Olaparib (8) – Lynparza®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer has submitted, as part of the dossier, the results of the ongoing, double-blind, randomised, controlled OlympiA trial, in which olaparib is compared with placebo.

Adults with early-stage germline BRCA-mutated, HER2-negative breast cancer with a high risk of recurrence; following neoadjuvant or adjuvant chemotherapy; adjuvant therapy

• It is therefore concluded that olaparib offers a minor additional benefit compared with a watch-and-wait approach.
• Overall, the certainty of evidence for the observed additional benefit is classified as an indication.
• mortality
  • In the OlympiA trial, overall survival was defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant advantage was observed in favour of olaparib compared with watchful waiting.
  • The median survival time has not yet been reached in either treatment group.
• Morbidity – Recurrences (recurrence rate and disease-free survival)
  • In this benefit assessment, relapses are considered in terms of both the relapse rate and disease-free survival as endpoints.
  • Both analyses include the following events: ipsilateral invasive recurrence, locoregional invasive recurrence, distant recurrence, contralateral invasive breast cancer, secondary primary tumour (not breast cancer), ductal carcinoma in situ and death from any cause.
  • A statistically significant advantage in favour of olaparib compared with watchful waiting is evident both when operationalised as an event rate and in the analysis of time to event.
  • The absolute difference in the recurrence rate is 8.0% (138 events out of 921 patients (15%) vs. 210 events out of 915 patients (23%)).
  • When considering both endpoints, a considerable overall advantage for olaparib over watchful waiting is observed in terms of preventing recurrence.
• quality of life
  • EORTC QLQ-C30
  • With regard to health-related quality of life, a statistically significant disadvantage was observed on the global health status scale compared with watchful waiting for olaparib.
  • However, the 95% CI of the SMD does not lie entirely outside the non-significant range [−0.2; 0.2]. It cannot therefore be concluded that the effect is clinically relevant.
  • For the functional scales – physical function, role functioning, cognitive functioning, emotional functioning and social functioning – no statistically significant difference was observed between the treatment arms in any case.
  • In summary, in the quality of life category, there are no advantages or disadvantages of olaparib compared with watchful waiting.
• Side effects – severe adverse events (CTCAE grade ≥ 3) and discontinuation due to AEs
  • For the endpoints of severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs, a statistically significant disadvantage was observed compared with watchful waiting for olaparib.
• Overall assessment
  • For the benefit assessment of olaparib as monotherapy or in combination with endocrine therapy for the adjuvant treatment of germline BRCA-mutated, HER2-negative early-stage breast cancer with a high risk of recurrence following neoadjuvant or adjuvant chemotherapy, results are available from the ongoing, double-blind, randomised, controlled OlympiA trial for the endpoint categories of mortality, morbidity, health-related quality of life and side effects.
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of olaparib compared with watchful waiting.
  • In the morbidity category, with regard to recurrences – operationalised as recurrence rate and disease-free survival – there is a statistically significant difference in favour of olaparib compared with watchful waiting.
  • The prevention of recurrence is an essential therapeutic goal in the present curative treatment setting.
  • In this regard, olaparib shows a relevant advantage over watchful waiting.
  • With regard to patient-reported symptoms, there are no differences of clinical significance overall.
  • In the category of quality of life, there are no advantages or disadvantages of olaparib compared with watchful waiting.
  • With regard to side effects, there are statistically significant disadvantages of olaparib compared with watchful waiting for the endpoints of severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs, as well as, in detail, for specific adverse events.
  • Overall, therefore, the advantages – improved overall survival and prevention of recurrence – are offset by disadvantages in terms of side effects.
  • The disadvantages in terms of side effects are weighed against the aim of curative treatment.
  • Overall, the advantages outweigh the disadvantages, meaning that an additional benefit can be established.
  • In assessing the extent of the additional benefit, the observed effect in terms of preventing recurrence is of particular significance.
  • Taking into account the recurrence rates in both treatment groups and the absolute difference in these rates, the G-BA concludes that, in the overall assessment of this case, it cannot be assumed with sufficient certainty that there is an extent of a considerable additional benefit.

Courtesy translation only, please refer to the German original.