Dreicer Discusses Optimizing Treatment in mCRPC

Robert Dreicer, MD

As oncologists await the next major treatment advances in metastatic castration-resistant prostate cancer (mCRPC), the key in the interim is to optimize the available therapies, says Robert Dreicer, MD.

“Right now, we’ve hit a little bit of a time delay in terms of the therapies that have been developed,” said Dreicer. “Clearly, the next wave of therapies are DNA mismatch repair, targeted therapies, but even that is only going to impact a quarter, perhaps, of patients with castration-resistant disease. So it’s really about optimizing the therapies that we have, as we begin to think about new drugs or new combinations that may be able to push us down the road a little bit.”

One available agent that Dreicer said oncologists are still focused on unleashing the full potential of is radium-223. Optimal use of this treatment remains mostly unknown, with current efforts focusing on exploring the agent’s potential in combination regimens.

For example, a phase III trial is randomizing patients with bone predominant mCRPC to radium-223 plus abiraterone acetate (Zytiga) or abiraterone alone (NCT02043678). Additionally, a randomized phase IIa study is evaluating the efficacy and safety of radium-223 in combination with abiraterone or enzalutamide (Xtandi) in patients with mCRPC to investigate bone-scan response, radiological progression-free survival, overall survival, and skeletal events (NCT02034552).

OncLive: Please provide an overview of your presentation at the CFS.

In an interview with OncLive at the 2016 Chemotherapy Foundation Symposium (CFS), Dreicer, associate director, Clinical Research, deputy director, University of Virginia Cancer Center, discussed ongoing developments in mCRPC, including the latest approaches with radium-223.Dreicer: We reviewed the current state of what we know about next-generation antiandrogen therapies. These therapies have been around for a couple of years now, and one of the striking findings that all clinicians deal with is the cross-resistance to both enzalutamide and abiraterone. This is a major clinical dilemma, and we’re sort of in between recognizing multiple different resistance pathways, but not necessarily being able to predict, with any of the assays available—including AR-V7, probably the most well-defined resistance pathway.

Are there any agents or trials in development seeking to answer these questions?

So, we’re really left with making clinical judgments about when a patient might go from one drug to another, and that might depend on prior response, clinical setting, or whether the patient is symptomatic. It’s this kind of clinical management paradigm that we’re in, until we can develop predictive biomarkers to really give us data-driven ways to make decisions.We were disappointed earlier this year when the trial of galeterone—which was an agent that was hoped to be able to overcome AR-V7 resistance—was stopped prematurely. There are other next-generation compounds in development, and the AR-V7 assay is moving its way to commercialization. I think this is an area that has active research ongoing.

What sort of progress would you like to see a year from now?

Can we talk about the new assay that will be commercialized soon? How does it work, and what do we know about it?

Do we understand why this resistance develops?

What are the next steps with radium-223?

What are some ongoing studies with radium-223?

This year, we’re a little distracted because of the mutational directed therapeutics that have become really exciting, but fundamentally, this is an AR-driven disease, so this is going to be an area of great importance for us to develop new compounds and understand how to overcome resistance. There’s a lot of work going on, though we’re really not too close to having those answers, but at least the work is progressing.I think we’d like to have AR-V7 assays that are validated and commercially available. We’d like to see more prospective data to validate what the Hopkins group had demonstrated, because although the data were very profoundly interesting, they were small numbers, and prospective validation from other centers would be very useful before we incorporate that into our daily practice. We’d also like to see in that time space some new compounds that may have abilities to overcome some of the resistance pathways, because we’re obviously looking to use the AR pathway downstream.It is an assay that was developed at Hopkins, and they’re working with commercial sponsors. Obviously it’s a proprietary circulating tumor cell assay. One of the challenges is that not all patients have circulating tumor cells, and all of these things have to be worked out. I suspect that, even with a good assay that’s validated, it’s not going to be universally useful. So I think the key is that we need data, and even if an assay was available tomorrow, if it’s not really carefully validated, making decisions upfront—meaning a patient who has not received either compound—I think that would be a little problematic. It might be useful for a patient who has progressed on one, and you’re really looking to make a decision about why you shouldn’t use the alternative drug, and things like that. But again, a lot of this work has yet to really be done in a compelling way, where I would be comfortable using it in the clinic tomorrow.There are several resistance pathways that have been identified. AR-V7 is just one. At least a dozen have been identified, and it’s not inconceivable that several will be active in the same patient. I think that if we tried to suggest that we understood this issue very well, we’d be overstating the issue a little bit. We have quite a lot to learn.Radium-223 is a very unique agent, and it’s one of the 2 approved therapies in advanced prostate cancer that is not an AR-targeted therapy. It makes some intrinsic sense to take multiple different pathways to treat a disease, and therefore the combining of agents like abiraterone and enzalutamide with radium-223 is a very intriguing and appropriate set of studies to do—not only because we’re trying to figure out if we can do better in terms of getting better responses, more prolonged responses, changed progression-free survival, things like that, but frankly from an economic perspective. Before we start combining very expensive agents, we need some indication that there’s a rationale to do that. So I think it’s clearly an important thing to study. Do I think we’re anywhere close to knowing the answers to that? I don’t think so, but the studies are ongoing, so that’s good.A number of studies are being done, including retreatment studies, studies to look at more than 6 cycles of therapy, the 6 being somewhat arbitrary. The retreatment paradigm is very intriguing, especially in patients who may have benefitted. Again, remember, one of the challenges with radium-223 is that there’s not really objective antitumor activity. It’s a bone-targeted therapy; PSA responses are not common.

Anecdotally, how have you seen that agent specifically impact patients in terms of quality of life?

Therefore, radium-223 is still one of those therapies that we wonder how to optimally integrate it into the management paradigm, and again, because it’s bone-targeted, patients with more than minimal nodal disease really are not great candidates. That’s another reason to think about combinatorial treatment, so there are a lot of things about radium-223 that remain to be addressed, and I think its uptake in the community is still patchy. I think some of that is practice patterns, and understanding where it may be best applied, so more data will certainly help clinicians in the community to figure out when radium-223, or radium-223 combinations, may be best for their patients.I tend to use it in a pre-docetaxel setting most of the time. These are patients who meet the label, in terms of having some minimal to moderate pain. Pain relief is a little hard to gauge. Again, many of these patients are not that symptomatic, and of course, all of our patients have osteoarthritis. It’s a challenge, one that’s not typical when we compare it to challenges associated with sipuleucel-T (Provenge). There’s no real true way to understand objective antitumor activity.

Do you think that there will be a newer or second-generation version of radium-223? Is there going to be some competition there?

What do you think is important for community oncologists to take away from all of this?

Therefore, if you can treat someone with 6 cycles of therapy, and their disease has not overtly progressed, is it because of, in spite of [the therapy?] We know from the randomized trial that there is a survival benefit, so in a sense, when we use these therapies, because a pain endpoint was not baked into the randomized trial, it’s a little hard to tell a patient, “Look we’re doing this to try to minimize your pain. What we’re trying to do is, we know that there’s a decrease in symptomatic skeletal events, and that there may be a survival benefit.” And I think that that’s how we approach patients today. I’d like more data to be able to be a bit more definitive.That’s an interesting question. Because it’s a unique molecule, because of its sparing of the bone marrow and relatively well-tolerated profile, it lends itself to integration earlier in the disease course where it’s going to be studied, and it lends itself to combinatorial therapies. I suspect we’re going to see more and more of this. It’s a bone-trophic disease, and therefore, there are going to be a lot of people thinking about this. Can you have a “better” radium-223? I don’t know the answer to that, so I think time will tell how this goes. But I think the future is really likely in combinations of therapies, as opposed to radium-223 as a monotherapy.Right now, we’ve hit a little bit of a time delay in terms of the therapies that have been developed. Clearly, the next wave of therapies are DNA mismatch repair, targeted therapies, but even that is only going to impact a quarter, perhaps, of patients with castration-resistant disease. So it’s really about optimizing the therapies that we have, as we begin to think about new drugs or new combinations that may be able to push us down the road a little bit.

Immunotherapy—other than sipuleucel-T—has not been widely used. The checkpoints have been a little slower in prostate cancer because early data wasn’t as compelling, although recent data presented at ESMO suggested that looking at checkpoints or other combinations may be very reasonable in some subsets of patients.

Optimally using the drugs we have and figuring out sequencing, which really will be a clinical judgment until we get more data—that’s what we sort of need to walk away with to try to better care for our patients.