Olaparib (2) – Lynparza®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer refers in the dossier to the results of the randomised, double-blind, placebo-controlled Phase 2 trial D081C00019 (Trial 19), in which the efficacy of olaparib was investigated.
  • For the benefit assessment, the pharmaceutical manufacturer also cites in the dossier the results of the randomised, double-blind, placebo-controlled Phase 3 trial SOLO2.

Adult female patients with a platinum-sensitive recurrence of high-grade epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer who respond (completely or partially) to platinum-based chemotherapy.

• For olaparib as monotherapy for maintenance treatment in adult female patients with platinum-sensitive recurrence of high-grade epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer, who have responded to platinum-based chemotherapy (complete or partial response), there is a hint of a minor additional benefit.
• mortality
  • overall survival
  • For the endpoint of overall survival, the meta-analytic evaluation of both studies shows a statistically significant advantage for olaparib compared with placebo (hazard ratio = 0.74 [0.59; 0.94], p-value = 0.011).
  • In Study 19, the median survival benefit compared with placebo was 2 months (29.8 months versus 27.8 months, median).
  • In the SOLO2 study, the median survival time had not been reached in either study arm at the first data cut-off.
  • This advantage in overall survival is assessed as a moderate prolongation of life.
• Morbidity – Health status (EQ-5D VAS)
  • Health status was not assessed in Study 19.
  • In the SOLO2 study, health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • The 95% confidence intervals for the standardised mean differences (Hedges’ g) do not lie entirely outside the irrelevance range [−0.2; 0.2], meaning it cannot be concluded that these effects are clinically relevant.
  • The responder analyses show no significant difference between the treatment arms in each case. The additional benefit for olaparib compared with the appropriate comparator therapy, ‘watchful waiting’, is not proven for this endpoint.
• Quality of life – Functional Assessment of Cancer Therapy – Ovarian (FACT-O)
  • Health-related quality of life was assessed for both Study 19 and the SOLO2 study using the total score of the FACT-O questionnaire.
  • For the SOLO2 and Study 19 trials, there was no statistically significant difference between the treatment arms.
  • Consequently, no advantage or disadvantage can be identified for olaparib compared with the appropriate comparator therapy ‘watchful waiting’ in terms of the treatment’s effects on health-related quality of life.
• Side effects
  • Total adverse events (AEs)
  • For the endpoints ‘serious adverse events’ (SAE) and ‘therapy discontinuation due to AEs’, no statistically significant effects were observed in the meta-analysis.
  • For the endpoint ‘severe AEs’ (CTCAE grade ≥ 3), the meta-analytic evaluation of both studies revealed a statistically significant disadvantage for olaparib (hazard ratio = 1.90 [1.34; 2.68], p-value < 0.001); specifically, the negative effect was observed for the specific AE ‘anaemia’ (CTCAE grade ≥ 3).
  • With regard to other specific AEs, a statistically significant disadvantage for olaparib was observed for both ‘nausea’ and ‘vomiting’.
  • Overall, the results on side effects show that olaparib is associated with negative effects compared with the appropriate comparator therapy ‘watchful waiting’, due to an increase in severe AEs (CTCAE grade ≥ 3), in particular ‘anaemia’ (CTCAE grade ≥ 3) and the specific AEs “nausea” and “vomiting”.
• Overall assessment
  • With regard to overall survival, the meta-analysis of the two studies shows a statistically significant advantage for treatment with olaparib, which is assessed as a moderate prolongation of survival.
  • With regard to health status, there is no statistically significant difference between the treatment groups.
  • The data on patient-reported quality of life show that neither an advantage nor a disadvantage can be identified with regard to the effects of olaparib compared with the appropriate comparator therapy ‘watchful waiting’ on health-related quality of life.
  • With regard to adverse event endpoints, olaparib is associated with a disadvantage compared with the appropriate comparator therapy ‘watchful waiting’, in particular due to an increase in severe adverse events (CTCAE grade ≥ 3), specifically the adverse event ‘anaemia’ (CTCAE grade ≥ 3), as well as an increase in the specific adverse events ‘nausea’ and ‘vomiting’.
  • In the overall assessment, the disadvantage in terms of side effects is considered relevant, but is not classified as so serious as to warrant a downgrading of the extent of the additional benefit. Consequently, a minor additional benefit is identified for olaparib compared with the appropriate comparator therapy ‘watchful waiting’ in the maintenance treatment of adult female patients with a platinum-sensitive recurrence of high-grade epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.
• This assessment is based on the results of the randomised, double-blind, placebo-controlled Phase 3 registration trial SOLO2 and the Phase 2 trial 19, in which the efficacy of olaparib was investigated.
• Consequently, there are uncertainties regarding the transferability of the study results to real-world clinical practice.
• Taking all the uncertainties described into account, there is, on the whole, a hint that olaparib offers additional benefit.

Courtesy translation only, please refer to the German original.