Olaparib (7) – 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

• Consequently, the G-BA concludes that additional benefit is not proven with olaparib in combination with bevacizumab compared with bevacizumab alone.
• mortality
  • For the endpoint of overall survival, there is no statistically significant difference between the treatment groups in the patient population relevant to the assessment (with positive HRD status).
  • There is an effect modification by the characteristic ‘outcome of first-line therapy’ for overall survival.
  • No additional benefit is identified for the endpoint of overall survival.
• Morbidity – Symptoms
  • Based on these analyses, a statistically significant advantage in favour of olaparib in combination with bevacizumab was observed for the endpoints ‘insomnia’, ‘hormonal symptoms’ and ‘side effects of chemotherapy’.
  • For the endpoints ‘nausea and vomiting’ and ‘loss of appetite’, a statistically significant disadvantage was observed for olaparib in combination with bevacizumab.
  • Overall, the results do not indicate any predominant advantage or disadvantage with regard to symptoms.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • The difference between the treatment groups is not statistically significant in terms of the mean difference.
  • Consequently, there is neither an advantage nor a disadvantage in terms of health status.
• Morbidity – Progression-free survival 1 (PFS1)
  • PFS1 is statistically significantly prolonged with olaparib in combination with bevacizumab compared with bevacizumab alone.
  • Taking the above aspects into account, the PFS1 endpoint is not used for the benefit assessment.
• Morbidity – Progression-Free Survival 2 (PFS2)
  • With olaparib in combination with bevacizumab, PFS2 is statistically significantly prolonged compared with bevacizumab.
  • Taking the aspects listed into account, the PFS2 endpoint is not used for the benefit assessment.
• Morbidity – Recurrences
  • The results for the endpoints relating to ‘recurrence’ are therefore not taken into account in this assessment.
• Health-related quality of life
  • For the ‘global health status’ endpoint, there is no statistically significant difference between the treatment groups.
  • In the overall assessment of the results, there are no relevant differences in health-related quality of life with regard to the patient population relevant to the assessment.
• Side effects – Adverse events (AE)
  • Adverse events (AEs) are recorded up to 30 days after the end of treatment.
• Side effects – Serious adverse events (SAEs)
  • No statistically significant difference was observed between the treatment groups for serious adverse events.
• Side effects – Severe AEs (CTCAE grade ≥ 3)
  • There was no statistically significant difference between the treatment groups in terms of 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 difference in favor of olaparib in combination with bevacizumab compared with bevacizumab alone, which is a disadvantage.
• Side effects – Specific AEs
  • For olaparib in combination with bevacizumab, there is a statistically significant disadvantage compared with bevacizumab with regard to the specific AEs (nausea) (PT) and the specific severe AEs (CTCAE grade ≥ 3) anaemia (PT) and fatigue and asthenia (PT).
  • For the specific severe AEs (CTCAE grade ≥ 3) hypertension (PT), there is a statistically significant advantage for olaparib in combination with bevacizumab.
  • Overall, there was no statistically significant difference between the treatment groups in terms of side effects relating to the endpoints of serious AEs and severe adverse events (CTCAE grade ≥ 3).
  • In detail, the specific AEs predominantly show negative effects of olaparib in combination with bevacizumab compared with bevacizumab alone.
• Overall assessment
  • For the assessment of the additional benefit of olaparib in combination with bevacizumab, the double-blind, randomised controlled PAOLA-1 trial provides results comparing it with bevacizumab in terms of mortality (overall survival), morbidity (symptoms and health status), quality of life and side effects.
  • In the mortality endpoint category, the available results for the overall survival endpoint, relating to the patient population relevant for assessment (with positive HRD status), show no statistically significant difference.
  • For the endpoints in the morbidity category, treatment with olaparib in combination with bevacizumab showed positive effects with regard to symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-OV28) in terms of insomnia, hormonal symptoms and side effects of chemotherapy, as well as negative effects with regard to the endpoints of nausea and vomiting and loss of appetite.
  • Overall, therefore, there is no predominant benefit or disadvantage with regard to 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 bevacizumab alone.
  • With regard to side effects, there was no statistically significant difference between the treatment groups for the endpoints of serious AEs and severe adverse events (CTCAE grade ≥ 3).
  • For the endpoint of treatment discontinuation due to AEs, there is a disadvantage associated with olaparib in combination with bevacizumab.
  • However, taking into account the clinical relevance – given that moderate disadvantages were observed only for the endpoint ‘discontinuation due to AEs’ and, in detail, for specific AEs – the disadvantages associated with side effects do not reach an extent that would justify less benefit in the overall assessment.
  • Overall, the G-BA concludes that the additional benefit of olaparib in combination with bevacizumab is not proven compared with bevacizumab alone.

Courtesy translation only, please refer to the German original.