Bayer HealthCare has announced that the European Commission ( EC ) has granted marketing authorisation for Xofigo 1000 kBq/ml, solution for injection ( Radium Ra 223 dichloride ) for the treatment of adults with castration-resistant prostate cancer ( CRPC ), symptomatic bone metastases and no known visceral metastases.
This decision follows a positive recommendation from the European Committee for Medicinal Products for Human Use ( CHMP ) in September of this year.

Bone metastases occur in the majority of men living with castration-resistant prostate cancer and can result in pain and even death.

The approval of Xofigo is based on data from the pivotal Phase III ALSYMPCA ( ALpharadin in SYMptomatic Prostate CAncer ) trial.

In ALSYMPCA, Radium 223 reduced the risk of death by 30.5 per cent 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.

The ALSYMPCA trial was a Phase III, randomized, double-blind, placebo-controlled international study of Radium 223 dichloride vs. placebo in patients with CRPC, 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 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 ( OS ). 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 have provided 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 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 ( 558/600 [ 93% ] vs. 290/301 [ 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.

Prostate cancer is the second most commonly diagnosed malignancy in men worldwide. In 2008, an estimated 899,000 men were diagnosed with prostate cancer and 258,000 died from the disease worldwide. Prostate cancer is the sixth leading cause of death from cancer in men.
A majority of men with castration-resistant prostate cancer have symptomatic 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 one of the main causes of morbidity and death in patients with castration-resistant prostate cancer.

Xofigo is an alpha particle-emitting pharmaceutical. Xofigo’s active moiety mimics calcium and selectively targets bone, specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite. The high linear energy transfer of alpha emitters ( 80 keV/micrometer ) leads to a high frequency of double-strand DNA breaks in adjacent tumour cells, resulting in a potent cytotoxic effect. Additional effects on the tumour microenvironment including osteoblasts and osteoclasts also contribute to the in vivo efficacy. The alpha particle range from Xofigo is less than 100 micrometers ( less than 10 cell diameters ), which minimises damage to the surrounding normal tissue. ( Xagena )

Source: Bayer Health Care, 2013

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