Radium-223-dichlorid (1) – Xofigo®

• Clinical trials
  • The assessment of the extent of the additional benefit is therefore based on the results of the ALSYMPCA trial. This was a randomised, controlled, double-blind Phase III trial in which radium-223 was compared with placebo.

Patients for whom treatment with docetaxel is an option

• For patients eligible for treatment with docetaxel, an additional benefit over the appropriate comparator therapy is not proven.
• The pharmaceutical manufacturer’s dossier presents what it terms a ‘qualitative indirect comparison’, based on various RCTs on docetaxel and one RCT on radium-223.
• However, such a comparison does not allow for valid conclusions.
• An adjusted indirect comparison, which might be suitable for demonstrating additional benefit, is not available.
• Overall, the comparison submitted by the pharmaceutical manufacturer is not suitable for drawing conclusions regarding the additional benefit of radium-223 compared with docetaxel.
• There are therefore no relevant data available to assess the additional benefit compared with the appropriate comparator therapy.

Patients for whom treatment with docetaxel is not an option

• For patients for whom treatment with docetaxel is not an option, there is an indication of considerable additional benefit compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the additional benefit of radium-223 as considerable, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• Compared with the appropriate comparator therapy, there is, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, there is a considerable improvement in the therapy-relevant benefit, as a moderate prolongation of survival and, in addition, an alleviation of serious symptoms are achieved.
• mortality
  • overall survival
  • In the radium-223 treatment group, there was a statistically significant prolongation of overall survival compared with best supportive care (HR: 0.70, CI: 0.58–0.83, p-value < 0.001).
  • The median survival time in the radium-223 group was 14.9 months compared with 11.3 months in the best supportive care (BSC) group, representing a median survival benefit of 3.6 months.
  • For the assessment of additional benefit at the level of the overall survival endpoint, the result for the overall population is therefore used, which shows a moderate prolongation of survival and thus a considerable additional benefit of radium-223 compared with best supportive care.
• Morbidity – time to first symptomatic skeletal event
  • To assess the additional benefit in terms of morbidity, results are available for the endpoint ‘time to first symptomatic skeletal event’.
  • In the ALSYMPCA trial, the first symptomatic skeletal event occurred after a median of 15.6 months in patients treated with radium-223. Compared with the BSC group, which had a median of 9.8 months, treatment with radium-223 demonstrated a statistically significant prolongation of 5.8 months (HR: 0.66 [0.52; 0.83], p < 0.001).
  • The result for the composite endpoint is based primarily on the individual component ‘time to first external radiotherapy for the relief of skeletal symptoms’ – Compared with the other events, the administration of external radiotherapy to alleviate skeletal symptoms was by far the most common first event to occur.
  • The a priori planned subgroup analysis for one of the endpoints indicates an indication of a difference in treatment outcome depending on whether the patient received concomitant bisphosphonate therapy in addition to the study medication.
  • Whilst a statistically significant advantage in favour of radium-223 was observed in the group receiving concomitant bisphosphonate therapy, the group without concomitant bisphosphonate therapy showed a numerical advantage for radium-223, this was not statistically significant.
  • The assessment of additional benefit therefore relates to the overall population.
• quality of life
  • FACT-P
  • The FACT-P (Functional Assessment of Cancer Therapy – Prostate) is a disease-specific questionnaire for the treatment of patients with prostate cancer.
  • Due to the non-robust result from the only usable analysis and in view of the other limitations, there are, on the whole, insufficiently reliable results for the FACT-P endpoint to enable an assessment of the additional benefit with regard to quality of life.
  • EQ-5D
  • Health-related quality of life was also assessed in the ALSYMPCA study using the generic EQ-5D questionnaire.
  • The EQ-5D results are therefore not taken into account in this assessment.
• Side effects
  • In the ALSYMPCA study, adverse events were recorded up to 12 weeks after the end of treatment.
  • Serious adverse events occurred in 45.2% of patients in the radium-223 treatment group, compared with 53.8% of patients receiving best supportive care. This difference is statistically significant (RR: 0.84 [0.73; 0.96], p = 0.014) and indicates an advantage of radium-223 treatment for this endpoint.
  • The severe adverse events (CTCAE Grade 3 or 4) recorded in the study occurred with comparable frequency in both treatment groups, with no statistically significant difference (54.0% and 59.1%, respectively).
  • With regard to adverse events of particular interest, diarrhoea is considered here due to its frequency, the difference between the treatment groups and its relevance to patients.
  • When assessing the additional benefit in terms of side effects, an overall analysis of the endpoints reveals neither an advantage nor a disadvantage of radium-223 compared with best supportive care.
• Overall assessment
  • For patients for whom treatment with docetaxel is not an option, an overall assessment of the results regarding mortality, morbidity and side effects indicates that radium-223 offers additional benefit over best supportive care in terms of the therapeutic effects on mortality and morbidity.
  • The results show that treatment with radium-223, compared with best supportive care, achieves a moderate prolongation of survival and thus a considerable additional benefit.
  • Furthermore, the endpoint ‘time to first symptomatic skeletal event’ indicates a reduction in serious symptoms or a delay in the onset of serious complications arising from the disease.
  • There are insufficient robust results available to assess health-related quality of life.
  • Taken together, a considerable additional benefit of radium-223 compared with best supportive care is identified for the overall population.
  • Classifying the extent of the additional benefit as ‘major’ is not justified, as, particularly with regard to the prolongation of survival and the effects on disease-specific morbidity, the extent achieved does not constitute a sustained and significant improvement in treatment-related benefit—one not previously achieved with the appropriate comparator therapy— even from the perspective of curing a disease or achieving long-term freedom from serious symptoms.

Courtesy translation only, please refer to the German original.