Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen

Evidence-based recommendations on abiraterone (Zytiga) for castration-resistant metastatic prostate cancer in adults who have had previous treatment with a docetaxel-containing regimen.

# Guidance
Abiraterone in combination with prednisone or prednisolone is recommended as an option for the treatment of castrationresistant metastatic prostate cancer in adults, only if:
their disease has progressed on or after one docetaxelcontaining chemotherapy regimen, and
the manufacturer provides abiraterone in accordance with the commercial access arrangement as agreed with NHS England.
People currently receiving abiraterone in combination with prednisone or prednisolone whose disease does not meet the criteria in 1.1 should be able to continue therapy until they and their clinician consider it appropriate to stop.# The technology
Abiraterone acetate (Zytiga, Janssen) is a selective inhibitor of androgen biosynthesis which is taken orally. It irreversibly blocks cytochrome P17 (an enzyme involved in the production of testosterone), thereby stopping androgen synthesis in the adrenal glands, prostate tissue and the prostatic tumour. Abiraterone has a UK marketing authorisation for use 'with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxelbased chemotherapy regimen'. For prostate cancer that was previously considered 'hormone refractory,' the term 'castration resistant' is now used because the cancer still depends on hormones to activate androgen receptors, but no longer responds to traditional androgenreducing treatments.
The summary of product characteristics lists the following common adverse reactions to abiraterone: peripheral oedema, hypokalaemia, hypertension and urinary tract infection. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The cost of abiraterone is 2,930 for 120 tablets (excluding VAT; British national formulary  63, March 2012). Abiraterone is administered as a single dose of 1 g per day, taken as four 250mg tablets. The company has agreed a commercial access arrangement with NHS England, the details of which are confidential. This commercial access arrangement was agreed in July 2016, after guidance publication. It presents a change to the pricing arrangement that was considered during development of this guidance. The pricing arrangement considered during guidance development was that the manufacturer of abiraterone (Janssen) had agreed a patient access scheme with the Department of Health. This involved a single confidential discount being applied to the list price of abiraterone. The Department of Health considered that this patient access scheme did not constitute an excessive administrative burden on the NHS. The commercial access arrangement agreed in July 2016 replaces the PAS and therefore the PAS no longer applies.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of abiraterone and a review of this submission by the Evidence Review Group (ERG; appendix B). The decision problem addressed by the manufacturer considered whether treatment with abiraterone plus prednisolone was clinically effective compared with mitoxantrone (with or without prednisolone) or best supportive care for castrationresistant metastatic prostate cancer previously treated with a docetaxelcontaining regimen and whether abiraterone treatment reflected a costeffective use of NHS resources.
The manufacturer carried out a systematic literature search to identify all relevant trials and studies of abiraterone and potential comparators for the treatment of castrationresistant metastatic prostate cancer. The manufacturer identified four studies of abiraterone following previous chemotherapy: one randomised controlled trial (COUAA301) and three single arm trials (COUAA304, COUAA003, COUAABMA). Four randomised controlled trials comparing mitoxantrone plus prednisolone with other treatments were also identified by the manufacturer, but there were no other trials to link this evidence to the COUAA301 trial and enable an indirect comparison of abiraterone and mitoxantrone. The manufacturer's clinicaleffectiveness evidence for abiraterone was derived solely from the COUAA301 trial (a phase III, placebocontrolled, randomised, doubleblind, multicentre trial carried out across 130 sites in 13 countries, including the UK). In this trial, patients whose disease had progressed on or after docetaxel therapy and who had an Eastern Cooperative Oncology Group (ECOG) performance score of 02 were treated with either abiraterone (four 250mg tablets) in combination with prednisone or prednisolone (n=797) or with placebo (four tablets) in combination with prednisone or prednisolone (n=398). Patients in both groups continued treatment until disease progression was documented on the basis of the prostatespecific antigen (PSA), radiographic imaging, and clinical findings. Study followup was up to 60 months.
The baseline demographics and disease characteristics were similar between the two treatment groups in the COUAA301 trial: 93% of patients were white, the median age was 69 years and 28% of patients were 75 years or older. Among patients randomised to abiraterone plus prednisone or prednisolone (hereafter the 'abiraterone group'), 70% had previously received one prior course of docetaxel chemotherapy only (designated as the 'one prior chemotherapy' subgroup), compared with 69% of patients randomised to placebo plus prednisone or prednisolone (hereafter the 'prednisolone group'). The proportion of patients with an ECOG performance score of 2 (reflecting worse performance than a score of 0 or 1) was 10% and 11% in the abiraterone and prednisolone groups respectively. The majority of patients in both treatment groups (approximately 70%) had radiographic progression with or without PSA progression at baseline; 89% of patients in the abiraterone group and 90% of patients in the prednisolone group had bone metastases.
The primary outcome of the COUAA301 trial was overall survival, defined as the time from randomisation to death from any cause. A 'primary' analysis was conducted after 552 deaths (12.8 months median followup) for the whole (intentiontotreat) population. This was on the basis of a planned interim analysis after 534 deaths (67% of the 797 deaths at the planned final analysis). In the planned interim analysis ('primary' analysis), median survival was statistically significantly longer in the abiraterone group than in the prednisolone group (14.8 months compared with 10.9 months, hazard ratio  0.65, 95% confidence interval  0.54 to 0.77). Following this analysis, and because of a significant beneficial effect of abiraterone, the trial stopped. Followup continued, and an 'updated' analysis was conducted after 775 deaths (20.2 months median followup) for the whole population and the one prior chemotherapy subgroup. For the whole population, median survival continued to be statistically significantly longer in the abiraterone group than the prednisolone group (15.8 months compared with 11.2 months, HR 0.74, 95% CI 0.64 to 0.86). Subgroups with an ECOG performance score of 01 or 2 and subgroups who had received one or more prior chemotherapy regimens were explored by the manufacturer. For the one prior chemotherapy subgroup, median survival was also statistically significantly longer in the abiraterone group than the prednisolone group (17.0 months compared with 11.7 months, HR 0.71, 95% CI 0.60 to 0.86). The manufacturer stated that statistical testing showed that the relative overall survival benefit of abiraterone was not statistically significantly different between the one prior chemotherapy subgroup and the subgroup with more than one prior chemotherapy.
Two secondary outcomes in the COUAA301 trial were radiographic progressionfree survival (time with no radiographically documented disease progression) and 'modified' progressionfree survival (based on time to death or one of the following: PSA progression, radiographic progression, increase in glucocorticoid use, pain progression, a skeletalrelated event, or initiation of a new cancer therapy). Treatment with abiraterone statistically significantly decreased the risk of radiographically documented disease progression or death compared with prednisolone in the primary analysis (HR 0.67, 95% CI 0.59 to 0.78, p<0.0001). A significantly decreased risk was also observed in the updated analysis. The median radiographic progressionfree survival was identical in the primary and updated analyses: 171 days in the abiraterone group and 110 days in the prednisolone group. Treatment with abiraterone also significantly decreased the risk of disease progression based on the criteria for 'modified' progressionfree survival compared with prednisolone in the primary analysis (HR 0.63, 95% CI 0.55 to 0.72, p<0.0001). A significantly decreased risk was also observed in the updated analysis (results provided as academic in confidence).
The manufacturer indicated that expert opinion had suggested that the endpoints of 'modified' progressionfree survival and radiographic progressionfree survival, as defined in the COUAA301 trial, did not necessarily represent the time at which trial participants stopped the study drug because of disease progression. On this basis, the manufacturer argued that treatment discontinuation was the most appropriate proxy for progressionfree survival in the economic model. The manufacturer presented rates of time to discontinuation for both the whole population (primary and updated analyses) and the one prior chemotherapy subgroup (updated analysis only). For the whole population, the median time to treatment discontinuation for the abiraterone group was significantly longer than in the prednisolone group in the primary analysis (8 months compared with 4 months), with similar results in the updated analysis. For the one prior chemotherapy subgroup, the median time to treatment discontinuation was also significantly longer for the abiraterone group than the prednisolone group and the difference between the two groups was slightly larger than that observed for the whole population (results provided as academic in confidence).
Additional outcomes in the COUAA301 trial included PSA response rates, defined as the proportion of patients with a 50% or greater decrease in PSA confirmed by a second measurement at least 4 weeks later, and objective tumour response rates, defined according to Response Evaluation Criteria in Solid Tumours (RECIST). In the primary analysis for the whole population, confirmed PSA response was statistically significantly greater in the abiraterone group than in the prednisolone group (29.1% compared with 5.5%, p<0.0001).
The most common adverse reactions (occurring in 10% of participants in COUAA301) reported in both treatment groups were anaemia, vomiting, hot flushes, anorexia, pain in extremities, diarrhoea, musculoskeletal pain, asthenia, dyspnoea, headache, urinary tract infection, weight loss and muscle weakness. For the primary analysis, the most frequently reported grade 3 or 4 adverse reactions in the abiraterone and prednisolone groups were fatigue, anaemia, back pain and bone pain. Adverse reactions relating to mineralocorticoid excess (hypertension, hypokalaemia and oedema), cardiac disorders and hepatotoxicity were more frequent in the abiraterone group than the prednisolone group (55% compared with 44%). Cardiac disorders (primarily grade 1 or 2) were more commonly reported in the abiraterone group than in the prednisolone group (13% compared with 11%, p=0.14). Adverse reactions resulting in death or the need to discontinue study treatment were less frequent in the abiraterone group.
The manufacturer presented updated analyses for three healthrelated quality of life measures for which data were collected in the COUAA301 trial: the brief pain inventory short form (BPISF), the brief fatigue inventory short form (BFISF), and the functional assessment of cancer therapyprostate (FACTP). Neither the EQ5D nor any other utility measure was collected in the COUAA301 trial. Analyses indicated that a statistically significantly greater proportion of patients in the abiraterone group compared with the prednisolone group experienced an improvement for all three outcome measures (p<0.001). The manufacturer reported that the proportion of patients who had progression or decline in the outcome measures related to pain, functionality and fatigue did not significantly differ between the two treatment groups. However, patients in the abiraterone group experienced statistically significantly longer time to progression for all three outcome measures compared with the prednisolone group (p<0.05). The manufacturer concluded that evidence from the COUAA301 trial suggests that patients receiving abiraterone are more likely to experience less pain and fatigue, have improved functional status, and have a longer time before their pain, functional status and fatigue worsen.
The manufacturer submitted an economic model to compare the cost effectiveness of the three treatments: abiraterone plus prednisolone (hereafter 'abiraterone'), prednisolone alone (hereafter 'prednisolone'), and mitoxantrone plus prednisolone (hereafter 'mitoxantrone'). The manufacturer developed a survivalbased decision model with three health states: preprogression, postprogression and dead. People with castrationresistant metastatic prostate cancer were assumed to enter the model in the preprogression state having already received treatment with docetaxelbased chemotherapy. The model assumed that people who experienced disease progression would enter the postprogression state. The model assumed that people who received abiraterone did not take it after their disease had progressed, but would continue taking prednisolone or prednisone. The model assumed that patients in the mitoxantrone and prednisolone treatment groups would also continue taking prednisolone or prednisone until death. For the analysis of abiraterone compared with mitoxantrone, the model further assumed for mitoxantrone treatment a maximum duration of 30 weeks (median duration of 12 weeks) in the basecase analysis.
For its basecase analysis, the manufacturer's preferred population was comprised of people who had received one prior chemotherapy only. The number of people remaining in each health state after each cycle of the model (3 weeks, based on the dosing cycle of mitoxantrone) was calculated directly from the overall survival and progressionfree survival curves from the one prior chemotherapy subgroup of the COUAA301 trial. Time in the postprogression state was calculated as the difference between overall survival and progressionfree survival. The model used a lifetime horizon of 10 years. The analysis took an NHS and personal social services perspective and discounted costs and benefits at 3.5%.
The key parameters of clinical effectiveness in the model were progressionfree and overall survival, which, for the basecase analysis, the manufacturer derived from data from the updated analysis for the 'one prior chemotherapy' subgroup of the COUAA301 trial. The manufacturer assumed in the basecase analysis that progressionfree survival and overall survival did not differ between treatment with mitoxantrone and treatment with prednisolone or prednisone. The manufacturer argued that this assumption was justified because available evidence suggests that mitoxantrone compared with corticosteroids does not extend survival in people without prior chemotherapy, and therefore it would not be expected to extend survival in people who had received chemotherapy. In the basecase analysis, the manufacturer used data from the abiraterone arm of the COUAA301 trial to model overall survival for abiraterone, and data from the prednisolone arm to model overall survival for mitoxantrone and for prednisolone. The manufacturer used data from KaplanMeier curves up to the point at which 10% of patients remained in the trial. After this, the manufacturer extrapolated the overall survival curves assuming a constant hazard rate (exponential function).
In the basecase analysis, the manufacturer modelled progressionfree survival for patients taking abiraterone who had received only one prior chemotherapy. The model assumed that when patients discontinued abiraterone treatment they moved from the preprogression to the postprogression health state. Treatment discontinuation rates were based on data from the COUAA301 trial for patients who had only one prior chemotherapy, and were used as a proxy for progressionfree survival (see section 3.5). To estimate time spent in the preprogression state, the manufacturer took KaplanMeier (time to treatment discontinuation) survival data from the one prior chemotherapy subgroup of the COUAA301 trial up to the point at which 5% of participants remained at risk. Beyond this 5% cutoff, the manufacturer extrapolated survival curves assuming a constant hazard rate. The manufacturer used data from KaplanMeier curves for patients in the prednisolone group who had received one prior chemotherapy to model progressionfree survival for patients taking mitoxantrone or prednisolone. The manufacturer did not extrapolate these data further because just over 2% of patients were still on treatment (that is, their condition had not progressed).
In the basecase analysis, the manufacturer also modelled overall survival based on KaplanMeier survival curves for the one prior chemotherapy subgroup from the COUAA301 trial. As for progressionfree survival, the manufacturer extrapolated overall survival using a constant hazard but, because of greater censoring, chose a cutoff of 10% and applied it to all three treatment groups.
In the model, the key differences between the mitoxantrone group and the prednisolone group were the treatment durations (maximum duration of mitoxantrone treatment was 30 weeks) and costs (mitoxantrone was associated with more adverse reactions and therefore higher costs). The 30week maximum duration of mitoxantrone treatment (ten 3weekly cycles) was taken from the TROPIC trial, which compared cabazitaxel plus prednisolone with mitoxantrone plus prednisolone in patients with metastatic prostate cancer who had received docetaxel chemotherapy. Mitoxantrone was associated with less pain than prednisolone, and the manufacturer assumed that this lower level of pain was equal to that for abiraterone. However, because more treatmentrelated adverse reactions with mitoxantrone were observed in the TROPIC trial, mitoxantrone was associated with a smaller gain in healthrelated quality of life compared with abiraterone.
Utility values for the preprogression and postprogression health states were identified by the manufacturer in two studies that specifically collected EQ5D utility values in men with metastatic prostate cancer (Sandblom et al. 2004; Sullivan et al. 2007). Sandblom et al. estimated utility values in Swedish men (n=1,442) with prostate cancer (metastatic or nonmetastatic) in the year before death. The manufacturer stated that this study provided good estimates of utility for the postprogression health state but did not provide an accurate estimate of utility for people who had stable disease after receiving further treatment following progression on or after docetaxel treatment (defined as the preprogression health state for the purpose of the analysis) in the UK. Sullivan et al. collected utility values for men (n=280) with metastatic prostate cancer in an observational study carried out across Europe, Australia and North America at baseline and at 3, 6 and 9 months followup. The baseline utility was 0.635 for the whole cohort and 0.715 for the UK subgroup (n=29). The manufacturer stated that Sullivan et al. had not provided separate utility values for people whose disease had progressed and those whose disease had not progressed, and therefore the study did not provide suitable utility values for the postprogression health state.
Therefore, to estimate utility values for the preprogression state, the manufacturer undertook a twostage analysis to convert FACTP data from the COUAA301 trial into EQ5D utility values. In the first stage, the manufacturer analysed data from a manufacturersponsored crosssectional study in five European countries (including the UK) of 291 patients with castrationresistant metastatic prostate cancer who completed both FACTP and EQ5D questionnaires. The data were used to develop an algorithm to map FACTP data to EQ5D using an ordinary least squares (OLS) regression model and the UK EQ5D tariff. In the second stage, the manufacturer used this mapping algorithm to convert FACTP data from patients in both treatment groups in the COUAA301 trial who had only one prior chemotherapy to EQ5D utility values. The manufacturer then applied a separate regression analysis to derive an effect of treatment on utility. The manufacturer did not explicitly model adverse reactions, but instead assumed that any differences in adverse reactions between patients taking abiraterone or prednisolone were reflected in the overall utility values estimated from the FACTP mapping algorithm.
In the basecase analysis the manufacturer applied different preprogression utility values to the abiraterone and prednisolone groups (utility values provided as academic in confidence). The manufacturer also applied the preprogression utility value for abiraterone to the mitoxantrone group. In order to estimate the impact of grade 3 or 4 adverse reactions from mitoxantrone on the utility of the preprogression state, the manufacturer conducted a separate regression, which estimated an average utility decrement based on the occurrence of at least one adverse reaction. The manufacturer estimated that, based on the average number of grade 3 or 4 adverse reactions reported for abiraterone (from the COUAA301 trial) and mitoxantrone (from the TROPIC trial), mitoxantrone increased the occurrence of grade 3 or 4 adverse reactions by 32% compared with abiraterone. This resulted in a small utility decrement for mitoxantrone compared with abiraterone (utility values provided as academic in confidence).
The manufacturer noted that the COUAA301 trial did not collect FACTP data beyond the point of disease progression (treatment discontinuation). Therefore, the manufacturer used the study by Sandblom et al. to provide an estimate of utility for the postprogression state. In this study, utility values ranged from 0.58 in men with 812 months to live to 0.46 in those with less than 4 months to live. Based on the average utility observed for men in the last 8 months of life, the manufacturer used a utility value of 0.50 for the postprogression state in the economic model. This postprogression utility value was applied for all three treatment groups.
The manufacturer included the costs of drug treatment as costs of drug acquisition, administration and monitoring. Under the terms of the patient access scheme approved by the Department of Health, the cost of a 3week cycle of abiraterone, based on a daily dose of 1 g, is commercial in confidence and not reported here. Dosing of mitoxantrone is determined by body surface area. The manufacturer assumed a value of 2.02 m2, based on the average body surface area observed in the TROPIC trial. Based on a cost of 100 per 20mg vial, and assuming a patient needs two vials, the cost of mitoxantrone used in the model was 200 per 3week cycle. The model also assumed that a person receiving treatment with mitoxantrone would need one outpatient visit per 3week cycle, resulting in a total cost of 448.45 per 3week cycle. The cost of prednisolone was 1.03 for a 28tablet (5mg) pack (1.55 per 3week cycle at 10 mg daily). Because patients were taking prednisolone with abiraterone and with mitoxantrone, this cost was included for all three treatments and was assumed to continue after treatment with abiraterone and with mitoxantrone was discontinued until death. The costs of mitoxantrone and prednisolone were taken from the BNF (edition 61).
The model also included the costs of scheduled followup consisting of clinical visits, diagnostic imaging and clinical laboratory tests to monitor the status of the disease. To estimate scheduled UK medical resource utilisation in each treatment group, the manufacturer convened a clinical consensus panel, consisting of five oncologists and three oncology nurse specialists. Based on statistical analysis of data from the COUAA301 trial, the manufacturer estimated that unscheduled medical resource utilisation (because of unplanned clinical events) would be similar for patients whether taking abiraterone or prednisolone alone. Therefore, the manufacturer applied a oneoff fixed cost of unplanned, eventrelated resource utilisation in the pre and postprogression states to patients taking abiraterone or prednisolone alone. For patients receiving mitoxantrone, the manufacturer assigned the extra costs of treating grade 3 or 4 adverse reactions based on data from the TROPIC trial. The costs of other drugs (including bisphosphonates in the pre and postprogression states for people taking any of the three treatments, and granulocyte colonystimulating factor  to treat febrile neutropenia in the abiraterone and mitoxantrone groups) were also included in the model. Based on results from the UK subpopulation of the COUAA301 trial, in which a small proportion of patients received subsequent chemotherapy treatments, including taxanes and anthracenediones, the manufacturer assumed that a proportion of people in each treatment group would receive three cycles of cabazitaxel in the postprogression state. The manufacturer also estimated resource utilisation and costs for endoflife care based on clinical expert opinion. These costs were applied for the last 3 months of life for patients taking any of the three treatment regimens.
The manufacturer's original basecase deterministic costeffectiveness results for the one prior chemotherapy subgroup showed that mitoxantrone was extendedly dominated, that is, the incremental costeffectiveness ratio (ICER) of mitoxantrone compared with prednisolone was higher than that of the next most effective alternative (abiraterone). The comparison between abiraterone and prednisolone alone resulted in an ICER of 52,851 per QALY gained (incremental costs and incremental QALYs provided as commercial in confidence). The manufacturer's original basecase probabilistic ICERs were similar. The manufacturer's original basecase deterministic costeffectiveness results for the whole trial population showed that mitoxantrone was extendedly dominated by abiraterone and prednisolone alone whereas the comparison between abiraterone plus prednisolone and placebo plus prednisolone resulted in an ICER of 63,233 per QALY gained (incremental costs and incremental QALYs provided as commercial in confidence).
The manufacturer conducted a number of oneway sensitivity analyses on various model parameters which included: altering the time horizon from 10 years to 4, 6, or 8 years, varying the discount rates for costs and benefits from 3.5% each to 0% and 6%, using a Weibull instead of an exponential function to extrapolate survival beyond the cutoff point of the KaplanMeier curve for both progressionfree and overall survival, using alternative estimates of utility for pre and postprogression health states and for the effect on utility of treatment with abiraterone, and varying a number of cost input parameters (50%). The results of these oneway sensitivity analyses indicated that the original basecase ICERs were fairly insensitive to changes in most, but not all, of the input parameters. Decreasing the baseline utility value for the preprogression state to 0.538 increased the ICER significantly, resulting in an ICER for treatment with abiraterone compared with prednisolone of 77,000 per QALY gained. In one scenario analysis, the manufacturer assumed that patients taking mitoxantrone remained in the preprogression state for longer than patients taking prednisolone only (HR 0.77). This scenario resulted in an ICER of 21,038 per QALY gained for mitoxantrone compared with prednisolone and an ICER of 62,843 per QALY gained for abiraterone compared with mitoxantrone. Results of the probabilistic sensitivity analysis showed that prednisolone had the highest probability (100%) of being cost effective at a level of 20,000 to 30,000 per QALY gained, whereas abiraterone had the highest probability of being cost effective at over 50,000 per QALY gained.
The ERG was satisfied with the methodological quality of the COUAA301 trial and considered that it provided persuasive evidence that abiraterone offers a survival advantage in patients with castrationresistant metastatic prostate cancer. However, the ERG stated that the one prior chemotherapy subgroup differed from the COUAA301 trial population and, because it was smaller, it had reduced statistical power for comparison of outcomes between the treatment arms. The ERG commented that the manufacturer had submitted a relatively straightforward economic model comparing the relevant comparators following docetaxel chemotherapy, and had closely adhered to the NICE reference case requirements for economic analysis.
The ERG commented that the factors with the most influence on the cost effectiveness of abiraterone compared with prednisolone and with mitoxantrone were the differences in the EQ5D utility values attached to the pre and postprogression health states for all three treatments, which the manufacturer had derived from different sources. The ERG noted that the mapping function, developed and used by the manufacturer to determine preprogression utility values, had yet to appear in a peerreviewed publication. The ERG noted that the preprogression utility value for patients taking abiraterone, which was estimated from a function mapping FACTP to EQ5D, was similar to or higher than EQ5D utility values for men of similar age taken from a survey of the general UK population living in the community (Kind et al. 1998). This survey reported average EQ5D visual analogue scores of between 0.800 and 0.750 for men aged between 60 and 79 years. The ERG's clinical advisers suggested that, because the COUAA301 trial may have been oversubscribed, the population selected could have been fitter than generally seen in clinical practice.
The ERG noted that because most patients in the crosssectional study used to derive the mapping function were receiving chemotherapy, both their FACTP scores and EQ5D utilities would probably be lower than for patients in the COUAA301 trial who were not taking chemotherapy, but who received abiraterone or prednisolone. The ERG argued that this could have resulted in the FACTP mapping function converting FACTP values outside the reliable range of the mapping function, which would increase the uncertainty around the manufacturer's derived EQ5D utility values. The ERG noted that the manufacturer derived the mapping function from a restricted set of patients who provided FACTP scores both at baseline and over the course of the trial, but that over time, a declining proportion of trial participants who remained on treatment provided FACTP scores. The ERG further noted that the manufacturer's regression analysis was based on changes from baseline rather than on absolute values of the scores and that the baseline scores among those reporting FACTP scores after baseline may have been higher in the prednisolone group than in the abiraterone group. The ERG suggested that patients receiving prednisolone who reported FACTP scores after baseline may have had a smaller change in their scores than patients receiving abiraterone because they had less severe disease at baseline.
The ERG had some concerns about the manufacturer's approach to the regression analysis used to estimate separate preprogression utility values for treatment with abiraterone and prednisolone. The ERG noted that the utility values used in the manufacturer's model implied that utility dropped when a patient discontinued treatment (disease progressed) but that the manufacturer assumed a larger utility decrement for discontinuing treatment with abiraterone than for discontinuing prednisolone. The ERG considered this preprogression utility value to be an overestimate, which, by increasing the utility decrement when moving from the preprogression to the postprogression state, would exaggerate the benefit of remaining on abiraterone treatment. The ERG also noted that the utility decrement applied when moving from stable to progressive disease was lower in 'Cabazitaxel for hormonerefractory metastatic prostate cancer previously treated with a docetaxelcontaining regimen' (NICE technology appraisal guidance 255) than that used in this appraisal.
The ERG explored the manufacturer's methods for extrapolating overall survival and suggested that the manufacturer's decision to extrapolate beyond a cutoff of 10% of trial participants atrisk was arbitrary. However, the ERG was aware that when the manufacturer applied a cutoff of 5% in sensitivity analyses there was little impact on the ICERs for abiraterone compared with prednisolone. In contrast, the ERG's exploratory analyses using cutoffs ranging from 0% to 20% showed that the cutoff of 10% used by the manufacturer resulted in a relatively low ICER compared with other cutoff points. The ERG noted that when extrapolating progressionfree survival, the manufacturer chose different cutoff points (or none at all) depending on the treatment. The ERG noted that when data from KaplanMeier survival plots of the prednisolone group were used in the economic model, 2% of patients remained in the preprogression state, which may have slightly underestimated progressionfree survival for the mitoxantrone and prednisolone treatment groups compared with abiraterone. The ERG also noted that the KaplanMeier curve for treatment discontinuation had an unusual shape, with many patients discontinuing treatment over a period of a few weeks at approximately 60 days into treatment. In the ERG's view, this was unlikely to represent actual disease progression which would be better represented by fitting a parametric distribution.
The ERG noted that there was uncertainty around the most appropriate functions for extrapolating overall survival and progressionfree survival in the manufacturer's model. The ERG commented that by using patientlevel trial data to generate KaplanMeier curves for overall survival (up to the cutoff) the manufacturer considered all time points. The ERG argued that patientlevel KaplanMeier data, although representing observed data, may be less applicable to patients outside the COUAA301 trial than wellfitting parametric distributions. The ERG commented that when extrapolating overall survival using a constant hazard, the manufacturer used only two time points (baseline and cutoff). The ERG considered that this approach was less reasonable than applying a parametric distribution to the data representing all time points.
The ERG and manufacturer conducted exploratory analyses to assess the impact of fitting alternative parametric functions to data reflecting overall survival and progressionfree survival from the COUAA301 trial. In response to requests from the ERG for clarification, the manufacturer indicated that the bestfitting parametric distributions (according to Akaike and Bayesian information criteria) were: a Weibull distribution for overall survival in the abiraterone group, a lognormal distribution for overall survival in the prednisolone group, and a loglogistic distribution for progressionfree survival for both abiraterone and prednisolone. The ERG and the manufacturer agreed that the lognormal distribution should not be used to extrapolate overall survival because its long tail resulted in implausibly long survival. The ERG also noted that when the loglogistic distribution was fitted to data for time to treatment discontinuation, the resulting curve crossed the extrapolated part of the KaplanMeier overall survival curve from the manufacturer's base case so that some patients appeared to remain in the preprogression state after death, which is clinically impossible. In the ERG's view, a Weibull distribution should have been used to estimate overall and progressionfree survival for abiraterone and for prednisolone alone at all time points rather than using extrapolated KaplanMeier curves. The ERG acknowledged that both approaches were associated with uncertainty. When the ERG fitted the Weibull parametric distribution to overall survival in both the abiraterone and prednisolone groups and an extrapolated (constant hazard) KaplanMeier curve for progressionfree survival, the ICER for abiraterone compared with prednisolone was 56,339 per QALY gained. When the ERG fitted its preferred distribution, that is, a Weibull parametric distribution to overall survival and progressionfree survival in both the abiraterone and prednisolone groups, the ICER for abiraterone compared with prednisolone increased to 58,116 per QALY gained.
In addition to fitting the Weibull distribution to estimate overall survival and progressionfree survival, the ERG made changes to cost and utility parameters in the economic model. The ERG revised administration costs to reflect the costs of oncology outpatient visits and of administering mitoxantrone, and varied the proportion of patients receiving bisphosphonates following progression. The ERG amended the manufacturer's regression analysis of utility for progressionfree survival for patients who take prednisolone only. With these changes, mitoxantrone continued to be extendedly dominated and the ERG's revised basecase ICER for abiraterone compared with prednisolone was 60,084 per QALY gained.
The ERG conducted additional oneway sensitivity analyses for its revised basecase analysis. When the ERG varied the costs for unplanned use of medical resources, the ICERs for abiraterone compared with prednisolone ranged from 60,492 to 67,554 per QALY gained. When the ERG varied utility estimates (provided as academic in confidence), ICERs for abiraterone compared with prednisolone ranged from 63,281 to 72,469 per QALY gained. When the ERG extrapolated overall survival for prednisolone using the truncated lognormal distribution, the ICER for abiraterone compared with prednisolone was 70,217 per QALY gained. Mitoxantrone continued to be extendedly dominated in all sensitivity analyses.
In response to the appraisal consultation document, the manufacturer revised the confidential discount under the patient access scheme agreed with the Department of Health. The manufacturer also amended the economic model to reflect the changes to costs suggested by the ERG. These included changes to administration costs to reflect the costs of oncology outpatient visits and of administering mitoxantrone, and changes to the proportion of patients receiving bisphosphonates following disease progression. As a result of these changes and the revised discount under the patient access scheme, the manufacturer's deterministic basecase ICER for abiraterone compared with prednisolone decreased to 46,800 per QALY gained for the one prior chemotherapy subgroup and to 52,851 per QALY gained for the whole population (incremental costs and incremental QALYs provided as commercial in confidence).
The manufacturer conducted a number of oneway sensitivity analyses (see section 3.22) using the amended model for the one prior chemotherapy subgroup, resulting in ICERs for abiraterone compared with prednisolone of 42,904 to 51,110 per QALY gained. In all analyses, ICERs were most sensitive to changes to the utility value for the preprogression health state and to the statistical approach used to model overall survival. When a utility value of 0.715 (taken from the UK subgroup of the study by Sullivan et al. 2007) was assigned to the preprogression state, the ICER increased to 51,110 per QALY gained for abiraterone compared with prednisolone. When a Weibull parametric distribution was used to model overall survival, the ICER increased to 49,911 per QALY gained for abiraterone compared with prednisolone. The probabilistic sensitivity analysis showed that abiraterone had a 67% probability of being cost effective at 50,000 per QALY gained.
The ERG reviewed the amended model and revised analyses provided by the manufacturer in response to the appraisal consultation document. The ERG noted that the manufacturer's amended model retained extrapolation of the KaplanMeier curves using a constant hazard to model overall and progressionfree survival as well as the original utility values for the pre and postprogression health states. The ERG confirmed that the manufacturer had amended administration costs in the model to reflect the costs of oncology outpatient visits as suggested by the ERG. However, the ERG had concerns about the application of a halfcycle correction to the drug costs in the model by the manufacturer. The ERG noted that amending this halfcycle correction in the model would increase the drug costs by approximately half the monthly cost and would slightly increase the ICERs.
After amending the manufacturer's regression analysis of utility for the preprogression health state, the ERG conducted exploratory analyses on the manufacturer's amended model to assess the impact of fitting different curves to estimate survival. For the one prior chemotherapy subgroup, the ERG's basecase ICER for abiraterone compared with prednisolone was 53,140 per QALY gained when a Weibull parametric distribution was used to estimate overall survival and progressionfree survival. When the one prior chemotherapy subgroup was used with a Weibull distribution to estimate overall survival and a KaplanMeier curve for progressionfree survival, the ERG's basecase ICER was 52,186 per QALY gained. When the whole trial population was used with a Weibull distribution to estimate overall survival and the KaplanMeier curve for progressionfree survival, the ERG's basecase ICER was 60,038 per QALY gained. The ERG also conducted a number of sensitivity analyses in which it varied the utility values for the pre and postprogression health states using values for metastatic prostate cancer identified by the manufacturer in a literature review plus those used in the cabazitaxel appraisal (TA 255). This resulted in ICERs ranging from 52,362 to 71,358 per QALY gained for the one prior chemotherapy subgroup. The ICERs from all of the ERG's analyses further increased when the ERG amended the halfcycle correction applied by the manufacturer to the drug costs (ICERs provided as commercial in confidence).
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA259/history.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of abiraterone, having considered evidence on the nature of castrationresistant metastatic prostate cancer and the value placed on the benefits of abiraterone by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed the place of abiraterone in the clinical pathway of care for people with castrationresistant metastatic prostate cancer. The Committee noted that the main treatment options for patients whose disease progresses after firstline docetaxel include mitoxantrone, best supportive care, and retreatment with docetaxel (which is not recommended by current NICE guidance). The Committee heard from clinical specialists that mitoxantrone is used rarely in UK clinical practice because there is little evidence that people who take it live longer, but the commissioning expert informed the Committee that 20%30% of patients at this stage of the disease are treated with mitoxantrone. The Committee also heard from the clinical specialists that they would be unlikely to offer abiraterone to patients with an ECOG performance score of 2.
The Committee heard from the patient experts that the most important benefits of abiraterone were extension to life and improved quality of life, including less pain and improved mental and physical health. The Committee also heard that patient experts believed that adverse reactions to abiraterone treatment were tolerable and comparable to those associated with hormone treatment. The patient experts also commented that another advantage of abiraterone is that patients can take it orally at home.

# Clinical effectiveness
The Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of abiraterone. The Committee agreed with the manufacturer and the ERG that, although mitoxantrone was listed as a comparator in the scope, differences in the COUAA301 and the TROPIC trials made it difficult to indirectly compare mitoxantrone with abiraterone. The Committee heard from clinical specialists that participants in the COUAA301 trial were likely to be healthier than those who would receive abiraterone treatment in UK clinical practice. However, it acknowledged that, in response to the appraisal consultation document, a number of comments from clinical organisations suggested that participants in the COUAA301 trial would be similar to patients who would be considered for abiraterone treatment in UK clinical practice.
The Committee considered the different ways that progressionfree survival had been defined in the COUAA301 trial: radiographic evidence of progressionfree survival, 'modified' progressionfree survival and time to treatment discontinuation. The Committee noted that determining progressionfree survival from radiographic evidence was difficult because patients entered the study already with metastatic disease and could die of prostate cancer without any evidence of further radiological progression. The Committee heard from the clinical specialists that disease progression is not determined with a single measure and that they would also consider progression of a patient's symptoms. The Committee discussed whether discontinuing abiraterone treatment was an adequate proxy for progression of disease. The Committee heard from clinical specialists that in general patients stop treatment at approximately the same time as their disease progresses, but noted that some patients in the COUAA301 trial continued to take abiraterone after their disease had progressed. The Committee also noted that most patients in the COUAA301 trial discontinued abiraterone treatment for reasons other than disease progression. The Committee acknowledged uncertainty around this measure, but agreed that of the measures of disease progression in the COUAA301 trial, time to treatment discontinuation was the most reasonable indicator of disease progression.
The Committee discussed the results for the COUAA301 trial and noted that abiraterone was associated with a statistically significant improvement in median overall survival and median progressionfree survival (based on time to treatment discontinuation) compared with prednisolone for both the whole (intentiontotreat) population and the manufacturer's basecase population (patients who had received only one prior docetaxelcontaining chemotherapy regimen), with an improvement in median overall survival of 4.6 and 5.3 months respectively, in the manufacturer's updated analysis. The Committee also noted that patients receiving abiraterone were more likely to experience an improvement in symptoms, including pain, functional status and fatigue. The Committee therefore concluded that the evidence demonstrated that abiraterone was an effective secondline treatment for castrationresistant metastatic prostate cancer.
The Committee considered the manufacturer's basecase population of patients who had received one prior chemotherapy in the COUAA301 trial. The Committee noted that this subgroup did not match the population for which abiraterone is licensed (the therapeutic indication in the marketing authorisation does not stipulate only one prior chemotherapy) but probably reflected the population in England and Wales for whom abiraterone would be considered. The Committee noted that in the COUAA301 trial the relative median overall survival benefit for abiraterone was higher in the subgroup with one prior chemotherapy than in the subgroup with more than one prior chemotherapy, but tests for interaction showed that the difference between these two groups was not statistically significant. The Committee heard that the manufacturer considered the number of prior chemotherapies sufficiently important as a prognostic factor (in that more than one chemotherapy would imply a later stage of disease, more previous adverse reactions and more treatmentresistant tumours) to include it as a stratification factor for randomisation. The Committee also heard from the manufacturer that the difference in relative median overall survival benefit for abiraterone between the one prior chemotherapy subgroup and the subgroup who received more than one prior chemotherapy was supported by results for progressionfree survival and other related outcomes from the COUAA301 trial. The difference was also supported by overall survival results from published studies of other secondline treatments for castrationresistant metastatic prostate cancer. The Committee accepted that this population was likely to reflect patients who would be treated with abiraterone in UK practice, and who would have better treatment outcomes because they have less advanced disease. Therefore, the Committee concluded that it was reasonable based on biological plausibility and the prespecification of this group in the COUAA301 trial (as a stratification factor) to accept this patient subgroup and its associated effectiveness data as the basecase for the analysis.
The Committee considered the evidence on adverse reactions associated with abiraterone. The Committee was aware that abiraterone may cause hypertension, hypokalaemia and fluid retention as a consequence of an increased mineralocorticoid concentration. The Committee noted that adherence to abiraterone in the COUAA301 trial was generally high and reflective of abiraterone use in clinical practice, and that adverse reactions were generally manageable and reversible. The Committee also noted that abiraterone is not associated with the more severe adverse reactions that can occur with cytotoxic drugs such as mitoxantrone. The Committee heard from the clinical specialists that abiraterone is a welltolerated oral medication. The Committee concluded that abiraterone is generally safe and that any associated adverse reactions are tolerable.

# Cost effectiveness
The Committee considered the manufacturer's economic model, the assumptions on which the parameters were based, and the critique and exploratory analyses conducted by the ERG. The Committee concluded that the model closely adhered to the NICE reference case for economic analysis.
The Committee considered the comparator treatments (placebo plus prednisolone and mitoxantrone with or without prednisolone) and the population included in the economic model. The Committee noted that in the basecase analysis the manufacturer assumed that overall survival and progressionfree survival were the same for patients taking mitoxantrone and patients taking prednisolone. The Committee agreed that, in the absence of any direct or indirect comparative data and the absence of published evidence showing any survival benefit for mitoxantrone in a population without prior chemotherapy, this assumption was reasonable.
The Committee considered the overall survival curve used in the manufacturer's economic model. The Committee noted that estimates related to overall survival were taken from the 'updated' analyses, which the Committee preferred to the 'primary' analyses. The Committee also noted that the manufacturer had modelled overall survival using KaplanMeier survival analysis of patientlevel data from the COUAA301 trial up to a cutoff point at which a small proportion (10%) of patients were still alive. Beyond this, the manufacturer had extrapolated overall survival using a constant hazard. The Committee considered that the KaplanMeier survival curves specifically reflected the COUAA301 trial population and whether a wellfitting parametric distribution would be more applicable to all patients for whom abiraterone may be a potential therapy in clinical practice. The Committee noted that the 10% cutoff chosen by the manufacturer for overall survival produced a relatively favourable ICER compared with other possible cutoff points. The Committee heard from the manufacturer that fitting a specific parametric distribution to the overall survival curve was not necessary because survival data in the COUAA301 trial were almost complete and because additional analyses suggested that no single parametric function provides a better fit to the data than others. The Committee accepted that it may have been more appropriate to use a wellfitting parametric curve to extrapolate overall survival, but was also sympathetic to the manufacturer's argument that it is appropriate to use the observed KaplanMeier data when trial data were almost complete.
The Committee considered the modelling of progressionfree survival in the manufacturer's basecase analysis. The Committee noted that time to treatment discontinuation was used as a proxy for disease progression in the economic model. The Committee was aware that the manufacturer was unable to determine the proportion of patients among those who discontinued therapy who met criteria for disease progression. The Committee agreed with the ERG that using time to treatment discontinuation as a proxy for disease progression was acceptable because of concerns about using radiographic imaging to monitor disease progression in prostate cancer. However, the Committee considered that, although time to treatment discontinuation may provide a reliable estimate of treatment costs in the model, it was less clear whether it provided a reliable estimate of the QALY gains associated with being in the preprogression state. The Committee was also aware that disease is likely to progress before patients stop abiraterone. However, the Committee concluded that changing the duration of progressionfree survival did not significantly alter the ICERs associated with treatment with abiraterone relative to treatment with prednisolone.
The Committee noted the manufacturer's inconsistent approach to extrapolating progressionfree survival beyond the data observed in the trial, with extrapolation beyond the time at which 5% of the population remained for abiraterone, and no extrapolation for prednisolone. The Committee also considered the ERG's concerns that the shape of the KaplanMeier survival curve for treatment discontinuation in the prednisolone group was unusual, with a high proportion of patients discontinuing treatment over a narrow time period after approximately 60 days of treatment. The Committee agreed that this was unlikely to represent actual disease progression and that a wellfitting parametric distribution should have been used. The Committee noted that when the manufacturer used a Weibull parametric distribution to extrapolate progressionfree survival beyond the 5% cutoff for abiraterone, the basecase ICER increased slightly from 46,800 to 47,200 per QALY gained. The Committee accepted that, although it would have been more appropriate to use a wellfitting parametric curve to extrapolate progressionfree survival, data for time to treatment discontinuation in the COUAA301 trial were virtually complete and thus the impact on the ICER of using alternative assumptions was minimal.
The Committee considered the utility values used in the economic model for the preprogression and the postprogression health states. The Committee was aware that the manufacturer had not provided EQ5D values for health states obtained directly from patients, which would have been in line with the preferred methods recommended by NICE, but had derived utility values for the preprogression state from an algorithm that mapped FACTP scores to EQ5D utility values from a separate crosssectional dataset of patients with castrationresistant metastatic prostate cancer. The Committee also noted that this mapping algorithm produced utility values that differed according to treatment. The Committee was aware that patients contributing to the crosssectional dataset may have differed from the population in the COUAA301 trial and from patients who might receive abiraterone in the UK. The Committee also heard from the manufacturer that its mapping algorithm had not been externally validated. The Committee noted that the mapping algorithm resulted in preprogression utility values which were similar to or higher than utility values observed in the agematched general population. In the Committee's view this might not be reasonable because people with metastatic prostate cancer would be expected to have a poorer quality of life than people without prostate cancer. However, it heard from the manufacturer and consultees that, because patients in the COUAA301 trial had few comorbidities and had been fit enough to receive chemotherapy, it was not implausible that they would have a similar healthrelated quality of life to people of the same age in the general UK population. The Committee also noted that the utility values for the preprogression state were slightly higher than those used in the appraisal of cabazitaxel for metastatic hormonerefractory prostate cancer (TA255) (derived from interim analysis of a small study). The Committee acknowledged a sensitivity analysis from the manufacturer which showed that when a published utility value of 0.715 (from the UK subgroup of Sullivan et al. 2007) was assigned to the preprogression state, the ICER increased to 51,110 per QALY gained for abiraterone compared with prednisolone. However, the Committee was aware that the utility value taken from Sullivan et al. was based on a small patient subgroup and that this study may have included patients at different stages of prostate cancer. Additionally, the Committee also heard from one clinical specialist that the estimated utility gain for abiraterone compared with prednisolone may have been underestimated and, as a result, the ICER may have been overestimated. The Committee concluded that there was uncertainty about the validity of the utility values for the preprogression health state derived from the manufacturer's FACTP mapping algorithm, but that no other robust utility value for the preprogression health state was currently available.
The Committee noted that the COUAA301 trial did not collect FACTP data after patients stopped treatment and therefore the manufacturer identified a utility value for the postprogression state from the literature (see section 3.18). This value was lower than that estimated by the ERG from the manufacturer's FACTP mapping algorithm for patients at the end of treatment. The Committee acknowledged that the utility value estimated from patients at the end of treatment in the COUAA301 trial was based on a small group of patients healthy enough to complete the questionnaire after treatment discontinuation. The Committee also heard from the manufacturer that this utility value was measured at the start of progression and would not reflect the mean utility experienced by a patient throughout progression up to the time of death. The Committee acknowledged that although patients were considered to be in the preprogression state for the purposes of the model, they already had metastatic disease and would be unlikely to have the decrease in utility modelled by the manufacturer when progressing further to the postprogression state (defined only by stopping treatment). However, the Committee noted that a patient's healthrelated quality of life could be very poor in the last months of life and that the postprogression utility value should also reflect this. Additionally, the Committee heard from the manufacturer that the utility difference between the preprogression and postprogression health states was within the range used in recent technology appraisals of treatments for metastatic and advanced solid tumours. The Committee noted that a smaller utility difference between the preprogression and postprogression health states would increase the ICER. The Committee concluded that uncertainty remained about the true difference in utility values between the preprogression and postprogression states in the economic model, but that no other robust utility values that correctly capture the changes in healthrelated quality of life in progressed disease were currently available.
The Committee considered the assumptions related to resource use in the manufacturer's economic model. The Committee noted that the ERG was generally satisfied with these assumptions. The Committee also noted that, in response to the appraisal consultation document, the manufacturer had made corrections to resource use suggested by the ERG (see section 3.32). The Committee was informed by the ERG that the manufacturer had incorrectly applied a halfcycle correction to the drug costs in the model, and that changing this increased the drug costs by approximately half the monthly cost. The Committee was satisfied that the change to the halfcycle correction to drug costs would probably result in only small increases in the ICER.
The Committee considered the most plausible ICERs presented by the manufacturer and also by the ERG in its exploratory analyses. The Committee agreed that, for nearly all analyses presented, mitoxantrone was extendedly dominated by abiraterone. In the Committee's view, a reasonable starting point for its decision was the manufacturer's basecase ICER for abiraterone plus prednisolone compared with prednisolone alone of 46,800 per QALY gained for the one prior chemotherapy subgroup (when the discount agreed in the patient access scheme was included). The Committee agreed that the ICER would increase by a small amount if the model correctly accounted for the halfcycle correction to drug costs. The Committee noted that use of a lower utility value for the preprogression health state or the assumption of a smaller difference in utility between the preprogression and postprogression health states would further increase the ICER. However, the Committee agreed that more reliable utility values for the preprogression and postprogression health states were not available. The Committee also noted that the ICER would increase slightly if a parametric curve were used to model overall and progressionfree survival. However, the Committee agreed that it was acceptable to use the observed KaplanMeier data given the completeness of the survival data in the COUAA301 trial. The Committee therefore agreed that once these factors had been taken into account, the most plausible ICER was likely to be higher than the manufacturer's basecase estimate for the one prior chemotherapy subgroup, but would be under 50,000 per QALY gained.
The Committee was mindful that the NICE 'Guide to the methods of technology appraisal' states that there should be a strong case for accepting an ICER above 30,000 per QALY gained and judgements should specifically take account of:
the degree of certainty around the ICER
any strong reasons to indicate that the assessment of the change in healthrelated quality of life has been inadequately captured
whether the innovative nature of the technology adds demonstrable and distinctive benefits of a substantial nature which may not have been adequately captured in the QALY measure.
The Committee discussed whether the assessment of the change in healthrelated quality of life had been inadequately captured in the economic analysis. The Committee considered that abiraterone may offer a step change in treatment because it is lifeextending rather than only palliative but that this element of innovation would already be accounted for when moving from an ICER of 20,000 to 30,000 per QALY gained. The Committee concluded that abiraterone offers a step change in treatment because it is an oral drug taken by patients at home, and is associated with few adverse reactions. The benefit related to being an oral drug was not captured in the analysis because the model applied the same utility benefit to abiraterone as to mitoxantrone. The Committee therefore acknowledged that abiraterone provides healthrelated quality of life benefits other than those captured in the QALY calculation for patients currently receiving mitoxantrone, and that the ICER would decrease when these benefits were taken into consideration. The Committee heard that a portion of the profits from sales of abiraterone would contribute to publically funded medical research within the UK. However, the Committee concluded that although health benefits were likely to accrue from this research, these did not contribute to healthrelated quality of life as defined within the 'Guide to the methods of technology appraisal'.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with 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:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The Committee discussed whether abiraterone fulfilled the criteria for consideration as a lifeextending, endoflife treatment. For castrationresistant metastatic prostate cancer that has progressed after firstline chemotherapy, the Committee agreed that the first criterion related to life expectancy was fulfilled, because life expectancy from trials including patients randomised to best supportive care was less than 15 months. The Committee considered by how much abiraterone extended life. It noted that in the manufacturer's basecase economic analysis the estimated mean overall survival gain for abiraterone was greater than 3 months (median overall survival gain 4.6 months; mean overall survival gain commercial in confidence). The Committee concluded that an improvement of more than 3 months in mean overall survival had been robustly demonstrated. The Committee was aware that the population included in the marketing authorisation was likely to be larger than that for cabazitaxel given that abiraterone can be administered at home, and that some patients who would be unlikely to tolerate chemotherapy might take abiraterone. The Committee understood from estimates obtained from the appraisal of cabazitaxel that approximately 3500 people with hormonerefractory metastatic prostate cancer received docetaxel in England and Wales in 2011, and that, according to estimates provided by the manufacturer, approximately 70% of these (n=2,500) would be able to receive secondline abiraterone treatment in line with the marketing authorisation. The Committee noted from the manufacturer's response to the appraisal consultation document that in the future abiraterone may be licensed for use earlier in the treatment of castrationresistant prostate cancer but acknowledged that any future extensions to the marketing authorisation remain uncertain and should not be taken into consideration when estimating the number of patients currently eligible for treatment. In the Committee's view, abiraterone was licensed for a small population and therefore meets the criteria for an endoflife treatment. The Committee concluded that the additional weight to be assigned to the original QALY benefits in this patient group fell within the range considered acceptable for an endoflife treatment. The Committee therefore recommended abiraterone in combination with prednisolone or prednisone as an option for the treatment of castrationresistant metastatic prostate cancer that has progressed on or after one docetaxelcontaining chemotherapy regimen.
The Committee discussed whether any equality issues required consideration in this appraisal. The Committee was aware that people who are undergoing or have completed male to female gender reassignment can develop prostate cancer. The Committee therefore concluded that this appraisal should refer to 'people' rather than to men. Furthermore, the Committee had been made aware that these patients may find it uncomfortable to attend male urology clinics; however, the Committee agreed that the treatment of prostate cancer would be likely to be provided in oncology clinics.

# Summary of Appraisal Committee's key conclusions
TA259
Appraisal title: Abiraterone for castrationresistant metastatic prostate cancer previously treated with a docetaxelcontaining regimen
Section
Key conclusion
Abiraterone in combination with prednisone or prednisolone is recommended as an option for the treatment of castrationresistant metastatic prostate cancer in adults, only if:
their disease has progressed on or after one docetaxelcontaining chemotherapy regimen, and
the manufacturer provides abiraterone in accordance with the commercial access arrangement as agreed with NHS England.
The Committee concluded that the available evidence demonstrated that abiraterone was a clinically effective secondline treatment for castrationresistant metastatic prostate cancer.
The Committee agreed that, although the most plausible ICER was likely to be higher than the manufacturer's basecase estimate of 46,800 per QALY gained for the one prior chemotherapy subgroup, it was likely to be less than 50,000 per QALY gained.
The Committee concluded that abiraterone offers a step change in treatment because it is an oral drug taken by patients at home, and is associated with few adverse reactions.
The Committee concluded that abiraterone fulfilled the criteria for consideration as a lifeextending, endoflife treatment. The Committee also concluded that the additional weight that would need to be assigned to the original QALY benefits in this patient group was within the range considered acceptable for an endoflife treatment.
Current practice
Clinical need of patients, including the availability of alternative treatments
The main treatment options for patients whose disease progresses after firstline docetaxel include mitoxantrone, best supportive care, and retreatment with docetaxel (which is not recommended by current NICE guidance). The Committee heard from clinical specialists that mitoxantrone is used rarely in UK clinical practice. The Committee also heard from the clinical specialists that they would be unlikely to offer abiraterone to patients with an ECOG performance score of 2.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on healthrelated benefits?
The Committee heard from the patient experts that the most important benefits of abiraterone were extension to life and improved quality of life, including less pain and improved mental and physical health. The Committee also heard that patient experts believed that adverse reactions to abiraterone treatment were tolerable and comparable to those associated with hormone treatment.
The Committee concluded that abiraterone offers a step change in treatment because it is an oral drug taken by patients at home, and is associated with few adverse reactions.
What is the position of the treatment in the pathway of care for the condition?
Abiraterone has a UK marketing authorisation for use 'with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxelbased chemotherapy regimen'.
Adverse reactions
The Committee was aware that abiraterone may cause hypertension, hypokalaemia and fluid retention as a consequence of an increased mineralocorticoid effect. The Committee noted that adverse reactions were generally manageable and reversible. The Committee concluded that abiraterone is generally safe and that any associated adverse reactions are tolerable.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The manufacturer's clinicaleffectiveness evidence was derived solely from the COUAA301 trial (a phase III, placebocontrolled, randomised, doubleblind, multicentre trial carried out across 130 sites in 13 countries, including the UK).
Relevance to general clinical practice in the NHS
The Committee heard from clinical specialists that participants in the COUAA301 trial were likely to be healthier than those who would receive abiraterone treatment in UK clinical practice. However, it acknowledged that, in response to the appraisal consultation document, a number of comments from clinical organisations suggested that participants in the COUAA301 trial would be similar to patients who would be considered for abiraterone treatment in UK clinical practice.
Uncertainties generated by the evidence
The Committee acknowledged uncertainty around the measure used for determining disease progression in the COUAA301 trial. However, it agreed that of the different ways of defining disease progression in the COUAA301 trial, time to treatment discontinuation was the most reasonable indicator of disease progression.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The manufacturer's basecase analysis included a subgroup of the COUAA301 trial who had received one prior chemotherapy.
The Committee accepted that this population was likely to reflect patients who would be treated with abiraterone in UK practice, and who would have better treatment outcomes because they have less advanced disease. Therefore, the Committee concluded that it was reasonable based on biological plausibility and the prespecification of this group in the COUAA301 trial (as a stratification factor) to accept this patient subgroup and its associated effectiveness data as the basecase for the analysis
Estimate of the size of the clinical effectiveness including strength of supporting evidence
Abiraterone was associated with a statistically significant improvement in median overall survival and median progressionfree survival (based on time to treatment discontinuation) compared with prednisolone for both the whole (intentiontotreat) population and the one prior chemotherapy subgroup.
The primary analysis of the whole (intentiontotreat) population of the COUAA301 trial reported that median overall survival was statistically significantly longer in the abiraterone group than the prednisolone group (14.8 months compared with 10.9 months, hazard ratio  0.65, 95% confidence interval  0.54 to 0.77).
Median progression free survival (measured by time to treatment discontinuation) in the primary analysis of the whole population for the abiraterone group was statistically significantly longer than in the prednisolone group (8 months compared with 4 months), with similar results in the updated analysis.
The Committee concluded that the evidence demonstrated that abiraterone was an effective secondline treatment for castrationresistant metastatic prostate cancer.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer submitted an economic model comparing three treatments: abiraterone (plus prednisolone), prednisolone alone, and mitoxantrone (plus prednisolone).
The manufacturer developed a survivalbased decision model with three health states: preprogression, postprogression and dead. The model used a lifetime horizon of 10 years.
The Committee concluded that the model closely adhered to the NICE reference case for economic analysis.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee accepted that, although it may have been more appropriate to use a wellfitting parametric curve to extrapolate overall and progressionfree survival, it was acceptable to use the observed KaplanMeier data from the COUAA301 trial to estimate survival because survival data in the trial were almost complete.
Incorporation of healthrelated qualityoflife benefits and utility values. Have any potential significant and substantial healthrelated benefits been identified that were not included in the economic model, and how have they been considered?
The Committee concluded that there was uncertainty about the validity of the utility values for the preprogression health state derived from the manufacturer's FACTP mapping algorithm, but that no other robust utility value for the preprogression health state was currently available.
The Committee concluded that uncertainty remained about the true difference in utility values between the preprogression and postprogression states in the economic model, but that no other robust utility values that correctly capture the changes in healthrelated quality of life in progressed disease were currently available.
The benefit related to being an oral drug was not captured in the analysis because the model applied the same utility benefit to abiraterone as to mitoxantrone. The Committee therefore acknowledged that abiraterone provides healthrelated quality of life benefits other than those captured in the QALY calculation for patients currently receiving mitoxantrone, and that the ICER would decrease when these benefits were taken into consideration.
Are there specific groups of people for whom the technology is particularly cost effective?
Not applicable.
What are the key drivers of cost effectiveness?
The Committee noted that use of a lower utility value for the preprogression health state or the assumption of a smaller difference in utility between the preprogression and postprogression health states would further increase the ICER. The Committee also noted that the ICER would increase slightly if a parametric curve were used to model overall and progressionfree survival.
Most likely costeffectiveness estimate (given as an ICER)
The Committee agreed that, for nearly all analyses presented, mitoxantrone was extendedly dominated by abiraterone. In the Committee's view, a reasonable starting point was the manufacturer's basecase ICER for abiraterone plus prednisolone compared with prednisolone alone of 46,800 per QALY gained for the one prior chemotherapy subgroup. The Committee agreed that the ICER would increase by a small amount if the model correctly accounted for the halfcycle correction to drug costs. The Committee noted the uncertainty about the utility values, but agreed that more reliable utility values for the preprogression and postprogression health states were not available. The Committee also noted that the ICER would increase slightly if a parametric curve were used to model overall and progressionfree survival, but that it was acceptable to use the observed KaplanMeier data given the completeness of the survival data in the COUAA301 trial.
The benefit related to abiraterone being an oral drug was not captured in the analysis because the model applied the same utility benefit to abiraterone as to mitoxantrone. The Committee therefore acknowledged that abiraterone provides healthrelated quality of life benefits other than those captured in the QALY calculation for patients currently receiving mitoxantrone.
The Committee therefore agreed that once these factors had been taken into account, the most plausible ICER was likely to be higher than the manufacturer's basecase estimate for the one prior chemotherapy subgroup, but would be less than 50,000 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
The company has agreed a confidential commercial access arrangement with NHS England.
A simple patient access scheme was agreed, and taken into account, during guidance development. This was replaced in July 2016 by the commercial access arrangement. The patient access scheme no longer applies.
Endoflife considerations
The Committee agreed that the criteria related to short life expectancy (less than 24 months) without treatment, extension to life (at least 3 months) with treatment and small patient population were met. Therefore, the Committee concluded that abiraterone meets the criteria for an endoflife treatment.
Equalities considerations and social value judgements
The Committee was aware that people who are undergoing or have completed male to female gender reassignment can develop prostate cancer. The Committee therefore concluded that this appraisal should refer to 'people' rather than to men.

# Related NICE guidance

# Published
Cabazitaxel for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen (2012) NICE technology appraisal guidance 255
Prostate cancer: diagnosis and treatment (2008) NICE guideline CG58
Docetaxel for the treatment of hormone refractory prostate cancer (2006) NICE technology appraisal guidance 101
Improving outcomes in urological cancers (2002) NICE guideline CSG2# Review of guidance
The guidance on this technology will be considered for review in April 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveJune 2012# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.