Date: 2013-07-17
Type of information:
phase: 3
Announcement: publication of results from the phase III ALSYMPCA study in The New England Journal of Medicine
Company: Algeta (Norway) Bayer Healthcare (Germany)
Product: Alpharadin®/Xofigo® (radium-223 dichloride)
Action mechanism: Radium 223 is an alpha particle-emitting radioactive therapeutic agent with an anti-tumor effect on bone metastases. The active ingredient in radium 223 is the alpha particle-emitting isotope radium-223, which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The high linear energy transfer of radium-223 may cause double-strand DNA breaks in adjacent cells, resulting in an anti-tumor effect on bone metastases. The alpha particle range from radium-223 is less than 100 micrometers which may limit the damage to the surrounding normal tissue.
Disease: castration-resistant prostate cancer with bone metastases
Therapeutic area: Cancer - Oncology
Country: international study
Trial
details: The ALSYMPCA study (ALpharadin in SYMptomatic Prostate CAncer patients) is a double-blind randomized, placebo-controlled phase III clinical trial evaluating the potential of Alpharadin to treat castration-resistant prostate cancer (CRPC) patients with bone metastases. The trial enrolled 921 patients in more than 100 centers in 19 countries. Patients were stratified based on their baseline alkaline phosphatase (ALP) level, current bisphosphonate use and whether or not they had received docetaxel prior to study enrollment. The study treatment consisted of up to six intravenous injections of radium 223 or placebo each separated by an interval of four weeks. The primary efficacy endpoint is overall survival. The trial also evaluates both the safety profile of the treatment and its impact on quality of life.
The trial began in June 2008 and is being conducted at more than 140 clinical centers worldwide, including 14 centers in the USA. Completion of the enrolment of the targeted 900 patients has been achieved in January 2011.
Latest
news: * On July 17, 2013, Algeta has announced that data from the pivotal phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial of its drug radium Ra 223 dichloride (radium 223) in castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases and no known visceral metastatic disease are published in the 18 July 2013 issue of the New England Journal of Medicine (NEJM) (Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer, Parker, C. et al. New England Journal of Medicine 2013; 369;3). These data supported the FDA approval of radium 223 (Xofigo® injection) in May 2013.
In ALSYMPCA, radium 223 reduced the risk of death by 30.5 percent compared to placebo, a significant risk reduction (HR=0.695). This overall survival (OS) benefit was observed in patients who were treated with the chemotherapy docetaxel prior to study enrollment and in those who were not. All patients in the study were treated with best standard of care in addition to radium 223 or placebo. Researchers performed both a pre planned interim analysis (n=809) and an updated analysis (n=921) in this study. The overall survival benefit was the same in both analyses.
Radium 223 significantly improved OS in the overall study population at the interim analysis (HR=0.695, (95% CI 0.552-0.875), p=0.00185); median OS was 14.0 months with radium 223 plus best standard of care vs. 11.2 months with placebo plus best standard of care. These findings were supported by the updated analysis in which radium 223 showed improvement in OS (HR=0.695, (95% CI 0.581-0.832); median OS was 14.9 vs. 11.3 months).
The OS impact of radium 223 was consistent in both patients who received treatment with docetaxel prior to study enrollment and in those patients who did not receive prior docetaxel treatment. In the interim analysis, radium 223 reduced the risk of death by 25 percent (HR=0.755) compared to placebo in patients who received docetaxel prior to study enrollment and by 39 percent (HR=0.611) in those who did not. In the updated analysis, compared with placebo, radium 223 reduced the risk of death by 29 percent (HR=0.710) in those who were given prior docetaxel and by 26 percent (HR=0.745) in those who were not.
The main secondary endpoints in the ALSYMPCA trial provide further support for the efficacy of radium 223. In the interim analysis, radium 223 significantly prolonged the time to the first symptomatic skeletal event (SSE) compared with placebo (median 15.6 months vs. 9.8 months, respectively; HR=0.658, p<0.001).
In addition, radium 223 significantly delayed the time to ALP progression (HR=0.167, p<0.00001) and time to prostate-specific antigen (PSA) progression (HR=0.643, p<0.00001). These are two important biomarkers for CRPC with bone metastases; ALP is a marker that indicates bone health, and PSA is a marker often used to track prostate cancer disease progression. Similar results were observed in the updated analysis.
In the ALSYMPCA trial, the most common adverse drug reactions (greater than or equal to 10 percent) in patients receiving radium 223 were nausea, diarrhea, vomiting, and peripheral edema. Grade 3 and 4 treatment-emergent adverse events were reported among 57 percent of patients treated with radium 223 and 63 percent of placebo-treated patients. The most common hematologic laboratory abnormalities (greater than or equal to 10 percent) were anemia, lymphopenia, leukopenia, thrombocytopenia, and neutropenia.
* On October 1, 2012, further data and analysis from the phase III ALSYMPCA study of radium-223 dichloride (Alpharadin) in patients with castration-resistant prostate cancer with bone metastases have been presented at the ESMO 2012 Congress (Vienna, Austria; 28 September - 2 October 2012).
Safety of chemotherapy after radium-223 dichloride (Poster 936 - Sartor, O. et al. Safety of cytotoxic chemotherapy following radium-223 chloride (Ra-223) therapy in the phase 3 ALSYMPCA study in patients with castration-resistant prostate cancer (CRPC) with bone metastases)
The first analysis, conducted post-hoc and presented by Dr. Oliver Sartor (Medical Director Tulane Cancer Center, Tulane Medical School, New Orleans, LA, and Principal Investigator for US arm of ALSYMPCA), found that, based on the limited sample size (n=147), hematologic safety profiles for patients receiving chemotherapy after radium-223 dichloride were similar to those for patients receiving chemotherapy after placebo.
The cohort for this analysis consisted of all patients who received chemotherapy after administration of radium-223 dichloride or placebo. The proportion of patients receiving subsequent chemotherapy was 93/614 (15%) in the radium-223 dichloride group and 54/307 (18%) in the placebo group. The most common chemotherapeutic agents administered after study drug treatment were docetaxel (n=105), mitoxantrone (n=23), and cyclophosphamide (n=19).
Administering chemotherapy after the study drug had no deleterious effect on patient overall survival (OS). In the 147 patients from the ALSYMPCA study receiving chemotherapy after study drug, median OS from start of chemotherapy was 15.6 months in the radium-223 dichloride group and 14.6 months in the placebo group (P = 0.663).
Quality of Life assessment (Poster 898PD - Parker, C. et al. Updated survival, quality of life (QOL), and safety data of radium-223 chloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) with bone metastases from the phase 3 double-blind, randomized, multinational study (ALSYMPCA).
The second, preplanned, analysis, from all 921 patients recruited into ALSYMPCA and presented by Dr. Christopher Parker (Institute of Cancer Research and Royal Marsden Hospital, Sutton, UK, and Principal Investigator for ALSYMPCA), concluded that radium-223 dichloride showed significantly better preservation of quality of life (QOL), with improved functioning and well-being, compared to placebo, as well as confirming previously reported survival and safety endpoints.
Radium-223 dichloride improved the QOL response rate versus placebo (27% vs 18% p < 0.05), and better preserved QOL over time versus placebo (FACT-P: p < 0.05). QOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EuroQoL (EQ-5D) instruments, both well validated instruments in prostate cancer.
* On September 24, 2011, Bayer HealthCare Pharmaceuticals has announced positive data on Alpharadin® (radium-223 chloride) from the Phase III ALSYMPCA. The study met its primary endpoint by significantly improving overall survival by 44% (p=0.00185, HR=0.695) in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases.
All of the main secondary endpoints were met, including delay in time to first skeletal-related events (SREs). These data will be presented during the Presidential Session at the 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden (Abstract No. 1LBA: Presidential Session I: Best and Late Breaking Abstracts, Saturday 24 September, 13.45 (CEST), Hall A1). The 2011 European Multidisciplinary Cancer Congress is the 16th congress of the European CanCer Organisation (ECCO), the 36th congress of the European Society for Medical Oncology (ESMO) and the 30th congress of European Society for Therapeutic Radiology and Oncology (ESTRO). The data showed that patients who were treated with Alpharadin® had the following outcome:
• A median overall survival of 14 months compared to 11.2 months for the placebo group,
• Median time to first SREs of 13.6 vs. 8.4 months (64% improvement, HR=0.610, p=0.00046),
• Total alkaline phosphatase (ALP) normalization in 33% of patients taking Alpharadin vs. 1% of patients on placebo (p<0.001); and
• A 49% improvement in time to prostate-specific antigen (PSA) progression (HR=0.671, p=0.00015).
The overall safety and tolerability profile for Alpharadin® was consistent with previous study results. The most common non-hematologic adverse events (occurring in at least 15% of patients) included bone pain (43% vs. 58%), nausea (34% vs. 32%), diarrhea (22% vs. 13%), constipation (18% vs. 18%) and vomiting (17% vs. 13%); and the most common hematologic adverse events included anemia (27% vs. 27%). In respect to Grade 3 to 4 adverse events, the most common events included bone pain (18% vs. 23%).The trial was halted earlier this year following a pre-planned interim analysis to offer patients on the placebo arm treatment with Alpharadin®.
* On June 6, 2011, Bayer Healthcare has announced that the Phase III ALSYMPCA trial evaluating Alpharadin® (radium-223 chloride), which is exclusively licensed from Algeta, in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases met its primary endpoint by significantly improving overall survival. Based on a recommendation from the Independent Data Monitoring Committee (IDMC), following a pre-planned interim analysis, the study will be stopped and patients on the placebo arm will be offered treatment with Alpharadin®. The overall survival result was statistically significant (two-sided p-value = 0.0022, HR = 0.699, the median overall survival was 14.0 months for Alpharadin and 11.2 months for placebo). The safety and tolerability of Alpharadin® were consistent with previous Phase I and Phase II trial outcomes and did not show any new or unexpected changes in the safety profile of Alpharadin®.
The company is evaluating the filing strategy for Alpharadin® based on the IDMC's recommendation to stop this study and will offer patients in the placebo arm treatment with Alpharadin®.
