Olaparib (9) – Lynparza®

• Clinical trials
  • PAOLA-1 is a multicentre, double-blind, randomised controlled trial comparing olaparib in combination with bevacizumab to bevacizumab alone.

Adult female patients with advanced (FIGO stages III and IV) high-grade epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer, who have achieved a response (complete or partial) following completion of first-line platinum-based chemotherapy in combination with bevacizumab; disease associated with homologous recombination deficiency (defined by either a BRCA1/2 mutation and/or genomic instability); maintenance therapy

• In its overall assessment, the G-BA has identified a hint of considerable additional benefit for olaparib in combination with bevacizumab.
• mortality
  • In the PAOLA-1 trial, overall survival is defined as the time from randomisation to death, regardless of the underlying cause of death.
  • For the endpoint of overall survival, a statistically significant difference in favour of olaparib in combination with bevacizumab was observed in the patient population relevant to the assessment (with positive HRD status).
  • The extent of the prolongation in overall survival achieved is assessed as a significant improvement.
  • There is an effect modification by the characteristic ‘outcome of first-line treatment’ for overall survival.
  • Accordingly, for the former group of patients (NED [PDS] and NED / CR [Chemo]), there is a statistically significant effect in favour of olaparib in combination with bevacizumab. For the latter group of patients (NED / CR [IDS] and PR), however, no significant difference is observed between the treatment groups.
  • In light of the uncertainties described, the existing data on the observed effect modification by the characteristic ‘outcome of first-line therapy’ in the present operationalisation is not considered sufficient to derive separate conclusions regarding additional benefit in the overall assessment with the requisite certainty.
• Morbidity – Symptoms
  • Symptoms are assessed in the PAOLA-1 study using the symptom scales of the disease-specific questionnaire EORTC QLQ-C30 and the disease-specific supplementary module for ovarian cancer, EORTC QLQ-OV28.
  • For the endpoints ‘nausea and vomiting’ and ‘loss of appetite’, a statistically significant disadvantage was observed in relation to olaparib when used in combination with bevacizumab.
  • Overall, there is no predominant advantage or disadvantage in terms of symptoms.
• Morbidity – Health Status (EQ-5D Visual Analogue Scale)
  • General health status is assessed using the EQ-5D visual analogue scale.
  • No statistically significant differences were observed between the treatment arms. Consequently, there is neither an advantage nor a disadvantage in terms of health status.
• quality of life
  • Health-related quality of life is assessed in the PAOLA-1 study using the functional scales of the disease-specific questionnaire EORTC QLQ-C30 and the scales of the disease-specific supplementary module for ovarian cancer, the EORTC QLQ-OV28.
  • For all other endpoints, there is no statistically significant difference between the treatment groups.
  • In the overall analysis of the results, there are no relevant differences in health-related quality of life within the patient population relevant for evaluation.
• Side effects (AEs)
  • Adverse events occurred in almost all participants in the PAOLA-1 study. The results for the endpoint ‘Total adverse events’ are presented here only as supplementary information.
• Side effects – Serious adverse events (SAEs)
  • No statistically significant difference was observed between the treatment arms with regard to serious adverse events.
• Side effects – Severe AEs (CTCAE grade ≥ 3)
  • No statistically significant difference was observed between the treatment groups for severe adverse events with a CTCAE grade of ≥ 3.
• Side effects – Discontinuation due to AEs
  • For the endpoint of therapy discontinuation due to an AE, there was a statistically significant disadvantage compared with olaparib in combination with bevacizumab compared with bevacizumab alone.
• Side effects – Specific AEs
  • Olaparib in combination with bevacizumab showed a statistically significant disadvantage compared with bevacizumab in terms of the specific AEs (nausea) (PT) and the specific severe AEs (CTCAE grade ≥ 3) anaemia (PT) and fatigue (PT).
  • For the specific severe AEs (CTCAE grade ≥ 3) hypertension (PT), there is a statistically significant advantage for olaparib in combination with bevacizumab.
  • For the endpoints myelodysplastic syndrome and acute myeloid leukaemia, there was no statistically significant difference between the treatment groups in either case.
  • An overall review of the results regarding side effects reveals a disadvantage for olaparib in combination with bevacizumab in terms of the endpoint ‘discontinuation due to AEs’. In detail, for the specific AEs, there are predominantly negative effects of olaparib in combination with bevacizumab compared with bevacizumab alone.
• Overall assessment
  • For the endpoint of overall survival, a statistically significant difference in favour of olaparib in combination with bevacizumab was observed in the relevant patient population (with positive HRD status).
  • The extent of the prolongation in overall survival achieved is assessed as a significant improvement.
  • For the endpoints in the morbidity category, treatment with olaparib in combination with bevacizumab showed positive effects in terms of symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-OV28) with regard to the endpoints of insomnia, hormonal symptoms and side effects of chemotherapy, as well as negative effects with regard to the endpoints of nausea, vomiting and loss of appetite. Overall, therefore, there is no predominant advantage or disadvantage in terms of symptoms.
  • For the endpoint of general health status (assessed using the EQ-5D VAS), there was no statistically significant difference between the treatment groups.
  • For health-related quality of life (assessed using the EORTC QLQ-C30 and EORTC QLQ-OV28), there were no major differences between treatment with olaparib in combination with bevacizumab and treatment with bevacizumab alone.
  • With regard to the endpoint category of side effects, olaparib in combination with bevacizumab showed a disadvantage in the endpoint of treatment discontinuation due to AEs. In detail, for the specific AEs, there were predominantly negative effects of olaparib in combination with bevacizumab compared with bevacizumab alone.
  • In its overall assessment, the G-BA concludes that olaparib in combination with bevacizumab offers a considerable amount of additional benefit.

Courtesy translation only, please refer to the German original.