Elsevier

The Lancet Oncology

Volume 15, Issue 12, November 2014, Pages 1397-1406
The Lancet Oncology

Articles
Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial

https://doi.org/10.1016/S1470-2045(14)70474-7Get rights and content

Summary

Background

Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223.

Methods

In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751.

Findings

Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56–0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52–0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3–4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3–4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3–4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups.

Interpretation

Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use.

Funding

Algeta ASA and Bayer HealthCare Pharmaceuticals.

Introduction

Trials with docetaxel were the first to show a survival advantage in patients with advanced castration-resistant prostate cancer,1, 2 leading to regulatory approval and rapid incorporation of docetaxel plus prednisone into treatment strategies.3 Despite survival benefit, docetaxel can also be associated with toxic effects, including fatigue and myelosuppression,1, 2, 4 and many patients with castration-resistant prostate cancer are not healthy enough to receive docetaxel (eg, because of poor performance status or comorbidities) or they decline treatment.5, 6, 7, 8 Although the proportion of patients with castration-resistant prostate cancer who receive docetaxel varies geographically, no world region reports more than 60% of patients receiving docetaxel before death.6, 7, 8

In the past 5 years, treatment options for patients with castration-resistant prostate cancer have increased: previous phase 3 trials with sipuleucel-T,9 cabazitaxel,10 abiraterone acetate,11, 12 and enzalutamide13, 14 showed improved survival outcomes. All of these trials apart from the sipuleucel-T trial9 were restricted to either chemotherapy-naive or post-docetaxel patients. No previous phase 3 trial studied patients regarded as unsuitable for, or unwilling to receive, docetaxel. Despite advances in the treatment of castration-resistant prostate cancer, patients eventually progress; a need remains for effective and tolerable treatments, including those who are unsuitable for or decline docetaxel.

Radium-223 dichloride (radium-223) is a novel targeted α-emitter that selectively binds to areas of increased metabolic activity in bone metastases. It emits high-energy α-particles with ultra-short penetration (<100 μm; 2–10 cell diameters) to effectively induce cytotoxicity in target areas, while limiting damage to surrounding normal tissue, including bone marrow.15, 16, 17, 18 The phase 3 ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) trial of radium-223 plus best standard of care versus placebo plus best standard of care in patients with castration-resistant prostate cancer and symptomatic bone metastases was unique because it enrolled both patients who had received previous docetaxel treatment and those who were unsuitable for or had declined docetaxel.19 Importantly, previous use of docetaxel was a prespecified trial stratification factor used to account for potential differences in efficacy or safety between docetaxel subgroups. In the intention-to-treat analysis, radium-223 significantly improved median overall survival compared with placebo (14·9 months vs 11·3 months; hazard ratio [HR] 0·70, 95% CI 0·58–0·83; p<0·0001), significantly prolonged median time to first symptomatic skeletal event (15·6 months vs 9·8 months; HR 0·66, 0·52–0·83; p=0·0004), and was well tolerated.19, 20 These results led to the regulatory approval of radium-223 for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastases; there was no regulatory restriction related to previous docetaxel use, since survival efficacy was shown for both groups.21

The design of ALSYMPCA afforded an opportunity to study whether the efficacy or safety of radium-223 varies on the basis of previous docetaxel use in men with castration-resistant prostate cancer and symptomatic bone metastases. Here we report results from a prespecified docetaxel subgroup analysis for the efficacy and safety of radium-223 in patients who did or did not receive docetaxel before enrolment into the study. Importantly, in our safety analyses for the docetaxel subgroups we investigated whether previous docetaxel use would predispose radium-223-treated patients to myelosuppression.

Section snippets

Study design and patients

ALSYMPCA was a phase 3, randomised, double-blind, placebo-controlled, multinational study done at 136 centres in 19 countries to compare efficacy and safety of radium-223 plus best standard of care with placebo plus best standard of care in patients with castration-resistant prostate cancer and symptomatic bone metastases. This prespecified docetaxel subgroup analysis was designed to assess the effect of previous docetaxel use on the efficacy and safety of radium-223.

Eligible patients were men

Results

921 patients were randomly assigned in ALSYMPCA between June 12, 2008, and Feb 1, 2011 (614 to the radium-223 group and 307 to the placebo group) and were included in the intention-to-treat population. 526 (57%) of these 921 patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group; figure 1).

Table 1 shows patient demographic and baseline disease characteristics.

Discussion

In this prespecified docetaxel subgroup analysis for the ALSYMPCA trial, radium-223 significantly prolonged overall survival compared with placebo in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. This effect of radium-223 was seen in both docetaxel subgroups for most of main secondary efficacy endpoints (all apart from time to first symptomatic skeletal event in patients with no previous docetaxel use). Additionally,

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