Niraparib (1) – Zejula®

• Clinical trials
  • The NOVA trial is a multicentre, randomised, double-blind, placebo-controlled Phase III trial investigating the efficacy and safety of niraparib compared with placebo in two independent cohorts (gBRCAmut and non-gBRCAmut) in adult female patients with recurrent platinum-sensitive carcinoma of the ovary or fallopian tubes, or with primary peritoneal carcinomatosis, who are in remission (complete or partial) following platinum-based chemotherapy.

Niraparib as monotherapy for maintenance treatment in adult female patients with recurrent platinum-sensitive, poorly differentiated serous carcinoma of the ovary, fallopian tubes or primary peritoneal carcinoma, who are in remission (complete or partial)

• mortality
  • overall survival
  • The secondary endpoint of overall survival was defined as the time from randomisation to death from any cause.
  • At the time of the data cut-off (30 May 2016), the median survival had not yet been reached in either cohort due to the minor number of events.
  • Due to the low overall number of events and the high proportion of censored cases (> 80 %) at the data cut-off date of 30 May 2016, the results for overall survival should be considered immature.
  • The stratified analysis of OS shows no statistically significant differences between niraparib and placebo in either cohort (gBRCA-mut and non-gBRCA-mut) (HR = 0.91; 95% CI: [0.36; 2.28] and HR = 0.74; 95% CI: [0.45; 1.20], respectively).
• morbidity
  • Progression-free survival (PFS)
  • The primary endpoint, ‘progression-free survival’, was defined as the time from randomisation to the first occurrence of disease progression or death from any cause, whichever occurred first.
  • In the gBRCAmut cohort, the hazard ratio (HR) in the stratified analysis was 0.27 (95% CI: [0.17; 0.41]; p < 0.0001). The median PFS1, calculated using the Kaplan-Meier estimator, was 21 months in the gBRCAmut cohort treated with niraparib and 5.5 months in the control group. This results in a difference of 15.5 months in favour of the treatment in the intervention arm.
  • In the non-gBRCAmut cohort, the hazard ratio (HR) was 0.45 (95% CI: [0.34; 0.61]; p < 0.0001). The median PFS1 was 9.3 months in the niraparib arm and 3.9 months in the control arm. This results in a difference of 5.4 months in favour of treatment with niraparib.
  • 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. 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.
  • PRO instruments (EQ-5D VAS and neuropathy questionnaire (CIPN))
  • Data are reported only for the follow-up assessment time point for those women in whom the study doctor confirmed progression. Data from the follow-up for all women who discontinued treatment are not available.
  • Due to the lack of reference to the ITT population in the analysis of the individual treatment weeks and the associated minor response rates, the results of the EQ-5D VAS and the neuropathy questionnaire are not presented in the benefit assessment and are not taken into account.
• quality of life
  • Quality of life was assessed using the FOSI questionnaire.
  • No study is available to determine the psychometric quality of this questionnaire.
  • Furthermore, it cannot be conclusively assessed whether the FOSI captures all symptoms relevant to the condition.
  • The scale captures neither the frequency nor the patient-specific significance of the symptoms.
  • Furthermore, only aggregated results were presented for the FOSI; no analysis of the individual items is available.
  • This gives rise to major uncertainties regarding the interpretability of the results.
  • For this reason, the results for this endpoint could not be taken into account in the benefit assessment.
• Side effects
  • The reference population was the safety population, comprising a total of 546 patients (n = 201 in the gBRCAmut cohort and n = 345 in the non-BRCAmut cohort).
  • Adverse events occurred in both cohorts among all study participants in the active treatment arm and among almost all study participants in the placebo arm (gBRCAmut cohort: niraparib n=136 (100 %); placebo n = 61 (93.8); non-gBRCAmut cohort: niraparib n = 231 (100 per cent); placebo n = 110 (96.5 per cent)).
  • Serious adverse events occurred in 30% and 31% of patients on niraparib and in 11% and 17% of patients on placebo, respectively. These events were therefore statistically significantly more common with niraparib than with placebo in both cohorts (gBRCA-mutation cohort: RR = 2.9; 95% CI: [1.4; 6.0]; p=0.0055; non-gBRCAmut cohort: RR = 1.7; 95% CI: [1.1; 2.6]; p = 0.0227).
  • Severe adverse events of NCI-CTCAE grade ≥ 3 occurred in 80% and 71% of patients on niraparib, and in 22% and 24% of patients on placebo, respectively. These events also indicate a disadvantage with niraparib compared with placebo in both cohorts (gBRCA-mutation cohort: RR = 3.7; 95% CI: [2.3; 5.9]; p < 0.0001; non-gBRCAmut cohort: RR = 3.0; 95% CI: [2.1; 4.2]; p < 0.0001).
  • Adverse events leading to discontinuation of study medication occurred in 13% and 16% of patients on niraparib, and in 2% and 3% of patients on placebo, respectively. These events were also statistically significantly more common with niraparib than with placebo in both cohorts (gBRCA-mutation cohort: RR = 8.6; 95% CI: [1.2; 63.1]; p = 0.0342; non-gBRCA mutation cohort: RR = 5.9; 95% CI [1.9; 18.8]; p = 0.0026).
  • With regard to specific adverse events, niraparib showed a less favourable side-effect profile compared with placebo in terms of disorders of the blood and lymphatic system (anaemia, thrombocytopenia, neutropenia), vascular disorders (hypertension) and general disorders and administration site conditions (fatigue).
  • Despite differences in treatment duration between the two study groups, no adequate exposure-adjusted analyses (such as time-to-event analyses) are presented. The potential for bias in the AEs is classified as high, as a direct comparison of adverse events is based on unadjusted rates or effect estimators.
  • In summary, both the gBRCAmut cohort and the nongBRCAmut cohort showed higher risks of serious AEs, severe AEs (NCI-CTCAE grade ≥ 3), AE leading to discontinuation of the study medication, and specific AE.
  • Overall, therefore, a clear disadvantage for niraparib in terms of side effects can be inferred for the endpoint category of adverse events.

Courtesy translation only, please refer to the German original.