Enzalutamide for metastatic hormone‑relapsed prostate cancer previously treated with a docetaxel‑containing regimen

4 Consideration of the evidence

The Committee reviewed the data available on the clinical and cost effectiveness of enzalutamide, having considered evidence on the nature of metastatic hormone‑relapsed prostate cancer and the value placed on the benefits of enzalutamide by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.1 The Committee discussed the clinical management of metastatic hormone‑relapsed prostate cancer in people who have received docetaxel‑containing chemotherapy. It understood from the clinical specialists that there are few treatment options available for patients at this stage of the disease, and that enzalutamide represents an effective treatment. The Committee heard from the clinical specialists that enzalutamide is likely to be used at the same point in the treatment pathway as abiraterone, by patients who have received at least 1 course of cytotoxic chemotherapy. The Committee heard from the patient experts that enzalutamide is an oral treatment that, unlike abiraterone, does not need to be taken on an empty stomach, making it more convenient to take. It also heard that, with abiraterone, some patients may need to reduce their dose to prevent liver toxicity, whereas enzalutamide is less likely to cause liver toxicity. The Committee understood from the patient experts that patients' quality of life is affected by whether or not the patient is receiving treatment, and appreciated that patients with the condition would value even small improvements in quality of life. The Committee agreed with the clinical specialists and patient experts that enzalutamide would be a valuable treatment option for patients with metastatic, hormone-relapsed prostate cancer after at least 1 cytotoxic chemotherapy regimen.

4.2 The Committee was aware that the Cancer Drugs Fund offers enzalutamide to patients whose disease has progressed on or after docetaxel-containing therapy, but not if patients have previously received abiraterone. The Committee noted comments received from patient organisations and members of the public in response to the second appraisal consultation document. Most of the comments opposed the preliminary recommendation restricting the use of enzalutamide to those who have not previously received abiraterone because it was felt that this placed a significant restriction on access. The Committee acknowledged the concern of patients, in particular that more than 7000 people had signed a Prostate Cancer UK petition calling for this restriction to be removed. The Committee noted comments from the manufacturer and professional organisations acknowledging the absence of robust clinical evidence on the most effective sequencing of enzalutamide and abiraterone. The Committee noted concerns that restricting enzalutamide to patients who had not previously received abiraterone may influence the order in which clinicians offer the drugs. It also considered the small, single-arm observational studies provided by the manufacturer in response to the second appraisal consultation document (see section 3.17) that suggested that enzalutamide is less effective at reducing PSA concentration in patients who have been treated with abiraterone. The Committee heard from the clinical specialist that these results reflect clinical practice because there is usually a decreasing response to a drug the further down the treatment pathway it is received. Therefore, enzalutamide would be expected to produce a lower response rate after cytotoxic chemotherapy with docetaxel followed by abiraterone than after cytotoxic chemotherapy alone. The Committee heard from the clinical specialists that patients might stop abiraterone for a number of clinical reasons, including drug toxicity, intolerance or disease progression; it noted that these clinical circumstances are likely to influence the effectiveness of subsequent treatment with enzalutamide. The Committee further heard from the clinical specialist that, in clinical practice, clinicians would like to be able to offer enzalutamide after abiraterone (particularly to patients who experience liver toxicity on abiraterone). Acknowledging the limitations of the observational studies (see section 3.20) and the uncertainty around the evidence base for sequential treatment, the Committee agreed that a proportion of patients may benefit from treatment with enzalutamide after abiraterone. However, the Committee agreed that the observational studies were not suitable to inform a conclusion on the magnitude of the effectiveness of enzalutamide after treatment with abiraterone.

4.3 The Committee discussed the manufacturer's decision problem, noting that the manufacturer had chosen to exclude mitoxantrone as a comparator for enzalutamide even though it had been listed as a comparator in the final scope for this appraisal. The Committee heard from the clinical specialists that mitoxantrone was standard care years ago, and that newer treatments such as abiraterone have displaced its use in clinical practice so that its use in the NHS is now negligible. It further heard that although mitoxantrone improved quality of life, it did not prolong survival. The Committee was also aware that mitoxantrone is not licensed for treating metastatic hormone‑relapsed prostate cancer, and is not included in existing NICE guidance for prostate cancer. The Committee concluded that it was appropriate for the manufacturer to have excluded mitoxantrone as a comparator in its decision problem.

4.4 The Committee discussed the relevance of the 2 comparators, abiraterone and best supportive care, in relation to the population covered by the marketing authorisation for enzalutamide. The Committee was aware that Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen (NICE technology appraisal guidance 259) recommends abiraterone for treating hormone‑relapsed metastatic prostate cancer only if patients' disease progressed during or after treatment with 1 course of docetaxel-containing cytotoxic chemotherapy. The Committee therefore agreed that abiraterone is a suitable comparator for enzalutamide only for the same population for which abiraterone is recommended by NICE. It also agreed that comparing enzalutamide with best supportive care would be appropriate for the subset of the population covered by the marketing authorisation for which abiraterone is not recommended (that is, patients with hormone-relapsed disease who have received 2 or more cytotoxic chemotherapy regimens). As such, the Committee concluded that both comparators specified in the manufacturer's decision problem were appropriate, but for different populations.

4.5 The Committee considered the evidence on the clinical effectiveness of enzalutamide, noting that it came mainly from AFFIRM. It agreed that AFFIRM was a good-quality trial and relevant to the decision problem. The Committee noted that, in the trial, enzalutamide was associated with a statistically significant improvement in median overall survival of 4.5 months compared with placebo (final cut-off date 16 December 2011). It also noted that there was a statistically significant difference in quality of life for patients receiving enzalutamide compared with placebo, as measured using Functional Assessment of Cancer Therapy‑Prostate (FACT‑P). The Committee concluded that, compared with best supportive care, enzalutamide was a clinically effective treatment for patients with metastatic hormone‑relapsed prostate cancer whose disease progressed on or after at least 1 docetaxel-containing cytotoxic chemotherapy.

4.6 The Committee considered the different definitions of progression‑free survival used by the manufacturer in its submission, namely, radiographic progression‑free survival, modified progression‑free survival and time to treatment discontinuation. The Committee was aware that determining progression‑free survival from radiographic evidence in AFFIRM was difficult because patients entered the trial with metastatic disease and could die without evidence of further radiographic progression. The Committee heard from the clinical specialists that no single measure is routinely used to determine disease progression, and that clinicians take into account each patient's clinical, radiological and biochemical results. The Committee noted that the patient experts stressed the importance of judging how well a treatment works by how well patients feel on that treatment. The Committee discussed whether stopping treatment was a reasonable proxy for disease progression. It heard from the clinical specialists that patients are regularly monitored and their treatment is stopped, and they are offered an alternative option when their disease is considered to have progressed. The Committee noted that, of those who stopped enzalutamide in AFFIRM, the primary reason for stopping treatment in about 55% of patients was disease progression. The Committee agreed that patients are likely to stop treatment in clinical practice before all the criteria applied in AFFIRM have been met. Although the Committee appreciated the uncertainty around measuring progression‑free survival, it concluded that, of the measures described by the manufacturer, time to treatment discontinuation was the most reasonable.

4.7 The Committee discussed the manufacturer's indirect comparison between enzalutamide and abiraterone. It noted that the proportion of patients who received prednisone in the placebo groups of AFFIRM and COU‑AA‑301 differed (AFFIRM 45.6%, COU‑AA‑301 100%) because patients need to take abiraterone, but not enzalutamide, together with corticosteroids. The Committee heard from the clinical specialists that, at this advanced stage of the disease, patients would have already received corticosteroids before starting docetaxel therapy, and their disease may have developed resistance to corticosteroids. The Committee discussed the possibility that corticosteroids could reduce survival, for example, if a patient developed corticosteroid-induced diabetes, but was not presented with any evidence. The Committee concluded that corticosteroids were unlikely to affect survival, and that AFFIRM and COU‑AA‑301 could be used to compare enzalutamide and abiraterone indirectly. The Committee noted that comments received in response to the first appraisal consultation document pointed out that follow-up in COU‑AA‑301 was longer than in AFFIRM (20.2 months compared with 15.0 months) at the time points at which the manufacturer compared overall survival data from the 2 trials. The comments suggested that this biased the comparison against abiraterone because the treatment effect was time-dependent (that is, the effectiveness of abiraterone tapered in the long term), so the estimated hazard ratios could not be compared in an indirect comparison. The Committee agreed that, whenever possible, the most mature datasets should be compared and that both datasets used for the indirect comparison provided this (for AFFIRM and COU‑AA‑301, the longest follow-up for any patient was 15.0 months and 20.2 months respectively). The Committee was aware that the manufacturer's indirect comparison showed no statistically significant difference in overall survival between enzalutamide and abiraterone. The Committee concluded that using these datasets was acceptable for the indirect comparison.

4.8 The Committee considered the adverse reactions and skeletal‑related events associated with enzalutamide in relation to the economic modelling. It noted that adherence to enzalutamide in AFFIRM was generally high and adverse reactions were generally manageable and reversible. However, the Committee was aware of the increased risk of seizures with enzalutamide treatment, and noted that the summary of product characteristics advises caution when administering enzalutamide to people with a history of seizures or other predisposing factors for seizures. It was satisfied that these provisions would help minimise the risk of seizures in susceptible patients. The Committee discussed the skeletal‑related events that occurred during AFFIRM. It was concerned that the incidence of spinal cord compression appeared high in both treatment groups in the trial, but heard from the clinical specialists that, although spinal cord compression is a serious and potentially fatal complication, it is more likely to be diagnosed in a clinical trial before neurological damage occurs. Overall, the Committee concluded that no adverse events or skeletal‑related events needed special consideration in the context of the economic modelling.

4.9 The Committee discussed the relevance of the manufacturer's cost‑effectiveness evidence to the patient populations for which enzalutamide would be considered. It agreed that enzalutamide should be compared with abiraterone for the same population for whom abiraterone is recommended by NICE (that is, only after 1 docetaxel-containing regimen), and with best supportive care for the subset of the population covered by the marketing authorisation for whom abiraterone is not recommended (that is, patients who have received 2 or more cytotoxic chemotherapy regimens). However, the Committee was aware that the evidence presented by the manufacturer in its original submission related to the overall population (that is, patients who had received 1 or more cytotoxic chemotherapy regimens). The Committee noted that, compared with the survival benefit of enzalutamide for the overall population (hazard ratio [HR] 0.62), the trial results suggested that the survival benefit of enzalutamide was higher for patients who had received 1 previous cytotoxic chemotherapy regimen (HR 0.59), and lower for those who had received 2 or more regimens (HR 0.74). The Committee considered that patients who had received only 1 previous course of cytotoxic chemotherapy would be less likely to have advanced disease and more likely to have better outcomes than the overall trial population, which would improve the cost effectiveness of enzalutamide for this subgroup. Therefore, the Committee concluded that it could develop a recommendation only for patients who had received 1 previous docetaxel-containing cytotoxic chemotherapy based on evidence for the overall population. The Committee also agreed that to develop recommendations for enzalutamide for treating patients who had received 2 or more cytotoxic chemotherapy regimens, it is necessary to consider data on the baseline expected survival and a robustly modelled incremental cost‑effectiveness ratio (ICER) for these patients.

4.10 The Committee discussed how the manufacturer modelled overall survival for abiraterone, noting that this parameter is key to the cost effectiveness of enzalutamide compared with abiraterone. It was aware that the manufacturer assumed that the survival benefit of abiraterone varied over time, such that beyond 16.6 months after starting treatment, the hazard ratio was greater than 1 (implying that, during that time, there was a higher risk of death for patients who took abiraterone than those who took placebo). The Committee discussed the most plausible way to model the life span of patients who took abiraterone, noting that in COU‑AA‑301 (Fizazi et al. 2012), the Kaplan–Meier curves for abiraterone and placebo initially diverged then converged (that is, the relative treatment effect of abiraterone improved then worsened), and crossed around 24 months after starting treatment. The Committee heard from the clinical specialists that they did not believe that this represented the natural history of the disease and that, in their opinion, the survival benefit of abiraterone is unlikely to vary over time in clinical practice. The clinical specialists suggested that the shape of the Kaplan–Meier curves may reflect the rigid criteria for stopping treatment in COU‑AA‑301, in that patients who would have stopped abiraterone in clinical practice (and received other therapy) instead continued taking abiraterone in the trial despite their disease having progressed under normal clinical criteria. The Committee agreed that this may have biased the overall survival end point against abiraterone and introduced uncertainty. Because of this, the Committee did not agree with how the manufacturer modelled overall survival for abiraterone, preferring to take a conservative approach. The Committee was aware that the Evidence Review Group (ERG) explored a more conservative approach than the manufacturer by assuming a hazard ratio of 1.0 beyond 25 months after starting treatment. However, the Committee considered that the ERG's scenario may not be conservative enough because it applied a hazard ratio that varied up to 25 months. The Committee concluded that, given the clinical experience with abiraterone, assuming a constant hazard ratio over the entire time horizon would be the most plausible scenario to model overall survival for abiraterone. However, it appreciated that all the modelling scenarios would be associated with some degree of uncertainty.

4.11 The Committee considered how the manufacturer modelled progression-free survival in its base-case analysis, noting that the manufacturer used time to treatment discontinuation as a proxy for disease progression. It agreed that the manufacturer's approach was acceptable because of concerns about using radiographic imaging to monitor disease in patients with prostate cancer. The Committee was aware that in AFFIRM, some patients' disease had progressed before they stopped treatment. The Committee noted that when the manufacturer applied modified progression‑free survival instead of time to treatment discontinuation as a proxy for progression‑free survival in a scenario analysis, the manufacturer's base‑case ICER for enzalutamide compared with abiraterone decreased from £14,800 to £13,500 per QALY gained. The Committee concluded that using an alternative definition of progression-free survival did not significantly change the ICER for enzalutamide compared with abiraterone.

4.12 The Committee considered the EQ‑5D utility value chosen by the manufacturer to model health-related quality of life for patients at baseline. It noted that EQ‑5D data were collected only at study sites in certain European countries (n=209). Although the Committee appreciated that a larger sample would have reduced uncertainty around this estimate, it agreed that the sample size was adequate compared with those used in previous appraisals for the same indication. It also noted that the manufacturer's utility value was lower than those used in other appraisals for the same stage of the disease. The Committee concluded that it was appropriate for the manufacturer to have used the EQ‑5D utility value from AFFIRM at baseline.

4.13 The Committee discussed the increase in utility attributed to being 'on‑treatment' with enzalutamide or abiraterone, noting that the manufacturer applied different values for the 2 treatments. It was aware that, to estimate the utility increase for enzalutamide, the manufacturer mapped FACT‑P data onto EQ‑5D using a mapping algorithm that it had not externally validated, and that the ERG could not verify. The Committee noted that the ERG considered that there was no evidence to assume different utility increases for enzalutamide and abiraterone, and that the ERG preferred excluding these estimates from the model. The Committee, noting the patient experts' experience, agreed that including 'on‑treatment' utility increases reflected patient experience, but that there is no evidence to assume different values for enzalutamide and abiraterone. The Committee concluded that the modelling should incorporate the same utility increase for both treatments.

4.14 The Committee discussed the decrease in utility that occurs with disease progression (−0.085). It was aware that the manufacturer estimated this value from Sandblom et al. (2004) as the decrease in utility from 16–8 months before death to 8–0 months before death in this study. The Committee noted that the ERG argued that these time intervals should match the time in the stable- and progressive-disease states in Sandblom et al., not in AFFIRM, because the time patients spent in each state may have differed in Sandblom et al. and AFFIRM. The Committee agreed that the utility decrease for disease progression applied by the manufacturer in the model did not represent the decrease in utility experienced by patients whose disease had progressed in AFFIRM. The Committee noted that when the ERG explored an alternative utility value of −0.07, as used in NICE technology appraisal 259, there was little impact on the ICERs. Without another more robust value of the utility decrease for disease progression, the Committee concluded that the value used by the manufacturer was acceptable for its decision-making in this appraisal.

4.15 The Committee discussed the estimates of costs and resource use chosen by the manufacturer. It noted that the manufacturer had to assume the patient access scheme discount for abiraterone in the model because the discount is commercial in confidence, and was not provided by the manufacturer of abiraterone for this appraisal. The Committee would have preferred a situation in which the manufacturer of enzalutamide could have applied the actual discount for abiraterone in its economic model. The Committee acknowledged that both the manufacturer and the ERG provided sensitivity analyses varying the discount in the model. The Committee initially expressed concern that the manufacturer assumed no hospitalisation costs in the model, which the Committee considered did not reflect 'real life'. It heard from the manufacturer that these costs were not included because AFFIRM did not collect data on hospitalisation and because hospitalisation costs were marked as confidential in the manufacturer's submission for abiraterone from NICE technology appraisal 259. On this basis, the Committee considered that, if hospitalisation costs had been included, the incremental costs for enzalutamide compared with abiraterone may have changed, and concluded that the analysis should account for costs of hospitalisation. However, in response to consultation, the manufacturer noted that it had assumed in the model that the costs of adverse events, skeletal-related events and terminal care would capture all hospitalisation costs. The Committee concluded that this approach could be considered appropriate and that it did not need to consider hospitalisation costs further.

4.16 The Committee was concerned that the costs and QALYs for abiraterone produced by the manufacturer's model were not in line with those reported in NICE technology appraisal 259. It noted that neither the manufacturer nor the ERG could compare the 2 analyses because of the confidential information in the manufacturer's submission for abiraterone. The Committee was aware that, in NICE technology appraisal 259, the base-case analysis modelled a subset of the population covered by the marketing authorisation. It was also aware that assumptions and model inputs differed, notably the underlying survival curves estimated from patient-level data, how overall survival was modelled for abiraterone, and hospitalisation costs. The Committee appreciated the difficulty in comparing the 2 analyses and that there would remain some uncertainty around the ICERs, concluding that this issue could not be resolved within the remit of a single technology appraisal.

4.17 The Committee discussed the most plausible ICER for enzalutamide compared with abiraterone for patients who had received 1 previous cytotoxic chemotherapy regimen. It agreed that modelling overall survival for abiraterone should assume a constant hazard ratio over time, and that the analysis should incorporate the same 'on-treatment' utility increase for enzalutamide and abiraterone, and the actual patient access scheme discount for abiraterone. The Committee noted that, after consultation, the ERG provided analyses assuming a constant overall survival hazard ratio over time for abiraterone and equal 'on-treatment' utility increases for enzalutamide and abiraterone of 0.04, but not reflecting the actual patient access scheme discount for abiraterone. This analysis gave an ICER of £22,600 per QALY gained for enzalutamide compared with abiraterone. The Committee was aware that the ICERs for enzalutamide would be lower for patients who had received only 1 course of cytotoxic chemotherapy. The Committee accepted that the available ICER was associated with some degree of uncertainty but, on balance, it was satisfied that the ICER for enzalutamide compared with abiraterone would remain below £30,000 per QALY gained. The Committee agreed that taking into account the correct patient access scheme for abiraterone would not change its conclusion. It therefore concluded that enzalutamide could be recommended as an option for treating hormone‑relapsed metastatic prostate cancer in adults whose disease has progressed during or after 1 docetaxel‑containing cytotoxic chemotherapy regimen, only if the manufacturer provides enzalutamide with the discount agreed in the patient access scheme.

4.18 The Committee acknowledged that, in response to the first appraisal consultation document, the manufacturer provided additional evidence for the subgroup of patients who had received 2 or more previous courses of cytotoxic chemotherapy, and for whom the Committee determined that best supportive care would be the appropriate comparator. The Committee was aware that this subgroup was pre-specified in AFFIRM's study protocol, represented around 27% of the total trial population, and did not include any patients who had received abiraterone. The Committee was aware that, although the hazard ratio presented by the manufacturer (0.66) suggested that enzalutamide was somewhat less effective in the subgroup than in the overall population, the manufacturer did not provide statistical tests to establish whether the treatment effect varied according to the number of courses of cytotoxic chemotherapy patients had received. Therefore, it could not conclude that enzalutamide was less effective in the subgroup than in the overall population. The Committee noted that the ICER estimated by the manufacturer for the subgroup was £45,500 per QALY gained and that, using an 'on-treatment' utility increase of 0.04 for enzalutamide, the ERG estimated an ICER of £48,000 per QALY gained. The Committee recognised that these ICERs were higher than the ICER range of £20,000–30,000 per QALY gained normally considered to represent a cost‑effective use of NHS resources. It therefore agreed to consider this subgroup in the context of the 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. To apply this advice, normally all the following criteria must be met:

4.19 The Committee considered the criterion for short life expectancy. It noted that the manufacturer and the ERG estimates of median survival for the subgroup patients receiving best supportive care were 12.8 months and 12.3 months respectively. The Committee concluded that enzalutamide fulfilled the criterion for short life expectancy.

4.20 The Committee considered the criterion that treatment offers an extension to life of normally at least an additional 3 months. It noted that, over a 10‑year time horizon, the economic model predicted that enzalutamide would extend mean overall survival in the subgroup by 3.8 months compared with best supportive care. The Committee discussed whether this estimate was robust. Firstly, it was concerned that the 95% confidence interval around it was wide (0.9 months to 7.4 months), indicating that this was an imprecise and uncertain estimate. However, the Committee noted that the manufacturer's estimated extension to mean survival for the overall population reflected a more certain estimate (value and confidence interval are commercial in confidence). It also noted that the evidence presented by the manufacturer suggested that the baseline expected survival and the relative treatment effect of enzalutamide were similar in the subgroup and the overall population, with the confidence intervals around the hazard ratios for overall survival overlapping substantially (0.48 to 0.90 in the subgroup and 0.52 to 0.73 in the overall population). Given the evidence on the survival benefit of enzalutamide for the overall population and the comparability of this benefit to the subgroup, the Committee agreed that enzalutamide was likely to extend life by more than 3 months in the subgroup. It also agreed that the wide confidence interval around the subgroup estimate was likely to be because of the small patient numbers in the subgroup. Secondly, to further explore the uncertainty around the estimate of life extension for the subgroup, the Committee considered estimates resulting from modelling the life span of patients over time horizons shorter than 10 years. It noted that, when the time horizon was shortened to 5 years, the mean survival benefit of enzalutamide remained longer than 3 months. Thirdly, the Committee noted that the estimated difference in median overall survival of 3.6 months was close to the estimated difference in the mean, suggesting that the probability distribution underlying the mean estimate was unlikely to be skewed and that the mean estimate was likely to be valid. The Committee agreed that the remaining uncertainty around the true value of the extension to mean survival could be accepted because NICE recommends abiraterone as a treatment option after docetaxel therapy, so a decreasing number of patients would be offered, or choose, a second course of cytotoxic chemotherapy instead of abiraterone. Balancing all these factors with the uncertainty around the estimate of the extension to life, the Committee was satisfied that the evidence supported that enzalutamide would extend life by at least an additional 3 months on average. It therefore concluded that enzalutamide fulfilled the criterion for life extension.

4.21 The Committee considered the criterion that the treatment is licensed or otherwise indicated for small patient populations. It noted the manufacturer's suggestion that the overall population that would be eligible for enzalutamide in England and Wales in 2013 was around 3000 patients. The Committee noted that this estimate was in line with those accepted by committees that appraised other technologies for the same indication. The Committee concluded that enzalutamide fulfilled the criterion for small patient populations and would be considered an end-of-life treatment as defined by NICE for patients who have previously received 2 or more cytotoxic chemotherapy regimens. The Committee agreed that the magnitude of the additional weight that would need to be assigned to the QALY benefits for the subgroup who received 2 or more previous cytotoxic chemotherapy regimens would justify enzalutamide being recommended as a cost-effective use of NHS resources for these patients, if the manufacturer provides enzalutamide with the discount agreed in the patient access scheme.

4.22 The Committee discussed whether enzalutamide represents an innovative treatment. It noted that enzalutamide has a different mechanism of action from other anti‑androgens, including other androgen receptor antagonists, such as flutamide and bicalutamide; it blocks binding of androgens to androgen receptors, prevents activated androgen receptors from migrating to the nucleus, and blocks the interaction of the activated androgen receptor with DNA in the nucleus. The Committee agreed that this mechanism of action is a 'step‑change' compared with other androgen receptor antagonists. However, it concluded that this element of innovation would already be accounted for when moving from a maximum acceptable ICER of £20,000 per QALY gained to £30,000 per QALY gained.

4.23 The Committee considered if it could make a decision on the cost effectiveness of enzalutamide after treatment with abiraterone, noting that it had not been presented with sufficient evidence to inform a decision on the clinical effectiveness of the sequential use of enzalutamide after abiraterone (see section 4.2). The Committee noted comments received in response to the second appraisal consultation document expressing concerns about singling out abiraterone as prior treatment amongst others that were excluded from the trial. However, because the Committee also has to take cost effectiveness into consideration, and both enzalutamide and abiraterone are costly treatments, it is prudent for the Committee to establish the cost effectiveness of sequential treatment before recommending it for routine care. The Committee agreed that the comparator for enzalutamide given after treatment with abiraterone would be best supportive care, and that the ICER for enzalutamide compared with best supportive care was at the top end of the ICER range that has previously been considered to represent cost-effective treatments when the end-of-life criteria were fulfilled. The Committee noted that some of the observational studies provided by the manufacturer in response to the second ACD consultation suggested that enzalutamide had a lower effect on reducing PSA concentration when given after abiraterone than when given to patients who have not received abiraterone before, which was in line with the natural history of the disease described by the clinical specialists (see section 4.2). In the absence of other robust evidence, the Committee agreed that it was unclear how the cost effectiveness of enzalutamide would change in the post-abiraterone setting. The Committee therefore concluded that it was not possible to make a conclusion on the clinical and cost-effectiveness of enzalutamide when given after abiraterone on the basis of the evidence it had considered. The Committee acknowledged the manufacturer's current efforts to collect data on the efficacy of enzalutamide after abiraterone as part of the pharmacovigilance plan and concluded that, until these data or results from other robust studies are available, it could not make any recommendations on the sequential use of enzalutamide and abiraterone.