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New HTA Decisions in Scotland
December 2021
Drug name
LYNPARZA® (olaparib)
Company
AstraZeneca UK Ltd
Decision date
05/11/2021
Therapeutic area
Cancer
Therapeutic sub area
Ovarian cancer
Decision
Recommended (PACE)
Indication
In combination with bevacizumab for the maintenance treatment of adult patients with advanced (FIGO stages III and IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy in combination with bevacizumab and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a BRCA1/2 mutation and/or genomic instability.
Decision Detail
Following a full submission assessed under the orphan equivalent medicine process, olaparib (Lynparza®) is accepted for use within NHS Scotland. This advice applies only in the context of approved NHS Scotland Patient Access Scheme (PAS) arrangements delivering the cost-effectiveness results upon which the decision was based, or PAS/ list prices that are equivalent or lower. This advice takes account of the views from a Patient and Clinician Engagement (PACE) meeting.
Summary
In a phase III study (PAOLA-1), maintenance treatment with olaparib plus bevacizumab significantly prolonged progression-free survival (PFS) compared with placebo plus bevacizumab in patients with advanced ovarian cancer who responded to first-line standard therapy including bevacizumab. The company submitted a cost-utility analysis of olaparib in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial (FIGO Stages III and IV) highgrade ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum based chemotherapy in combination with bevacizumab and whose cancer is associated with HRD-positive status defined by either a BRCA1/2-mutation and/or genomic instability. There were a number of limitations with the analysis which include the following: • Comparative evidence versus olaparib monotherapy was lacking. Since olaparib monotherapy is the current standard of care for patients with Stage 3/4 BRCA mutation disease, its absence as a comparator in the submission was noted as a significant weakness by SMC. Hence, no conclusions regarding the cost effectiveness of olaparib combination treatment versus monotherapy could be drawn from the analysis presented; • The use of a cure mixture model may overestimate predicted long-term survival. The company used a cure-mixture model in place of a standard parametric model to estimate long-term survival. This model assumes that the model population consists of two groups: a 'cured’ population and a population whose cancer would progress. People predicted to be progression free at 5 years were considered 'cured' and were assumed to have the same mortality as the UK general population. However PAOLA-1 data is currently immature with only 3-year PFS data being available, and hence evidence of any long term curative effect of olaparib, beyond 5 years, on the basis of this study is lacking. Whilst studies for other PARP inhibitors have shown that a subgroup of patients remain cancer free beyond 10 years, suggesting a curative effect, this has not yet been proven for olaparib in combination with bevacizumab; • There is uncertainty about the long-term PFS estimates for olaparib with bevacizumab. There is a lack of a plateau in the Kaplan-Meier curve for PFS beyond 36 months which undermines claims of long-term treatment benefit and sustained PFS in excess of 5 years. The standard parametric models for extrapolating PFS were excluded from the base case analysis on grounds of under-predicting 5-year PFS. This rationale may be defensible for the comparator arm since model estimates were lower than those observed for patients on placebo/routine surveillance in other studies, but perhaps less so for the treatment arm. Whilst observed 5-year PFS from a trial on olaparib monotherapy was substantially higher than predictions from the fully parametric models, there remains empirical uncertainty in the absence of longer term data from PAOLA-1. • There is uncertainty about the overall survival due to data immaturity and the decision to set overall survival curves equal to that of PFS; • Comparative evidence versus routine surveillance was lacking. Current standard of care for stage 3 patients in Scotland is routine surveillance following first-line platinum-based chemotherapy. However, the marketing authorisation for olaparib states bevacizumab must be part of first line treatment. The company has included the additional cost of bevacizumab as part of first line treatment in the analysis versus routine surveillance, but has assumed that treatment effect is equivalent to that of the primary comparator (i.e. bevacizumab maintenance treatment). Since this is a conservative assumption, the QALY gains associated with routine surveillance as a comparator are likely to be lower than those presented in the base case analysis; • HRD testing costs were excluded from the base case analysis but was helpfully explored in the analyses. Since HRD testing is not standard practice in Scotland, the use of olaparib plus bevacizumab would be associated with an uplift in resources for laboratory testing. There is also considerable uncertainty about the estimated cost per HRD test and whether it accurately reflects testing costs in practice. Testing costs may vary if there are alternatives to the patented test used in the PAOLA-1 study, including in-house testing. Furthermore, there could be practical limitations to obtaining tissue samples for HRD testing due to the greater than standard use of neo-adjuvant chemotherapy in Scotland. The Committee considered the benefits of olaparib in the context of the SMC decision modifiers that can be applied when encountering high cost-effectiveness ratios and agreed that as plaparib is an orphan equivalent medicine, SMC can accept greater uncertainty in the economic case. After considering all the available evidence and the output from the PACE process, the Committee accepted olaparib for use in NHS Scotland.