Enzalutamide/Radium-223 Combo Shows Tolerability in mCRPC

Benjamin L. Maughan, MD, PharmD

Combining radium-223 dichloride (Xofigo) with enzalutamide (Xtandi) is safe and feasible for patients with metastatic castration-resistant prostate cancer (mCRPC), according to data presented at the 2018 ASCO Annual Meeting.

A total of 49 patients was randomized to either the combination (n = 35) or enzalutamide monotherapy (n = 14). Radium-223 was administered intravenously at a standard dose of 55 kBq/kg once every 4 weeks for a total of 6 injections, and enzalutamide at 160 mg/day until disease progression or unacceptable toxicities. In addition to safety, researchers analyzed changes in bone metabolism markers.

Data from the single-center, phase II trial showed that serious adverse events (AEs) were similar in both arms regardless of subset attribution. Specifically, there was no incidence of skeletal-related events (SREs) in either arm, according to Benjamin L. Maughan, MD, PharmD. Longer follow-up is needed to determine whether the combination has clinical activity.

OncLive: Please provide some background on the radium-223 and enzalutamide combination.

In an interview with OncLive, Maughan, an instructor in the Division of Medical Oncology at Huntsman Cancer Institute, discussed the tolerability of combining radium-223 and enzalutamide, as well as the next steps with this combination.Maughan: With mCRPC—and more broadly speaking with prostate cancer in general—there's a growing trend toward doing more intense combination therapy…A combination that's been attractive [in mCRPC] is one of novel hormonal therapy, either abiraterone acetate (Zytiga) or enzalutamide, in combination with radium-223. All 3 of these agents are known to improve overall survival. They also have nonoverlapping toxicities. Therefore, the combinatory approach is certainly one potentially attractive way to improve outcomes.

The challenge is that there is some signal from recent studies that abiraterone plus radium-223 increases the fracture risk in patients. That makes many people cautious about doing the other hormonal novel therapy that is FDA approved in this space.

We reported safety data of enzalutamide plus radium-223 in a prospective trial that was performed at Huntsman Cancer Institute. What we found in this randomized study—patients were randomized to either the combination or enzalutamide alone—the combination did have more cytopenias than enzalutamide alone, as one would expect. Cytopenias are not an AE you see with enzalutamide, but it is with radium-223. However, the incidence of cytopenias was not greater than what you would see in radium-223 alone.

How long was the follow-up with these data?

What do you expect to see with this combination in terms of efficacy?

Why is there a trend of more intense combination therapies, as you mentioned?

More importantly, the question of the day is what the potential risk of this combination is in terms of SREs. In our study, there was no significant increase in these events, which were defined by fractures, symptomatic bone pain, etc. We also didn't see any fractures in our study, either with the combination or the enzalutamide arm. We certainly need more follow-up to be able to more convincingly say that these data are encouraging.The follow-up at the time of the ASCO deadline cutoff is slightly less than 1 year. The follow-up needs to go out further, so we can convincingly say that this combination does not increase the risk of fractures. However, the fact that we have seen no fractures to date is highly encouraging.This is the second most important question. It's obviously critical for us to see whether this combination is effective along with being safe. We will be able to answer this pretty well since it's a randomized study. At the time of the ASCO deadline, the primary efficacy results were not yet mature, but it has subsequently matured. Therefore, we are hoping to present these at upcoming meetings. There is more to come.This started with the CHAARTED trial, which looked at androgen deprivation therapy upfront. Since then, we have consistently seen more studies following the same direction. There are a lot of trials ongoing; for example, some are looking at chemotherapy plus hormonal therapy and abiraterone for metastatic hormone-sensitive disease. Triplet combinations in place of dual combinations are starting to emerge. In mCRPC, there are studies looking at abiraterone plus enzalutamide or radium-223 plus enzalutamide, and multiple other combinations.

What other therapies could be used in combination with radium-223?

Were there any other prostate cancer studies you wanted to share insight on?

In the targeted therapy space, there are trials of enzalutamide plus PI3K inhibitors, and there is olaparib (Lynparza) plus abiraterone—so there are many trials in the works. It really all stems from the breakthrough that Dr Christopher Sweeney demonstrated with the CHAARTED study. If you can find a combination that's tolerable, it can be more effective. This likely has to do with delaying the emergence of resistance.There are a number of combinations that people have suggested that are interesting, but there aren't any in significant development at the moment. People have suggested that because radium-223 works by DNA damage that it could be a good partner with olaparib. The potential concern there is that they do have overlapping toxicities. It's a potentially attractive option.The only other one that is really striking to me was presented during the oral abstracts session [at the 2018 ASCO Annual Meeting] of abiraterone and olaparib. This was intriguing for a couple of reasons. One was because multiple studies have shown that olaparib is effective in biomarker-positive patients, so those with homologous recombinant defects. Biomarker-negative patients will rarely respond. Unfortunately, the subpopulation of biomarker-positive patients is only about 20% of prostate cancers overall. There are a lot of caveats around that.

Maughan B, Hoffman J, Morton K, et al. Safety data from a phase II randomized trial of radium-223 dichloride (ra-223) plus enzalutamide (enza) vs. enza alone in men with metastatic castration refractory prostate cancer (mCRPC). J Clin Oncol. 2018;36(suppl;abstr 5057)