3 Committee discussion
The evaluation committee considered evidence submitted by AstraZeneca, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.
Clinical need
BRCA mutation-positive HER2-negative high-risk early breast cancer
3.1 The patient experts explained that BRCA mutation-positive HER2‑negative high-risk early breast cancer is an aggressive form of cancer with poor outcomes. They also explained that it can be very distressing for people with the condition. It includes hormone receptor-positive and triple-negative breast cancer, the latter having the poorest prognosis. The patient experts explained that there are limited treatment options available for the condition, particularly for triple-negative breast cancer. They thought that many people who have had olaparib appreciated having access to an extra treatment option that has been shown to improve survival. People with HER2‑negative high-risk early breast cancer often worry about the increased risk of their cancer returning after treatment. Also, people with BRCA mutation-positive breast cancer have concerns about whether their relatives have the BRCA1 or 2 mutations and so an increased risk of developing cancer. Having a treatment that has been shown to improve outcomes has a positive effect on mental health. One of the patient experts who had had olaparib highlighted that it is a convenient oral treatment, and only infrequent hospital visits are needed for monitoring. They explained that olaparib's side effects were manageable. They also said that they were able to continue their usual daily activities and maintain a good quality of life while having it, although they did have fatigue. The committee concluded that olaparib would be a welcome adjuvant treatment option to improve outcomes in people with BRCA mutation-positive HER2‑negative high-risk early breast cancer.
Treatment pathway
Relevant comparator
3.2 The committee noted that current standard care for BRCA mutation-positive HER2‑negative high-risk early breast cancer is neoadjuvant chemotherapy followed by surgery and surveillance, or surgery followed by adjuvant chemotherapy. The most common chemotherapy regimen is an anthracycline taxane combination plus a platinum therapy. People with hormone receptor-positive HER2‑negative breast cancer may also have adjuvant endocrine therapy after surgery. The committee noted that olaparib would be used after neoadjuvant or adjuvant chemotherapy, either:
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as monotherapy in triple-negative early breast cancer, or
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with endocrine treatment in hormone receptor-positive HER2‑negative early breast cancer.
Because olaparib would be used in addition to any current therapies, the committee agreed that the relevant comparator was routine monitoring for cancer recurrence.
Clinical evidence
Generalisability of OlympiA
3.3 The clinical evidence came from OlympiA, a randomised double-blind placebo-controlled trial (n=1,836). It was done in 23 countries worldwide and included 106 people from the UK. The trial compared olaparib with placebo in people with (germline) BRCA mutation-positive HER2‑negative high-risk early breast cancer. People in the trial had either had neoadjuvant or adjuvant treatment at the point of randomisation. The criteria for defining high risk in OlympiA were:
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for people with triple-negative breast cancer who had neoadjuvant chemotherapy: residual invasive cancer in the breast, the resected lymph nodes (non-pathological complete response) or both at the time of surgery
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for people with hormone receptor-positive HER2‑negative breast cancer who had neoadjuvant chemotherapy: residual invasive cancer in the breast, the resected lymph nodes (non-pathologic complete response) or both at the time of surgery, and a score of 3 or more based on pretreatment clinical and post-treatment pathological stage, receptor status and histological grade
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for people with triple-negative breast cancer who had adjuvant chemotherapy: node-positive or node-negative cancer with a primary tumour of 2 cm or more
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for people with hormone receptor-positive HER2‑negative breast cancer who had adjuvant chemotherapy: 4 or more pathologically confirmed positive lymph nodes.
The clinical experts explained that the criteria for defining high risk were representative of how olaparib would be used in the NHS. They also explained that people with hormone receptor-positive HER2‑negative breast cancer (17.7%) in OlympiA were selected as having cancer with an equivalent high risk of relapse as people with triple-negative breast cancer (82.3%). The clinical experts explained that, in clinical practice, a higher proportion of people would have hormone receptor-positive HER2‑negative breast cancer. They said that the proportions in the trial reflected the lower prevalence of BRCA mutations in people with hormone receptor-positive HER2‑negative breast cancer, and their later enrolment into the trial. The committee agreed that the definition of high-risk early breast cancer in OlympiA was appropriate. It concluded that the trial was broadly generalisable to people who would have olaparib in the NHS.
Clinical effectiveness
3.4 The primary outcome in OlympiA was invasive disease-free survival. Secondary outcomes included distant disease-free survival and overall survival. A statistically significant difference in all 3 outcomes was shown with olaparib compared with placebo:
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Invasive disease-free survival at 4 years was 82.7% in the olaparib arm and 75.4% in the placebo arm (a difference of 7.3%, 95% confidence interval [CI] 3.0% to 11.5%).
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Distant disease-free survival at 4 years was 86.5% in the olaparib arm and 79.1% in the placebo arm (a difference of 7.4%, 95% CI 3.6% to 11.3%).
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Overall survival at 4 years was 89.8% in the olaparib arm and 86.4% in the placebo arm (a difference of 3.4%, 95% CI -0.1 to 6.8%).
The committee noted that event rates were low: 82.7% of people in the olaparib arm and 75.4% in the placebo arm were alive and cancer-free after 4 years. But it concluded that, in the full trial population, adjuvant treatment with olaparib had been shown to improve invasive disease-free survival, distant disease-free survival and overall survival compared with placebo. Also, it agreed that low rates are expected in people who have recently had surgery and chemotherapy with curative intent.
Efficacy of olaparib in subgroups
3.5 For the subgroup of people in OlympiA who had triple-negative breast cancer, olaparib statistically significantly improved invasive disease-free survival compared with placebo. For the subgroup of people with hormone receptor-positive HER2‑negative breast cancer, the results were consistent with the overall population but were not statistically significant. The clinical experts advised that this was because:
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of the smaller sample size and lower number of events in that subgroup (see section 3.3)
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OlympiA was not powered to detect differences in subgroups at the latest data cut-off (median 3.5‑year follow up).
They also explained that they did not expect to see any difference in treatment effect between the 2 HER2‑negative subgroups in the trial. Also, the committee noted the company's comment that there was no evidence of statistical heterogeneity between subgroups. The committee accepted these comments.
Economic model
Model design
3.6 The company presented a 5‑state semi-Markov model to estimate the cost effectiveness of adjuvant treatment with olaparib compared with routine monitoring in people with BRCA mutation-positive HER2‑negative high-risk early breast cancer previously treated with adjuvant or neoadjuvant chemotherapy. The 5 health states were: disease-free; non-metastatic breast cancer (local recurrence); early-onset metastatic breast cancer (recurrence within 2 years); late-onset metastatic breast cancer (recurrence after 2 years); and death. The model estimated the cost effectiveness of olaparib in people with triple-negative breast cancer and people with hormone receptor-positive HER2‑negative breast cancer separately. The EAG described the model as high-quality and largely aligned with NICE's methods for economic evaluation. The committee concluded that the model was suitable for decision making.
Extrapolating recurrence
3.7 There was no long-term data from OlympiA to use in the economic model. So, the company and the EAG had to extrapolate the data and make assumptions about recurrence using expert opinion and the published literature. The company used a log-normal distribution to model the risk of recurrence in both the triple-negative and hormone receptor-positive HER2‑negative breast cancer populations. The EAG agreed with the log-normal distribution for the triple-negative population but thought that this was too optimistic for the hormone receptor-positive HER2‑negative population. It preferred the generalised gamma distribution. This gave the smallest difference in long-term invasive disease-free survival for this subgroup. It also resulted in there being an equal risk of recurrence in the olaparib and placebo groups at an earlier time point (5.4 years compared with 14.5 years in the company's model). The company provided scenario analyses varying the time point at which the risk of recurrence was equal, but this only had a small effect on incremental cost-effectiveness ratios (ICERs). The committee agreed that there was insufficient evidence to make an informed decision about whether a log-normal or generalised gamma distribution was more suitable without further follow up from the trial. It noted the clinical experts' opinion that, for long-term invasive disease-free survival, there was little difference between the 2 distributions.
Risk of recurrence in triple-negative breast cancer population
3.8 For people with hormone receptor-positive HER2‑negative breast cancer, the company and EAG assumed that the risk of recurrence remained elevated throughout the lifetime horizon of the model. But, for people with triple-negative breast cancer, the company and EAG made different assumptions. The company assumed that, after 5 years, there was a 0% chance of recurrence, while the EAG assumed a 5% risk from year 5 to year 15. The clinical experts explained that most recurrences in people with triple‑negative breast cancer occur in the first 2 to 3 years after diagnosis. They also said that the risk of recurrence after 5 years is very low, although it is not likely to be 0%. They estimated that there may be a 2% to 3% risk of recurrence between year 5 and year 8, and 0% after 8 years. The committee concluded that assuming a 2% to 3% risk of recurrence between year 5 and year 8, while uncertain, was reasonable.