Elsevier

The Lancet Oncology

Volume 15, Issue 7, June 2014, Pages 738-746
The Lancet Oncology

Articles
Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial

https://doi.org/10.1016/S1470-2045(14)70183-4Get rights and content

Summary

Background

Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases.

Methods

In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751.

Findings

Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5–18·0] vs 9·8 months [7·3–23·7]; hazard ratio [HR]=0·66, 95% CI 0·52–0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53–0·85) and spinal cord compression (HR=0·52, 95% CI 0·29–0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35–1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28–1·82).

Interpretation

Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases.

Funding

Algeta and Bayer HealthCare Pharmaceuticals.

Introduction

Skeletal events arise from disease-related complications of bone metastases.1, 2 In patients with metastatic castration-resistant prostate cancer, skeletal events occur frequently, and are a major cause of prostate cancer-specific morbidity and increased economic burden of the disease.3, 4, 5, 6 Skeletal events are regularly defined as pathological bone fracture, spinal cord compression, orthopaedic surgical intervention, or radiation to bone.7, 8, 9, 10, 11 Bone metastases and skeletal events are associated with reduced survival in metastatic castration-resistant prostate cancer;12 skeletal events are known to impair quality of life and, in the case of spinal cord compression, lead to neurological damage.1 Thus, prevention and delay of skeletal events are important objectives in managing patients with metastatic castration-resistant prostate cancer.

Historically, skeletal events were monitored in clinical trials through periodic radiological review and referred to in the medical literature as skeletal-related events.7, 8, 9, 10, 11 Skeletal events that are symptomatic and identified clinically are different from asymptomatic radiologically detected events, and are a more clinically relevant endpoint. Events assessed in this manner are called symptomatic skeletal events.13

Radium-223 dichloride (radium-223) is a targeted α-emitter that emits high-energy, localised α-particles, with a tissue range of less than 100 μm.14 As a calcium mimetic, radium-223 has a natural bone-seeking capability and preferentially binds to newly formed bone matrix, targeting osteoblastic metastatic lesions.15, 16 The high-energy, short-range α-particle radiation predominantly induces irreparable double-stranded DNA breaks resulting in potent cytotoxic activity localised to target areas, while minimising damage to bone marrow and adjacent healthy tissue.15, 16, 17

Efficacy and safety of radium-223 were assessed in a phase 3 multinational study (ALSYMPCA) comparing radium-223 plus best standard of care versus placebo plus best standard of care in patients with castration-resistant prostate cancer and bone metastases.18 Overall survival was significantly longer with radium-223 than with placebo (median survival: 14·9 months vs 11·3 months; hazard ratio [HR] 0·70; 95% CI 0·58–0·83; p<0·0001) and was well tolerated, with low myelosuppression rates and few adverse events.18 These results led to the approval from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)13 of radium-223 for treating patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastases.

Here we present secondary endpoint data from ALSYMPCA, along with post-hoc analyses to further establish the effect of radium-223 on symptomatic skeletal events in men with castration-resistant prostate cancer and bone metastases.

Section snippets

Study design and patients

ALSYMPCA was a phase 3, randomised, double-blind, placebo-controlled study done at 136 centres (appendix) in 19 countries in patients with metastatic castration-resistant prostate cancer. Eligible patients were aged 18 years or older; had progressive, symptomatic castration-resistant prostate cancer with two or more bone metastases on bone scintigraphy and no known visceral metastases; were receiving best standard of care; and had received docetaxel, or were not eligible for, or had declined

Results

Results of the ALSYMPCA trial have been reported previously.18 Of the 921 patients enrolled in ALSYMPCA and included in the symptomatic skeletal event analysis, 614 were randomly assigned to radium-223 and 307 to placebo (intention-to-treat population; figure 1) from June 12, 2008, to Feb 1, 2011. Patient demographics and baseline characteristics were well balanced between treatment groups,18 with 511 (83%) patients in the radium-223 group and 268 (87%) patients in the placebo group with six or

Discussion

In the phase 3 ALSYMPCA study, median time to first symptomatic skeletal event was significantly longer with radium-223 than with placebo. Furthermore, the risk of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases was reduced by radium-223 compared with placebo. The effect of radium-223 on time to developing first symptomatic skeletal events was noted regardless of previous docetaxel use, baseline ALP value, or bisphosphonate use at study

References (22)

  • F Saad et al.

    A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma

    J Natl Cancer Inst

    (2002)
  • Cited by (0)

    View full text