Darolutamid (2) – Nubeqa®

• Clinical trials
  • The pharmaceutical manufacturer has submitted data from the randomised, double-blind Phase III ARASENS trial for the benefit assessment, in which darolutamide in combination with docetaxel and ADT was compared with placebo in combination with docetaxel and ADT.

Adult men with metastatic hormone-sensitive prostate cancer (mHSPC)

• Consequently, the G-BA has determined that darolutamide in combination with docetaxel and ADT offers a considerable additional benefit compared with docetaxel in combination with ADT for the treatment of adult men with metastatic hormone-sensitive prostate cancer.
• Based on the available evidence, the certainty of the findings is therefore classified as ‘indication’.
• mortality
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of darolutamide in combination with docetaxel and ADT compared with the control arm.
  • The extent of the advantage achieved in overall survival is assessed as a marked improvement.
• Morbidity – Symptomatic skeletal events
  • The composite endpoint of symptomatic skeletal events assessed in the ARASENS study is defined as the time from randomisation to the first documented occurrence of any of the following: external beam radiotherapy to alleviate skeletal symptoms, new symptomatic pathological bone fractures, the onset of spinal cord compression, or tumour-related orthopaedic surgery.
  • For the combined endpoint, there is a statistically significant advantage of darolutamide in combination with docetaxel and ADT compared with the control arm.
• Morbidity – Most severe pain
  • For the endpoint of most severe pain, assessed using item 3 of the BPI-SF, the time-to-event analysis shows a statistically significant difference in favour of darolutamide in combination with docetaxel and ADT compared with the control arm.
• Morbidity – Impairment due to pain
  • For the endpoint ‘impairment due to pain’, assessed using items 9a–g of the BPI-SF, the mean differences indicate a statistically significant difference in favour of darolutamide in combination with docetaxel and ADT.
  • However, the 95% confidence interval for the standardised mean difference does not lie entirely outside the irrelevance range of –0.2 to 0.2. It cannot therefore be concluded that the observed effect is clinically relevant.
• Morbidity – Symptoms (NFPSI-17)
  • For the TSE subscale, there is a statistically significant difference in favour of darolutamide in combination with docetaxel and ADT. However, the 95% confidence interval for the standardised mean difference does not lie entirely outside the non-significant range of -0.2 to 0.2. It cannot therefore be concluded that the observed effect is clinically significant.
• quality of life
  • In line with the above comments on the NFPSI-17, the ARASENS study does not provide any data on health-related quality of life.
• Side effects – serious adverse events (SAEs), severe adverse events (CTCAE grade ≥ 3), therapy discontinuations due to adverse events
  • There are no statistically significant differences between the treatment arms for the endpoints SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
• Side effects – Specific adverse events
  • In detail, with regard to specific AEs, there are statistically significant disadvantages for darolutamide in combination with docetaxel and ADT with respect to the endpoints ‘skin and subcutaneous tissue disorders’ (SOC, severe AE) and ‘hypertension’ (PT, severe AE); by contrast, there is a statistically significant advantage for the endpoint ‘bone pain’ (PT, severe AE).
• Overall assessment
  • For the endpoint of overall survival, there is a clear advantage for darolutamide in combination with docetaxel and ADT compared with docetaxel in combination with ADT.
  • In the morbidity endpoint category, advantages were observed for darolutamide in combination with docetaxel and ADT for the endpoints of symptomatic skeletal events and worst pain. With regard to patient-reported symptoms, as assessed using the NFPSI-17 questionnaire, there were no major differences between the treatment arms that were relevant to the evaluation.
  • The ARASENS study does not provide any data on health-related quality of life.
  • With regard to side effects, there are no differences between the treatment arms that are relevant to the benefit assessment. In detail, with regard to specific adverse events alone, there were disadvantages for the endpoints ‘skin and subcutaneous tissue disorders’ (SOC, severe AE) and ‘hypertension’ (PT, severe AE), as well as an advantage for the endpoint ‘bone pain’ (PT, severe AE).
  • Overall, therefore, the positive effects in the endpoint categories of mortality and morbidity are not offset by any disadvantages.

Courtesy translation only, please refer to the German original.