Enzalutamid (5) – Xtandi®

• Clinical trials
  • The ENZAMET trial is a multicentre, randomised, open-label trial comparing enzalutamide in combination with ADT against ADT in combination with non-steroidal antiandrogens (NSAAs).
  • The ARCHES trial is a multicentre, double-blind, parallel-group RCT comparing enzalutamide in combination with ADT against placebo in combination with ADT.
  • The STAMPEDE study is a randomised, open-label, multi-arm, multi-stage platform study comparing various systemic active ingredients (INN) (12 arms in total) in advanced or metastatic prostate cancer.
  • The CHAARTED study is an open-label, randomised controlled trial comparing treatment with docetaxel in combination with ADT against ADT alone in patients with metastatic prostate cancer.

Adult men with metastatic hormone-sensitive prostate cancer

• mortality
  • As the results of the STAMPEDE study show a low risk of bias and those of the ARCHES study show a high risk of bias, the requirement for certainty of results to carry out an adjusted indirect comparison is not met.
  • No conclusion regarding additional benefit can be drawn with sufficient certainty of results.
  • An additional benefit is therefore not proven.
• morbidity
  • Symptoms were assessed in the ARCHES and STAMPEDE studies using, in some cases, different measurement tools.
  • No usable data are available for an indirect comparison. An additional benefit is therefore not proven.
  • For the endpoint of symptomatic skeletal events, there are no usable data available for an adjusted indirect comparison.
  • This is justified by the insufficient similarity of the endpoints in the two studies, ARCHES and STAMPEDE.
  • No data are available for an indirect comparison of the health status endpoint, as this endpoint was not assessed in the STAMPEDE study. An additional benefit is therefore not proven.
  • In summary, in the morbidity category, the additional benefit of enzalutamide + ADT is not proven.
• quality of life
  • In the ARCHES study, data on health-related quality of life were collected using the FACT-P and EORTC QLQ-PR25 measurement instruments. However, the EORTC QLQ-PR25 can only be analysed in combination with the core questionnaire EORTC QLQ-C30.
  • In the STAMPEDE study, data were collected using the EORTC QLQ-C30 and the EORTC QLQ-PR25. Due to the different measurement tools used in the studies, it is not possible to carry out an indirect comparison.
  • In the quality of life category, therefore, the additional benefit of enzalutamide + ADT is not proven.
• Side effects
  • Adverse events occurred in almost all participants in the STAMPEDE study. In the ARCHES study, an AE was observed in 86% of patients.
  • For the SAE, the adjusted indirect comparison shows a statistically significant advantage in favour of enzalutamide + ADT compared with docetaxel + prednisolone + ADT.
  • However, due to the differing observation periods in the control and intervention arms of the STAMPEDE study, this advantage can only be inferred with a sufficiently reliable effect estimate for the period of the first 6 to 7 months after the start of treatment. No conclusions can be drawn beyond this period.
  • Due to the high potential for endpoint-specific bias in the ARCHES and STAMPEDE studies, the requirement for certainty of results needed to carry out an adjusted indirect comparison is not met. No conclusions regarding relevant differences can be drawn with sufficient certainty of results.
  • An additional benefit is therefore not proven.
  • No data are available for an indirect comparison of the endpoint ‘discontinuation due to adverse events’, as this endpoint was not recorded in the STAMPEDE study. Additional benefit is not proven for this endpoint.
  • Overall, with regard to side effects, enzalutamide + ADT shows an advantage in terms of serious adverse events (SAEs). However, due to the varying observation periods across the treatment arms of the STAMPEDE study, this advantage can only be inferred with a sufficiently reliable effect estimate for the first 6 to 7 months following the start of treatment. No conclusions can be drawn beyond this period. No conclusions can be drawn regarding relevant differences in severe AEs with sufficient certainty of results. No data are available from the indirect comparison for the endpoint of discontinuation due to AEs. For these reasons, no additional benefit for enzalutamide + ADT can be established with the required certainty in the ‘side effects’ category.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of enzalutamide in combination with androgen deprivation therapy for the treatment of adult men with metastatic hormone-sensitive prostate cancer, results are available on mortality, morbidity and side effects compared with the appropriate comparator therapy.
  • This assessment is based on an adjusted indirect comparison of the ARCHES (enzalutamide + ADT vs. placebo + ADT) and STAMPEDE (docetaxel + prednisolone + ADT vs. ADT) via the bridge comparator placebo + ADT and ADT, respectively.
  • The final data from the ARCHES study, submitted during the commenting procedure, were assessed by the IQWiG in an addendum and have been taken into account here.
  • For the endpoint of overall survival, the requirement for certainty of results to carry out an adjusted indirect comparison has not been met. An additional benefit with regard to overall survival is therefore not proven.
  • For the categories of morbidity and health-related quality of life, no usable data are available from the adjusted indirect comparison. For instance, symptoms and health-related quality of life were assessed in some cases using different measurement instruments. For the endpoint of symptomatic skeletal events, it is not assumed that there is sufficient endpoint-related similarity between the two studies.
  • Overall, with regard to side effects, enzalutamide + ADT shows an advantage in terms of serious adverse events. However, due to the differing observation periods across the study arms in the STAMPEDE trial, this advantage can only be inferred with a sufficiently reliable effect estimate for the first 6 to 7 months following the start of treatment. No conclusions can be drawn beyond this period. No conclusions can be drawn regarding relevant differences in severe AEs with sufficient certainty of the results. No data are available from the indirect comparison for the endpoint of treatment discontinuation due to AEs. For these reasons, no additional benefit for enzalutamide + ADT can be established with the required certainty in the ‘side effects’ category as a whole.
  • In its overall assessment, the G-BA therefore concludes that additional benefit is not proven from enzalutamide + ADT compared with docetaxel + prednisolone + ADT in the treatment of metastatic hormone-sensitive prostate cancer.

Courtesy translation only, please refer to the German original.