Apalutamid (1) – Erleada®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer submitted data from the pivotal registration trial SPARTAN for the therapeutic indication of apalutamide. This was a randomised, double-blind, placebo-controlled, parallel-group trial.

Adult men with non-metastatic castration-resistant prostate cancer (nm-CRPC) who are at high risk of developing metastases

• Overall, based on the advantage observed for the endpoint of symptomatic progression, the G-BA concludes that apalutamide offers a minor additional benefit compared with the appropriate comparator therapy.
• Taken as a whole, the uncertainties described justify classifying the certainty of the evidence as a hint of additional benefit.
• mortality
  • Overall survival was defined in the SPARTAN study as the time from randomisation to death from any cause.
  • By the data cut-off date of 19 May 2017, a total of 104 patients had died, 62 in the intervention arm and 42 in the comparator arm. Given the 2:1 randomisation ratio, this corresponds to a proportion of 7.9% and 10.5% respectively. The median survival time has not yet been reached in either arm; there is no statistically significant difference in overall survival (hazard ratio (HR): 0.70; [95% confidence interval (CI): 0.47; 1.04]; p-value 0.076).
  • An additional benefit of apalutamide is not proven in terms of overall survival.
• Morbidity – Metastasis-Free Survival (MFS)
  • In the SPARTAN study, the endpoint MFS was defined as the time from randomisation to the first occurrence of a confirmed radiographically detectable bone or soft-tissue metastasis, or until death.
  • Median MFS was statistically significantly prolonged by 24.81 months in the intervention group compared with the control group (median 40.51 vs. 15.70 months; HR: 0.30 [95% CI: 0.24; 0.36]; p < 0.0001;).
  • 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 (radiographic detection of metastases) 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 interpretability of the results for this endpoint in terms of patient-relevant benefit, which is why the MFS endpoint is not taken into account in this assessment.
  • As regards the question of whether MFS can be regarded as a surrogate for overall survival, the analyses submitted by the pharmaceutical manufacturer in the dossier do not provide sufficient evidence that MFS is a valid surrogate endpoint for overall survival in this indication.
• Morbidity – time to initiation of cytotoxic chemotherapy
  • The endpoint ‘time to initiation of cytotoxic chemotherapy’ was defined in the SPARTAN study as the time from randomisation to the start of cytotoxic chemotherapy for prostate cancer.
  • Notwithstanding the fundamental question of whether the endpoint ‘time to initiation of cytotoxic chemotherapy’ should also be reflected in other relevant endpoints in order to be considered clinically relevant, in the present case there are significant uncertainties regarding the interpretability of the results for this endpoint, which mean that no conclusions regarding additional benefit can be drawn from the available data.
  • The results for the endpoint ‘time to first subsequent chemotherapy’ are therefore not taken into account in this assessment.
• Health-related quality of life – FACT-P
  • Health-related quality of life was self-reported by patients in the SPARTAN study and assessed using the FACT-P questionnaire. No statistically significant difference in the total score was observed.
  • Only the total score is included in the assessment of additional benefit, as this provides a comprehensive view of the data on patients’ health-related quality of life.
• Side effects – Total adverse events (AEs)
  • In the SPARTAN study, approximately 97 per cent of patients in the intervention arm and approximately 93 per cent of patients in the control arm experienced an adverse event.
  • The results for the endpoint ‘Total adverse events’ are presented for supplementary information only.
• Overall assessment
  • For the benefit assessment of apalutamide in the treatment of adult men with non-metastatic castration-resistant prostate cancer who are at high risk of developing metastases, the SPARTAN study provides results on overall survival, morbidity, health-related quality of life and side effects.
  • In the mortality endpoint category, there is no statistically significant difference in overall survival between the study arms. Further data on overall survival from the study, which is currently still ongoing, are pending. An additional benefit of apalutamide for overall survival is not proven.
  • In the morbidity endpoint category, only some of the available endpoints or study results allow valid conclusions to be drawn. Here, an advantage from treatment with apalutamide is evident only for the endpoint ‘symptomatic progression’. Based on the available data, this effect is interpreted as a moderate improvement in symptoms that has not previously been achieved. 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 apalutamide, particularly as key information regarding the circumstances surrounding the decision to treat with or without chemotherapy is lacking.
  • With regard to health-related quality of life, treatment with apalutamide shows neither positive nor negative effects.
  • In the endpoint category of side effects, statistically significant differences are evident only for specific adverse events. There are both advantages and disadvantages here; however, taking into account their extent and clinical significance, these do not influence the overall assessment of the additional benefit in a weighed decision.
  • Overall, based on the advantage observed for the endpoint ‘symptomatic progression’, the G-BA concludes that apalutamide offers a minor additional benefit compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.