Benjamin L. Maughan, MD, PharmD
A phase II trial evaluating the combination of radium-223 dichloride (Xofigo) and enzalutamide (Xtandi) met its primary endpoint of reducing bone metabolism markers in patients with metastatic castration-resistant prostate cancer (mCRPC), according to data presented at the 2018 ESMO Congress.1
In this randomized study (NCT02199197), men with progressive mCRPC were treated with 160 mg of enzalutamide daily with or without radium-223 at the standard dose of 55 kBq/kg intravenously every 4 weeks for 6 cycles. Researchers evaluated changes in N-telopeptide from baseline to end of treatment or disease progression.
Results showed a significant decline in N-telopeptide levels in those who received the combination versus patients who were given enzalutamide alone, with no additional safety signals, explained lead study author Benjamin L. Maughan, MD, PharmD.
In safety data of the enzalutamide/radium-223 combination that were presented at the 2018 ASCO Annual Meeting, the regimen was found to be safe and feasible for patients with mCRPC.2
In an interview with OncLive
, Maughan, a genitourinary medical oncologist, assistant professor in the Division of Medical Oncology, Huntsman Cancer Institute, discussed the activity of the combination of radium-223 and enzalutamide in patients with mCRPC.
OncLive: Could you tell us about the phase II trial evaluating the radium-223/enzalutamide combination in mCRPC?
: This [trial] is just testing a hypothesis that has been proven in the metastatic hormone-sensitive space, which is the idea that intensifying treatment upfront is more efficient than sequential single-agent therapy. This is not the only the study to test this hypothesis in [patients with] metastatic CRPC, but it is in the same theme. [For the trial], we looked at men who had bone-only metastases. We randomized them in a 2:1 fashion to receive either the combination of radium-223 and enzalutamide or enzalutamide alone.
What are the findings reported thus far?
Earlier, at the 2018 ASCO Annual Meeting, we reported safety data for this combination. [The rationale for this] was due, in part, to a press release that came out looking at a similar combination, abiraterone acetate plus prednisone plus radium-223. In that study, we saw an increased risk of death and fractures in the combination arm versus the control arm. In our study, we found that the combination [of radium-223 and enzalutamide] was safe. Cytopenias were observed at the same rate as radium-223 alone. Importantly, when we reported this at the 2018 ASCO Annual Meeting, there were no fractures in our patients.
At the 2018 ESMO Congress, [we reported] on the efficacy [of the combination]. In terms of the primary endpoint of reduction in bone metabolism markers, we saw a significant decrease in the change of bone metabolism markers from the time of enrollment to the end of the radium-223 period. The combination was more effective in reducing bone metabolism markers compared with [the use of] enzalutamide alone. We think this [finding] is reflective of better disease control. We say this because one of the secondary endpoints was prostate-specific antigen (PSA) response, and PSA progression-free survival was longer in the combination [arm].
What are the next steps for this research?
Overall, what [these findings] demonstrate is the hypothesis that has been proven true in the hormone-sensitive space, is likely better in the castration-resistant setting as well: Intensive therapy is better. The key is to find therapies that are tolerable together. This is a particularly important point, especially at the 2018 ESMO Congress, where the full data on that press release I mentioned earlier was presented. We saw no additional safety signals in our study. Only 2 patients in our study were on bone-modifying therapy, while about 35% of the patients in the other study were.
What are some exciting therapies coming down the pike in prostate cancer?
First of all, we would like to see validated results of [data presented at the 2018 ESMO Congress] in the surgical setting. That would substantially change how we think about and treat a large population of men with prostate cancer; it would also open a whole new avenue of treatment for those with oligometastases. Not only should we treat the prostate, but what about aggressive systemic therapy also directed at the metastases? This would allow us to personalize therapy even more.
Nowadays, we look at castration-resistant disease, castration-sensitive disease, and so on, and everyone is put into those groups until they progress on ADT. If we can learn more about the biology, that [would be] really fascinating. In addition, there are a couple of trials coming out that will look at even more intensive therapy. Right now, the standard is dual treatment with chemotherapy or ADT, or novel hormone therapy plus ADT. Now, there are a couple of trials that have just finished enrollment. We should hear read-outs for these trials within the next year.
Is there any added concern regarding the toxicity of these intensive treatments?
With the dual treatments, there was not much concern, but as we start to look at triplet regimens, there is definitely worry, specifically in terms of quality of life and fatigue. Chemotherapy, ADT, and hormone therapy all cause fatigue on their own, so [using them] in combination definitely does not help. This is important because, remember, these patients are at high risk of fractures. If they are too fatigued to stay up and [be] active, it is only going to make that problem worse.
- Maughan BL, Hahn A, Hoffman J, et al. Randomized phase III trial of radium-223 (RA) plus enzalutamide (EZ) vs. EZ alone in metastatic castration refractory prostate cancer (mCRPC). Ann Oncol. 2018;29(suppl):8. doi: 10.1093/annonc/mdy284.034.
- Maughan BL, Hoffman JM, 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).