Adding Bone Drugs to Radium-223 May Enhance Benefit in mCRPC

Daniel Heinrich, MD

Men with bone-metastatic castration-resistant prostate cancer (mCRPC) appeared to derive additional benefits from treatment with radium-223 with concomitant bone-targeted therapies, according to data from an extended-access program.¹

After a median follow-up of 7.5 months from initial injection of radium-223, patients on concomitant denosumab had yet to reach a median overall survival (OS), whereas patients treated with radium-223 alone had a median survival of 13.4 months.

The addition of bisphosphonate therapy to radium-223 did not appear to influence survival but was associated with prolongation of the time to a first symptomatic skeletal event (SSE), as compared with radium-223 alone, as reported at 2016 ESMO Congress.

“The objective of an extended access program is to make the drug available to more patients before the drug is actually approved,” said study author Daniel Heinrich, MD, a medical oncologist at Akershus University Hospital in Lorenskog, Norway. “The information gathered from such a program can help us understand how a drug is being used and how it might be used to maximize the benefits to patients.”

Although the data were collected prospectively, the analysis was retrospective, and patients were not specifically assigned to treatment groups with and without concomitant use of bone-targeted agents, Heinrich added.

“With those limitations in mind, interestingly, we observed a slight divergence of the survival curves with concomitant denosumab, leading to a little bit longer survival, and we did not see that with concomitant use of bisphosphonates,” he said during a poster presentation. “Even with the limitations surrounding the data collection, that’s a finding that is worth pursuing in future trials.”

The suggestion of a survival benefit with concomitant denosumab came from a previously reported analysis of data from an early access program. The earlier report, which examined a variety of treatment-related factors, showed longer OS in patients treated with abiraterone acetate (Zytiga), enzalutamide (Xtandi), or denosumab, in addition to radium-223 as compared with those who received only radium-223 for the treatment of CRPC associated with bone metastases.²

In the current analysis, investigators examined another cohort of patients from an early access-program. The analysis focused specifically on the potential effects of concomitant use of bone-modifying agents, including denosumab and bisphosphonates.

The study included 696 patients who received at least one dose of radium-223. Of those, 127 received concomitant denosumab, 125 received concomitant bisphosphonates, and 435 received radium-223 without bone-modifying drugs. Heinrich and colleagues reported that 27 patients treated with concomitant denosumab also received abiraterone or enzalutamide, as did 35 patients treated with bisphosphonates and 77 patients who received radium-223 without bone-modifying agents.

The data showed 141 deaths among patients who received no bone-modifying drugs, resulting in a median OS of 13.4 months. Among patients who received denosumab in addition to radium-223, 33 died, and in that subgroup, the median OS could not yet be determined.

With respect to the patients who received bisphosphonates in addition to radium-223, 35 died, resulting in a median OS of 12.7 months for the subgroup, no different from the patients who received radium-223 without bone-modifying agents.

The analysis of time to first SSE showed a median interval of 15.8 months for patients who received radium-223 without bone-modifying agents. The subgroup who received concomitant denosumab had a median duration of 17 months to first SSE, which did not differ from the patients who received radium-223 without bone-modifying agents.

In the subgroup of patients treated concomitantly with bisphosphonates, the median time for first SSE had yet to be reached.

“If you think about it, this is quite logical,” Heinrich said of the data regarding bisphosphonate use and SSE. “Bisphosphonates lead to higher accumulation of calcium in bones. Calcium is pushed into the bone by those drugs. Radium is biochemically similar to calcium, so it should be pushed into the bone, especially in places where there is high bone turnover, like with a metastasis. This is a logical combination, but we cannot draw any conclusions from the data because this is not a randomized trial. But it does stimulate thoughts for future studies.”

Neither denosumab nor bisphosphonates added to the toxicity of radium-223 alone. The overall rate of adverse events, as well as rates of grade 3/4 adverse events, serious adverse events, and adverse events leading to discontinuation, was similar among patients who received radium-223 alone or with either type of bone-modifying agent.

References

1. Saad F, Heidenreich A, Heinrich D, et al. Radium-223 with concomitant bone-targeting agents in metastatic castration-resistant prostate cancer (CRPC) patients treated in an international early access program (EAP). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 750P.
2. Saad F, Carles J, Gillessen S, et al. Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial. Lancet Oncol. 2016;17(9):1306-1316.