Enzalutamid (1) – Xtandi®

• Clinical trials
  • The AFFIRM trial was a randomised, double-blind, multicentre (156 centres), placebo-controlled trial involving a total of 1,199 men with metastatic, castration-resistant prostate cancer whose disease had progressed during or after docetaxel therapy.

Treatment of metastatic, castration-resistant prostate cancer in adult men whose disease progresses during or after chemotherapy with docetaxel

• For patients with metastatic, castration-resistant prostate cancer whose disease progresses during or after chemotherapy with docetaxel, 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 enzalutamide 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.
• The certainty of the evidence (probability of additional benefit) is classified as ‘indication’, as only the results from one randomised clinical trial (the AFFIRM registration trial) were presented.
• Mortality – Overall survival
  • For the endpoint ‘overall survival’, a statistically significant difference in favour of enzalutamide was observed (hazard ratio: 0.63 [95% confidence interval: 0.53; 0.75]), with an absolute prolongation of median overall survival of 4.8 months.
  • Overall, the ‘overall survival’ endpoint demonstrated a considerable additional benefit of enzalutamide compared with best supportive care, as a moderate prolongation of survival was achieved.
• Morbidity – time to first skeletal-related event
  • For the endpoint ‘time to first skeletal-related event’, the results of the presented study showed a statistically significant difference in favour of enzalutamide, with a median difference of 3.4 months compared with the control arm (hazard ratio: 0.69 [95% confidence interval: 0.57; 0.84]).
  • With regard to this patient-relevant endpoint, enzalutamide leads to a reduction in the seriousness of the disease’s symptoms.
• Morbidity – time to pain progression
  • For this endpoint, the intervention arm receiving enzalutamide showed an advantage over the control arm receiving best supportive care alone (hazard ratio: 0.56 [95% confidence interval: 0.41; 0.78]).
  • The result for this endpoint indicates a noticeable alleviation of the disease for patients.
• Morbidity – change in pain intensity
  • For this endpoint, the intervention arm receiving enzalutamide showed an advantage compared with the control arm receiving only best supportive care (mean difference: –0.99 [95% confidence interval: –1.29; –0.69]).
  • The results for this endpoint also indicate a noticeable alleviation of the condition for patients.
• Health-related quality of life
  • There is insufficient usable data available for the assessment of health-related quality of life.
  • For the reasons stated, the results on health-related quality of life could not be included in the benefit assessment.
• Side effects
  • Adverse events were observed in the vast majority of patients in both study arms due to the advanced stage of the disease (98.1% in the intervention arm and 97.7% in the control arm).
  • Nevertheless, when considering the proportions of treatment-naïve patients experiencing an AE whilst on enzalutamide, a statistically significant reduction in the number of severe AEs (CTCAE grade ≥ 3) was observed (relative risk: 0.85 [95% confidence interval: 0.76; 0.96]).
  • Overall, a significant reduction in serious side effects and a notable reduction in other side effects were observed with enzalutamide treatment compared with best supportive care.
• Conclusion
  • For the endpoint ‘overall survival’, there is a considerable additional benefit of enzalutamide compared with best supportive care, as a moderate prolongation of survival was achieved.
  • The results for the endpoints ‘time to first skeletal-related complication’, ‘time to first skeletal-related complication’ and ‘change in pain intensity’ demonstrate a reduction in serious symptoms of the disease and, respectively, a noticeable alleviation of the disease for patients through enzalutamide compared with best supportive care.
  • The analysis of side effects provided indications of a significant reduction in serious side effects and a notable reduction in other side effects during treatment with enzalutamide.
  • Taken as a whole, this therefore results in consistent positive effects across all endpoints included in the benefit assessment within the endpoint categories of mortality, morbidity and side effects.
  • Taken together, the G-BA concludes that there is considerable additional benefit.
  • A classification as ‘major additional benefit’ is not justified in this case.
• Overall assessment
  • On balance, there are therefore consistent positive effects across all endpoints included in the benefit assessment within the endpoint categories of mortality, morbidity and side effects.

Courtesy translation only, please refer to the German original.