Olaparib (1) – Lynparza®

• Clinical trials
  • Study 19 is a randomised, double-blind, multicentre, placebo-controlled Phase II trial investigating the efficacy and safety of olaparib in patients with platinum-sensitive recurrent serous ovarian cancer.

a) Olaparib (Lynparza™) as monotherapy for maintenance treatment in adult female patients with platinum-sensitive recurrence of BRCA-mutated (germline and/or somatic) high-grade serous epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer, who respond to platinum-based chemotherapy (complete or partial response)

• For olaparib (Lynparza™) as monotherapy for the maintenance treatment of adult female patients with a platinum-sensitive recurrence of BRCA-mutated (germline and/or somatic) high-grade serous epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer, who respond to platinum-based chemotherapy (complete or partial response), there is a non-quantifiable additional benefit.
• The G-BA classifies the extent of the non-quantifiable additional benefit of olaparib on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• mortality
  • overall survival
  • With regard to overall survival, there is no statistically significant difference between olaparib and placebo in the patient population with a BRCA mutation relevant to the assessment. 37 patients (50.0%) in the intervention arm and 34 patients (54.8%) in the control arm had died by the time of the current data cut-off (HR: 0.73; 95% CI: [0.45; 1.17]; p = 0.192).
  • The analyses of overall survival, excluding results from centres where follow-up treatment with a PARP inhibitor was possible, are subject to a high degree of uncertainty. These analyses are therefore not used by the G-BA to derive any additional benefit.
• morbidity
  • Progression-free survival (PFS)
  • The median progression-free survival was 11.2 months in the intervention arm and 4.3 months in the placebo arm (HR: 0.18; 95% CI: [0.10; 0.31]; p < 0.001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of this endpoint is already assessed as a standalone endpoint via the secondary endpoint of overall survival. Furthermore, the ‘disease progression’ component of morbidity in the PFS assessment was not determined on the basis of symptoms, but rather by means of imaging procedures. Taking the aforementioned aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding the extent of the additional benefit remains unaffected by this.
  • FACT/NCCN Ovarian Symptom Index (FOSI)
  • The FOSI is not valid for assessing morbidity parameters.
  • The G-BA therefore does not use the FOSI to derive any additional benefit.
  • Time to first clinically confirmed progression (TFST)
  • Criteria for operationalising the point in time at which follow-up therapy was initiated have not been defined in advance by the pharmaceutical manufacturer, nor have they been empirically recorded. Furthermore, there were shortcomings in the data collection regarding follow-up therapies.
  • The TFST is therefore not used by the G-BA to derive any additional benefit.
• Health-related quality of life
  • Functional Assessment of Cancer Therapy – Ovarian (FACT-O)
  • The assessment of quality of life using the FACT-O was discontinued at the time of the primary data analysis. In the BRCAm patient population relevant to the assessment, evaluable data were available at baseline for only 116 patients (63 on olaparib, 53 on placebo).
  • In the FACT-O responder analysis, 39 patients in the olaparib arm and 31 patients in the comparator arm experienced a deterioration of at least 9 points. The difference in time to deterioration (3.2 months versus 4.4 months) is not statistically significant (HR: 1.04; 95% CI: [0.65; 1.69]; p = 0.869).
  • An improvement in the FACT-O score was observed in 17 patients in the intervention arm and 11 patients in the control arm. The difference is not statistically significant (RR: 1.30; 95% CI: [0.67; 2.53]; p = 0.439).
  • Trial Outcome Index (TOI)
  • The TOI and FACT-O are assessed in the same way and are partly identical. This gives rise to the problem of artificial duplication of outcome parameters; the multiple analysis of the same data requires a corresponding adjustment to the threshold for acceptable probability of error.
  • The TOI is therefore not used by the G-BA to derive any additional benefit.
• Side effects
  • An adverse event was documented for the majority of patients in Study 19 (97.3% in the intervention arm vs. 93.5% in the control arm).
  • Adverse events of CTCAE grade ≥ 3 occurred in 39.2% of patients treated with olaparib, compared with 17.7% of patients treated with placebo. Although the difference between the study arms is statistically significant (RR: 2.21; 95% CI: [1.20; 4.05]; p = 0.010), it is of limited interpretability given the differences in treatment duration (median treatment duration with olaparib: 511.6 days; with placebo: 210.1 days).
  • There was no statistically significant difference between olaparib and placebo in the number of patients experiencing at least one serious adverse event (SAE).
• Conclusion
  • The G-BA classifies the extent of the non-quantifiable additional benefit of olaparib on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease. There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
  • In the present case, the limited evidence base is particularly relevant to the decision, as it does not allow for a valid and meaningful assessment of the results to quantify the additional benefit. Consequently, a quantitative comparative assessment of the extent of the effect and a quantification of the additional benefit based on the data provided are not possible.

Courtesy translation only, please refer to the German original.