson, MD: I think the point you’re making is also the point we have to make to the patient. It’s easy—as you said, most of us do it—to use abiraterone and then enzalutamide or enzalutamide and then abiraterone, even though the response rate to the second AR-targeted therapy is around 15% at best. We still used it, and a lot of that sequencing was used because the patients said, “Well, I don’t want to get chemotherapy. Isn’t there another oral drug you can give?” Now not only do you know the data, but you can also share it with your patient. Say, “Well, we could do that, but your response rate, your quality of life, and your pain response will be better if we go straight to the chemotherapy.” They’re all assuming that quality of life is going to be worse. Now we can say “No, we have data. Not only is your response rate going to be higher, but the quality of your life is also going to be better.”

Alicia K. Morgans, MD, MPH: It’s patient-reported data too, which is most compelling for patients. It’s not just the physician or CTCA [Cancer Treatment Centers of America] and the adverse events that they’ve recorded. It’s actually the patients themselves saying that it’s better.

Transcript Edited for Clarity

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