Therapeutic Sequencing for CRPC Based on Recent Data
Panelists: Joe OSullivan, MD, Queens University; Nicholas James, MBBS, PhD University of Birmingham; Noel Clarke, MBBS, Christie Hospital
Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: With regard to radium-223 after the ERA 223 study, comparing the European label with the United States label, the big difference is restrictions on abiraterone [acetate] [Zytiga] combinations. In Europe, we’re looking at restrictions after second-line therapy and recommending it for patients who have a higher volume of metastatic disease. How do you think this is going to affect your practice, Noel? Do you think it will affect your use of radium-223? How do you define a line of therapy? If a patient has up-front docetaxel, would that count as a lone therapy for when they become castrate resistant?
Noel Clarke, MBBS, FRCS, ChM: We work our way to this. What we know is that the clinicians are working on instinct. You use docetaxel in your patients who are hormone sensitive. You will tend to use abiraterone second line, or enzalutamide [Xtandi], and vice versa. When clinicians were [questioned] about this in the advanced-prostate setting, they were asked what they would administer as a first-line therapy. My own feeling is that I regret the pushing of radium-223 further back in that disease cycle. It’s going to have better benefit further up; that’s how we would still view it.
Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: In my practice, it most likely comes after a novel hormonal agent in the next line. What’s your situation?
Nicholas James, MD: If somebody has a rising prostate-specific antigen, metastatic disease, and no symptoms, there is [a] split answer as to whether you should administer hormone therapy. If you shifted it slightly and said the patient is symptomatic, or the patient has a short response to their first-line hormone therapy, it flips in favor of chemotherapy. The more symptomatic, the more hypothetical the case. What people use first certainly varied according to the exact nature of the metastasis.
Those with high-volume disease and a high progression rate tend to revive chemotherapy as their first-line treatment. It’s reasonable to then give radium as the second treatment in that setting. There’s enough wiggle room in the European [Society for Medical Oncology Clinical Practice] Guidelines around eligibility and feasibility, which you can choose to do. We know that if you shut it down too late, especially in the patients who are rapidly progressing, they’re going to get liver metastasis. You can treat soft-tissue disease with abiraterone and enzalutamide but not radium-223. It makes sense to use [them] before you’ve got it, otherwise you’ve lost the therapy.
I would like to ask another question regarding docetaxel up front. What are you treating if you’re not treating the castrate refractory component. You reduce the rate of CRPC complications by giving it up font. I would do that as a line of therapy, which I think is quite legitimate. If you look at the wording, it says, “treatment for CRPC.” In reality, it doesn’t change things much.
Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: How do you define eligibility? Is there room for flexibility?
Nicholas James, MD: Yes, particularly in relation to chemotherapy. If you use a novel hormone therapy first line and you’re working in the United Kingdom, you can’t give a second one. Your second therapy has to be either chemotherapy or radium-223. If you’re not eligible for chemotherapy, there’s a system [to] determine that. The European Medicines Agency [EMA] is clear that those patients can have radium. You have to remember that if you’re administering chemotherapy first line, you’re hard-pressed to say somebody not eligible for abiraterone or enzalutamide can have radium-223. That’s a tougher argument to run.
Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Yeah.
Nicholas James, MD: Then you’d answer what the patient wants in terms of timing. The patient not wanting it yet is a reason.
Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I completely agree. Would you agree with that, Noel?
Noel Clarke, MBBS, FRCS, ChM: Yes. You’ve got to have a discussion, which is to put this into language that they can understand. It’s confusing enough for clinicians—imagine what it’s like for a patient. We need to help them as much as possible with the decision-making process.
Nicholas James, MD: I thought the EMA made a great evidence-based decision because, if you have an up-front novel hormonal therapy, there [are] no data as to whether you should give docetaxel with radium-223 or docetaxel with cabazitaxel [Jevtana]. There’s absolutely no data on the proper sequencing.
Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It needs to be a patient-driven decision.
Nicholas James, MD: It seems strange to say you have another treatment first line when the ALSYMPCA trial came out. Half the patients didn’t have chemotherapy, which then had to be forced before you can give radium-223. It’s not borne out by any data whatsoever that I’m aware of.
Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: There is one ongoing clinical trial combing radium-223 with a novel hormonal, which is the PEACE III [MB1] trial combing enzalutamide with radium-223.
Nicholas James, MD: I applaud what they’re doing. It’s a good question to address, and I think they’ve kept their nerve and continued the study. They’ve [done] what perhaps other researchers should have done, which was add the bone-protecting agent. The independent data monitoring committee (IDMC) will look carefully at bone-related incidences. I’m glad they’re doing it; it’s a terrific trial group.
Noel Clarke, MBBS, FRCS, ChM: Yes. We have no insight track on this, but the IDMC must have looked at the safety data very carefully.
Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It’s encouraging.