Olaparib (3) – Lynparza®

• Clinical trials
  • OlympiAD is a multicentre, open-label, randomised controlled trial comparing olaparib with chemotherapy of the clinician’s choice, using capecitabine, vinorelbine or eribulin.

Adult patients with HER2-negative, locally advanced or metastatic breast cancer with germline BRCA1/2 mutations; who have previously received therapy with an anthracycline and a taxane in a (neo)adjuvant or metastatic setting, or who are unsuitable for these treatments

• For the treatment of adult patients with HER2-negative, locally advanced or metastatic breast cancer with germline BRCA1/2 mutations who have previously been treated with an anthracycline and a taxane in the (neo)adjuvant or metastatic setting, or who were unsuitable for these treatments, there is a hint of a minor additional benefit.
• Overall, based on the advantages in the ‘side effects’ endpoint category, the G-BA concludes that olaparib offers a minor additional benefit compared with capecitabine, vinorelbine or eribulin.
• Given that, due to the open-label study design of the OlympiAD trial, a high potential for bias is to be expected in the ‘side effects’ category and no usable data are available for the endpoint categories of ‘morbidity’ and ‘health-related quality of life’, only a hint of additional benefit can be inferred in terms of the certainty of the findings.
• mortality
  • In the OlympiAD study, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • For the endpoint of overall survival, no statistically significant difference was observed between the treatment arms in the study’s overall population.
  • Consequently, no additional benefit is identified for the endpoint of overall survival.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the OlympiAD study and was defined as the time from randomisation to disease progression (determined by a central, blinded, independent radiological committee (BICR) using the RECIST criteria version 1.1) or death, regardless of the underlying cause of death.
  • PFS was statistically significantly prolonged by a median of 2.8 months in the intervention arm compared with the control arm (median 7.0 vs. 4.2 months; HR: 0.58 [95% CI: 0.43; 0.80]; p = 0.0009).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. In this study, the ‘mortality’ component of the endpoint was assessed via the ‘overall survival’ endpoint as a standalone endpoint. The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (radiologically determined disease progression according to the RECIST criteria). Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• quality of life
  • To assess health-related quality of life, the OlympiAD study used the functional scales of the disease-specific EORTC QLQ-C30 questionnaire.
  • As, with regard to the responder analyses of the functional scales, the proportion of patients excluded from the analyses differs to a significant extent between the treatment groups on almost all scales (a difference of more than 15 percentage points), the reliability of the results of these analyses must also be regarded as insufficient. Consequently, the responder analyses are not taken into account in the present assessment. The same applies to the corresponding continuous analyses.
  • There are therefore no usable data available on health-related quality of life.
• Side effects – Adverse events (AE)
  • In the OlympiAD trial, an adverse event occurred in 97.6% of patients in the intervention arm, compared with 95.6% of patients in the control arm.
• Overall assessment
  • Results from the open-label, randomised, controlled OlympiAD trial are available for the assessment of the additional benefit of olaparib compared with capecitabine, vinorelbine or eribulin in terms of mortality (overall survival), morbidity, quality of life and side effects.
  • In the mortality endpoint category, the available results for the overall survival endpoint, based on the study’s overall population, show no statistically significant effect. No additional benefit is identified for the overall survival endpoint.
  • For the endpoints in the categories of morbidity (symptoms) and health-related quality of life, no usable data are available, as the certainty of the results from the submitted analyses must be regarded as insufficient given the relevant differences in the proportion of patients excluded from the analysis between the treatment groups.
  • With regard to side effects, Olaparib shows advantages over capecitabine, vinorelbine or eribulin in terms of the endpoints of severe adverse events (CTCAE grade 3 or 4) and treatment discontinuation due to AEs. No difference is observed for the endpoint ‘serious AEs’. With regard to specific AEs, the positive effects of olaparib predominate. In the ‘side effects’ category, therefore, an overall advantage of olaparib over capecitabine, vinorelbine or eribulin can be identified.
  • In its overall assessment, the G-BA concludes that, based on the advantages in the ‘side effects’ endpoint category, olaparib offers a minor additional benefit compared with capecitabine, vinorelbine or eribulin.

Courtesy translation only, please refer to the German original.