Olaparib (10) – Lynparza®

• Clinical trials
  • The PROpel trial is a randomised, controlled, double-blind Phase III trial comparing olaparib in combination with abiraterone and prednisone or prednisolone against abiraterone and prednisone or prednisolone.

a1) Adults with metastatic castration-resistant prostate cancer (mCRPC) for whom chemotherapy is not clinically indicated and who have not previously received treatment for mCRPC – adults with a BRCA mutation

• Consequently, the G-BA has determined that olaparib in combination with abiraterone acetate and prednisone or prednisolone offers a considerable additional benefit for patients with untreated mCRPC and a BRCA mutation, compared with abiraterone acetate in combination with prednisone or prednisolone.
• Particularly given the uncertainty as to the extent to which chemotherapy was clinically contraindicated for all patients in the PROpel study, the evidence provides a hint of additional benefit.
• mortality
  • For patients with a BRCA mutation, there is a statistically significant difference in overall survival in favour of olaparib in combination with abiraterone and prednisone or prednisolone compared with abiraterone and prednisone or prednisolone.
  • In this regard, the extent of the prolongation in overall survival achieved is assessed as a very significant improvement.
• Morbidity – pain-related impairment (BPI-SF items 9a–g)
  • For patients with a BRCA mutation, a statistically significant difference is observed in one of the endpoints, demonstrating a relevant advantage of olaparib in combination with abiraterone and prednisone or prednisolone compared with abiraterone and prednisone or prednisolone.
• Morbidity – Symptomatic skeletal-related events (SSRE)
  • For patients with a BRCA mutation, this endpoint shows a statistically significant difference, indicating a clear advantage of olaparib in combination with abiraterone and prednisone or prednisolone compared with abiraterone and prednisone or prednisolone.
• Morbidity – Relative progression-free survival (rPFS)
  • In the overall population, rPFS is statistically significantly prolonged with olaparib in combination with abiraterone and prednisone or prednisolone compared with abiraterone in combination with prednisone or prednisolone.
  • The rPFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
• Morbidity – Most severe pain (BPI-SF Item 3) and pain intensity (BPI-SF Items 3–6)
  • For the endpoints of worst pain, assessed using BPI-SF Item 3, and pain intensity, assessed using BPI-SF Items 3–6, no statistically significant differences were observed between the treatment groups.
• Morbidity – Health status (EQ-5D VAS)
  • No usable data are available for the health status endpoint, assessed using the EQ-5D visual analogue scale (VAS), as the proportion of patients who were censored on Day 1 – and were therefore not included in the analysis – exceeds 30 per cent.
• Health-related quality of life – FACT-P
  • For patients with a BRCA mutation, there is a clear advantage of olaparib in combination with abiraterone and prednisone or prednisolone compared with abiraterone and prednisone or prednisolone.
• Side effects – Serious adverse events (SAEs)
  • For patients with a BRCA mutation, there is no statistically significant difference between the treatment groups.
• Side effects – Severe adverse events (CTCAE grade ≥ 3)
  • For the endpoints of severe adverse events, there was a statistically significant disadvantage for olaparib in combination with abiraterone and prednisone or prednisolone compared with abiraterone in combination with prednisone or prednisolone in the overall population.
• Side effects – Therapy discontinuations due to adverse events (AEs)
  • For the endpoints of therapy discontinuations due to adverse events, there was a statistically significant disadvantage for olaparib in combination with abiraterone and prednisone or prednisolone compared with abiraterone in combination with prednisone or prednisolone in the overall population.
• Side effects – Specific adverse events
  • In detail, statistically significant disadvantages compared to olaparib in combination with abiraterone acetate and prednisone or prednisolone were observed for the specific adverse events: diarrhoea (PT, AEs), nausea (PT, AEs), reduced appetite (PT, AEs), injury, poisoning and procedure-related complications (SOC, SUEs), pulmonary embolism (PT, severe AEs) and anaemia (PT, severe AEs) in the overall population.
• Overall assessment
  • Overall, advantages are evident in terms of mortality, morbidity and health-related quality of life.
  • These are offset by disadvantages in the ‘side effects’ endpoint category.
  • On balance, olaparib in combination with abiraterone and prednisone or prednisolone offers a considerable additional benefit compared with abiraterone in combination with prednisone or prednisolone for patients with untreated metastatic castration-resistant prostate cancer with a BRCAmutation.

a2) Adults with metastatic castration-resistant prostate cancer (mCRPC) for whom chemotherapy is not clinically indicated and who have not received prior treatment for mCRPC – adults without a BRCA mutation (BRCA wild-type)

• The conclusion is that the additional benefit of olaparib in combination with abiraterone acetate and prednisone or prednisolone is not proven compared with abiraterone acetate in combination with prednisone or prednisolone for patients with untreated mCRPC and without a BRCA mutation.
• mortality
  • For patients without a BRCA mutation, there is no statistically significant difference between the treatment groups.
• Morbidity – impairment due to pain (BPI-SF items 9a–g)
  • For patients without a BRCA mutation, there was no statistically significant difference between the treatment groups.
• Morbidity – Symptomatic skeletal-related events (SSRE)
  • For patients without a BRCA mutation, there is no statistically significant difference between the treatment groups.
• Morbidity – Progression-free survival (rPFS)
  • In the overall population, rPFS is statistically significantly prolonged with olaparib in combination with abiraterone and prednisone or prednisolone compared with abiraterone in combination with prednisone or prednisolone.
  • The rPFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
• Morbidity – Most severe pain (BPI-SF Item 3) and pain intensity (BPI-SF Items 3–6)
  • For the endpoints of worst pain, assessed using BPI-SF Item 3, and pain intensity, assessed using BPI-SF Items 3–6, no statistically significant differences were observed between the treatment groups.
• Morbidity – Health status (EQ-5D VAS)
  • No usable data are available for the health status endpoint, assessed using the EQ-5D visual analogue scale (VAS), as the proportion of patients who were censored on Day 1 – and were therefore not included in the analysis – exceeds 30 per cent.
• Health-related quality of life – FACT-P
  • For patients without a BRCA mutation, there is no statistically significant difference between the treatment groups, meaning that there are neither advantages nor disadvantages for this patient group.
• Side effects – severe adverse events (CTCAE grade ≥ 3)
  • For the endpoints of severe adverse events (AEs), there is a statistically significant disadvantage of olaparib in combination with abiraterone and prednisone or prednisolone compared with abiraterone in combination with prednisone or prednisolone in the overall population.
• Side effects – Therapy discontinuations due to adverse events (AEs)
  • For the endpoints of therapy discontinuations due to adverse events (AEs), there was a statistically significant disadvantage for olaparib in combination with abiraterone and prednisone or prednisolone compared with abiraterone in combination with prednisone or prednisolone in the overall population.
• Side effects – Specific adverse events
  • In detail, statistically significant disadvantages compared to olaparib in combination with abiraterone acetate and prednisone or prednisolone were observed for the specific adverse events: diarrhoea (PT, AEs), nausea (PT, AEs), reduced appetite (PT, AEs), injury, poisoning and procedure-related complications (SOC, SUEs), pulmonary embolism (PT, severe AEs) and anaemia (PT, severe AEs) in the overall population.
• Overall assessment
  • Taking the results as a whole, there are neither benefits nor disadvantages in the endpoint categories of mortality, morbidity and health-related quality of life.
  • In contrast, there are disadvantages in the endpoint category of side effects, particularly the SUEs.
  • However, the extent of the negative effects is not considered severe enough to justify the conclusion of ‘less benefit’ when viewed in the overall context.

b) Adults with metastatic castration-resistant prostate cancer (mCRPC) for whom chemotherapy is not clinically indicated and who have already received prior treatment for mCRPC

• The additional benefit is not proven.
• Study 8, which is relevant to the benefit assessment, was not cited by the pharmaceutical manufacturer in the dossier for the benefit assessment.
• Although the study documents were submitted subsequently as part of the commenting procedure, the data were not processed in accordance with the module template.

Courtesy translation only, please refer to the German original.