Darolutamid (3) – Nubeqa®

• Clinical trials
  • Both studies were randomised, double-blind, controlled, multicentre Phase III trials.

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

• The additional benefit is not proven.
• Overall, therefore, there are neither positive nor negative effects of darolutamide in combination with ADT compared with apalutamide in combination with ADT.
• mortality
  • For the endpoint of overall survival, the adjusted indirect comparison shows no statistically significant difference between darolutamide in combination with ADT and apalutamide in combination with ADT.
  • An additional benefit from darolutamide in combination with ADT is not proven in terms of overall survival.
• Morbidity – Symptomatic skeletal events
  • In the studies, the composite endpoint of symptomatic skeletal events comprises the following sub-components:
  • Undergoing percutaneous radiotherapy to alleviate skeletal symptoms (ARANOTE) or undergoing bone radiotherapy (TITAN)
  • new symptomatic pathological fractures (ARANOTE) or the occurrence of a new symptomatic pathological fracture (TITAN)
  • Occurrence of spinal cord compression (ARANOTE and TITAN)
  • tumour-related orthopaedic surgery (ARANOTE) or surgical intervention on the bone (TITAN)
  • However, the dossier lacks information on the occurrence of the individual sub-components for the TITAN study. This information would be necessary to assess the results of this endpoint, for example, to be able to draw conclusions about the direction of effect of the sub-components. Consequently, no suitable data are available for the TITAN study for benefit assessment; the indirect comparison submitted by the pharmaceutical manufacturer for this endpoint is therefore not taken into account.
• Morbidity – Fatigue (BFI) and health status (EQ-5D VAS)
  • In the ARANOTE study, no data on fatigue and health status were collected using the BFI or EQ-5D VAS. An adjusted indirect comparison is therefore not possible.
• Morbidity – Most severe pain (BPI-SF Item 3)
  • For the endpoint of worst pain, the pharmaceutical manufacturer has submitted responder analyses for the indirect comparison regarding the time to confirmed worsening as well as to confirmed improvement, in each case by at least 2 points.
  • The responder analyses submitted are not suitable for benefit assessment in the present situation. In the ARANOTE and TITAN studies, the median observation periods in the intervention and control arms are, at first glance, sufficiently comparable. However, over the course of the ARANOTE study, there is a continuous decline in the proportion of completed questionnaires, which differs between the study arms and cannot be explained solely by patients who died during the observation period. It cannot therefore be reliably assumed that the observation periods were sufficiently comparable throughout the course of the study.
  • However, due to the declining questionnaire response rate over the course of the ARANOTE study—which differed between the study arms—there would not be sufficient certainty of results for this operationalisation to allow an adjusted indirect comparison to be carried out.
• Morbidity – impairment due to pain (BPI-SF items 9a–9g)
  • For the indirect comparison, the pharmaceutical manufacturer provides responder analyses covering the period up to the first deterioration or first improvement.
• morbidity
  • Overall, therefore, there are no suitable data available in the morbidity endpoint category for an indirect comparison of the ARANOTE and TITAN studies; alternatively, the endpoints in the ARANOTE study exhibit a high potential for bias, which means that the certainty of results required to carry out an adjusted indirect comparison is not available.
• Quality of life – FACT-P
  • With regard to the FACT-P, the pharmaceutical manufacturer provides, for the indirect comparison, responder analyses of the time to first deterioration as well as to first improvement, each by 10 points.
  • For the benefit assessment, responder analyses must be submitted with a response threshold of at least 15 per cent of the scale range of the assessment tool used. The 15 per cent response threshold for the FACT-P total score is 23.4 points. The dossier contains results on the time to deterioration by 23.4 points exclusively for the ARANOTE study, but not for the TITAN study. The indirect comparison submitted by the pharmaceutical manufacturer instead, relating to the time to deterioration by 10 points, does not meet the requirements and is therefore not taken into account for the benefit assessment.
• Side effects – Total adverse events (AEs)
  • Adverse events occurred in almost all patients in the ARANOTE and TITAN studies. The results are presented here for supplementary information only.
• Overall assessment
  • For the assessment of the additional benefit of darolutamide in combination with androgen deprivation therapy (ADT) for the treatment of metastatic hormone-sensitive prostate cancer, results are presented based on an adjusted indirect comparison using the procedure described by Bucher et al. Results on overall survival and side effects are presented in comparison with the appropriate comparator therapy, apalutamide in combination with ADT.
  • For the endpoint of overall survival, the adjusted indirect comparison shows no statistically significant difference. With regard to overall survival, therefore, an additional benefit of darolutamide in combination with ADT is not proven.
  • For the patient-reported endpoints relating to symptoms, health status and health-related quality of life, no usable data are available for an adjusted indirect comparison, or the requirements for the certainty of results necessary to carry out an indirect comparison are not met.
  • With regard to side effects, the adjusted indirect comparison shows no statistically significant differences for the endpoints of serious adverse events (SAE) and severe adverse events (CTCAE grade ≥ 3). For the endpoint ‘therapy discontinuation due to AEs’, there is insufficient certainty of results to carry out an adjusted indirect comparison.
  • In detail, the indirect comparison also shows no statistically significant difference for the specific AE ‘fall’ (PT).
  • Overall, therefore, there are neither positive nor negative effects of darolutamide in combination with ADT compared with apalutamide in combination with ADT. An additional benefit of darolutamide in combination with ADT is therefore not proven.

Courtesy translation only, please refer to the German original.