Experts Discuss Treatment Sequencing Strategies in CRPC

E. David Crawford, MD

As the treatment landscape for patients with metastatic castration-resistant prostate cancer (CRPC) continues to evolve, optimal strategies are becoming more apparent on how to best sequence the multitude of novel therapies that have been approved in the past decade.

OncLive: What factors guide your selection of frontline therapy for men with CRPC?

To gain insight into current best practices and strategies that are on the horizon, OncLive spoke with two of the leading experts in the field: E. David Crawford, MD, endowed chair in Urologic Oncology at the University of Colorado, and Leonard G. Gomella, MD, senior director for Clinical Affairs at Jefferson Kimmel Cancer Center.Crawford: We are entering an era of castration-resistant prostate cancer where we are trying to really personalize it to the patient, and not just throw out a big net and say, “everybody fits into this one.” You look at how fast they got there, how they got there, what prior treatments they received—many other things like that.

The good thing is, we have a whole bunch of things to treat patients with. In general, they are not for patients who are sort of “circling the drain,” but for the minimally symptomatic patient.

What I normally would do is think about things I really want to get into the patient—things like immunotherapy or sipuleucel-T. I sort of consider that a platform you really build on. The question is, “Do you start with an androgen biosynthesis inhibitor? Do you start out with radium-223? Do you start out with things like anti-androgens, such as enzalutamide? Do you put combinations together?” Those are all conversations you need to have with the patient.

Right now, people are doing things like sequencing. I think we need to start thinking beyond that. We need to think about the fact that, in most cancers that we cure, it’s not sequencing “A, B, C, and D,” it’s putting “A, B, C, D” together and treating the patient. It may not be for a lifetime; it may be a short time. That is certainly the case for certain lymphomas, leukemias, and testicular cancers, and I think the same thing really applies to prostate cancer.

Currently, I think people tend to start out with the better-tolerated agents and then move to the drugs that have more significant side effects. That means that chemotherapy has been pushed to the end of the line again. But, in newly diagnosed patients, that’s different.

Leonard G. Gomella, MD

Gomella: When we look at managing patients with castration-resistant prostate cancer, we have many options available to us right now. We are learning, as time goes on, that certain agents are best used early in the course of the disease; meanwhile, other agents may be used early but may be optimally used later. A classic example of that is using sipuleucel-T very early in the course of CRPC, when patients are minimally symptomatic or asymptomatic. It is probably not a good idea to use it later when people have a lot of pain or other symptoms.

In general, we like to use agents such as immunotherapy with sipuleucel-T early in the disease. Other agents are certainly valid to use. The androgen receptor-pathway blockers enzalutamide and abiraterone are certainly fair to use early in the course of the disease. More recently, for patients with metastatic castration-resistant prostate cancer, there tends to be use of chemotherapy a little bit later in the course of the disease. However, that is variable depending on local practice patterns and how the medical oncologists really feel about the use of chemotherapy.

Which do you use first and why: abiraterone acetate or enzalutamide?

Radium-223 is out there, also. The difference with radium-233 is it can be used across the spectrum of the disease, but it tends not to be used early in current practice. It tends to be used a little bit later. However, using it early is something that is under investigation, as well.Crawford: How do you sequence abiraterone and enzalutamide? Again, a lot of things influence that decision. Has the patient been on anti-androgen therapies before? Had he received ketoconazole? Did he receive this or that? It is a lot of things.

In general, I use both. I sort of look at the studies out there and offer patients the opportunity to get abiraterone, and I discuss the risks and benefits associated with that. It’s the same with enzalutamide. It’s not an easy question to answer. The question goes really beyond that, too—putting things together. Does it make sense to put them both together? I don’t know. We need to look at that.

Gomella: In general, the agents are both very effective for metastatic castration-resistant prostate cancer. They are both oral agents, and they are fairly easily used in the outpatient setting.

How has your real world experience with these agents differed from the clinical trial results?

There are some general rules of the road that we follow in our multidisciplinary clinic when we treat men with these agents. For example, if someone has a history of seizure disorders and head trauma, or anything related to the central nervous system, we tend to avoid enzalutamide. If someone has very brittle diabetes or significant problems with the management of their diabetes, we tend to avoid abiraterone. But, to be fair, both of them are very good agents in the frontline setting.Crawford: Clinical trials are very narrow. Most of them start out at post-chemotherapy or pre-chemotherapy, and now it is even in patients who are newly diagnosed, metastatic, or have rising PSA. Even enzalutamide is being used in active surveillance programs. The great thing is that you now have these tools, and they’re different. People who go on clinical trials are a very select group of men, in a way.

Now, we have a broader brush we can use to treat them. We’ll use enzalutamide earlier in the disease, or we’ll use abiraterone or radium-223 earlier in the disease. Radium-223 started out as a drug that patients sort of received post-chemotherapy. Half of the people on the clinical trial ended up receiving pre-chemotherapy. Now we know, because of that, it is better to receive it pre-chemotherapy. It’s not for people who are sort of “circling the drain” with the disease.

Gomella: In general, what we whave learned is that the clinical trials are fairly representative of what we see. The side effect profiles that sometimes get reported in the clinical trial may not be as important as we see in the real world setting. A good example is a lot of people are afraid, or a lot of providers may be afraid, of using prednisone along with an agent such as abiraterone.

However, it has really been shown that the incidence of steroid-related side effects is really very low compared to what might have been thought in some of the earlier clinical trials. A paper is coming out that addresses the fact that the steroid-related adverse events with abiraterone are extremely rare and not usually that significant.