Darolutamid (1) – Nubeqa®

• Clinical trials
  • The benefit assessment of darolutamide is based on the results of the pivotal, randomised, double-blind Phase III ARAMIS trial.

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

• Consequently, the G-BA has determined that darolutamide, for the treatment of adult men with non-metastatic castration-resistant prostate cancer who are at high risk of developing metastases, compared with the appropriate comparator therapy – a watchful waiting approach whilst continuing existing conventional ADT – a considerable additional benefit.
• Based on the available evidence, the certainty of the evidence is therefore classified as ‘indication’.
• mortality
  • Overall survival was defined in the ARAMIS study as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant difference between the treatment arms in favour of darolutamide was observed at both the first and second data cut-offs.
  • Although darolutamide leads to an improvement in overall survival, the extent of the effect of darolutamide 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.
  • Furthermore, the results for the overall survival endpoint in both study arms are based on minor event rates.
• Morbidity – Metastasis-Free Survival (MFS)
  • In the ARAMIS study, the endpoint MFS was defined as the time from randomisation to the first occurrence of a radiographically detectable bone or soft-tissue distant metastasis confirmed according to RECIST 1.1 criteria, or until death.
  • MFS was statistically significantly prolonged in the intervention arm compared with the control arm.
  • In the present operationalisation, the endpoint MFS is a composite endpoint comprising the 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; for this reason, the MFS endpoint is not taken into account in this assessment.
• Morbidity – Symptomatic skeletal events
  • The composite endpoint of symptomatic skeletal events, as defined in the ARAMIS study, is operationalised as the time from randomisation to the first documented occurrence of the following components: ˗ external beam radiotherapy to alleviate skeletal symptoms ˗ new symptomatic, pathological bone fractures ˗ occurrence of spinal cord compression ˗ tumour-related orthopaedic surgery
  • For the combined endpoint, darolutamide showed a statistically significant advantage over the watch-and-wait approach.
  • In both the darolutamide arm and the placebo arm, the median time to event has not yet been reached.
• Health-related quality of life – FACT-P
  • Health-related quality of life was self-reported by patients in the ARAMIS study and assessed using the FACT-P questionnaire.
  • The responder analyses submitted by the pharmaceutical manufacturer, relating to a deterioration in the FACT-P total score of ≥ 10 points, are used.
  • At week 16, a statistically significant difference in the FACT-P total score was observed between the treatment arms, in favour of darolutamide.
  • Overall, therefore, there is a significant improvement in health-related quality of life with darolutamide compared with the watch-and-wait approach.
• Side effects – Total adverse events (AEs)
  • Adverse events (AEs) occurred in almost all study participants.
• Overall assessment
  • For the benefit assessment of darolutamide in the treatment of adult men with non-metastatic castration-resistant prostate cancer who are at high risk of developing metastases, results are available for the endpoint categories of mortality, morbidity, health-related quality of life and side effects from the ARAMIS trial.
  • The improvement achieved by darolutamide 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. Furthermore, the results in both study arms are based on minor event rates.
  • In the morbidity endpoint category, treatment with darolutamide demonstrates patient-relevant advantages for endpoints such as symptomatic skeletal events, as well as prostate cancer-specific invasive procedures and pain progression (measured using BPI-SF Item 3 and the initiation of opioid therapy). Based on the available data in the morbidity endpoint category, the effects are assessed as a significant improvement in symptoms that has not been achieved previously. The alleviation of serious symptoms and the avoidance of prostate cancer-specific invasive procedures are considered to be of significant importance in the current treatment context.
  • Furthermore, data on health-related quality of life are available for this assessment; these were reported by patients and collected using the prostate cancer-specific FACT-P questionnaire. These data show a major improvement in health-related quality of life for darolutamide compared with a watch-and-wait approach.
  • With regard to side effects, neither an advantage nor a disadvantage can be identified for darolutamide compared with a watch-and-wait approach. Statistically significant differences are observed only in the specific adverse events. Here, there is an advantage for darolutamide over a watch-and-wait approach for one endpoint and a disadvantage for darolutamide over a watch-and-wait approach for another endpoint.
  • In the overall assessment of the available results for patient-relevant endpoints, darolutamide shows exclusively advantages compared with a watch-and-wait approach across the endpoint categories of mortality, morbidity and health-related quality of life. This is not offset by any disadvantages in terms of side effects. Overall, there is a significant improvement in treatment-related benefit that has not been achieved before.

Courtesy translation only, please refer to the German original.