Researchers involved in three Phase II European multicenter studies have reported that Alpharadin® (radium-223), an alpha emitter, is effective and well tolerated for the treatment of men with hormone refractory prostate cancer (HRPC) with metastatic bone lesions. The details of these studies were presented at the Joint ECCO 15 – 34th ESMO Multidisciplinary Congress in Berlin, September 20-24 2009.[1]

Patients with HRPC with metastasis to bone have a number of treatment options, but most of these are associated with significant toxicities. In addition to chemotherapy and radiotherapy, there are two FDA-approved bone targeted radioisotopes: Strontium-89 (Metastron®) and Samarium-153/lexidronam (Quadramet®). Thrombocytopenia and leucopenia are common side effects of these isotopes. Radium-223 is an alfa emitter that may be less marrow toxic than Strontium-89 or Samarium-153 due to the short distance of activity and a half-life of 11 days. 

Researchers from Sweden published the results of a Phase I study of Alphardin for the treatment of bone metastasis from prostate and breast cancer in Clinical Cancer Research in 2005 showing that this approach was feasible and tolerable.[2] 

Researchers from Sweden and Norway reported that Alpharadin was associated with significant palliation in patients with HRPC with painful skeletal metastases. These results were published in 2007 in Lancet Oncology. In this study 64 patients with HRPC with skeletal metastases were randomly allocated to receive four infusions of Alpharadin or placebo at four-week intervals in conjunction with palliative external beam radiotherapy. These authors reported that bone alkaline phosphatase levels decreased by 66% in the group receiving Alpharadin compared with a 9% increase in the control group. Time to first skeletal-related event in the Alpharadin group was 14 months compared with 11 months in the control group. Time to prostate antigen progression was 26 weeks in the radium-223 group compared with eight weeks in the control group. Median overall survival was 65.3 weeks in the Alpharadin group and 46.4 weeks in the control group. Importantly, hematologic toxicity was not different between the two groups. The only increased toxicity identified in the treatment arm was constipation. These authors concluded that Alpharadin had a significant effect on bone alkaline phosphatase and improved survival compared with placebo; furthermore, side effects were minimal.

At the ECCO 15 – 34th ESMO Congress, a two-year follow-up of these initial 64 patients was presented.[3] Thirty percent of patients treated with Alpharadin survive compared with 13% in the control group. For patients who received all four injections of Alpharadin, median survival was 93 weeks compared with 49 weeks in the control group. Patients with fewer skeletal lesions who were more fit appeared to benefit the most from Alpharadin. Side effects were minimal.

Also at the ECCO 15 – 34th ESMO Congress, researchers from several European centers reported the results of a randomized dose-seeking study in 121 men with metastatic HRPC.[4] This study defined the dose for the ongoing Phase III trial called ALSYMPCA, which was 50 kBq/kg every four weeks for six cycles. The third study presented at the ECCO 15 -34^th ESMO Congress involved 100 men with HRPC with painful skeletal metastases who were treated on four different dose levels of a single dose of Alpharadin.[5] Patients had significant pain relief at all dose levels occurring gradually between the second and eighth week. The highest dose levels appeared to be the most effective. Significant decreases in bone alkaline phosphatase were observed at the highest dose level. This study showed that a single dose of Alpharadin can significantly palliate pain from skeletal metastases.

Comments: These studies, taken together, suggest that Alpharadin may become an important drug for the control of bone lesions in patients with HRPC. The current ongoing Phase III trail should clearly define the role for Alpharadin in the treatment of HRPC.

Reference:

[1] Parker C, Hoskin P, Pascoe S, et al. A double blind, randomised, dose finding, phase II, muliticentre study of radium-223 for the treatment of patients with metastatic castration-refractory prostate cancer (CRPC): Eudra CT number: 2005-003680-22. European Journal of Cancer Supplements, Vol 7 No 2, September 2009, page 406, abstract O-7003.