Olaparib (5) – Lynparza®

• Clinical trials
  • The benefit assessment is based on the results of the double-blind, randomised, multicentre POLO trial comparing olaparib with placebo.

Adult patients with germline BRCA1/2 mutations who have metastatic pancreatic adenocarcinoma and whose disease has not progressed following at least 16 weeks of first-line platinum-based chemotherapy, for maintenance therapy

• For adult patients with germline BRCA1/2 mutations who have metastatic pancreatic adenocarcinoma and whose disease has not progressed following at least 16weeks of first-line platinum-based chemotherapy, for maintenance therapy; the additional benefit is not proven.
• mortality
  • With regard to the results for the overall survival endpoint, there is no statistically significant difference between the two treatment arms.
  • This event occurred in 41 patients (44.6%) receiving olaparib and in 30 patients (48.4%) receiving placebo.
  • There is therefore no proof of additional benefit from olaparib for the overall survival endpoint.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was the primary endpoint in the POLO study and was defined as the time from randomisation to the occurrence of radiological progression according to RECIST criteria version 1.1 or death.
  • PFS was statistically significantly prolonged in the olaparib arm compared with the control group.
  • The prolonged PFS with olaparib in the POLO study was not associated with any advantage in terms of morbidity or quality of life; rather, olaparib was associated with disadvantages regarding symptoms in the endpoints of nausea and vomiting.
  • In summary, the available data do not indicate that the statistically significant prolongation of progression-free survival with olaparib is associated with an improvement in morbidity or health-related quality of life.
  • The results for the PFS endpoint are therefore not taken into account in this assessment.
• Morbidity – Symptoms (nausea and vomiting)
  • For the endpoint of nausea and vomiting, there is a statistically significant difference in favor of olaparib compared with placebo that is associated with a disadvantage.
  • This disadvantage is considered relevant; consequently, an overall disadvantage is identified with regard to morbidity.
• Morbidity – Health status according to EQ-5D VAS
  • Health status was assessed in the POLO study using the EQ-5D visual analogue scale (VAS).
  • The standardised mean differences show no statistically significant difference between the treatment arms.
• quality of life
  • Health-related quality of life was assessed using the functional scales of the EORTC QLQ-C30 and EORTC QLQ-PAN26 questionnaires, operationalised as the time to confirmed clinical deterioration of ≥ 10 points at two consecutive visits.
  • Overall, in the health-related quality of life endpoint category, there were no significant advantages or disadvantages for olaparib compared with watchful waiting for the overall study population.
  • An effect modification was observed for the physical function endpoint based on the characteristic of age.
  • For patients aged ≥ 65 years, a statistically significant difference was observed to the disadvantage of olaparib compared with placebo.
  • For patients < 65 years of age, no statistically significant difference was observed between the treatment groups.
  • However, as the observed effect modification cannot be conclusively assessed, it is not taken into account in the assessment of additional benefit.
• Side effects – Adverse events (total AEs)
  • In the POLO study, 95.6% of patients in the intervention arm and 93.3% of patients in the comparator arm experienced an adverse event.
  • The results for the endpoint ‘Total adverse events’ are presented for supplementary information only.
• Side effects – severe adverse events (CTCAE grade 3 or 4)
  • There is no statistically significant difference between the treatment arms in the POLO study.
• Side effects – Discontinuation due to AEs
  • The event duration analysis shows no statistically significant difference between the treatment groups for the endpoint ‘discontinuation due to AEs’.
• Side effects – Specific AEs (reduced appetite)
  • For the endpoint ‘reduced appetite’ (PT, AEs), the time-to-event analyses show a statistically significant difference in favour of olaparib compared with placebo, representing a disadvantage.
  • There may be some qualitative overlap with the ‘nausea and vomiting’ endpoint within the ‘symptoms’ endpoint category.
• Overall assessment
  • For the benefit assessment of olaparib as monotherapy for maintenance treatment in adult patients with germline BRCA1/2 mutations who have metastatic pancreatic adenocarcinoma and whose disease did not progress following at least 16-week course of platinum-based treatment as part of first-line chemotherapy. Results from the POLO trial are available for overall survival, morbidity, health-related quality of life and side effects compared with watchful waiting, operationalised as placebo.
  • Due to the particularly poor prognosis, overall survival is considered of particular importance in this therapeutic indication.
  • There is no statistically significant difference in the survival analysis between olaparib and watchful waiting.
  • An additional benefit of olaparib for overall survival is therefore not proven.
  • In the morbidity endpoint category, a statistically significant disadvantage compared with placebo is evident for the endpoint of nausea and vomiting.
  • This disadvantage is assessed as relevant, which is why an overall disadvantage is identified with regard to morbidity.
  • In the quality of life endpoint category, there are no significant advantages or disadvantages for olaparib compared with watchful waiting.
  • In the side effects endpoint category, there were no significant differences between the treatment arms in the Polo study for the endpoints of SUEs, severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs.
  • In detail, for the specific AE ‘decreased appetite’ (PT, AE), there is a statistically significant disadvantage compared with placebo for olaparib.
  • Overall, no advantage or disadvantage can be identified with regard to side effects.
  • On balance, the disadvantage in the morbidity endpoint category is not considered serious enough to justify a conclusion of less benefit overall.
  • It is therefore concluded that additional benefit from olaparib is not proven compared with a ‘wait-and-see’ approach.

Courtesy translation only, please refer to the German original.