Enzalutamid (3) – Xtandi®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer cites in the dossier the results of the pivotal registration trial PROSPER for this new indication for enzalutamide.
  • This is a randomised, double-blind, placebo-controlled parallel-group trial.

Adult men with non-metastatic castration-resistant high-risk prostate cancer (CRPC)

• mortality
  • In the PROSPER study, overall survival was defined as the time from randomisation to death from any cause.
  • The median survival time has not yet been reached in either arm; there is no statistically significant difference in overall survival (hazard ratio (HR): 0.83; [95% confidence interval (CI): 0.65; 1.06]; p-value 0.134).
  • A further interim analysis and the final data cut-off for overall survival from the currently ongoing study are still pending.
• Morbidity – Metastasis-Free Survival (MFS)
  • In the PROSPER study, the endpoint MFS was defined as the time from randomisation to the first evidence of radiographic progression according to RECIST 1.1 criteria at any time, or death within 112 days of discontinuation of study medication without evidence of radiographic progression.
  • Median MFS was statistically significantly prolonged by 21.9 months in the intervention group compared with the control group (median 36.6 vs. 14.7 months; HR: 0.29 [95% CI: 0.24; 0.35]; p < 0.001).
  • In the present study, the MFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • In this study, the morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (radiologically determined disease progression according to the RECIST criteria) and thus solely on the basis of primarily asymptomatic findings that are not directly relevant to the patient.
  • Consequently, there are major uncertainties regarding the validity of the results for this endpoint in terms of patient-relevant benefit, which is why the ‘metastasis-free survival’ (MFS) endpoint is not taken into account in this assessment.
  • Furthermore, based on the arguments presented in the pharmaceutical manufacturer’s dossier regarding the question of whether MFS can be regarded as a surrogate for the patient-relevant endpoint of overall survival, there is insufficient evidence to demonstrate that MFS is a valid surrogate endpoint for overall survival in this indication.
• Quality of life – FACT-P
  • Health-related quality of life was reported by patients in the PROSPER study and assessed using the FACT-P questionnaire.
  • For the same reasons mentioned above, the responder analysis for ‘time to first deterioration’ is also used to calculate the overall score; this analysis reveals no statistically significant differences between the treatment groups.
  • Only the FACT-P total score is included in the assessment of additional benefit, as this provides a comprehensive view of the patients’ health-related quality of life.
• Side effects – Total adverse events (AEs)
  • In the PROSPER study, approximately 87% of patients in the intervention arm and approximately 77% of patients in the comparator arm experienced an adverse event.
• Overall assessment / Conclusion
  • Results from the PROSPER study are available for the benefit assessment of enzalutamide in the treatment of adult men with non-metastatic high-risk castration-resistant prostate cancer (CRPC CRPC), results from the PROSPER study are available on overall survival, morbidity, health-related quality of life and side effects.
  • In the mortality endpoint category, the available data show no statistically significant difference in overall survival between the study arms.
  • In the endpoint category of morbidity, only some of the available endpoints or study results allow for valid conclusions. On this basis, no overall advantages or disadvantages of treatment with enzalutamide can be identified.
  • With regard to the endpoint ‘metastasis-free survival’, there are major uncertainties regarding the interpretability of the results in terms of patient-relevant benefit; for this reason, this endpoint is not taken into account in the present assessment.
  • Similarly, the results for the endpoint ‘time to initiation of cytotoxic chemotherapy’ do not allow for any valid conclusions regarding the additional benefit of enzalutamide, particularly as key information on the circumstances surrounding the decision to treat with or without chemotherapy is not available.
  • With regard to health-related quality of life, treatment with enzalutamide shows neither positive nor negative effects.
  • In the endpoint category of side effects, statistically significant differences are observed only for specific adverse events. There are both advantages and disadvantages here; however, taking into account their extent and clinical significance, these are not considered significant enough to warrant an impact on the overall assessment of additional benefit.
• Overall assessment / Conclusion
  • For the benefit assessment of enzalutamide in the treatment of adult men with non-metastatic high-risk castration-resistant prostate cancer (CRPC), CRPC), results from the PROSPER trial are available on overall survival, morbidity, health-related quality of life and side effects.
  • In the mortality endpoint category, the available data show no statistically significant difference in overall survival between the study arms.
  • In the endpoint category of morbidity, only some of the available endpoints or study results allow for valid conclusions. On this basis, no overall advantages or disadvantages of treatment with enzalutamide can be identified.
  • With regard to the endpoint ‘metastasis-free survival’, there are major uncertainties regarding the interpretability of the results in terms of patient-relevant benefit; consequently, this endpoint is not taken into account in the present assessment.
  • Similarly, the results for the endpoint ‘time to initiation of cytotoxic chemotherapy’ do not allow for any valid conclusions regarding the additional benefit of enzalutamide, particularly as key information regarding the circumstances surrounding the decision to treat with or without chemotherapy is not available.
  • With regard to health-related quality of life, treatment with enzalutamide shows neither positive nor negative effects.

Courtesy translation only, please refer to the German original.