Combination Treatment Strategies with Radium-223 for mCRPC - Michael Morris

July 10, 2022

Michael Morris joins Alicia Morgans in a discussion on combination therapies with Radium-223 for treating metastatic castration-resistant prostate cancer (mCRPC). Radium-223 is a bone-targeted alpha therapy and has been shown to prolong survival in patients with symptomatic mCRPC to the bone. Drs. Morris and Morgans highlight the DORA trial and focus on how combinations of treatment that either work by similar or different mechanisms of action can really amplify the survival benefits that we see with monotherapy approaches. The idea is targeting tumors and targeting the bone with therapies that don't have overlapping toxicity can be beneficial to patients and prolonged survival. The DORA trial is currently accruing at many centers in the United States and in Netherlands.


Michael Morris, MD, Medical Oncologist Clinical Director, Genitourinary Medical Oncology Service & Prostate Cancer Section Head, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

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, I'm so excited to be at ASCO 2022, speaking today with Dr. Michael Morris. Thank you so much for speaking with me.

Michael Morris: Thank you for having me, Alicia. It's a pleasure to be here.

Alicia Morgans: Wonderful. And a pleasure to talk with you. And I wanted to talk with you about combination therapies with Radium-223. I know you're the PI of one of the exciting trials, the DORA trial. Can you tell me a little bit about what the thought process is as you're thinking about these combination approaches? Why are you doing this and how do you make those rational combinations?

Michael Morris: Whether you're talking about chemotherapy or radiopharmaceutical therapy, we don't have any monotherapy in prostate cancer that's curative. And we have plenty of examples, how combination therapy is salutary to patients over and above one treatment alone. We only have to look at the entire arena of castration sensitive disease with abiraterone and enzalutamide, apalutamide. And now with triple therapy with PEACE-1 and ARASENS.

How combinations of treatment that either work by similar or different mechanisms of action can really amplify the survival benefits that we see with monotherapy approaches. That philosophy is being applied here in DORA to the idea of doing a compartment based therapy in which we treat the bony compartment, which basically hosts most metastatic disease in prostate cancer with tumor directed therapy in the form of chemotherapy. Both drugs alone, prolong survival, the drugs combined together are well tolerated, as we showed in earlier studies. And so the idea is targeting tumor and targeting bone in with therapies that don't have overlapping toxicity can be beneficial to patients and prolonged survival.

Alicia Morgans: And we've seen that in other solid tumors, where we combine different drugs together and certainly have a synergistic effect, not just an additive effect. And, so tell me a little bit about the DORA trial. Where does it stand in terms of its ongoing process?

Michael Morris: DORA is accruing at many centers in the United States and in Netherlands. We're actually looking to onboard several other countries. The patient population is metastatic CRPC. They do not have to have exclusively bony disease. They can have a fair amount of nodal disease, just asymptomatic nodal disease, and a limited amount of visceral disease as well in order to be eligible for the trial. They have to be chemotherapy candidates, because everybody does get docetaxel. It's a randomization of docetaxel versus docetaxel and radium. Radium is given every other dose of docetaxel and docetaxel is given to a maximum of nine treatments. And it is accruing well and patients are tolerating it well. I'm blinded to any interim results just as the PI of the trial, but DSMB, as a number of times said, "Keep on going." And so we are, it's going quite well.

Alicia Morgans: When I remember there was a phase two trial that looked at these, or maybe it was a phase 1b to-

Michael Morris: Phase 1/1b yes.

Alicia Morgans:A 1/1b. And it was a number of years ago though. And it really nicely set up this ability to roll into this larger trial. And it was, I think, looking at the dosing of docetaxel to try to make sure that you had an effective but safe dose. So what are the doses that you're giving of these drugs?

Michael Morris: So on the monotherapy arm, patients get the standard 75 milligrams per meter squared. On the combination arm we found in the early faced study that given 75 milligrams per meter squared with full doses of radium did lead us to believe that there was an excess amount of neutropenic fever. So we're using the step down dose of 60 milligrams per meter squared for the chemotherapy component of the combination arm.

But when you look at the cumulative doses, the cumulative dose exposure to docetaxel in that early study, they were pretty close to each other. That is, docetaxel at 60 and radium at its full phase three or FDA approved dose, is actually better tolerated from a heme perspective than doce at 75. So patients in the early phase trial actually got more doses at 60. And so the chemotherapy deficit is pretty small, comes within a dose basically of the monotherapy arm. We're using that same approach basically for the phase three and the DORA trial. And again, we see that it's quite well tolerated. And I can't say right now whether the total cumulative exposure to docetaxel is the same in both arms, but that's something that we'll see.

Alicia Morgans: Well, great. Well, one of the other things I thought was very interesting from that phase one trial is that the PSA responses seemed to be pretty robust with the combination. Can you comment on that at all?

Michael Morris: Yeah. We looked at a number of biomarkers. We looked at both PSA and as well, bone biomarkers, both of resorption and of deposition, and all of those biomarkers looked more profound and more prolonged in combination than they did with docetaxel monotherapy, as did median progression free survival. And so that's why ultimately we went to phase three.

Alicia Morgans: Wonderful. So as you think about this combination of radium with docetaxel, is there an attention in this trial to bone health?

Michael Morris: There is, yeah. We follow pretty meticulously all of the fragility fractures, SSEs, pathologic fractures, and as well track all of the bone protective agents that patients are on. There's very strong language in the protocol, strongly encouraging patients to receive bone protective agents because of the previous data ERA 223 showing increase in fragility fractures with radium and abiraterone. We wanted to track that phenomena really closely. That phenomena is aggregated, if you give adequate bone protection with either Denosumab or Zometa. And so we follow that very, very carefully. If a patient isn't getting it, then all sorts of queries, go to the investigator inquiring as to why they haven't gotten it so that we can document that and also track those patients and see what happens to them.

Alicia Morgans: Great. Well, really exciting. So as you think about the DORA trial and where we might go with this in the future, what would your message be to listeners?

Michael Morris: If DORA is positive, then that is an important component of future therapy. No matter what, chemotherapy will probably be a part of prostate cancer treatment, because all of our therapies that we've dealt developed over the last 15 years have resulted in ultimately patients relapsing and having a role for chemotherapy. Now, if chemotherapy with radium is superior to chemotherapy alone, for patients who at least have bone dominant, if not bone exclusive disease, that's an important thing to know. It will influence how we think about chemotherapy in the future. The question is whether that actually that promise will be manifested in DORA. And for that, we have to wait to see what the result is and we'll see.

Alicia Morgans: Well, that is a great message and a great approach by you and your team. And we really look forward to hearing the outcomes from the DORA trial and hopefully talking with you about some positive results in the future.

Michael Morris: I hope so.