3 Committee discussion

The appraisal committee (section 5) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.

Clinical need and current management

People with ovarian cancer have a high disease burden

3.1 The patient experts explained that relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer is a devastating condition. It is a huge emotional burden knowing that the disease can relapse at any time and there is no option for cure. People with a mutation in the BRCA 1 or BRCA 2 gene have the additional mental burden that members of their immediate family may also have the mutated gene. The clinical experts explained that survival rates and outcomes for ovarian cancer are worse in the UK than in other developed countries. This is likely to be because ovarian cancer is diagnosed at a later stage in the UK, and other countries have more radical surgical techniques and access to other drug treatments. The committee understood these factors and concluded that there is a high burden of disease for people with relapsed, platinum-sensitive ovarian cancer.

Niraparib is the only available targeted treatment option for people with relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer

3.2 The committee noted that niraparib, another poly‑ADP‑ribose polymerase (PARP) inhibitor, has a marketing authorisation for the same indication as olaparib. NICE guidance recommends niraparib for use within the Cancer Drugs Fund for maintenance treatment of ovarian, fallopian tube or peritoneal cancer (TA528). The only other available active treatment option for this population is chemotherapy.

People with ovarian cancer would welcome wider availability of olaparib with a more convenient administration schedule

3.3 NICE guidance currently recommends olaparib as a capsule formulation for maintenance treatment of relapsed, platinum-sensitive, ovarian, fallopian tube and peritoneal cancer that is BRCA mutation-positive, after response to second-line or subsequent platinum-based chemotherapy (TA381). When that appraisal was done, olaparib was licensed for use only in people with BRCA mutation-positive ovarian cancer. However the marketing authorisation has since been extended to cover a broader population irrespective of BRCA mutation status. Also, the current appraisal considers a new tablet formulation that according to the company will eventually replace the capsule formulation. One of the patient experts, who has been taking olaparib for a number of months, explained that having access to it has changed her life because it has minimal side effects and allows her to live a more normal life. The new tablet formulation is more convenient to take than the capsules, because it involves taking 4 tablets instead of 16 capsules per day and does not have any fasting restrictions. The clinical experts explained that it is better to use olaparib earlier in the treatment pathway than is recommended in TA381, because there is progressive loss of platinum sensitivity with repeated courses. Early treatment increases the chance of achieving treatment response and prolonging the disease-free period. The committee concluded that wider availability of olaparib, to extend periods of remission and improve quality of life, would be greatly valued by patients and their families.

Clinical evidence

It is reasonable to assume that the tablet and capsule formulations of olaparib have similar efficacy

3.4 The committee noted that the results of an open-label, dose-finding study (study 24) show that the 2 formulations of olaparib cannot be considered bioequivalent on a milligram for milligram basis. However, at the recommended doses, they have similar pharmacokinetic, efficacy, and tolerability profiles. The company supported this view and it believes that the evidence shows the tablet formulation to be at least as clinically effective as the capsule formulation. The European Public Assessment Report (EPAR) by the European Medicines Agency also states that the extrapolation of efficacy results obtained with capsule formulation to the tablet formulation is reasonably supported by pharmacokinetic data. Therefore the committee concluded that it is reasonable to assume that the tablet and capsule formulations have similar efficacy.

The clinical trials are generalisable to clinical practice in England

3.5 The clinical trial evidence came from 2 double-blind randomised placebo-controlled trials (study 19 and SOLO‑2). Study 19 evaluated the efficacy and safety of the capsule formulation of olaparib in people with platinum-sensitive relapsed ovarian cancer, irrespective of BRCA mutation status. SOLO‑2 assessed the efficacy and safety of the tablet formulation and only included people with a BRCA mutation. The committee considered that the patient characteristics in both trials are well balanced. Although the trials included only a few patients from the UK the clinical experts stated that they reflect clinical practice in England. Therefore the committee concluded that the trial evidence is generalisable to clinical practice in England.

Olaparib improves progression-free survival compared with placebo but the benefit appears to be greater in the BRCA mutation-positive subgroup

3.6 Progression-free survival is the primary endpoint in both study 19 and SOLO‑2. In study 19 there was a statistically significant improvement in progression-free survival in the overall population compared with placebo; 8.4 months with olaparib and 4.8 months with placebo, a difference of 3.6 months (hazard ratio [HR] 0.35, 95% confidence interval [CI] 0.25 to 0.49). However radiological assessments were not required after the primary data analysis, and therefore further mature data on progression-free survival are not available. The greatest benefit is in the BRCA mutation-positive group, which the clinical experts explained is because BRCA mutation status is a predictor of response to a PARP inhibitor. For the mutation-negative group the difference in median progression-free survival between olaparib and placebo is 1.9 months (HR 0.54, 95% CI 0.34 to 0.85), whereas for the mutation-positive subgroup the difference is 6.9 months (HR 0.18, 95% CI 0.10 to 0.31). The SOLO‑2 results also show a statistically significant benefit for olaparib compared with placebo for mutation-positive disease, a difference in medians of 13.6 months (HR 0.30, 95% CI 0.22 to 0.41, median follow-up of 22 months). The committee noted that although the SOLO‑2 results appear to be more favourable than the results for the BRCA mutation-positive subgroup from study 19, the confidence intervals of the hazard ratios between the 2 studies are overlapping. Based on these results the committee concluded that olaparib improves progression-free survival irrespective of BRCA mutation status, but people with BRCA mutation-positive disease may experience greater benefit.

More people are alive and relapse-free after several years of taking olaparib compared with standard care

3.7 The main overall survival results come from study 19 because the SOLO‑2 overall survival data are immature. In study 19, at a median follow up of 6.5 years, median overall survival in the overall population is 29.8 months with olaparib and 27.8 months with placebo (difference 2.0 months, HR 0.73, 95% CI 0.55 to 0.95). The committee noted that the difference between olaparib and placebo is not statistically significant at the level set for the analysis (p<0.0095), but it heard from clinical experts that the difference (if real) would be clinically meaningful. The committee noted that 13.5% of patients in the placebo group had PARP-inhibitor treatment after progression, which could have reduced the size of any difference between olaparib and standard care. The clinical experts explained that study 19 had identified a cohort of 'super-responders', many of whom were in remission without evidence of disease after 6 years (11% of patients in the olaparib group and less than 1% in the placebo group). They explained that this very long-term response is more common in people with a BRCA mutation, but around a third of super-responders do not have a BRCA mutation. However there are no methods currently available to identify these super-responders in advance. The committee concluded that olaparib leads to clinically important improvements in overall survival and that more people remain alive and relapse-free after several years on olaparib than on standard care.

Adverse events

Olaparib has a manageable adverse-event profile

3.8 The most common adverse events with olaparib in study 19 and SOLO‑2 were nausea, fatigue, vomiting, diarrhoea, anaemia and abdominal pain. Study discontinuations because of adverse events were low in both trials. Grade 3 or higher adverse events happened in 43.4% of patients in the olaparib group (compared with 21.9% for placebo) in study 19, and in 36.9% of patients in the olaparib group (compared with 18.2% for placebo) in SOLO‑2. The clinical and patient experts explained that olaparib is generally well tolerated and adverse effects can be readily managed, therefore the committee concluded that olaparib has a manageable adverse-effects profile.

Cost-effectiveness

The main economic model presented by the company is suitable for decision making

3.9 To estimate the cost effectiveness of olaparib compared with routine surveillance, the company presented a 3‑state (progression-free, progressed disease and death) partitioned survival model. The proportion of patients in each health state was estimated based on 1-knot spline modelling of data from study 19. Results were presented for the overall population and for subgroups based on BRCA mutation status. The ERG considered that the model structure is appropriate but preferred a 50‑year time horizon instead of the company's choice of 30 years, because a small proportion of patients were alive and progression-free at the end of the company's time horizon. The committee noted that this had only a small effect on the results and concluded that the model is suitable for decision making.

For modelling progression-free survival, time to treatment discontinuation is a better indicator of symptomatic progression than time to first subsequent therapy

3.10 For modelling progression-free survival the company used data on time to first subsequent therapy, because it considered this to be more clinically relevant for modelling clinical effectiveness than radiological disease progression. However, the ERG considered time to treatment discontinuation to be more reflective of real life clinical practice and used that in its amended base-case analysis. The committee noted that these are exploratory outcomes, defined post hoc after unblinding of data. The clinical experts explained that in UK clinical practice people stop taking olaparib following disease progression, defined by symptoms and increased levels of CA125 protein. Progression-free survival based on radiological progression, although a more robust and objective measure of clinical efficacy, may not fully reflect what happens in clinical practice. Also, the progression- free survival data are immature from both trials whereas time to treatment discontinuation and time to first subsequent therapy have more mature data. The committee noted that the mean estimates from the model showed greater similarity between the estimates for progression-free survival and time to treatment discontinuation than between progression-free survival and time to first subsequent treatment. Using time to first subsequent treatment for modelling progression meant that the health benefits of being progression-free would be accrued within the model, without associated treatment costs, favouring olaparib. The committee concluded that time to treatment discontinuation is a better indicator of symptomatic progression than that suggested by the company, which was time to first subsequent therapy.

The company's alternative model for the BRCA mutation-positive subgroup is not suitable for decision making

3.11 For the subgroup of patients with a BRCA mutation, the company presented an alternative model using data from both SOLO‑2 and study 19. This used mean progression-free survival and overall survival estimates, rather than a partitioned survival model structure. The ERG considered that the model structure is inappropriate and preferred the partitioned survival approach used in the company's main model. The ERG highlighted that the means-based structure does not incorporate the impact of weighting costs and utilities by the proportions of patients accruing these costs over time, and therefore produces simplified estimates of costs and quality-adjusted life years (QALYs). Also, the company estimated overall survival in the model by assuming a 2:1 ratio for overall survival and progression-free survival gain, based on a restricted means analysis of data from study 19. The ERG raised serious concerns about this assumption. It noted that the alternative model produces substantially higher survival gains for olaparib than the main model, which is not supported by the clinical trial results. Therefore the ERG considered that the assumptions of the alternative model are unreliable. The committee shared the ERG's concerns about the company's alternative modelling approach and the use of a 2:1 ratio for overall survival gain and progression-free survival gain, which had not been accepted as robust in a previous appraisal for ovarian cancer (TA528). The committee concluded that the 2:1 ratio is not adequately supported by trial evidence, therefore it did not accept the alternative model as suitable for decision making.

Olaparib is not cost effective compared with routine surveillance

3.12 The company's base-case incremental cost-effectiveness ratios (ICERs) using its main model, for the overall population and for the BRCA mutation-positive and mutation-negative subgroups, are substantially above the range that is normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained). None of the company's sensitivity analyses substantially changed the results. The ERG's amended base case produces slightly higher ICERs than those from the company, using the ERG's preferred assumptions (such as a longer time horizon of 50 years [see section 3.9] and using time to treatment discontinuation instead of time to first subsequent treatment to model progression-free survival [section 3.10]). The committee concluded that it could not recommend olaparib as a cost-effective use of NHS resources for people with recurrent, platinum-sensitive ovarian, fallopian tube and peritoneal cancer.

End of life

End-of-life criteria are not met for the overall population of people with relapsed, platinum-sensitive ovarian cancer

3.13 The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It noted that the company had made a case for applying the end-of-life criteria to the overall population of people with relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer that has responded to platinum-based chemotherapy. The committee noted that median overall survival in the placebo group of study 19 is 27.8 months, but the company's model estimates a mean life expectancy on routine surveillance of 38.4 months. The committee acknowledged that there are various sources of evidence that provide different estimates for life expectancy on routine surveillance. However it accepted that the company's main model is suitable for decision making (see section 3.10), and therefore it should take into account the life-expectancy estimates from that model to inform its decision about the end-of-life criteria. Because the trial results and the modelled estimates of life expectancy exceed 24 months, the committee was not persuaded that the end-of-life criteria are met for the overall population. It accepted that during the previous appraisal for olaparib capsules, the end-of-life criteria were considered applicable for a subgroup of patients who had had 3 or more lines of platinum-based chemotherapy. This is because of the poorer prognosis for this group of patients, who will be at least 6 months further on in the course of disease than people who have had 2 lines of platinum-based chemotherapy. However even taking this into account the tablet formulation is not cost effective in this subgroup. The committee concluded that the end-of-life criteria are not met for the overall population of people with relapsed, platinum-sensitive ovarian cancer.

Cancer Drugs Fund

Olaparib does not meet the criteria for inclusion in the Cancer Drugs Fund

3.14 Having concluded that olaparib could not be recommended for routine use, the committee considered whether it could be recommended for treating relapsed platinum-sensitive ovarian cancer within the Cancer Drugs Fund. The committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides. The committee recognised that PARP inhibitors are innovative treatments for relapsed ovarian cancer. However, the ICERs estimated by the company and the ERG for olaparib compared with routine surveillance (see section 3.12) are substantially above the range normally considered cost effective, and there is no plausible potential that olaparib would be cost effective in routine use. The committee also questioned whether further relevant clinical data would be available within the normal time frame of inclusion in the Cancer Drugs Fund.The committee concluded that olaparib does not meet the criteria for inclusion in the Cancer Drugs Fund for treating relapsed platinum-sensitive ovarian cancer.

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Olaparib for maintenance treatment of relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer