Abiraterone for metastatic hormone-relapsed prostate cancer not previously treated with chemotherapy

 

1   Appraisal Committee's preliminary recommendations

1.1  Abiraterone is not recommended within its marketing authorisation for treating metastatic hormone-relapsed prostate cancer in people who have no or mild symptoms after androgen deprivation therapy has failed and in whom chemotherapy is not yet clinically indicated.

1.2  People currently receiving treatment initiated within the NHS with abiraterone that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.

2   The technology

2.1  Abiraterone acetate (Zytiga, Janssen) is a selective androgen synthesis inhibitor that works by blocking CYP17 (17α‑hydroxylase). It blocks androgen production in the testes and adrenal glands, and in prostatic tumour tissue. Abiraterone is administered orally in combination with prednisolone or prednisone. It is indicated for ‘the treatment of metastatic castration resistant [hormone-relapsed] prostate cancer in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated’. It is also indicated for ‘the treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen’.

2.2   The summary of product characteristics lists the following adverse reactions for abiraterone as being very common (that is, occurring in 1 in 10 or more people): diarrhoea, urinary tract infection, hypokalaemia (low blood potassium concentrations), hypertension (high blood pressure) and peripheral oedema (swelling of the limbs). The summary of product characteristics states that ‘other important adverse reactions’ are cardiac disorders, hepatotoxicity and fractures. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3   The cost of abiraterone is £2930 for 120 tablets (excluding VAT; British National Formulary [BNF] 67). Abiraterone is administered as a single dose of 1 g per day, taken as 4 250‑mg tablets. The manufacturer of abiraterone (Janssen) has agreed a patient access scheme with the Department of Health. This involves a single confidential discount applied to the list price of abiraterone across all indications. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs may vary in different settings because of negotiated procurement discounts.

3   The manufacturer’s submission

The Appraisal Committee (section 9) considered evidence submitted by the manufacturer of abiraterone and a review of this submission by the Evidence Review Group (ERG; section 10).

Clinical effectiveness

3.1  The clinical-effectiveness evidence presented in the manufacturer’s submission comes from COU-AA-302, a worldwide trial in which 9% of the trial population came from the UK. This randomised controlled trial compared abiraterone plus oral prednisone/prednisolone (referred to hereafter as abiraterone) with placebo plus prednisone/prednisolone (referred to hereafter as placebo) in 1088 people; 546 people were allocated to the abiraterone arm (1 g abiraterone daily plus 5 mg prednisone/prednisolone twice daily) and 542 people were allocated to placebo plus prednisone/prednisolone 5 mg twice daily. Patients in the trial stopped abiraterone or placebo at disease progression, if they had not already stopped for another reason (for example, due to adverse reactions). The trial had a co-primary end point of radiographic progression-free survival and death (overall survival). The manufacturer shared the overall level of significance for the trial (0.05) between radiographic progression-free survival (0.01) and overall survival (0.04). After disease progression, patients in the trial were followed up for up to 60 months after stopping treatment or until the patient was lost to follow-up, or withdrew consent, and median follow-up was 27.1 months. The statistical plan called for a single pre-planned analysis for radiographic progression-free survival after 378 events had accumulated, and included 3 interim and 1 final analysis for overall survivalwhich coincided with 15%, 40%, 55% and 100% of the 773 deaths which the manufacturer had determined would be needed to find a difference between the 2 treatment arms. Because of the repeated analyses of overall survival, the p values at which the results could be considered ‘statistically significant’ were p<0.0001, 0.0005, 0.0034 and 0.040 respectively for each of the 4 analyses. The protocol stipulated that, if the outcome of radiographic progression-free survival was statistically significant but the interim analysis for overall survival was not statistically significant,then ‘the study will continue and the patients will be followed for survival until the required number of events is observed’. However, COU-AA-302 was unblinded before the results for overall survival reached statistical significance (between the second and third interim analyses) by the Independent Data Monitoring Committee (IDMC) becausethe IDMC considered abiraterone to have  a ‘highly significant advantage’ for patients despite the p value for overall survival not meeting the criteria for statistical significance. Three people subsequently crossed over from placebo to abiraterone before the third interim analysis. The manufacturer’s submission presented data from the second interim analysis (20/12/2011) and the third interim analysis (22/05/2012).

3.2   COU-AA-302 included patients with metastatic hormone-relapsed prostate cancer whose disease had progressed after androgen deprivation therapy and who had no or mild symptoms, defined by a brief pain inventory (BPI) score of 0 to 3, reflecting the worst pain on a scale of 0–10 in the last 24 hours; with a score of 0 or 1 being no symptoms, and 2 or 3 being mild symptoms. Patients with no or mild symptoms also had an Eastern Cooperative Oncology Group (ECOG) score of 0 (no symptoms) or 1 (symptoms but able to walk). In its response to clarification questions from NICE, the manufacturer stated that the study was not designed to exclude people who would have docetaxel in clinical practice, and that some of the patients included in the trial would likely have had docetaxel in the UK. However, the manufacturer did not provide an estimate of the proportion of patients in COU-AA-302 who were eligible for docetaxel in clinical practice. In COU-AA-302, 92.5% and 92.3% of people had a BPI score of 3 or less in the abiraterone and placebo arms respectively.

3.3   The median treatment duration in COU-AA-302 was 13.8 months in the abiraterone arm and 8.3 months in the placebo arm. Treatment was continued until disease progression (defined by radiographic progression or unequivocal clinical progression, for example, need for alternative cancer therapy), or if the patient had adverse reactions, started a new anticancer treatment, had medications prohibited by the trial or withdrew consent to participate in the trial. At the third interim analysis, most people in both treatment arms had stopped treatment: 77.3% of people in the abiraterone arm and 89.3% of people in the placebo arm. The main reason for stopping was disease progression (57% of people in the abiraterone arm and 68% of people in the placebo arm); 8.3% of people in the abiraterone arm and 6.1% of people in the placebo arm had stopped because of an adverse event. By the third interim analysis, 50.4% of people in the abiraterone arm and 64.2% of people in the placebo arm had had subsequent treatment, most (about 87%) of which in both trial arms was docetaxel. Eleven per cent of people in the abiraterone arm and 13% of people in the placebo arm went on to have cabazitaxel. Fourteen percent of people in the placebo arm and 7% of people in the abiraterone arm had abiraterone again, which deviated from study protocol that prohibited retreating with abiraterone.

3.4   Radiographic progression-free survival was defined as time from randomisation to 1 of the following: progression by bone scan (adapted Prostate Cancer Working Group criteria), CT or MRI (modified RECIST criteria); and death. CT or MRI and bone scanning were performed every 8 weeks after the first 24 weeks and every 12 weeks thereafter. An independent radiologist who was unaware of study group assignments determined radiographic progression-free survival, but only until unblinding, after which local radiologists determined progression. The intention-to-treat (ITT) population was used for all efficacy analyses.Although the study protocol specified one analysis of radiographic progression free survival (which was carried out on 20/12/2010) the manufacturer did not present the results from this analysis in its submission and continued to follow patients whose disease had not yet progressed for radiographic progression-free survival past this point. By 22/05/2012 (the point at which the manufacturer made its third interim analysis of overall survival), 292 (53.5%) of people in the abiraterone arm and 352 (64.9%) of people in the placebo arm had experienced radiological progression. The median time to radiographic progression-free survival was 16.5 months (95% confidence interval [CI] 13.8 to 16.8 months) in the abiraterone arm and 8.2 months (95% CI 8.0 to 9.4 months) in the placebo arm (HR 0.52, 95% CI 0.45 to 0.62, p<0.0001).

3.5   At the second interim overall survivalanalysis (when 40% of the 773 deaths on which the study was powered had occurred), 147 people in the abiraterone arm and 186 people in the placebo arm had died. This generated a hazard ratio of 0.75 (95% CI 0.61 to 0.93) and a p value of 0.0097; however, this p value was not low enough to meet the pre-specified level needed to show statistical significance (0.0005, see section 3.1). At the third interim analysis (when 55% of the 773 deaths on which the study was powered had occurred), 200 (36.6%) people in the abiraterone arm and 234 (43.2%) of people in the placebo arm had died. The median overall survival in the abiraterone arm was 35.3 months (95% CI 31.2 to 35.3 months) and 30.1 months (95% CI 27.3 to 34.1 months) in the placebo arm (HR 0.79, 95% CI 0.66 to 0.96, p=0.0151). Again, this p value did not meet the pre-defined value for statistical significance (p=0.0034, see section 3.1).

3.6  The manufacturer carried out a subgroup analysis of radiographic progression-free survival and overall survival in pre-defined subgroups based on baseline ECOG (0 or 1); BPI (0–1 or 2–3); bone metastasis only at study entry; age; and baseline prostate-specific antigen, among others. Abiraterone showed a longer time to radiographic progression than placebo in all subgroups. Similarly, overall survival was longer with abiraterone than placebo in all subgroups, but in some it was no longer statistically significantly different. In its response to clarification questions the manufacturer presented radiographic progression free survival and overall survival data for the subgroup of patients who had gone on to receive docetaxel in COU-AA-302. The manufacturer stated that the data was a post-hoc analysis and as such violated the principles of randomisation that is, it selected for patients in the trial with the worst prognosis. The manufacturer requested that the data remain commercial in confidence.

3.7   The manufacturer presented safety data from COU-AA-302 safety analyses using the ‘safety population’ (1082 people from the randomised population who had had at least 1 dose of any study medication). By the third interim analysis, the manufacturer reported that statistically significantly more people having abiraterone had adverse events and serious adverse events than people having placebo (relative risk [RR] 1.02, 95% CI 1.01 to 1.04 for ‘treatment emergent’ adverse events; and RR 1.28, 95% CI 1.07 to 1.54 for serious adverse events). Adverse events reported as ‘unlikely, possibly, or related to abiraterone, prednisone/prednisolone or placebo’ were classified as drug-related adverse events. No statistically significant difference in the rates of drug-related serious adverse events were reported (RR 1.14, 95% CI 0.81 to 1.61)but more people had drug-related grade 3–4 adverse events with abiraterone than with placebo (HR 1.30, 95% CI 1.03 to 1.65). The most frequently reported adverse events affecting 5% or more people were fatigue, back pain, arthralgia, nausea, peripheral oedema, constipation and diarrhoea, and they were mostly grade 1 or 2. Of these, peripheral oedema and diarrhoea were more common with abiraterone than placebo (peripheral oedema was experienced by 26.0% of people with abiraterone and 20.9% of people with placebo (RR 1.24, 95% CI 1.00 to 1.54), diarrhoea was experienced by 23.4% of people with abiraterone and 18.1% of people with placebo (RR 1.29, 95% CI 1.02 to 1.63)). The most frequently reported grade 3 or 4 adverse events were hypertension, back pain and increased alanine aminotransferase (ALT). Abiraterone was associated with more grade 3 or 4 increased ALT (5.5% compared with 0.7%, RR 7.47, 95% CI 2.65 to 21.07), increased aspartate aminotransferase (3.1% compared with 0.9%, RR 3.39, 95% CI 1.26 to 9.12) and dyspnoea (breathing difficulty) (2.6% compared with 0.9%, RR 2.79, 95% CI 1.01 to 7.69) but less hydronephrosis (retention of urine in the kidney causing swelling) (0.2% compared with 1.5% RR 0.12, 95% CI 0.02 to 0.99) than placebo.

3.8  The health-related quality of life of patients in COU-AA-302 was measured using the Functional Assessment of Cancer Therapy (FACT-general [G] and prostate cancer [P]) subscale on the first day of treatment and after 12, 20 and 28 weeks and every 12 weeks thereafter as well as when treatment was stopped. The manufacturer presented the results as the median time to a decrease of 10 or more points and the hazard ratio of abiraterone relative to placebo. People randomised to abiraterone showed a longer median time to a 10-point decrease in total FACT-P score (12.7 months, 95% CI 11.1 to 14.0) than people randomised to placebo (8.3 months, 95% CI 7.4 to 10.6), HR 0.79 (95% CI 0.67 to 0.93, p=0.0046). The analysis of FACT subscales showed a similar effect.

3.9   The ERG considered that the COU-AA-302 trial was the best source of clinical evidence and identified no further relevant studies. The ERG commented that a large number of people dropped out of COU-AA-302, but that the number of people who dropped out in both treatment arms was similar.

3.10   The ERG had concerns about how the manufacturer used data from the FACT-P measure in the submission because the manufacturer presented the results only as time-to-event data, and did not provide scores by treatment arm for baseline or follow-up. The ERG commented that the manufacturer stated that ‘the main drivers of reduced health-related quality of life reported by patients with mCRPC [metastatic castration-resistant prostate cancer] are bone pain, fatigue, sexual disturbances and interrupted social relationships’. Of these, the manufacturer only reported time to an increase in pain intensity (rather than the differences in pain intensity between the 2 treatment arms). The time to an increase in the worst pain intensity (an increase in baseline BPI score of 30% or more on 2 consecutive occasions) showed no difference between the 2 treatment arms.

3.11   Because the marketing authorisation implies that people go on to have docetaxel after using abiraterone, the ERG considered that abiraterone followed by docetaxel should be compared with watchful waiting followed by docetaxel. The ERG commented that there is very little evidence on the efficacy of docetaxel when given after abiraterone. It identified a single-arm retrospective study of 35 patients who had had abiraterone followed by docetaxel, suggesting that the effectiveness of docetaxel following abiraterone might be ‘seriously reduced’. In their discussion, the authors of the study commented that the ‘activity of docetaxel post-abiraterone appears lower than anticipated and no responses to docetaxel were observed in abiraterone refractory patients’. The ERG considered the data from COU-AA-302 for the subgroup of people who had had docetaxel by the third interim analysis, noting the limitations of thesedata outlined by the manufacturer(see section 3.6). The conclusions of the ERG’s analysis of this data cannot be presented here because these data are commercial in confidence.

Cost effectiveness

3.12  The manufacturer did not identify any published cost-effectiveness studies directly relevant to the decision problem,so it performed its own new analysis. The manufacturer produced an individual time-to-event model (discrete event simulation), tracking patients at an individual level through a sequence of treatments until they reached a maximum age of 100 years, which it assumedwould reflect a lifetime horizon. Costs were considered from the NHS and personal social services perspective and a 3.5% discount rate was applied. People entering the model were assigned to either an abiraterone or best supportive care strategy (the prednisone/prednisolone arm of COU-AA-302 was assumed to reflect best supportive care with an active monitoring strategy). People were modelled through 3 treatment phases (pre-docetaxel, on-docetaxel and post-docetaxel). In each treatment phase, people could have active treatment or best supportive care before starting an active treatment, or have best supportive care with palliative treatment after an active treatment. The model took into account a person’s suitability for subsequent treatment after ending an active treatment; for example, if a person’s disease progressed, the modelled patients were monitored in a pre-docetaxel best supportive care phase and their suitability to move on to docetaxel was assessed. Patients for whom docetaxel would be considered unsuitable (people with a Karnofsky performance status of 60% or more [approximately an ECOG performance status of less than 2]) transitioned to best supportive care and had no further treatment until death. Likewise, after patients completed treatment with docetaxel, they were monitored for disease progression. If a person’s disease progressed while taking docetaxel and they were fit enough for further treatment, they had either abiraterone (if they had not had it before) or best supportive care. Some people in COU‑AA‑302 had had cabazitaxel after docetaxel. Because cabazitaxel has a survival benefit compared with best supportive care, but is not recommended by NICE in Cabazitaxel for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen(NICE technology appraisal guidance 255), the manufacturer adjusted post-docetaxel survival estimates from COU-AA-302 to exclude the survival benefit associated with cabazitaxel. It was assumed that, after all treatment options were explored and the disease was progressing, best supportive care would evolve into an approach involving palliative care.

3.13  The model consisted of 17 prediction equations to estimate the time to starting treatment, time to stopping treatment and time to death within the treatment phases and also to estimate the disease status of the patient at a particular position in the modelled treatment pathway. The manufacturer constructed the equations in a series of steps, each requiring a number of decisions. It decided whether a separate equation was needed for the abiraterone and placebo arm. Most of the equations were not stratified by treatment, rather the same equation was used in each treatment arm and ‘treatment’ was used as a predictor. However, for ‘time from abiraterone or best supportive care to death’, a separate equation was derived for each treatment arm. Ten of the equations needed to include a parametric distribution to extrapolate from the trial data over a longer period of time. Parametric curves with the best fit to the survival curves from the ITT population from COU-AA-302 were used to extrapolate these data beyond the trial. To determine variables that affected the risk of an event or disease status,the manufacturer used data from 902 patients out of the 1088 ITT patient population (83%) who had complete data for the baseline variables of interest. For this, the manufacturer selected variables (covariates) that had a statistically significant association with the event/outcome of interest at a 10% level of statistical significance. The covariates differed between prediction equations. Two further variables that did not meet the 10% level of statistical significance were also included by the manufacturer in the prediction equations. The manufacturer justified this by stating that it was better to be inclusive and that, in some cases, statistical significance may not have been reached because of small patient numbers. The manufacturer assessed whether there were any covariates that were dependent on each other. The manufacturer compared the model’s predictions with the data from COU-AA-302.

3.14   The manufacturer derived utility values from 3 sources: a manufacturer-sponsored independent study, COU-AA-302, and the literature. To derive utility values associated with each treatment phase, the manufacturer carried out a study to gather UK-specific EQ-5D data over more treatment phases than the COU-AA-302 study assessed (including the ‘on-docetaxel’ and ‘post-docetaxel’ treatment phases). This ‘UK mCRPC patient utility study’ was an online survey of 163 men with mCRPC in the UK who had previously taken anti-androgen tablets for more than 1 month but had since stopped (unless they had had surgical castration). The study did not compare men taking abiraterone with men not taking abiraterone and assumed that patients experienced the same utility regardless of their treatment provided that they were in the same treatment phase. Patients with mCRPC were divided into the following subgroups:

• no or mild symptoms after androgen deprivation therapy had failed; chemotherapy not yet clinically indicated (n=50)
• symptoms after androgen deprivation therapy had failed; chemotherapy clinically indicated but not started (n=50)
• after androgen deprivation therapy had failed; having chemotherapy (n=17)
• after androgen deprivation therapy had failed; post chemotherapy, completed 1 or more cycles of chemotherapy (n=46).

The manufacturer has stated that the results from this utility study are academic in confidence and cannot be reported here.

3.15   For the base case, the utility values derived from the survey were supplemented with utility values derived from other sources. The utility value for people who were having best supportive care before death was assumed to be 0.5 based on a published study (Sandblom et al. 2004). The manufacturer also added a utility increment for people who had abiraterone(pre-docetaxel in the abiraterone arm) using utility values derived from mapping FACT-P data from COU-AA-302 to EQ-5D (see section 3.16). The utility increment cannot be reported here because the manufacturer has stated that it is academic in confidence. The manufacturer did not apply a utility decrement based on adverse events experienced on different treatments.

3.16  The manufacturer also presented utility values derived from mapping FACT-P to EQ-5D from the data collected in COU-AA-302 (see section 3.8), which it used in a scenario analysis. The manufacturer used data from an observational study of patients with mCRPC in 6 European countries (including the UK), in which both EQ-5D and FACT-P data were available to develop an algorithm to map FACT-P data to EQ-5D using an ordinary least squares regression model and the UK EQ-5D tariff. The manufacturer applied this mapping algorithm to map FACT-P data from patients in both treatment groups in the COU-AA 302 study to EQ-5D utility values. The results of the mapping study are academic in confidence and cannot be reported here.

3.17  The manufacturer grouped the use of medical resources into ‘scheduled’ and ‘unscheduled’. Scheduled resources included disease-related tests including imaging diagnostic and clinical laboratory tests. To determine the frequency of scheduled follow-up appointments over a 3‑month period during the different stages of the disease pathway, the manufacturer surveyed 53 oncologists. The manufacturer applied higher resource use for patients having abiraterone than for patients on best supportive care in both the pre- and post-docetaxel setting for the first 3 months of abiraterone treatment to account for the additional monitoring as specified in the summary of product characteristics. Thereafter, the manufacturer assumed that patients incurred the same costs in both treatment arms.

3.18   The manufacturer estimated the frequency of unplanned medical resource use from trial data (for example, adverse events while on treatment) using data from COU-AA-301 (for post-docetaxel abiraterone or best supportive care) and COU-AA-302 (for pre-docetaxel abiraterone or best supportive care). COU-AA-301, the key clinical trial in TA259, compared abiraterone plus prednisone/prednisolone to prednisone/prednisolone alone in people whose disease had progressed on or after docetaxel therapy and who had an ECOG performance status of 0 to 2. For people receiving docetaxel the manufacturer used the rates of grade 3 and 4 adverse events reported in the literature and consulted its clinical advisors on the costs of treating such events. The unplanned medical resource use associated with best supportive care was obtained from the COU-AA-301 trial. The unplanned use of resources per month were £93.79 for abiraterone, best supportive care (prednisone/prednisolone) and best supportive care (pre-docetaxel) and £380.29 while having docetaxel, best supportive care post-docetaxel, abiraterone post-docetaxel or best supportive care before death. The manufacturer also applied a one-off cost of £3598 per patient to account for palliative care in the last 3 months of the best supportive care phase.

3.19   The manufacturer applied the patient access scheme (which is commercial in confidence) for a 1 g daily dose of abiraterone (30.4 doses per month); £2.63 a month for 10 mg prednisone/prednisolone taken daily (30.4 doses per month) (applied in both the abiraterone and best supportive care arms) and £1550.14 per month for docetaxel (based on a dosing frequency of once every 3 weeks for a patient of average weight [based on the patient characteristics in COU-AA-302] and with a cost of £1069.50 for a 160‑mg vial of docetaxel). An additional administration cost of £214 was applied for docetaxel.

3.20  In the manufacturer’s deterministic base-case analysis, abiraterone was associated with an incremental cost of £26,404, 0.62 life years gained and 0.57 quality-adjusted life yearsgained (QALYs) compared with best supportive care. The estimated incremental cost-effectiveness ratio (ICER) was £46,722 per QALY gained. The manufacturer did not present a probabilistic ICER but presented the results of a probabilistic sensitivity analysisand cost effectiveness acceptability curves.

3.21  The manufacturer performed deterministic one-way sensitivity analyses. Increasing the post-androgen deprivation therapy baseline utility value by 20% had the largest effect and increased the ICER to £60,418 per QALY gained. The manufacturer presented 10 scenario analyses. It additionally presented its results without applying the patient access scheme price of abiraterone. The scenario without the patient access scheme had a large impact on the ICER; in all other scenario analyses, the ICER was between £45,393 (a scenario in which the post docetaxel survival was assumed to be comparable in both the abiraterone and best supportive care arms) and £50,163 per QALY gained (a scenario in which utility values were from the mapping of FACT-P data from COU-AA-302 to EQ-5D).

3.22  The ERG considered that it was appropriate for the manufacturer to develop a new model, but it did not think that using a discrete event stimulation model was the simplest or most transparent approach because it was more complicated to assess face validity and internal validity than, for example, a Markov model of health states.

3.23  When the ERG ran the model, the ICER for the manufacturer’s deterministic base case differed only slightly from that reported by the manufacturer (that is, the ICER was £46,756 per QALY gained rather than £46,722 per QALY gained). The ERG also noted that there was a small error in the cost-effective acceptability curves presented by the manufacturer in its submission. The ERG presented a revised summary of the manufacturer’s probabilistic sensitivity analysis suggesting that the probability of abiraterone being cost effective assuming £30,000, £40,000 or £50,000 per QALY gained was 0%, 10% and 67% respectively.

3.24  The ERG stated that the model structure lacked face validity because it did not allow the possibility of dying during abiraterone treatment or best supportive care with prednisone/prednisolone before docetaxel treatment or during post-docetaxel treatments. It noted that, in COU-AA-302, 5 patients had died before the end of abiraterone or placebo treatment.

3.25   The ERG commented that, the model population was not the same as the COU-AA-302 ITT population because it included only a subgroup of this population with complete baseline data for covariates; 186 patients from the ITT population (1088 people) were excluded because of missing baseline data. The manufacturer did not provide the characteristics of this subpopulation. In its clarification response, the manufacturer stated that there was not a statistically significant difference in the time to stopping treatment and overall survival between the ITT population and the population with complete baseline characteristic data. The ERG did not agree with the manufacturer’s statement that model predictions were consistent with the trial results because the ITT population was not used (but a subset) and therefore the model results were probably not fully comparable with the ITT results of COU-AA-302.

3.26   The ERG considered that using the EQ-5D utility values from the UK mCRPC utility study was the preferred approach given the uncertainty surrounding the mapped utility values based on the FACT-P responses from COU-AA-302. The ERG considered whether the utility value for the pre-docetaxel treatment phase would be expected to be different between treatment arms. In the base case, the ERG noted that the manufacturer had applied a utility increment to the abiraterone arm relative to the best supportive care arm (see section 3.15) and that the manufacturer stated that this was based on the benefits experienced on abiraterone compared with best supportive care with respect to pain and fatigue. The ERG did not agree with this approach because in COU-AA-302 abiraterone led to significantly more adverse events (both overall and grade 3–4) than best supportive care and the ERG considered it more appropriate to incorporate and apply separate utility decrements for each separate adverse event in the model. During clarification, the manufacturer provided 4 separate scenario analyses in which:

• The utility increment applied to the abiraterone arm was removed; this resulted in an ICER of £50,120 per QALY gained.
• The utility decrements for each separate adverse event were applied separately; this resulted in an ICER of £47,415 per QALY gained.
• The per-event costs for adverse events for the pre- and post-docetaxel treatment phases were incorporated; this resulted in an ICER of £46,686 per QALY gained.
• Combining the 3 scenarios above resulted in an ICER of £50,880 per QALY gained.

The ERG considered whether the post-docetaxel utility values would be expected to be different between the 2 treatment arms. It also considered the consistency of utility values presented for people after docetaxel treatment in the current submission and in the manufacturer’s submission for TA259. Following the clarification requests, the manufacturer provided a scenario in which the post-docetaxel baseline utility value of 0.780 (equivalent to the post-docetaxel utility value in TA259) was used and to which a post-docetaxel utility increment of 0.046 was applied by either adding it to the baseline utility value of 0.78 for abiraterone post-docetaxel in the best supportive care arm or subtracting it from 0.78 for best supportive care post-docetaxel in the abiraterone arm). These analyses resulted in ICERs of between £48,316 and £47,936 per QALY gained respectively.

3.27  The ERG stated that its preferred base case would include:

• A disutility of 0.046 to be applied in the post-docetaxel phase for patients not on abiraterone.
• The prediction equations used for time to stopping treatment, time to starting treatment and time to death to be derived from the full ITT population in COU-AA-302, to account for treatment effect on risk only and not include other risk predictors based on baseline characteristics.

Applying the first assumption (post-docetaxel disutility if not having abiraterone) to the manufacturer’s base case resulted in an ICER of £46,952 per QALY gained. Applying new risk equations based on the ITT population resulted in an ICER of £57,337 per QALY gained. The combination of these 2 scenarios (the ERG’s exploratory base case) resulted in an ICER of £57,668 per QALY gained.

3.28   The ERG noted that the post-docetaxel survival in the current model was much lower than at the same point in the care pathway in TA259, which had appraised the cost effectiveness of abiraterone taken after docetaxel compared with best supportive care. The ERG modified the prediction coefficients for the ‘time from post-docetaxel treatment continuation to death’ equation so that the post-docetaxel survival was similar to that estimated in TA259. This increased the ‘ERG exploratory base case’ ICER from £57,688 to £65,515 per QALY gained.

3.29   The ERG performed 3 additional sensitivity analyses that it tested in its ‘exploratory base case’:

• ·      The ERG stated that it was unclear how the manufacturer had applied the negative effect from treatment with cabazitaxel in COU-AA-302 in the model (see section 3.12). Therefore it tested a scenario without adjusting for cabazitaxel use in COU-AA-302. This decreased the ICER from the ERG’s exploratory base-case estimate of £57,668 to £56,671 per QALY gained.
• ·      The ERG stated that a log-logistic model as used in the manufacturer’s base case is often criticised for its long tail that may result in an unrealistic survival benefit. The ERG therefore used a Weibull model to extrapolate the data for time to stopping treatment with abiraterone or best supportive care, and time to death while on docetaxel treatment. This increased the ICER to £74,803 per QALY gained.
• ·      The ERG also stated that the criticisms of log-logistic models also apply to log-normal models. The ERG therefore used a Weibull model to extrapolate time to stopping docetaxel treatment and time to death after post-docetaxel active treatment rather than a log-normal distribution (as was used in the base case). This decreased the ICER from the ERG’s exploratory base-case estimate of £57,668 to £57,202 per QALY gained.

3.30    Full details of all the evidence are in the manufacturer’s submission and the ERG report

4   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 metastatic hormone-relapsed 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.

4.1   The Committee considered the treatment options in current practice in England for people with metastatic hormone-relapsed prostate cancer after androgen deprivation therapy has failed and who have no or only mild symptoms. The Committee heard from clinical specialists that,when cytotoxic chemotherapy is indicated, most people would have docetaxel. However, when people have no or mild symptoms, and to defer chemotherapy, and its adverse effects, clinicians may instead offer best supportive care including corticosteroids such as prednisolone or dexamethasone. The clinical specialists stated that they would generally offer docetaxel to people with rapidly progressing disease who were fit enough to have cytotoxic chemotherapy and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (or a WHO performance status consistent with this). They added that deferring docetaxel in this group would not be appropriate because the disease rapidly progresses and patients may not be fit enough to have it at a later date. The Committee heard from the clinical specialists that older people and people with comorbidities are less likely to be fit enough to have docetaxel, and that some patients chose not to have docetaxel. The Committee heard that abiraterone got a marketing authorisation in December 2012 for use before chemotherapy and that some patients get abiraterone through the Cancer Drugs Fund. It also heard from the clinical specialists that there isno consensus on how to decide whether to offer abiraterone to patients, but that clinicians would generally use it, in addition to best supportive care, to treat people with few symptoms to delay chemotherapy, or to treat people who are unable or do not wish to have chemotherapy. The Committee also understood from the clinical specialists that they switch patients whose disease has progressed from abiraterone to docetaxel if they are fit enough for docetaxel. The Committee understood that, when deciding whether to offer abiraterone, corticosteroids or docetaxel, clinicians would take into account a person’s fitness for chemotherapy, performance status, symptom severity and the patient’s views on taking chemotherapy.

4.2   The Committee heard from the patient experts about how important it is for patients to have the option of delaying chemotherapy. The patient experts explained that the adverse effects of chemotherapy are severe and may be particularly poorly tolerated by people who are older or who lack support from a partner or carer. The patient experts further stated that some people choose not to have cytotoxic chemotherapy to avoid the debilitating adverse effects and to maximise the quality of what remains of their lives, even if it may mean dying sooner. The Committee concluded that chemotherapy can reduce a person’s quality of life and that treatments that delay the need for chemotherapy are highly valued by patients.

Clinical effectiveness

4.3   The Committee noted that docetaxel was listed as a comparator in the final scope issued by NICE in 2012. It understood that the manufacturer did not present a comparison of abiraterone with docetaxel, noting that the marketing authorisation states that abiraterone is indicated for people for whom chemotherapy is not yet indicated. The Committee agreed that this was appropriate. It considered that a key comparison in this appraisal was of the sequence a) abiraterone followed by docetaxel and subsequent treatments, compared with b) watchful waiting (including best supportive care) followed by docetaxel and subsequent treatments (which in current clinical practice in England includes abiraterone) acknowledging that some patients may not receive docetaxel at any stage in the treatment pathway. The Committee accepted that clinical trials do not typically assess treatment sequences and that such a comparison would usually be modelled.

4.4  The Committee considered the results from the randomised placebo-controlled trial COU-AA-302, noting that this was a worldwide trial that recruited 9% of its patients from the UK. It was aware that people in both the abiraterone and placebo arms had prednisolone/prednisone. The Committee considered that the placebo arm reflected clinical practice in England before treatment with chemotherapy in line with the advice from the clinical specialists (see section 4.1). The Committee heard from the clinical specialists that the average age of people in COU-AA-302 was similar to that of the people who would have abiraterone in clinical practice in England. It heard that the triggers for stopping treatment in the trial broadly reflected treatment practice in England. The Committee heard from the manufacturer that the clinical trial included radiographic progression-free survival as a co-primary end point because this approach enabled the manufacturer to shorten the length of the trial by identifying results earlier in this patient population. It noted that the other component of  the co-primary end points was overall survival with 3 planned interim analyses and a final analysis. The Committee understood that the original protocol had been amended to include the third interim analysis for overall survival. The Committee noted that patients in the study stopped treatment when they had radiographic or unequivocal clinical progression, at which point they could have treatments including docetaxel. The clinical specialists stated that in clinical practice in England, people would have abiraterone or best supportive care until clinical signs of progression rather than radiographic progression, at which point they would switch to docetaxel within a week if fit enough to tolerate chemotherapy. The Committee concluded that COU-AA-302 generally reflected clinical practice in the UK and was relevant to address the decision problem.

4.5   The Committee was aware that COU-AA-302 was stopped (unblinded) early between the second and third interim analyses for overall survival and that, at both of these interim analyses, the results for overall survival did not show a statistically significant difference between the treatment arms according to the pre-specified statistical significance levels. The Committee heard from the manufacturer that, although there was not a statistically significant difference in overall survival between the treatment groups. the Independent Data Monitoring Committee had stopped the trial based on the strength of the results for radiographic progression-free survival, which favoured abiraterone. The Committee discussed the potential effects on the overall survival estimates of stopping the trial early. The Committee was aware that lack of statistical significance increased the chance that abiraterone does not, in reality, prolong life. Further, the Committee noted that a systematic review published in 2010 (Bassler et al.) had concluded that trials that stop early show a larger treatment effect than trials that run to completion, and that trials stopped early because of benefit are likely tooverestimate benefit by approximately 40%. The Committee concluded that abiraterone compared with placebo increased the time to radiographic progression, but whether it extended life was uncertain. It noted that people consented to participate in the study based on the original protocol, and they were not given the opportunity to consider this deviation from the protocol. The Committee considered that trial participants might regard this as unfair, undermining the value of the results, and reducing the value of their having taken part in the trial. Lastly, the Committee concluded that it was likely that the treatment effect of abiraterone on survival was overestimated.

4.6   The Committee considered the adverse events reported in COU-AA-302 and noted that there were more adverse events in the abiraterone arm than in the placebo arm. It heard from the clinical specialists that both arms of the trial included prednisolone, which itself is associated with adverse effects. The Committee noted the statements submitted by patient groups, which pointed out that patients usually can cope with the adverse effects of abiraterone that are usually mild and tolerable, particularly compared with those of docetaxel, and that one of the advantages of abiraterone is that it delays the debilitating effects of chemotherapy. The Committee concluded that abiraterone increases the risk of adverse events compared with prednisolone alone, but that the benefits in delaying the serious adverse effects associated with chemotherapy are seen by patients to outweigh the risks associated with abiraterone.

4.7  The Committee noted that the manufacturer had collected data on health-related quality of life using the Functional Assessment of Cancer Therapy (FACT-prostate cancer [P]) measure in COU-AA-302 until patients stopped abiraterone or best supportive care. The Committee noted that people having abiraterone had a longer median time to a 10-point decrease in FACT-P score than people having best supportive care. However, the Committee was not presented with absolute values for the whole population over the full period of follow-up, nor whether the 10-point decrease represented a clinically important effect. The Committee concluded that abiraterone slowed the decrease in quality of life relative to best supportive care but it was unclear whether this was clinically significant.

Cost effectiveness

4.8   The Committee noted that the manufacturer had developed a discrete event simulation model to compare the cost effectiveness of 2 treatment sequence strategies:

• abiraterone followed by docetaxel and subsequent treatments
• best supportive care followed by docetaxel and subsequent treatments (including abiraterone).

It understood that the manufacturer had chosen this type of model, rather than the more commonly used Markov model, because it allowed more flexibility to reflect the sequence of treatments a person might have in clinical practice and it also allowed the modelled response to treatments to depend on previous treatments a patient might have had. In addition, the manufacturer had suitable patient-level data from COU-AA-302 to develop this type of model. The Committee noted that in its submission for Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen (NICE technology appraisal guidance 259; hereafter referred to as TA259, which appraised abiraterone for metastatic hormone-relapsed prostate cancer taken after docetaxel), the manufacturer also had access to patient-level data but had used a Markov model. However, the Committee noted that TA259 related to people whose disease has progressed further along the treatment pathway with fewer subsequent available treatments. The Committee agreed that using a discrete event simulation model was not unreasonable, but that the manufacturer’s model was particularly complex. In particular, for each of the model’s 17 equations predicting time to events, the Committee noted that the manufacturer needed to make a large number of judgements when determining which variables to include in the prediction equations, which covariates to retain in the equations, and which parametric distribution to choose for extrapolation (see section 3.13 for how the prediction equations were determined). The manufacturer did not clearly pre-specify its approach to each of these judgements. Therefore, the Committee agreed that the model was not transparent enough for the Evidence Review Group (ERG) to fully validate and critique, and that this therefore limited the model’s value to inform the Committee.

4.9   The Committee was aware that, in its model, the manufacturer used data from COU-AA-302, reflecting a median 27.1 months of follow-up from the third interim analyses at which point the study was already unblinded (see section 4.5). The Committee understood that out of the 17 equations in the model there were 10 equations that needed extrapolating beyond the trial data from COU-AA-302. These included the equations that modelled time to starting or stopping treatments, and the survival of patients at different points in the treatment pathway. It noted that the overall survival in the model was predicted by combining these equations and reflected the modelled time spent in, and the number of people in, each treatment phase. The Committee discussed the way in which the manufacturer selected the parametric distribution for each of the equations in the model that needed extrapolating and was aware that the manufacturer estimated fits for:Weibull;log-normal; log-logistic exponential; and gamma functions selecting the distribution using statistical criteria and visual inspection. However, the Committee appreciated that it is also important to take into account face validity and whether extrapolation predicts realistic outcomes, both for the event modelled by each equation, and for the model as a whole, but that this had not been done by the manufacturer. The Committee concluded that the validity of the parametric extrapolations used in the model was uncertain.

4.10   In addition to its uncertainty surrounding the validity of the extrapolation in the model and the true magnitude of the treatment effect, the Committee understood that the manufacturer based the model on data from a subset of 902 people for whom data existed on all baseline characteristics needed to assess the covariates in the model (from the overall intention-to-treat (ITT)population of 1088 in COU-AA-302). The manufacturer was not able to provide the Committee with the list of the baseline characteristics needed to assess covariates, nor had it presented the characteristics for the 902 people on which it based the model (although it heard from the manufacturer that the characteristics of these 902 people were ‘very similar’ to the ITT population). The Committee was concerned that the selected group may not be representative of the ITT population, and of patients in England. Notably, the Committee questioned whether the manufacturer’s choice of population changed the modelled results. It noted the ERG’s comments that using the subgroup favoured abiraterone compared with best supportive care because people in the subgroup were treated withabiraterone for longer than people in the ITT population, and this would have the effect in the model that overall survival improved. Furthermore, the Committee noted that, when inspecting the Kaplan–Meier curve from the trial (the ITT population), it saw no difference in death rates between the abiraterone and best supportive care arms up to approximately day 540. Conversely, when looking at the manufacturer’s modelled curves using the subgroup of patients, the Committee noted that people in the abiraterone arm had a higher probability of survival than in the best supportive care arm before day 540. The Committee noted that the model results followed the trial results between day 540 and day 1080, at which point the trial data were unblinded. The Committee concluded that the model overestimated the survival benefit associated with taking abiraterone before docetaxel rather than using best supportive care before docetaxel.

4.11   The Committee further considered that the overall survival predicted by the manufacturer’s model after day 1080 (that is, during the period where data was extrapolated after the third interim analysis) and noted that people who had abiraterone followed by docetaxel and then another treatment not only lived longer than people in the control arm, but that this benefit extended up to and beyond 5 years. The Committee considered that there was uncertainty surrounding whether this assumption was plausible. The Committee concluded that the model may also overestimate the survival benefit associated with taking abiraterone before docetaxel (compared with best supportive care before docetaxel) after day 1080 when no trial data existed on which to validate the extrapolations. The Committee concluded that considerable uncertainty exists surrounding survival estimates from the model.

4.12   The Committee discussed the utility values used by the manufacturer in its model. It understood that the manufacturer derived utility values, by phase of treatment, from 3 sources:

• a survey it carried out in patients in the UK with metastatic hormone-relapsed prostate cancer (4 values)
• COU-AA-302 (1 value reflecting an uplift to utility experienced by people taking abiraterone before docetaxel, using FACT-P data mapped to EQ-5D)
• the literature (1 value for quality of life at the end of life).

The Committee considered that, when quality-of-life data are collected in a clinical trial, such as in COU-AA-302 (see section 4.7), it is preferred that these data are used to derive utility values in the model. However, the Committee noted that the way the manufacturer chose to present FACT-P data in COU-AA-302 (time to worsening of quality of life) made it impossible to compare them with data from other trials of treatment for metastatic hormone-relapsed prostate cancer. Additionally, the Committee had concerns about the manufacturer’s utility mapping study, which was used to map FACT-P data from COU-AA-302 to EQ-5D, because it had not been provided with evidence that the study had been validated (such as whether it had gone through peer review and publication) and the manufacturer had not carried out sensitivity analyses surrounding its mapping study assumptions. Furthermore, the Committee questioned the manufacturer’s choice of when to apply utility values derived from its mapping study. It noted that, in its base case, the manufacturer used the trial data mapped to EQ-5D data only to estimate the utility increment associated with receiving abiraterone. The Committee questioned the appropriateness of an increment, given that patients on abiraterone experience more adverse events than patients on best supportive care. The Committee also appreciated the ERG’s concerns that the manufacturer only applied this increment to people who had abiraterone before docetaxel, but not to people who had abiraterone after docetaxel. The Committee was aware that, for the post-docetaxel treatment phase in the model, the manufacturer chose lower utility values (based on its survey) than it had chosen in its previous submission for TA259, which appraised abiraterone after docetaxel. The Committee was unconvinced by the manufacturer’s argument presented in the meeting that the post-docetaxel population in TA259 differed from the post-docetaxel population in its current model. However, it acknowledged that the manufacturer had included a scenario in its response to clarification in which the post-docetaxel utility value was the same as that used in TA259, and in which people who had abiraterone after docetaxel had a utility increment of 0.046. The Committee concluded that there were many uncertainties surrounding the utility values used in the manufacturer’s model.

4.13   The Committee discussed the cost of docetaxel in the manufacturer’s model. It heard from the clinical specialists that the NHS now purchases non-proprietary docetaxel and that the price used by the manufacturer in the model seemed high. The Committee noted that the manufacturer used a price listed in the British National Formulary (BNF), and appreciated that the price of cheaper generic versions available to the NHS may not be listed in the BNF. The Committee concluded that it was unlikely that the cost of docetaxel assumed in the manufacturer’s model reflects the cost paid for docetaxel in the NHS in England. However, it expected that if docetaxel was to be available at a lower cost, this would worsen the case for abiraterone being a cost-effective use of NHS resources, because people who have best supportive care before docetaxel have longer treatment durations with docetaxel than people who have abiraterone before docetaxel.

4.14   The Committee considered the cost-effectiveness results. It noted that the manufacturer’s base-case incremental cost-effectiveness ratio (ICER) was £46,700 per QALY gained.The Committee was aware that the ICERs from the manufacturer’s one-way sensitivity analyses and scenario analyses generally ranged from £45,000 to £49,000 per quality-adjusted life year (QALY) gained. The Committee noted that, when the manufacturer increased the utility value for the pre-docetaxel treatment phase, changed the discount rate, used a Weibull rather than a log-logistic model to extrapolate first-line treatment duration, or used utility data mapped from FACT-P to EQ-5D instead of utilities derived from survey data, the ICER increased to over £50,000 per QALY gained. The Committee was concerned that the manufacturer had not presented a probabilistic ICER in its submission. It was also concerned that much of the uncertainty explored by the manufacturer in its sensitivity analyses reflected parameters in the prediction equations that were related to how patient characteristics might vary rather than uncertainty around effectiveness parameters (that is, uncertainties around how well a model related to the true effectiveness of abiraterone in clinical practice). The Committee further recognised that the manufacturer had not performed a sensitivity analysis around the treatment effect of abiraterone, noting that trials that stop early because of benefit, as COU-AA-302 did, in general overestimate the magnitude of benefit (see section 4.5). However, the Committee heard from the manufacturer that, when it modelled treatment effectiveness as a covariate in all of the equations in which effectiveness featured, the cost effectiveness of abiraterone compared with best supportive care worsened. The Committee further noted that the manufacturer’s choice of model made it more complicated to carry out a sensitivity analysis of effectiveness than with a Markov model. The Committee noted that it was not presented with results from a Markov model although the manufacturer stated in the meeting that it had developed one for the population in this appraisal. The Committee concluded that the manufacturer’s sensitivity analysis had demonstrated minimal impact on the base-case results, but that key areas of uncertainty had not been explored.

4.15   The Committee considered the analyses conducted by the ERG, in particular the ERG’s explorations of the manufacturer’s assumptions about survival in the model. It noted that the ERG had conducted a scenario analysis that explored the uncertainty around the survival estimates for the subset of 902 people with complete baseline characteristics. In this scenario, the ERG used the ITT population from COU-AA-302 to produce prediction equations with the only covariate being whether a patient had abiraterone or best supportive care. The Committee noted that this resulted in an ICER of £57,300 per QALY gained. The Committee heard from the manufacturer that it believed that using treatment as the only covariate would result in the model outputs being less similar to the trial results than a model using multiple covariates in the prediction equations. The Committee accepted that the ERG’s approach would be likely to underestimate any survival benefit between the modelled treatment sequences, but it considered that the manufacturer’s base case was likely to overestimate survival benefit (see sections 4.10 and 4.11). The Committee understood that the manufacturer had used a log-logistic or log-normal distribution to replace, and to extrapolate from, the trial data. The ERG suggested that these distributions have a long tail that may give results that are not plausible in that they provide improbably large values during the relatively long period of extrapolation (compared with the period of observed data). For example, the Committee heard from the ERG that the model predicted that patients wait about 6 months to start docetaxel having stopped abiraterone, which the Committee appreciated differed from clinical care in England based on testimony from the clinical specialists who described patients switching treatment within a week of progression (see section 4.3). The Committee therefore questioned the validity of the model. The Committee noted that replacing log-logistic distributions with Weibull distributions increased the ERG’s exploratory base-case ICER from £57,700 to £74,800 per QALY gained, whereas replacing all log-normal distributions had minimal impact, the ICER falling slightly to £57,200 per QALY gained. The Committee concluded that the choice of parametric distribution used in the prediction equations was a key driver of cost effectiveness in the model. However, because the Committee had not been presented with data with which it could assess the clinical and biological plausibility of the manufacturer’s model’s extrapolations, it was not possible to determine whether the manufacturer’s or the ERG’s preferred extrapolation was the most appropriate.

4.16  The Committee discussed whether abiraterone could be considered an efficient use of NHS resources. It concluded that there were many areas of considerable uncertainty in the model results, and that all the ICERs estimated both by the manufacturer and the ERG fell substantially above the range normally considered cost effective that is, £20,000 to £30,000 per QALY gained.

4.17   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 of 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 normally not exceeding a cumulative total of 7000 for all licensed indications in England.

In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.

4.18   To address whether metastatic hormone-resistant prostate cancer at this stage of therapy is associated with a mean life expectancy of less than 24 months, the Committee noted that the median overall survival in the control arm of COU-AA-302 was around 30 months. The Committee heard from the manufacturer in the meeting that the mean survival (estimated from the model for the best supportive care arm) was 32 months. The Committee also heard from the manufacturer that these estimates were in line with survival of patients randomised to best supportive care (rather than enzalutamide) in the PREVAIL trial of enzalutamide for metastatic hormone-relapsed prostate cancer that has not been previously treated with chemotherapy. The Committee appreciated that the criterion on life expectancyhad previously been met in TA259 where abiraterone is used after docetaxel, but that this was reasonable because abiraterone was used at a later phase in the disease process. The Committee considered the manufacturer’s assertion that people treated in the NHS would have a lower life expectancy than people in COU-AA-302 because, in the trial, people had active treatments after docetaxel. However, the Committee believed that the NHS, in which people can haveabiraterone after docetaxel (or cabazitaxel, which, although not recommended by NICE, can be prescribed following application to the Cancer Drugs Fund) did not offer worse care than the trial. The Committee further considered the clinical specialists’ comment that people in the NHS might be more likely than patients in the trial to have docetaxel, which prolongs life compared with best supportive care. The Committee considered that the mean life expectancy for people with metastatic hormone-relapsed prostate cancer was unlikely to be less than 30 months; and abiraterone at this stage in the treatment pathway did not meet the first end-of-life criterion for short life expectancy. Because the first criterion had not been met, the Committee did not conclude formally whether abiraterone met the subsequent criteria but it noted that, in assessing the patient population, the manufacturer had presented an estimate of the population eligible for abiraterone in England and Wales, rather than England only. The Committee concluded that not all of the end-of-life criteria had been met and the end-of-life criteria did not apply to abiraterone taken before docetaxel in the treatment pathway.

4.19   The Committee considered whether abiraterone was innovative and whether it had demonstrable and distinctive benefits of a substantial nature not adequately captured in the reference case QALY measure. The Committee noted that, although abiraterone is not a new technology, it is the first treatment available for this position in the treatment pathway and was innovative in this regard. It then considered whether the model captured the benefits of either having abiraterone at an earlier point in the treatment pathway when people had higher quality of life, or delaying the use of cytotoxic chemotherapy, such as docetaxel. The Committee agreed that the measurement of health-related quality of life did not capture these benefits but, based on the evidence presented, the weight of these benefits on the QALY calculation could not be determined. The Committee concluded that taking into account the benefit of delaying chemotherapy would be extremely unlikely to reduce the ICER for abiraterone to within the range usually considered a cost-effective use of NHS resources. Therefore the Committee could not recommend abiraterone for people with metastatic hormone-relapsed prostate cancerand no or mild symptoms who have not previously been treated with chemotherapy.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Abiraterone for metastatic hormone-relapsed prostate cancer not previously treated with chemotherapy		Section
Key conclusion
Abiraterone is not recommended within its marketing authorisation for treating metastatic hormone-relapsed prostate cancer in people who have no or mild symptoms after androgen deprivation therapy has failed and in whom chemotherapy is not yet clinically indicated The Committee concluded that there were many areas of considerable uncertainty in the model results, and that all the ICERs estimated both by the manufacturer and the ERG fell substantially above the range normally considered cost effective that is, £20,000 to £30,000 per QALY gained The Committee considered that the mean life expectancy for people with metastatic hormone-relapsed prostate cancer was unlikely to be less than 30 months and abiraterone at this stage in the treatment pathway did not meet the first end-of-life criterion for short life expectancy. The Committee concluded that not all of the end-of-life criteria had been met and the end-of-life criteria did not apply to abiraterone taken before docetaxel in the treatment pathway. The Committee considered that the model did not capture the benefits of either having abiraterone at an earlier point in the treatment pathway when people had a higher quality of life, or delaying the use of cytotoxic chemotherapy such as docetaxel, but that taking into account these benefits would be extremely unlikely to reduce the ICER for abiraterone to within the range usually considered a cost-effective use of NHS resources and therefore it could not recommend abiraterone for people with metastatic hormone-relapsed prostate cancer and no or mild symptoms who have not previously been treated with chemotherapy.			1.1 4.16 4.18 4.19
Current practice
Clinical need of patients, including the availability of alternative treatments		Patient experts stated how important it is to have the option of delaying chemotherapy because chemotherapy can reduce a person’s quality of life.	4.2
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		Although abiraterone is not a new technology, it is the first treatment available for this position in the treatment pathway and is innovative in this regard. There are benefits to delaying the use of cytotoxic chemotherapy such as docetaxel.	4.19
What is the position of the treatment in the pathway of care for the condition?		Clinicians would generally use abiraterone, in addition to best supportive care, to treat people with few symptoms to delay chemotherapy, or to treat people who are unable or do not wish to have chemotherapy.	4.1
Adverse reactions		Patient groups stated that patients usually can cope with the adverse effects of abiraterone that are usually mild and tolerable, particularly compared with those of docetaxel, and that one of the advantages of abiraterone is that it delays the debilitating effects of chemotherapy.	4.6
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The clinical-effectiveness evidence came from the randomised placebo-controlled trial COU-AA-302, a worldwide trial that recruited 9% of its patients from the UK.	4.4
Relevance to general clinical practice in the NHS		The Committee concluded that COU-AA-302 generally reflected clinical practice in the UK and was relevant to address the decision problem.	4.4
Uncertainties generated by the evidence		The Committee was aware that COU-AA-302 was stopped (unblinded) early between the second and third interim analyses for overall survival and that, at both of these interim analyses, the results for overall survival did not show a statistically significant difference between the treatment arms according to the pre-specified statistical significance levels. The Committee discussed the potential effects on the overall survival estimates of stopping the trial early. The Committee was aware that lack of statistical significance increased the chance that abiraterone does not, in reality, prolong life and that a systematic review published in 2010 (Bassler et al.) had concluded that trials that stop early show a larger treatment effect than trials that run to completion, and that trials stopped early because of benefit are likely to overestimate benefit by approximately 40%.	4.5
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		None were identified.
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee concluded that abiraterone compared with placebo increased the time to radiographic progression, but that whether it extended life was uncertain because the results for overall survival did not show a statistically significant difference and lack of statistical significance increased the chance that abiraterone does not, in reality, prolong life.	4.5
Evidence for cost effectiveness
Availability and nature of evidence		The Committee noted that the manufacturer had developed a discrete event simulation model to compare the cost effectiveness of 2 treatment sequence strategies: abiraterone followed by docetaxel and subsequent treatments and best supportive care followed by docetaxel and subsequent treatments (including abiraterone).	4.8
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee noted that the manufacturer’s model was particularly complex. It agreed that the model was not transparent enough for the Evidence Review Group (ERG) to fully validate and critique, and therefore limited the model’s value to inform the Committee. The Committee concluded that the validity of the parametric extrapolations used in the model was uncertain. The Committee was concerned that the selected group of 908 patients in the model may not be representative of the 1088 patients in the ITT population from the COU-AA-302 trial, and of patients in England.	4.8 4.9 4.10
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The Committee had concerns about the manufacturer’s utility mapping study, which was used to map FACT-P data from COU-AA-302 to EQ-5D, because it had not been provided with evidence that the study had been validated. There were also inconsistencies in the utility values used in this appraisal and in technology appraisal 259. The Committee concluded that there were many uncertainties surrounding the utility values used in the manufacturer’s model. The model did not capture the benefits of delaying the use of cytotoxic chemotherapy, such as docetaxel.	4.12 4.19
Are there specific groups of people for whom the technology is particularly cost effective?		None were identified.	4.16
What are the key drivers of cost effectiveness?		The Committee concluded that the choice of parametric distribution used in the prediction equations was a key driver of cost effectiveness in the model. Because the Committee had not been presented with data with which it could assess the clinical and biological plausibility of the manufacturer’s model’s extrapolations, it was not possible to determine whether the manufacturer’s or the ERG’s preferred extrapolation was the most appropriate.	4.15
Most likely cost-effectiveness estimate (given as an ICER)		The Committee concluded that all the ICERs estimated both by the manufacturer and the ERG fell substantially above the range normally considered cost effective that is, £20,000 to £30,000 per QALY gained. The manufacturer’s base-case ICER was £46,700 per QALY gained and its sensitivity analysis resulted in ICERs from £45,000 to above £50,000 per QALY gained. The ERG presented an ‘exploratory base case’ of £57,300 per QALY gained. Additional sensitivity analyses resulted in ICERs of £57,200 to £74,800 per QALY gained.	4.14, 4.15, 4.16
Additional factors taken into account
Patient access schemes (PPRS)		The manufacturer of abiraterone (Janssen) has agreed a patient access scheme with the Department of Health. This involves a single confidential discount applied to the list price of abiraterone across all indications.	2.3
End-of-life considerations		The Committee considered that the mean life expectancy for people with metastatic hormone-relapsed prostate cancer who had mild or no symptoms and for whom chemotherapy is not yet indicated was unlikely to be less than 30 months; and abiraterone at this stage in the treatment pathway did not meet the criterion for short life expectancy. The Committee concluded that not all end-of-life criteria had been met and the end-of-life criteria did not apply to abiraterone taken before docetaxel in the treatment pathway.	4.18
Equalities considerations and social value judgements		No equality issues were raised during the appraisal committee meeting.	n/a

 

 

5   Implementation

5.1     NICE has developed tools [update link] to help organisations put this guidance into practice (listed below). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6   Related NICE guidance

Details are correct at the time of consultation and will be removed when the final guidance is published. Further information is available on the NICE website.

Published

Prostate cancer: diagnosis and treatment NICE clinical guideline 175 (2014)

Denosumab for the prevention of skeletal-related events in adults with bone metastases from solid tumours NICE technology appraisal guidance 265 (2012)

Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen NICE technology appraisal guidance 259 (2012)

Cabazitaxel for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen NICE technology appraisal guidance 255 (2012)

Docetaxel for the treatment of metastatic prostate cancer NICE technology appraisal guidance 101 (2006)

Under development

Enzalutamide for the treatment of metastatic hormone relapsed prostate cancer previously treated with a docetaxel containing regimen. NICE technology appraisal guidance, publication expected June 2014.

7   Proposed date for review of guidance

7.1  NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in August 2017. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Amanda Adler
Chair, Appraisal Committee
April 2014

8   Appraisal Committee members, guideline representatives and NICE project team

8.1  Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3‑year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are 4 Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Amanda Adler (Chair)
Consultant Physician, Addenbrooke’s Hospital

Professor Ken Stein (Vice Chair)
Professor of Public Health, University of Exeter Medical School

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford

Professor John Cairns
Professor of Health Economics Public Health and Policy, London School of Hygiene and Tropical Medicine

Dr Lisa Cooper
Echocardiographer, Stockport NHS Foundation Trust

Mr Robert Hinchliffe
Clinical Senior Lecturer (Higher Education Funding Council for England; HEFCE) in Vascular Surgery and Honorary Consultant Vascular Surgeon, St George’s Vascular Institute

Mrs Anne Joshua
Pharmaceutical Advisor NHS 111/NHS Pathways

Dr Miriam McCarthy
Consultant, Public Health, Public Health Agency, Northern Ireland

Professor Ruairidh Milne
Director of Strategy and Development and Director for Public Health Research at the National Institute for Health Research (NIHR) Evaluation, Trials and Studies Coordinating Centre at the University of Southampton

Dr Peter Norrie
Principal Lecturer in Nursing, DeMontfort University

Mr Christopher O’Regan
Head of Health Technology Assessment and Outcomes Research, Merck Sharp & Dohme

Dr Sanjeev Patel
Consultant Physician and Senior Lecturer in Rheumatology, St Helier University Hospital

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Danielle Preedy
Lay member

Mr Alun Roebuck
Consultant Nurse in Critical and Acute Care, United Lincolnshire NHS Trust

Mr Cliff Snelling
Lay member

Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

Mr David Thomson
Lay member

Dr Nicky Welton
Senior Lecturer in Biostatistics/Health Technology Assessment, University of Bristol

Dr Nerys Woolacott
Senior Research Fellow, Centre for Health Economics, University of York
NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Dr Mary Hughes
Technical Lead

Zoe Charles
Technical Adviser

Jeremy Powell
Project Manager

9    Sources of evidence considered by the Committee

A. The assessment report for this appraisal was prepared by Kleijnen Systematic Reviews:

• Riemsma R, Ramaekers B, Tomini F et al. Abiraterone for the treatment of chemotherapy naïve metastatic castration-resistant prostate cancer, March 2014

B. The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, assessment report and the appraisal consultation document (ACD). Organisations listed in I, II and III were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination.

I. Manufacturers/sponsors:

• Janssen

II. Professional/specialist and patient/carer groups:

• British Association of Urological Surgeons
• British Uro-Oncology Group
• Cancer Research UK
• Prostate Cancer UK
• Royal College of Nursing
• Royal College of Physicians
• Tackle Prostate Cancer
• The Urology Foundation

III. Other consultees:

• Department of Health
• NHS England
• Welsh Government

IV. Commentator organisations (without the right of appeal):

• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Healthcare Improvement Scotland
• National Collaborating Centre for Cancer
• Sanofi

C. The following individuals were selected from clinical specialist and patient expert nominations from the consultees and commentators. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee’s deliberations. They gave their expert personal view on abiraterone by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr John Graham, Consultant Clinical Oncologist and Director, National Collaborating Centre for Cancer, nominated by the National Collaborating Centre for Cancer – clinical specialist
• Dr Simon Hughes, Consultant Clinical Oncologist, Guys and St Thomas’ NHS Trust, nominated by the British Uro-oncology Group – clinical specialist
• David Smith, Hon. Secretary, Tackle Prostate Cancer, nominated by Tackle Prostate Cancer – patient expert
• Stuart Watson, volunteer, Prostate Cancer UK, nominated by Prostate Cancer UK – patient expert

E. Representatives from the following manufacturers/sponsors attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Janssen