Bayer HealthCare has announced that data from the pivotal Phase III ALSYMPCA ( ALpharadin in SYMptomatic Prostate CAncer ) trial of its drug Radium 223 dichloride ( Radium 223 ) in castration-resistant prostate cancer patients with symptomatic bone metastases and no known visceral metastatic disease are published in the New England Journal of Medicine ( NEJM ). These data supported the Food and Drug Administration ( FDA ) approval of Xofigo injection in May 2013.

In ALSYMPCA, Radium 223 reduced the risk of death by 30.5% compared to placebo, a significant risk reduction ( hazard ratio, HR=0.695 ). This overall survival 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.

The ALSYMPCA trial was a Phase III, randomized, double-blind, placebo-controlled international study of Radium 223 dichloride vs placebo in patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.
The trial enrolled 921 patients in more than 100 Centers in 19 Countries. Patients were stratified based on whether or not they had received Docetaxel ( Taxotere ) prior to study enrollment. The study treatment consisted of best standard of care and up to six intravenous injections of Radium 223 or placebo each separated by an interval of four weeks.

The primary endpoint of the study was overall survival. A key secondary endpoint was time to first symptomatic skeletal event ( SSE ). SSE was defined as first use of external beam radiation therapy to relieve skeletal pain, new symptomatic pathologic bone fracture, occurrence of spinal cord compression or tumour-related orthopedic surgical intervention.

The overall survival 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% ( HR=0.755 ) compared to placebo in patients who received prior Docetaxel treatment and by 39% ( HR=0.611 ) compared with placebo in those who did not. In the updated analysis, Radium 223 reduced the risk of death by 29% ( HR=0.710 ) compared with placebo in those who were given prior Docetaxel and by 26% ( HR=0.745 ) compared with placebo in those who were not.

Radium 223 significantly improved overall survival in the overall study population at the interim analysis ( HR=0.695, p=0.00185 ); median overall survival was 14 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 the same significant improvement in overall survival ( HR=0.695; median overall survival was 14.9 vs 11.3 months ).

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 compared with placebo ( median 15.6 months vs 9.8 months, respectively; HR=0.658, p less than 0.001 ).

In addition, Radium 223 significantly delayed the time to alkaline phosphatase ( ALP ) progression ( HR=0.167, p less than 0.00001 ) and time to prostate-specific antigen ( PSA ) progression ( HR=0.643, p less than 0.00001 ). These are two important biomarkers for castration-resistant prostate cancer 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.

The number of patients experiencing adverse events was lower in the Radium 223 group compared with the placebo group ( 93% vs 96% ). Most adverse events associated with Radium 223 were mild to moderate. The most common adverse drug events ( greater than or equal to 10% ) in patients receiving Radium 223 were diarrhea, nausea, vomiting and thrombocytopenia. Grade 3 and 4 treatment-emergent adverse events were reported among 56.5% of Radium 223-treated patients and 62.5% of placebo-treated patients. The most common hematologic laboratory abnormalities ( greater than or equal to 5% ) were anemia, thrombocytopenia and neutropenia.

Radium 223 is an alpha particle-emitting radioactive therapeutic agent with an anti-tumour effect on bone metastases. The active ingredient 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-tumour effect on bone metastases. The alpha particle range from Radium 223 is less than 100 micrometers, which may limit damage to the surrounding normal tissues.

Prostate cancer is the most common non-cutaneous malignancy in men worldwide. A majority of men with castration-resistant prostate cancer have radiological evidence of bone metastases. Once the cancer cells settle in the bone, they interfere with bone strength, often leading to pain, fracture and other complications that can significantly impair a man's health. Bone metastases secondary to prostate cancer typically target the lumbar spine, vertebrae and pelvis. In fact, bone metastases are the main cause of morbidity and death in patients with castration-resistant prostate cancer.

Source: Bayer HealthCare, 2013

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