Abirateronacetat (3) – Zytiga®

• Clinical trials
  • Results from the randomised, double-blind, placebo-controlled, parallel-group LATITUDE trial are available to demonstrate the additional benefit compared with conventional androgen deprivation therapy.

High-risk patients with newly diagnosed, metastatic, hormone-sensitive prostate cancer

• mortality
  • overall survival
  • The median survival time has not yet been reached for the abiraterone acetate arms in either study. In the comparator arms, the median has already been reached and stands at 34.7 months in the LATITUDE study and 48.0 months in the STAMPEDE study.
  • Based on the available data, this effect on overall survival is interpreted as a significant improvement that has not yet been achieved.
• morbidity
  • Progression-free survival
  • Progression-free survival (PFS) was statistically significantly longer in patients treated with abiraterone acetate (meta-analysis: hazard ratio: 0.45 [0.40; 0.51]; p < 0.001).
  • The median PFS for patients in the LATITUDE trial was 33.0 months in the treatment arm versus 14.8 months in the control arm. In the control arm of the STAMPEDE trial, the median PFS was 24.0 months and had not yet been reached in the treatment group.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. In the studies under consideration, the ‘mortality’ component of the endpoint was assessed as a standalone endpoint via the ‘overall survival’ endpoint. The morbidity component was not assessed on the basis of symptoms, but in each case using imaging procedures. Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Pain
  • Brief Pain Inventory Short Form (BPI-SF)
  • In the LATITUDE trial, pain was assessed as a patient-reported endpoint using the BPI-SF questionnaire up to 30 days after the end of treatment.
  • The results show a statistically significant difference in favour of abiraterone acetate for the endpoint ‘time to worsening of worst pain’.
  • For the other two operationalisations, there is insufficient information on the clinical relevance of the respective response criterion; therefore the assessment is based on the continuous data recorded over the treatment period (Mixed-Effects Model Repeated Measures (MMRM) analysis for the ITT population). The 95% confidence intervals of the standardised mean differences (Hedges’ g) do not lie entirely outside the irrelevance range [−0.2; 0.2], meaning it cannot be concluded that these effects are clinically relevant.
  • Opiate use
  • For the LATITUDE study, analyses are available regarding ‘time to first opiate use’ and ‘time to chronic opiate use’ as indirect measures of pain. However, as in this case pain was also measured directly via the BPI-SF questionnaire as a patient-reported endpoint, only the data collected via the BPI-SF are used for the pain endpoint in the present assessment.
  • Skeletal-related events
  • For the endpoint ‘skeletal-related events’, the meta-analysis revealed heterogeneity between the LATITUDE and STAMPEDE studies; consequently, no pooled effect estimate is used to assess the additional benefit.
  • The secondary endpoint ‘time to skeletal-related event’ in the LATITUDE study comprised the individual components ‘time to first palliative radiotherapy to the bone’, ‘time to first surgical intervention on the bone’, ‘time to first clinical or pathological bone fracture’ and ‘time to first spinal cord compression’. The results showed a significant reduction both for the overall score (hazard ratio: 0.70 [95% CI: 0.54; 0.92]; p = 0.009) and for the individual component ‘time to first palliative radiotherapy of the bone’ (hazard ratio: 0.60 [95% CI: 0.44; 0.82]; p = 0.001).
  • For the STAMPEDE trial, the overall score for the composite endpoint also shows a statistically significant advantage in favour of abiraterone acetate (hazard ratio: 0.45 [95% CI: 0.36; 0.58]; p: not available); results for the individual components are not available.
  • Fatigue
  • Fatigue as perceived by patients was assessed in the LATITUDE study using the ‘Brief Fatigue Inventory (BFI)’ questionnaire.
  • For the endpoint ‘worst fatigue (BFI, Item 3)’, the responder analyses submitted by the pharmaceutical manufacturer in its statement regarding ‘time to worsening of worst fatigue (BFI, Item 3)’ submitted in the pharmaceutical company’s statement are used as response criteria of 3 and 6 points. The results show that, both when using a response criterion of 3 points (corresponding to a worsening of the worst fatigue by one severity level) and when using a response criterion of 6 points (corresponding to a worsening of the most severe fatigue by two severity levels), a statistically significant difference in favour of abiraterone acetate was observed.
  • For the endpoint ‘impairment due to fatigue (BFI, items 4a–f)’, the pharmaceutical manufacturer also submitted responder analyses along with its statement. However, there is insufficient information available regarding the clinical relevance of the response criterion. The assessment is therefore based on the continuous data recorded over the treatment period (Mixed-Effects-Model-Repeated-Measures (MMRM) analysis for the ITT population). The 95% confidence interval of the standardised mean difference (Hedges’ g) does not lie entirely outside the irrelevance range [−0.2; 0.2], meaning that it cannot be concluded that this effect is relevant.
  • EQ-5D visual analogue scale
  • General health status was assessed using the visual analogue scale (VAS) of the EQ-5D-5L questionnaire in the LATITUDE study. Responder analyses are available for the time to deterioration by a Minimum Important Difference (MID) of 7 and 10 points, each showing a statistically significant effect in favour of abiraterone acetate. The extent of this effect is minor.
  • In summary, in the category of morbidity – particularly with regard to the endpoints of skeletal-related events, fatigue and pain – an additional benefit of abiraterone acetate in combination with androgen deprivation can be observed compared with conventional androgen deprivation.

Courtesy translation only, please refer to the German original.