Alicia Morgans: Hi. I'm so excited to have here with me today Dr. Michael Morris, who is a Professor of Medicine and GU Medical Oncologist at Memorial Sloan Kettering Cancer Center. Thank you so much for joining me.

Michael Morris: Thank you for having me, Alicia.

Alicia Morgans: Wonderful. So I wanted to talk with you about the DORA study. Fascinating project that you've been working on for a few years looking at the combination of docetaxel and radium in men with metastatic CRPC. So tell us a little bit about this trial and what what you've found.

Michael Morris: Sure. Well, this concept is not a new one. That is a bone-seeking radiopharmaceutical, in particular one like radium-223, which prolongs life and also significantly delays time to first skeletal event, can really cover the entire bony compartment and provide a way of addressing metastatic cancer wherever it may be, as long as it's within the skeleton and at the same time address a directly anticancer therapy. In other words, dual compartment targeting. The concept has been around for a long time. We have never had until recently two agents that both prolong life to combine, but now that radium and docetaxel, both FDA-approved agents, we wanted to develop a strategy and then test one against the other.

And so we decided to take these two known active life-prolonging agents, develop a combination therapy. We had an initial dose escalation study which ran into an early Phase 2A randomized study which we recently published in which first we looked at what the appropriate dose of chemotherapy would be with radium. Although radium itself has nearly no marrow toxicity, the fact that you're giving chemotherapy does have an interaction. And so we did see a higher than we felt comfortable neutropenic fever rate when we used to docetaxel at full doses. And so we brought the docetaxel down to 60 milligrams per meter squared in combination with radium. We made some other alterations in order to make the regimen from a scheduling standpoint tolerable for the patients. Radium's usually given monthly, but with Q3 week docetaxel, thought that'd be a high burden in terms of patient visits, so we gave the radium every other docetaxel dose, so every six weeks, the docetaxel was given at 60 milligrams per meter squared, and then we ran off a very small randomized phase two study, two-to-one randomization in which patients got the combination versus docetaxel alone. Very safe in both arms.

Indeed, there was more hematologic toxicity in the monotherapy arm because we were using a higher dose of docetaxel then, and so there were more adverse events in the monotherapy arm than in the combination arm. We had quite favorable early biomarker data to suggest that there was more activity in the combination arm, better PSA declines, more profound and durable PSA declines, more profound and durable bone marker declines, delay in time to PSA progression, all in favor of the combination. So now we have the DORA trial, which is a randomized Phase III study sponsored by the PCCTC with funding provided by Bayer, and that's now open in the US and in the Netherlands. It's open and accruing well and it's been going quite well.

Alicia Morgans: That's wonderful. And just to speak a little bit to the endpoints of that Phase III trial, which is really looking to see if that combination can benefit these men longterm.

Michael Morris: These will all be men who have castration-resistant metastatic prostate cancer. They've all been through abiraterone, enzalutamide, perhaps other therapies even before they got a chemotherapy. It allows essentially for prior chemotherapies that they may have received before going on study, and then they're randomized to one of the two arms. It's a one-to-one randomization in DORA, and the primary endpoint because these patients are advanced, is overall survival.

I think what's important about DORA is that we've built in a host of biomarkers so that whether the trial is positive or negative, we're going to learn a huge amount about these patients. We have several imaging biomarkers because so little is known about the imaging changes for men who receive radium-223, cell-free DNA, two CTC assays in terms of enumeration and characterization, the usual clinical endpoints in terms of PSA decline, bone marker declines. So it's a really full package of both clinical endpoints and our correlative endpoints.

Alicia Morgans: So what would you say to clinicians who might be really interested in this strategy? And I have to say, I mean, it's really hitting mCRPC hard, and that I think is really attractive, but there's potentially concern about the toxicity that might come from these two agents, and you have a lot of experience in that in the Phase I and then going through the Phase II. So what would you say to those questions?

Michael Morris: A few things. So first of all, concerning the toxicity, this is really not a toxic regimen as we just talked about. The combination doesn't really show additional toxicity over and above docetaxel alone. And it's also from a trialist's perspective, a straightforward study. This is something that every investigator off protocol is familiar with docetaxel, is familiar with radium-223. From a therapeutic standpoint, this is an easy trial to participate in. From a patient perspective, this is a trial that when you're ready for chemotherapy, you're ready for chemotherapy. On the control arm, you're going to get nothing that is below what you would have gotten had you not been on the study at all. And if you're on the combination arm, you probably won't have any more side effects that had you just gotten chemotherapy. So I think it's easy from an investigator standpoint and from a patient standpoint.

Alicia Morgans: That's really important. And are you anticipating reaching accrual at some point in the near future and if not, how would patients or clinicians who want to be involved in this trial do that?

Michael Morris: So the PCCTC is a consortium of prostate cancer centers of excellence throughout the country, and there are now about 70 of those participating centers. We have a website on the PCCTC website that I think is like DORA.com or something pretty straightforward. But if they just went to the PCCTC website and looked at DORA, you can see each of the participating sites. They can also email me directly if they wish. And that's , and I will make sure that they find a center that's near them.

Alicia Morgans: Wonderful. And we'll make sure we put the link as well-

Michael Morris: Great. That'd be great.

Alicia Morgans: ... with this interview. So any idea on when you believe you'll finish accrual?

Michael Morris: We're still getting the sites open now, so we're just ramping up accrual, and so there's plenty of opportunity. We're also open in the Netherlands in case any of the viewers are in Holland.

Alicia Morgans: Wonderful.

Michael Morris: At a number of different sites there. So it's a 788 patient study. So I'd say we have a ways to go because we're just beginning now, but we anticipate it'll take a few years to accrue.

Alicia Morgans: Wonderful. Well, I am looking forward to having you come back and tell us about the progress of DORA.

Michael Morris: Absolutely. I'd be happy to.

Alicia Morgans: Wonderful. And we will post all of this information with this interview and I look forward to seeing the results when that time comes.

Michael Morris: Thanks very much, Alicia.

Alicia Morgans: Thank you.