Cabazitaxel for hormone-relapsed metastatic prostate cancer treated with docetaxel

4.5 The committee considered the clinical‑effectiveness evidence submitted by the company (see section 3.1). TROPIC was a large, open‑label, multinational, phase III, randomised trial comparing cabazitaxel plus prednisone or prednisolone (subsequently referred to as cabazitaxel) with mitoxantrone plus prednisone or prednisolone (subsequently referred to as mitoxantrone). The committee discussed whether the treatments that patients had before they entered the TROPIC trial were relevant to clinical practice in England, because the trial was conducted before abiraterone and enzalutamide were available. It was aware that in clinical practice in England, abiraterone and enzalutamide are sometimes offered before docetaxel (see section 4.1). The committee heard from the clinical experts that patients in TROPIC were on their second or third line of treatment, which means that the patients in the trial are similar to people who would have cabazitaxel in the NHS. The committee concluded that TROPIC provided estimates of efficacy that were generalisable to the NHS in England, although it was somewhat uncertain whether the magnitude of benefit observed in TROPIC would be observed in the NHS because of differences in treatment history between these 2 populations.

4.6 The committee noted that, in the company's opinion, the population relevant to the appraisal was represented by the subgroup of patients in TROPIC with an eastern cooperative oncology group (ECOG) performance score of 0 or 1 who had had 225 mg/m² or more of docetaxel. The company considered this subgroup relevant to clinical practice in England because people with an ECOG score above 1 are not suitable for treatment with chemotherapy, and 225 mg/m² or more of docetaxel is the minimum dose used in clinical practice. The committee agreed that this subgroup is closest in characteristics to the patients who would be offered cabazitaxel through the NHS in England.

4.7 The committee considered whether mitoxantrone is equivalent to best supportive care as proposed by the company. The committee questioned why the company had included mitoxantrone, which does not have a marketing authorisation in the UK for treating metastatic hormone‑relapsed prostate cancer, as the comparator in the pivotal trial. The clinical experts stated that, when the trial was designed, mitoxantrone was frequently used in clinical practice because there were few treatment options available. The committee considered the evidence submitted by the company to support equivalence of mitoxantrone and best supportive care. It noted that the Green et al. (2015) study showed no statistically significant difference in overall survival between mitoxantrone and prednisone (see section 3.2). The committee noted that although the evidence suggests no statistically significant difference between mitoxantrone and prednisone, this does not demonstrate equivalence. The committee concluded that, in the absence of evidence of equivalence, mitoxantrone could be considered similar to best supportive care.

4.8 The committee considered the results of TROPIC, focusing on the subgroup of people with an ECOG performance score of 0 or 1 who had had 225 mg/m² or more of docetaxel. The committee was aware that the TROPIC data were analysed in 2010 and that these results had been available to the committee for NICE's 2012 technology appraisal of cabazitaxel. The results showed that cabazitaxel prolonged survival and progression‑free survival compared with mitoxantrone (see table 1). The committee heard from the evidence review group (ERG) that a lack of blinding in the open‑label trial design could bias the results. The committee agreed that estimates of treatment effect for subjective outcomes such as pain and symptom deterioration (both of which were included in the definition of progression‑free survival) may be biased by the lack of blinding. The committee concluded that, in people with an ECOG performance score of 0 or 1 who had had 225 mg/m² or more of docetaxel, cabazitaxel compared with mitoxantrone improves overall survival and progression‑free survival. It further concluded that the estimated treatment effect for disease progression may be affected by bias within the trial design.

4.9 The committee considered the company's fixed‑effects network meta‑analysis comparing cabazitaxel with best supportive care, abiraterone and enzalutamide. The results showed that there was no significant difference in overall survival between cabazitaxel, abiraterone and enzalutamide (see section 3.9). It also showed that radiographic progression‑free survival was shorter with cabazitaxel than with enzalutamide. The committee noted that the incidence of anaemia and nausea was higher with cabazitaxel than with abiraterone and enzalutamide (see section 3.28). The committee was aware of a number of concerns about the network meta‑analysis:

4.10 The committee discussed the effectiveness of cabazitaxel compared with radium‑223 dichloride, noting that the company did not present any evidence for this comparison. The committee was aware of the ERG's crude comparison which suggested that median overall survival and progression‑free survival were similar for both cabazitaxel and radium‑223 dichloride (see section 3.41). The committee acknowledged that this basic comparison was at high risk of bias. It concluded that there was no evidence that cabazitaxel and radium‑223 dichloride have different effects on survival.

4.11 The committee considered the company's economic model, noting that it was a partitioned‑survival model (that is, the transitions between health states were derived from curves of progression‑free survival and overall survival). The model compared cabazitaxel with mitoxantrone, which was a proxy for best supportive care. The committee noted that the modelled population was the subgroup of people in TROPIC with an ECOG performance score of 0 or 1 who had had 225 mg/m² or more of docetaxel. It was aware that, in scenario analyses, the company compared cabazitaxel with abiraterone and, separately, with enzalutamide. When comparing cabazitaxel with abiraterone or enzalutamide, the modelled population was not the subgroup, but rather all randomised patients in TROPIC because the network meta‑analysis used this population. The committee concluded that the company's model was acceptable, but it should have included radium‑223 dichloride as a comparator.

4.12 The committee considered the estimates of overall survival in the company's model (see section 3.14), noting that in its original base case the company used a Weibull curve to extrapolate overall survival. The committee heard from the ERG that, in the early stages of the trial, some patients treated with cabazitaxel died from febrile neutropenia and that this may have affected the predicted survival times if using a single extrapolation curve. The committee was aware that, in response to a clarification question before the first committee meeting, the company presented a scenario analysis that used a piecewise extrapolation for cabazitaxel (see section 3.29). The piecewise extrapolation used the observed Kaplan–Meier curve from TROPIC for the first 2.1 months and a Weibull curve thereafter. The committee heard from the company that 2.1 months was chosen because the trial protocol was altered at this point to allow prophylaxis with granulocyte‑colony stimulating factor, which reduced the number of deaths from neutropenia. The committee heard that the ERG preferred the piecewise approach rather than a single Weibull curve. The committee accepted that the choice of 2.1 months as the time point for changing distribution was rational and clinically plausible. The committee concluded that a piecewise curve was the most appropriate method for modelling overall survival with cabazitaxel, and it noted that the company had adopted this approach in its response to consultation.

4.13 The committee discussed the source of efficacy estimates in the model. It heard during consultation that, when comparing cabazitaxel with best supportive care, the company preferred to use data from TROPIC instead of the results of the network meta-analysis. The company reiterated its concerns about the network meta-analysis and stated that it did not consider it appropriate to use indirect data to compare cabazitaxel with best supportive care. The committee agreed that it was appropriate to use TROPIC data when comparing cabazitaxel with best supportive care only. When comparing cabazitaxel with additional comparators (best supportive care, abiraterone and enzalutamide) the committee preferred a fully incremental analysis. The committee was aware that the only fully incremental analysis presented to the committee came from the ERG and used efficacy estimates from the random‑effects network meta‑analysis. The committee acknowledged that the network meta‑analysis had many limitations, but it did include the TROPIC data and it permitted a fully incremental analysis. The committee concluded that the appropriate efficacy estimates came from:

4.14 The committee considered the utility values in the company's economic model. It was aware that the company had not collected quality‑of‑life data in TROPIC, so it had used EQ‑5D utility values from an open‑label single‑arm study of 112 patients treated with cabazitaxel (the UK early access programme; see section 3.15). The committee heard from the ERG that people in the early access programme were less likely to have had multiple rounds of chemotherapy than patients in TROPIC (11% of patients in the UK early access programme had had at least 2 previous chemotherapy regimens compared with 31% in TROPIC). This meant that patients in TROPIC were likely to be more unwell than those in the early access programme. The committee was aware that the company had modelled a utility value of 0 for the final 3 months of life. It heard from the ERG that this reflected the assumed reduced quality of life towards the end of life for people with progressive disease. It heard from the ERG that the company applied this disutility to all people who died and not just to people who died with progressive disease. The committee was aware that the ERG preferred to remove the zero utility, and it noted that the company had done this in its analyses submitted in response to the appraisal consultation document. The committee acknowledged the limitations of using data from the UK early access programme but, in the absence of more robust evidence on health‑related quality of life, it concluded that the company had used the best available data to estimate utility values.

4.15 The committee considered the cost of drugs in the model, noting that the company used the price for mitoxantrone from the British national formulary (BNF) in its original base case. The committee considered that prices from the electronic marketing information tool (eMIT) are more appropriate for generic drugs because they reflect the average price paid by NHS hospitals. The committee concluded that it preferred to consider the eMIT price for mitoxantrone, and noted that the company had done this in its analyses submitted in response to the appraisal consultation document.

4.16 The committee considered the method used by the company to model stopping treatment with cabazitaxel or mitoxantrone. It heard from the ERG that the company's original base case had incorrectly calculated drug costs and utility values for people who stopped treatment for reasons other than disease progression. The committee was aware that, to correct for this, the ERG's exploratory analysis did not permit stopping treatment for reasons other than disease progression, death, or reaching the maximum 10 cycles of treatment. The committee concluded that it preferred the ERG's approach to modelling stopping treatment and it noted that the company had adopted this approach in its response to the appraisal consultation document.

4.17 The committee considered the company's choice of costs for patients in the post‑progression health state. It heard from the ERG that the company's original base case had used different estimates of cost for post‑progression treatments, depending on whether patients had cabazitaxel or one of the comparator treatments at the start of the model. The ERG preferred to use the same post‑progression treatment costs for cabazitaxel and each of the comparators. The committee was aware that the ERG used a UK clinical audit to estimate the costs of treatments after disease progression for cabazitaxel and all of the comparators. The committee noted that this reduced the incremental cost‑effectiveness ratio (ICER) when comparing cabazitaxel with mitoxantrone. The committee concluded that the model should use UK clinical audit data to inform post‑progression costs for all patients in the model and it noted that the company had done this in its response to the appraisal consultation document.

4.18 The committee considered the duration of treatment with cabazitaxel in the company's economic model, noting that the marketing authorisation does not specify a maximum number of cycles of treatment. The committee noted that the company had modelled a maximum of 10 cycles of treatment with cabazitaxel to reflect the maximum cycles permitted in TROPIC. The committee heard from the clinical experts that in clinical practice patients routinely have no more than 10 cycles. The clinical experts also advised that, if the committee were to recommend cabazitaxel, it would be appropriate to limit treatment to 10 cycles. The committee concluded that it was appropriate to limit cabazitaxel treatment to 10 cycles in the model.

4.19 The committee considered the company's rationale for not including wastage of cabazitaxel in its economic model. The committee was aware that the company had assumed wastage for mitoxantrone. It heard from the company that cabazitaxel is currently supplied in vials but, in the future, will be supplied to NHS trusts per milligram (see section 3.20). Under the new system, the NHS orders the number of milligrams of cabazitaxel needed per patient and the company facilitates the supply of cabazitaxel to the NHS hospital in a compounded intravenous‑infusion bag for each patient. The company advised that in the new arrangement the NHS only pays for the milligrams used. The company provided confirmation from NHS England that it is appropriate to supply and purchase cabazitaxel in this way. The committee was aware of the ERG's analyses, showing that using per-milligram pricing of cabazitaxel decreased the ICER for cabazitaxel compared with mitoxantrone (see section 3.34). The committee was satisfied with the information provided by the company and concluded that the economic model should include per‑milligram pricing of cabazitaxel, that is, the model should not include wastage. (After the guidance was published, the commercial access agreement was changed so that NHS trusts also have the option of purchasing cabazitaxel in vials; see section 2.3.)

4.20 The committee discussed the cost effectiveness of cabazitaxel, noting that the appropriate comparators depend on which treatments patients had had before (see section 4.3). It also noted that all analyses were limited because they did not include radium‑223 dichloride, which it agreed was a relevant comparator for people with symptomatic bone disease and no known visceral metastases.

4.21 For people who previously had abiraterone or enzalutamide, and for people whose disease is unsuitable for treatment with abiraterone or enzalutamide, the committee discussed the cost effectiveness of cabazitaxel compared with mitoxantrone (a proxy for best supportive care). The committee noted that the company's updated base‑case ICER (assuming no wastage of cabazitaxel and including the updated confidential patient access scheme discount) was £45,159 per quality-adjusted life year (QALY) gained (incremental costs £10,682; incremental QALYs 0.237). The committee agreed that it preferred to use probabilistic rather than deterministic ICERs, because probabilistic analyses reflect some of the uncertainty around the mean health and cost inputs in the model. The probabilistic ICER was £45,982 per QALY gained. The committee noted that, in line with its preferences, the company's updated analysis included the following assumptions:

4.22 For people who have not previously had abiraterone or enzalutamide, the committee discussed the cost effectiveness of cabazitaxel compared with abiraterone, enzalutamide and best supportive care. Enzalutamide has a confidential patient access scheme so NICE asked the ERG to perform a fully incremental analysis using the confidential discount. To avoid disclosing the confidential discount for enzalutamide, the detailed results of the analyses cannot be reported here. The analyses used the committee's preferred assumptions listed in section 4.21, except that overall survival with cabazitaxel was extrapolated with a Weibull curve because the ERG did not have full details of the committee's preferred piecewise curve. The committee considered the results of the ERG's incremental analysis which showed that cabazitaxel was extendedly dominated in both the deterministic and probabilistic analyses. An intervention is 'extendedly dominated' when it is more costly and less effective than a combination of 2 comparators. In this analysis, cabazitaxel was extendedly dominated by enzalutamide and best supportive care. The committee noted that abiraterone was also extendedly dominated by enzalutamide and best supportive care. The committee was aware that the results of the network meta-analysis, which informed the incremental analysis, were highly uncertain (see sections 4.9 and 4.10) and showed no statistically significant difference in overall survival or progression-free survival between the 3 treatments. It further noted that the ERG's analysis showed the total costs for cabazitaxel were lower than the total costs for abiraterone and enzalutamide. Although cabazitaxel also generated fewer total QALYs than abiraterone and enzalutamide the difference was small, especially compared with abiraterone. The committee noted that the analysis showed cabazitaxel is extendedly dominated by enzalutamide and best supportive care, but that this result was very uncertain because of the limitations of the network meta-analysis. The committee agreed that the relative cost effectiveness of the treatments was uncertain, but concluded that the analyses indicated cabazitaxel was likely to be less costly than enzalutamide and abiraterone.

4.23 The committee discussed the place of cabazitaxel in the treatment pathway, noting that it could potentially be used for people who previously had docetaxel followed by abiraterone, enzalutamide or radium‑223 dichloride. The committee appreciated that it had not seen evidence that cabazitaxel was clinically effective at this point in the pathway, and that the ERG's report noted there was 'no high‑quality evidence from prospective controlled trials to guide optimum sequencing of these agents after docetaxel treatment'. It was also aware that the economic modelling assumed that cabazitaxel was used instead of abiraterone or enzalutamide, rather than after these drugs. Accordingly, the committee was unable to make a recommendation on the use of cabazitaxel for people who had docetaxel followed by abiraterone, enzalutamide or radium‑223 dichloride.

4.24 The committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.

4.25 The committee considered the end‑of‑life criteria separately for 2 groups:

4.26 For people who had abiraterone or enzalutamide before docetaxel, and for people unsuitable for treatment with abiraterone or enzalutamide, the committee considered the short life‑expectancy criterion. The committee noted a literature review by West et al. (2014) of life expectancy in people with hormone‑relapsed prostate cancer that was presented by the company; it showed that for people treated with docetaxel the median overall survival was 19 months. The committee concluded that the short life‑expectancy criterion was met. The committee noted the results of TROPIC, which showed that cabazitaxel extended survival compared with mitoxantrone by a mean of 4.1 months in the subgroup of people with an ECOG performance score of 0 or 1 who had had 225 mg/m² ormore of docetaxel. The committee was aware of the uncertainty surrounding this estimate because the company based it on extrapolated data and because the people in the trial had not been treated with abiraterone or enzalutamide before docetaxel (because the trial was done before these treatments were available). Nonetheless, the committee concluded that the extension‑to‑life criterion was met. The committee discussed the population size, noting the company's estimate that 1,690 people in England would be eligible for treatment with cabazitaxel. The committee concluded that all of the end‑of‑life criteria were met for people treated with enzalutamide or abiraterone before docetaxel and for people unsuitable for treatment with abiraterone or enzalutamide.

4.27 The committee considered each end‑of‑life criterion in turn for people who had not had enzalutamide or abiraterone. For the criterion of short life expectancy, the committee agreed that the relevant estimates of life expectancy came from people who had docetaxel and then abiraterone, enzalutamide or – for selected patients – radium‑223 dichloride because these treatments were part of established care in the NHS. It noted the ERG's evidence showing that median overall survival in the intervention group of the trials of abiraterone and enzalutamide after docetaxel was 15.8 and 18.4 months respectively. The committee concluded that, even though the mean life expectancy would exceed the median life expectancy, the short life‑expectancy criterion was met. For the criterion of extension to life the committee noted that the network meta‑analysis showed no statistically significant difference in overall survival between cabazitaxel, abiraterone and enzalutamide. It also heard from the company that there was no robust evidence that cabazitaxel offered an extension to life of at least 3 months compared with abiraterone and enzalutamide. Therefore the committee concluded that this criterion was not met. The committee further concluded that the small population size criterion was met based on its considerations in section 4.26. Overall, the committee concluded that cabazitaxel did not meet the criteria for end‑of‑life consideration, in the group of people not previously treated with abiraterone or enzalutamide.

4.28 The committee considered whether cabazitaxel is an innovative technology. It heard from the company that cabazitaxel has been specifically developed to address docetaxel resistance. However, the committee was not presented with a case, substantiated by data, showing that cabazitaxel treatment adds demonstrable and distinctive benefits of a substantial nature that have not already been adequately captured in the QALY measure.

4.29 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.

4.30 The committee considered the use of cabazitaxel in people with metastatic hormone‑relapsed prostate cancer previously treated with docetaxel. The committee acknowledged that cabazitaxel was a clinically effective treatment that prolonged life and was valued by patients.

4.31 The committee agreed that it would have preferred to see analyses comparing cabazitaxel with radium‑223 dichloride for the subgroup of people with symptomatic bone metastases and no known visceral metastases after treatment with docetaxel. The committee heard from the company that only a small number of patients in TROPIC belonged to this subgroup, and it was not possible to extract data for these patients. The committee accepted that there was no evidence to inform a comparison of cabazitaxel with radium‑223 dichloride, and radium‑223 dichloride was a comparator for only a small subgroup. The committee was aware of advice from clinical and patient experts, and responses to consultation, stating that cabazitaxel and radium‑223 dichloride work in different ways and the choice of treatment is informed by the characteristics of the individual's disease, clinical experience and patient preference. The committee considered the ERG's analysis comparing the costs of cabazitaxel and radium‑223 dichloride (including the confidential patient access scheme discounts) and concluded that the costs of these drugs were not substantially different. Having considered all of the evidence carefully, the committee agreed that it was a good use of NHS resources to offer cabazitaxel as a treatment option.

4.32 The committee discussed the details of its recommendation. It agreed to recommend cabazitaxel only for people with an ECOG performance status of 0 or 1 who had previously had 225 mg/m² or more of docetaxel, because this reflects the subgroup from TROPIC that formed the basis of the evidence for clinical and cost effectiveness. The committee recommended cabazitaxel only if patients stop treatment when the disease progresses or after a maximum of 10 cycles (whichever happens first) because this reflects the use in the main trial and the assumptions in the economic model. The committee also recommended cabazitaxel only if trusts purchase compounded bags of cabazitaxel, because cabazitaxel would not be cost effective if the NHS were to purchase vials (because some cabazitaxel would be wasted, which increases the overall cost of treatment). (After the guidance was published, the commercial access agreement was changed so that NHS trusts also have the option of purchasing cabazitaxel in vials without incurring wastage costs; see section 2.3.) The committee concluded that cabazitaxel was both clinically and cost effective and could be recommended as a treatment option in the NHS, subject to the conditions in section 1.1.

4.33 The committee considered whether its recommendations were associated with any potential issues related to equality. The committee concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.