Bone metastases in advanced prostate cancer. Management

6/20/22, 12:19 AM 17128
Data from a limited number of patients indicate that a second course of six injections can be
given with minimal hematologic toxicity and some early effects on limiting disease progression
[12]. Additional experience will be required to further assess the role of retreatment.
There are no randomized trials that compare Ra-223 with other agents known to prolong
overall survival in patients with metastatic CRPC ( table 1). The optimal selection of candidates
for Ra-223 is not established [6]. The factors influencing the sequencing and combinations of
different therapies are discussed separately. (See "Overview of systemic treatment for
advanced, recurrent and metastatic castration-sensitive prostate cancer and local treatment for
patients with metastatic disease".)
Radium-223-based combinations — Ra-223 is being studied in combination with other
agents for the treatment of metastatic CRPC. However, a beneficial role for such combinations
has not been established, and at least some data suggest detrimental outcomes when Ra-223 is
combined with abiraterone. In view of these data, for most men, we suggest against initiating
Ra-223 and abiraterone at the same time. For men already receiving abiraterone, whether the
addition of Ra-223 might be safe and yield clinical benefit is unknown. If such an approach is
chosen, it would seem wise to ensure that the patient is also receiving a bone-modifying agent,
such as zoledronic acid or denosumab. Guidelines from the American Society of Clinical
Oncology (ASCO) specifically recommend against simultaneously initiating Ra-223 with
abiraterone and prednisone [1]. There is insufficient evidence to support concurrent use of Ra-
223 with other secondary therapies known to prolong survival in metastatic CRPC.
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In a seminal phase III trial [13], 806 men with bone-predominant metastatic CRPC who
were asymptomatic or minimally symptomatic and had received no prior chemotherapy
were treated with abiraterone plus prednisone/prednisolone and then randomized to
either Ra-223 or placebo. At a median follow-up of 22 months, more patients in the Ra-223
group had had at least one symptomatic SRE or had died (49 versus 47 percent of patients
in the placebo group). The primary endpoint was not met (median symptomatic SRE-free
survival was 22.3 months with Ra-223 plus abiraterone versus 26 months with abiraterone
alone), which translated into a 22 percent increased risk of skeletal events with Ra-223.
Fractures occurred in 29 percent of patients receiving combined therapy versus 11 percent
of the control group. Notably, only approximately 40 percent of the patients in either
group were receiving osteoclast inhibitors. The decrease in overall survival in the Ra-223
group, while potentially clinically meaningful, was not statistically significant (30.7 versus
33.3 months, HR 1.195, 95% CI 0.950-1.505).
These findings led Health Canada to recommend against the use of Ra-223 in combination
with abiraterone acetate plus prednisone/prednisolone, and led the European Medicines
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