Enzalutamid (4) – Xtandi®

• Clinical trials
  • The PROSPER trial was a randomised, double-blind, placebo-controlled, parallel-group trial.
  • A total of 1,401 patients with non-metastatic, castration-resistant, high-risk prostate cancer were enrolled in the trial and, in a 2:1 ratio, either to the enzalutamide arm (intervention arm) or the placebo arm (comparison arm).

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

• Consequently, the G-BA has determined that enzalutamide offers a minor additional benefit for the treatment of adult men with non-metastatic, castration-resistant, high-risk prostate cancer, compared with the appropriate comparator therapy of a watchful waiting approach whilst continuing existing conventional ADT.
• Consequently, the certainty of the evidence for the established additional benefit is classified as ‘indication’.
• mortality
  • In the PROSPER study, overall survival was defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant difference was observed between the treatment arms in favour of enzalutamide.
  • The median survival time was 67.0 months in the intervention arm and 56.3 months in the control arm, corresponding to a median extension of 10.7 months.
  • Although enzalutamide leads to an improvement in overall survival, the extent of the effect of enzalutamide compared with a watch-and-wait approach, taking into account the patients’ remaining life expectancy in the current treatment situation, is assessed as a relevant, but no more than a minor, improvement.
• 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.
  • The median MFS was statistically significantly prolonged by 21.9 months in the intervention arm compared with the control arm.
  • In the present operationalisation, 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 interpretability of the results for this endpoint in terms of patient-relevant benefit; for this reason, the MFS endpoint is not taken into account in this assessment.
• Morbidity – time to initiation of cytotoxic chemotherapy
  • In the PROSPER study, the endpoint ‘time to initiation of cytotoxic chemotherapy’ was defined as the time from randomisation to the start of cytotoxic chemotherapy.
  • For the present benefit assessment, the sensitivity analysis taking account of deaths is used.
  • The median time to the start of cytotoxic chemotherapy was prolonged by 16.7 months in the intervention arm.
  • The difference is statistically significant.
  • Notwithstanding the fundamental question of whether the endpoint ‘time to the start of cytotoxic chemotherapy’ should also be reflected in other relevant endpoints in order to be considered clinically relevant, there are significant uncertainties in the present case regarding the interpretability of the results for this endpoint, which mean that no conclusions regarding additional benefit can be drawn from the available data.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • Health status was assessed using the visual analogue scale of the EQ-5D questionnaire.
  • As in the initial assessment, the data on ‘time to first deterioration’ by ≥ 7 points and ≥ 10 points, respectively, are therefore used.
  • For both response criteria (≥ 7 points and ≥ 10 points), statistically significant advantages for enzalutamide compared with the watch-and-wait approach are evident.
  • In the intervention arm, the median time to deterioration in health status was prolonged by 3.6 months in each case.
• Morbidity – Pain: Brief Pain Inventory Short Form (BPI-SF)
  • Pain was assessed in the PROSPER study as a patient-reported endpoint using the BPI-SF questionnaire.
  • For the endpoints ‘Most Severe Pain’ (BPI-SF Item 3) and ‘Pain-Related Impairment’ (BPI-SF Items 9a–g), no statistically significant differences were observed between the treatment groups.
• 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.
  • There was no statistically significant difference in the total score between the treatment arms.
  • Only the total score is included in the assessment of additional benefit, as this provides a comprehensive overview of the patients’ health-related quality of life.
• Side effects – Total adverse events (AEs)
  • In the PROSPER study, approximately 94% of patients in the intervention arm and approximately 82% of patients in the comparator arm experienced an adverse event.
• Overall assessment
  • The improvement achieved by enzalutamide in the mortality endpoint category compared with a watch-and-wait approach is assessed, taking into account the patients’ remaining life expectancy in the current treatment situation, as a relevant improvement, but no more than a minor one.
  • In the morbidity endpoint category, 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 health-related quality of life, treatment with enzalutamide shows neither positive nor negative effects.
  • With regard to side effects, too, neither an advantage nor a disadvantage can be identified for enzalutamide compared with a watch-and-wait approach.
  • In the overall assessment of the available results on patient-relevant endpoints, the advantage in overall survival is not offset by any disadvantages in terms of morbidity, health-related quality of life or side effects.
• Overall assessment
  • Overall, there is an indication of a minor additional benefit of enzalutamide compared with a watch-and-wait approach, whilst maintaining the existing conventional androgen deprivation therapy.

Courtesy translation only, please refer to the German original.