Olaparib (6) – Lynparza®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted the results of the open-label, randomised, controlled PROfound trial comparing olaparib with abiraterone or enzalutamide.

Adult patients with metastatic castration-resistant prostate cancer (mCRPC); BRCA1/2-mutated (germline and/or somatic); progressive disease following prior treatment with abiraterone and/or enzalutamide

• A hint of considerable additional benefit.
• Consequently, the G-BA has determined that there is evidence of a considerable amount of additional benefit for olaparib compared with the appropriate comparator therapy.
• mortality
  • In the PROfound study, overall survival was defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a significant difference was observed between the treatment groups in favour of olaparib.
  • The prolongation of overall survival achieved with olaparib compared with abiraterone or enzalutamide is assessed as a clear improvement.
• Morbidity – Progression-free survival
  • Radiological progression-free survival (PFS) was the primary endpoint of the PROfound study and was defined as the time from randomisation to radiologically confirmed progression or to death, regardless of the underlying cause of death.
  • The results show a statistically significant prolongation of PFS with treatment with olaparib compared with abiraterone or enzalutamide.
  • Morbidity was assessed not primarily on the basis of disease symptoms, but solely on the basis of asymptomatic findings not directly relevant to the patient.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint. The overall conclusion regarding additional benefit remains unaffected by this.
• Morbidity – Pain (BPI-SF)
  • In the PROfound study, pain was assessed using the Brief Pain Inventory-Short Form (BPI-SF) questionnaire.
  • Impairment due to pain (BPI-SF items 9a–g): To assess the relevance of the result, the standardised mean difference in the form of Hedges’ g is used. In this case, the 95% confidence interval for the mean difference lies entirely outside the irrelevance range [−0.2; 0.2]. This allows a relevant advantage for olaparib to be inferred for the endpoint ‘disability due to pain’.
  • For the endpoint ‘impairment due to pain’, the statistically significant difference between the treatment groups in favour of olaparib is also evident on the basis of the supplementary analyses.
• Morbidity – Conclusion on morbidity
  • Overall, there are advantages in favour of olaparib for the patient-reported endpoints ‘worst pain’ and ‘impairment due to pain’, as well as for the endpoint ‘occurrence of spinal cord compression’.
  • No usable analyses are available for the health status endpoint, as assessed using the EQ-5D VAS scale.
  • Overall, a significant advantage in therapeutic benefit can be inferred for olaparib in the morbidity category.
• Quality of life – FACT-P
  • Health-related quality of life was assessed in the PROfound study using the FACT-P questionnaire.
  • In the dossier, the pharmaceutical manufacturer presented continuous analyses and responder analyses, operationalised as time to deterioration in quality of life. These are not taken into account, as the proportion of patients not included in the analysis is > 30% and is therefore not usable for the present benefit assessment.
• Side effects – Adverse events
  • The results for the endpoint ‘Total adverse events’ are presented solely for supplementary purposes.
  • In the PROfound study, 97.1% of patients in the intervention arm and 89.7% of patients in the comparator arm experienced an adverse event.
• Overall assessment
  • For the benefit assessment of olaparib for the treatment of metastatic castration-resistant prostate cancer with a BRCA1/2 mutation, the pharmaceutical manufacturer has submitted results from the PROfound study on the endpoint categories of mortality, morbidity, health-related quality of life and side effects.
  • In the PROfound study, the appropriate comparator therapy was implemented only for the patient population of patients for whom abiraterone and enzalutamide were deemed most suitable on an individual basis. Due to the lack of sufficiently suitable criteria for dividing the patient group into those for whom abiraterone or enzalutamide, or docetaxel or cabazitaxel on an individual basis, the present results are used to assess the additional benefit for the entire patient population within the indicated therapeutic indication.
  • For the endpoint of overall survival, there is a statistically significant advantage of olaparib over abiraterone or enzalutamide, which can be regarded as a marked improvement.
  • In terms of morbidity, an advantage was observed for treatment with olaparib for the endpoints ‘severe pain’ and ‘impairment due to pain’, as well as for the endpoint component ‘occurrence of spinal cord compression’. Overall, an advantage for olaparib can be inferred.
  • No usable analyses are available for the quality of life category.
  • With regard to the endpoints relating to side effects, despite the disadvantages observed for the specific side effects ‘anaemia’ and ‘nausea’, no overall advantage or disadvantage can be identified for treatment with olaparib.
  • Overall, olaparib shows a significant improvement in overall survival as well as further relevant advantages in the patient-reported morbidity endpoints. With regard to side effects, neither advantages nor disadvantages can be inferred. Therefore, despite the unusable data on quality of life, a considerable additional benefit for olaparib compared with the appropriate comparator therapy can be inferred for the treatment of metastatic, castration-resistant prostate cancer with a BRCA1/2 mutation.

Courtesy translation only, please refer to the German original.