Olaparib (4) – Lynparza®

• Clinical trials
  • The pharmaceutical manufacturer has submitted data from the randomised, double-blind, placebo-controlled and currently ongoing Phase III SOLO1 trial for the benefit assessment of olaparib.

Adult female patients with advanced (FIGO stages III and IV) BRCA1/2-mutated (germline and/or somatic), high-grade epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer, who have achieved a response (complete or partial) following completion of first-line platinum-based chemotherapy

• mortality
  • Overall survival is defined in the SOLO1 trial as the time from randomisation to death from any cause.
  • By the data cut-off date of 17 May 2018, a total of 82 patients had died: 55 in the intervention arm (21.2%) and 27 in the control arm (20.6%). The median survival time has not yet been reached in either study arm.
  • The time-to-event analysis shows no statistically significant difference between the treatment groups (hazard ratio (HR) = 0.95 [0.60, 1.53]; p-value = 0.890). An additional benefit of olaparib in the mortality category is therefore not proven.
  • It should be noted, however, that the results for the overall survival endpoint are as yet of limited interpretative value, particularly due to the minor event rates observed to date in the study arms and the relatively short follow-up period.
• morbidity
  • Overall, with regard to morbidity, the endpoints used for the assessment show neither advantages nor disadvantages associated with treatment with olaparib.
  • Progression-free survival 1 (PFS1)
  • PFS1 is the primary endpoint of the SOLO1 trial. It is defined as the time from randomisation to objective disease progression according to RECIST or death from any cause.
  • The median time to event is 13.8 months in the control arm; in the intervention arm, it has not yet been reached. The time-to-event analysis shows a statistically significant benefit in favour of olaparib (HR = 0.30 [0.23; 0.41]; p-value < 0.0001).
  • Taking the above aspects into account, the PFS1 endpoint is not used for the benefit assessment.
  • Progression-free survival 2 (PFS2)
  • In the SOLO1 trial, PFS2 is defined as the time from randomisation to the second disease progression (assessed by imaging, CA-125 measurement or on the basis of symptoms) or death following a first progression (PFS1).
  • In the SOLO1 trial, the median PFS2 had not been reached in the intervention arm at the first data cut-off on 17 May 2018. For the control arm, the median PFS2 at that time was 41.9 months. The survival analysis shows a statistically significant difference between olaparib and placebo.
  • Taking the above aspects into account, the PFS2 endpoint is not used for the benefit assessment.
  • Recurrences
  • The results for the endpoints relating to the ‘recurrences’ category are therefore not included in this assessment.
  • Health status (EQ-5D Visual Analogue Scale)
  • There are no statistically significant differences in the time to first deterioration.
• quality of life
  • Health-related quality of life is assessed in the SOLO1 study using the disease-specific FACT-O questionnaire.
  • The overall score for the mean change at month 24 shows a statistically significant disadvantage compared to olaparib.
  • However, the 95% confidence interval for the standardised mean difference (Hedges’ g) does not lie entirely outside the non-significant range of -0.2 to 0.2, meaning that it cannot be concluded that a relevant effect is present.
  • An additional benefit of olaparib is therefore not proven.
• Side effects
  • Total adverse events (AEs)
  • In the SOLO1 trial, approximately 99% of patients in the intervention arm and approximately 92% of patients in the comparator arm experienced an adverse event.
  • Serious AEs
  • In the SOLO1 study, approximately 21% of patients in the intervention arm and approximately 12% of patients in the comparator arm experienced a serious adverse event. The time-to-event analysis showed no statistically significant difference.
  • Severe AEs (CTCAE grade ≥ 3)
  • In the SOLO1 trial, approximately 39% of patients in the intervention arm and approximately 19% of patients in the comparator arm experienced a severe adverse event (CTCAE grade ≥ 3). The time-to-event analysis revealed a statistically significant disadvantage compared to olaparib.
  • Therapy discontinuation due to AEs
  • At the time of this data cut-off, approximately 12% of patients in the intervention arm and approximately 2% of patients in the comparator arm had discontinued treatment due to adverse events. The time-to-event analysis reveals a statistically significant difference between the treatment groups, to the detriment of olaparib.
  • Specific AE
  • With regard to specific adverse events, there were statistically significant disadvantages for olaparib compared to other drugs in the following areas: anaemia (PT, severe AE), taste disturbance (PT, AE), dyspnoea (PT, AE), nausea (PT, AE), stomatitis (PT, AE), vomiting (PT, AE), muscle spasms (PT, AE), asthenia (PT, AE) and mucositis (PT, AE).
  • Overall, the results regarding side effects indicate that olaparib has negative effects compared with a watch-and-wait approach, due to an increase in severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
• Overall assessment
  • For the benefit assessment of olaparib as monotherapy for the treatment of adult female patients with advanced (FIGO stages III and IV) BRCA1/2-mutated (germline and/or somatic) high-grade epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer, who have achieved a response (complete or partial) following completion of first-line platinum-based chemotherapy, results from the SOLO1 trial are available on overall survival, morbidity, health-related quality of life and side effects.
  • In the endpoint category of mortality, there is no statistically significant difference between olaparib and watchful waiting. An additional benefit of olaparib in terms of overall survival is therefore not proven.
  • With regard to morbidity, based on the endpoints used for evaluation, treatment with olaparib shows neither advantages nor disadvantages overall.
  • With regard to health-related quality of life, there is a statistically significant disadvantage compared to olaparib in the overall score of the disease-specific FACT-O questionnaire. However, it cannot be concluded with sufficient certainty that this effect is clinically relevant.
  • In the side effect category, olaparib showed negative effects compared with the appropriate comparator therapy, characterised by an increase in severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.

Adult female patients with advanced (FIGO stages III and IV) BRCA1/2-mutated (germline and/or somatic), high-grade epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer, who have achieved a response (complete or partial) following completion of first-line platinum-based chemotherapy

• According to the justification for the limitation in this resolution, the reason was that the data on overall survival available from the SOLO1 trial for the assessment were not yet sufficiently meaningful due to a low number of events at the time of the data cut-off.
• As further clinical data on overall survival from the SOLO1 trial were expected, which may be relevant to the assessment of the medicinal product’s benefits, it was justified to impose a limitation on the resolution until further scientific evidence for the assessment of the additional benefit of olaparib becomes available.
• The pharmaceutical manufacturer has informed the G-BA that, in the meantime, updated results on overall survival from the SOLO1 trial have become available. These are the results of a pre-specified data cut-off for overall survival at 7 years after the inclusion of the last study patient.
• For the reassessment of benefit following the expiry of the time limit, the dossier must present the results of the pre-specified data cut-off at 7 years following the enrolment of the last study patient, relating to overall survival as well as other patient-relevant endpoints used to demonstrate additional benefit, from the SOLO1 trial.
• mortality
  • The data on overall survival from the SOLO1 study available for the assessment were not yet particularly meaningful at the time of the data cut-off due to a minor number of events.
  • More recent results on overall survival from the SOLO1 study have since become available. These are the results of a pre-specified data cut-off for overall survival at 7 years after the inclusion of the last study patient.

Courtesy translation only, please refer to the German original.