Abiraterone for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer

Androgen deprivation therapy with or without docetaxel are the first-line treatment options for hormone-sensitive metastatic prostate cancer

3.1 The clinical experts explained in the first committee meeting in May 2018 that, in clinical practice, people with newly diagnosed hormone-sensitive metastatic prostate cancer have androgen deprivation therapy (ADT) alone or docetaxel plus ADT plus the oral corticosteroid prednisolone (from now on, 'docetaxel in combination'). NICE's guideline for prostate cancer recommends ADT in the form of continuous luteinising hormone-releasing hormone agonists, bilateral orchidectomy (removal of the testicles) or bicalutamide with ADT. The guideline also recommends docetaxel. Docetaxel is not licensed for hormone-sensitive metastatic prostate cancer, but NHS England commissions it for up to 6 cycles at this point in the treatment pathway. Docetaxel is administered intravenously with oral prednisolone 5 mg twice daily for 3 weeks. The clinical experts explained that orchidectomy and bicalutamide are rarely used in the NHS. The committee agreed that ADT includes luteinising hormone-releasing hormone agonists. It concluded that ADT alone and docetaxel in combination were appropriate comparators to abiraterone plus ADT plus 5 mg of the oral corticosteroid prednisone (from now on, 'abiraterone in combination').

It may be appropriate to consider separately abiraterone in combination when docetaxel is contraindicated or unsuitable

3.2 The committee recognised its obligation to appraise technologies across their marketing authorisations. This meant that, if abiraterone in combination were not cost effective across its marketing authorisation, the committee could consider a narrower population if there was a case for this. The company had noted in its original submission that there was a group of people for whom docetaxel was clinically unsuitable or who chose not to have docetaxel. The company proposed abiraterone in combination as an alternative treatment to ADT alone for this group, which it termed 'chemotherapy ineligible' in its submission for the third committee meeting. The Cancer Drugs Fund's clinical lead noted in the third meeting that, at that time (January 2020), up to two-thirds of people presenting with hormone-sensitive metastatic prostate cancer in England were having ADT alone. The committee noted that this included both people for whom docetaxel is contraindicated or unsuitable (the terminology agreed by the company, experts and committee in the fourth meeting) and people who choose not to have docetaxel. Apatient expert explained that there is an unmet need for an alternative treatment option to ADT alone for this group. The committee recognised that most people who currently choose to have ADT alone rather than docetaxel in combination may wish to avoid the adverse events associated with docetaxel. The committee agreed that patient choice was very important, but, for people who could have docetaxel, the comparators should be all current options in the NHS for treating high-risk hormone-sensitive metastatic prostate cancer. If abiraterone were clinically and cost effective, it would be recommended as an option for the populations who can and cannot have docetaxel. The committee agreed that it would be appropriate to define a group of people for whom docetaxel is contraindicated or unsuitable. It also agreed that the clinical and cost effectiveness of abiraterone in combination in this group should be considered if it were not cost effective for the whole population.

Identifying who cannot or should not have docetaxel involves assessing a person's risks and may include people who cannot take abiraterone

3.3 In its fourth meeting, the committee set out to understand more clearly how experts define people for whom docetaxel is contraindicated or unsuitable. The clinical and patient experts had previously explained that, although there are contraindications for docetaxel, defining the group for whom it is unsuitable is complicated. The committee had been aware that NHS England's commissioning policy indicates that someone may not be fit enough for docetaxel if they have a poor overall performance status (World Health Organization [WHO] performance 3 to 4), pre-existing peripheral neuropathy, poor bone marrow function or a life-limiting illness. The policy also states that docetaxel should be used with caution in people with a WHO performance status of 2 and that there are few absolute contraindications for docetaxel therapy. The Cancer Drug's Fund clinical lead explained that many factors besides a person's performance status may affect whether they could have docetaxel. One of these is patient choice after hearing the risks and benefits of each available treatment. In the fourth meeting, the clinical experts explained that, while creating an exhaustive list of criteria for this group is unfeasible, developing a framework would be possible. The clinical lead for the Cancer Drugs Fund clinical lead explained that a clinician assesses a person's suitability for having docetaxel based on contraindications, fitness, comorbidities and preference. An oncologist would identify and discuss with a patient the individual risks and benefits associated with any treatment option before starting treatment. People for whom docetaxel is unsuitable or contraindicated would include:

The first treatment for hormone-sensitive metastatic prostate cancer affects the type and number of follow-on treatments

3.4 The clinical experts explained that people who have docetaxel as first-line treatment in the hormone-sensitive setting can have docetaxel again for up to an additional 10 cycles in the hormone-relapsed setting. This is because the benefit of docetaxel is not exhausted when used for only 6 cycles. The Cancer Drugs Fund clinical lead explained that abiraterone and enzalutamide are commissioned by NHS England only once in the treatment pathway. This is because there is as yet no evidence of substantial clinical benefit for enzalutamide after abiraterone or for abiraterone after enzalutamide. The committee understood that people who have abiraterone in combination for hormone-sensitive prostate cancer have fewer options for active follow-on treatments than people who start with ADT alone, or docetaxel in combination. This is because people who started with abiraterone cannot have abiraterone or enzalutamide later in the treatment pathway. The committee noted that the sequence of follow-on treatments may vary from person to person, and that possible follow-on treatments include:

LATITUDE and STAMPEDE are both relevant for assessing the clinical effectiveness of abiraterone in combination in the whole population

3.5 Two randomised controlled trials have investigated the clinical effectiveness of abiraterone in combination in hormone-sensitive metastatic disease:

To compare abiraterone in combination with docetaxel in combination, estimates from STAMPEDE are preferred

3.6 For the comparison of abiraterone in combination with docetaxel in combination, the company was concerned that results from the subgroup of people with metastatic disease in STAMPEDE were not generalisable to the licensed population for abiraterone (see section 3.5). The company further stated that STAMPEDE was not statistically powered to detect a difference in survival in this post-hoc analysis. The company instead developed a network meta-analysis which, as well as including the direct data from STAMPEDE, included several other trials. The company argued that, given the uncertainties in the direct analysis, these additional trials contributed information to the estimated treatment effect of abiraterone compared with docetaxel. The trials included in the network were:

Abiraterone in combination extends survival compared with ADT alone in the whole population

3.7 Abiraterone in combination improved both progression-free and overall survival compared with ADT alone in LATITUDE and in people with high-risk metastatic disease in STAMPEDE. The size of improvement was similar in the 2 trials. In LATITUDE, median progression-free survival was 14.8 months with ADT alone and 33.0 months with abiraterone in combination (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.39 to 0.55). Based on the planned final analysis of overall survival, the median overall survival with ADT alone was 36.5 months and was 53.3 months with abiraterone in combination (HR 0.66, 95% CI 0.56 to 0.78). In STAMPEDE, at a median follow up of 3.3 years, the hazard ratio for progression-free survival in the high-risk metastatic subgroup was 0.46 (95% CI 0.36 to 0.59), and for overall survival was 0.54 (95% CI 0.41 to 0.70). Data from STAMPEDE shared after the appeal showed that the hazard ratio for overall survival was maintained with longer follow up (the data are academic in confidence and cannot be reported here). The committee concluded that abiraterone in combination improved both progression-free and overall survival compared with ADT alone. However, it noted that there was uncertainty about the magnitude of the long-term survival gain with abiraterone in combination. This was because of potential differences in the proportion of people who had life-extending treatments after disease progression on ADT in LATITUDE and STAMPEDE compared with clinical practice (see section 3.9).

Compared with docetaxel in combination, abiraterone may improve progression-free survival, but not overall survival

3.8 In people with metastatic disease in STAMPEDE, abiraterone in combination improved progression-free survival compared with docetaxel in combination (HR 0.69, 95% CI 0.50 to 0.95). However, for overall survival, the hazard ratio favoured docetaxel (HR 1.13, 95% CI 0.77 to 1.66). In the company's updated base case, rather than use the results reflecting a direct comparison from STAMPEDE, it used the results of the indirect network meta-analysis that included data from LATITUDE, CHAARTED, GETUG‑AFU 15 and STAMPEDE. This showed similar results to the direct comparison for progression-free survival. However, the point estimate for overall survival favoured abiraterone, but the credible interval included 1, that is, the possibility of no difference in benefit of 1 treatment over the other. The company considered these values to be academic in confidence so they cannot be reported here. Two of the clinical experts at the first meeting explained that a possible reason for a benefit in progression-free survival, but lack of benefit in overall survival, with abiraterone in combination compared with docetaxel in combination in STAMPEDE related to the treatments that people have later in the treatment pathway. People who had docetaxel in combination or ADT alone could still go on to have abiraterone and docetaxel, whereas people who had already had abiraterone could only go on to have docetaxel. The clinical experts involved in STAMPEDE confirmed that post-progression survival was shorter after abiraterone in combination than after ADT alone in this trial. Considering the direct and indirect comparisons, the committee concluded that abiraterone in combination improves progression-free survival, but not overall survival compared with docetaxel in combination.

Neither STAMPEDE nor LATITUDE likely capture all the benefit on overall survival of follow-on treatments used in NHS clinical practice

3.9 The committee recognised that life-extending treatments offered when the disease is no longer hormone sensitive (that is, is hormone relapsed) affects life-expectancy. Follow-on treatments in the unblinded UK STAMPEDE trial were expected to reflect what people would have in NHS clinical practice, for example, not getting abiraterone twice. This was because the choice of next treatment depended on knowing the first treatment. In STAMPEDE, people were aware of their treatment but, in the blinded LATITUDE trial, people were not. The committee noted that the trials differed from UK clinical practice in 2 ways:

No data are presented on the effectiveness of abiraterone compared with ADT specific to people for whom docetaxel is contraindicated or unsuitable

3.10 No evidence was presented of abiraterone's relative effectiveness compared with ADT alone specifically for the group of people for whom docetaxel is contraindicated or unsuitable. LATITUDE and STAMPEDE, the key clinical trials of abiraterone in this indication (see section 3.5), only included people with adequate haematological function, an ECOG status or WHO performance status of 0, 1 or 2 (meaning they were reasonably fit). Also, they did not have any condition that would interfere with them taking part in the trial. As part of the initial protocol all people recruited to STAMPEDE had to be able to have docetaxel because they had to able to have any of the treatments they could be randomised to in this trial. A clinical expert explained that, in 2013, the docetaxel arm of the trial closed but the trial continued to recruit to the ADT alone and abiraterone-in-combination arms (among others). This meant people recruited to the trial from this point could have included people for whom docetaxel was contraindicated or unsuitable. He noted that James et al. (2017) presented an analysis which showed that the hazard ratio for overall survival for abiraterone in combination compared with ADT was 0.69 (95% CI 0.53 to 0.90) between November 2011 and January 2013. This was when the docetaxel arm of the trial was open. After the docetaxel arm closed, the hazard ratio for data collected between April 2013 and January 2014 was 0.59 (95% CI 0.44 to 0.78). The ERG highlighted, and the committee agreed, that this did not provide the evidence specifically for the group of patients in whom docetaxel was contraindicated or unsuitable. This was because the 2013 to 2014 data would also have included people who could have docetaxel. The committee heard during its fourth meeting that STAMPEDE enrolled people who could take abiraterone, but could not have docetaxel. However, data specific to this group was not presented to the committee. The committee concluded that assessing data specific to the relevant population was preferred.

Abiraterone in combination appears less effective in people at risk for not being able to have docetaxel, but the data are limited and uncertain

3.11 No data were presented specifically for the group of people who cannot take docetaxel. So, the committee discussed the treatment effect of abiraterone in combination in people at risk for not being able to have docetaxel. It was aware that older people (see section 3.23) and people with poorer levels of performance status would be less likely to have docetaxel. It noted the available evidence from LATITUDE and STAMPEDE on subgroups based on age and performance status. For the comparison of abiraterone in combination with ADT alone from STAMPEDE, the committee noted effect modification by age. For overall survival, abiraterone was not as effective in people 70 years and over (HR 0.94, 95% CI 0.69 to 1.29) compared with people under 70 years (HR 0.51, 95% CI 0.40 to 0.65; test for interaction p value 0.003) (James et al. 2017). The committee noted a similar pattern in LATITUDE, in which the hazard ratio for overall survival for abiraterone in combination compared with ADT alone was: 0.65 (95% CI 0.50 to 0.84) for people under 65 years; 0.68 (95% CI 0.55 to 0.83) for people 65 years and over and 0.86 (95% CI 0·62 to 1·21) for people 75 years and over (Fizazi et al. 2019). The committee also noted an HR of 0.64 (95% CI 0.50 to 0.75) in people with an ECOG status of 0 or 1, and a HR of 1.42 (95% CI 0.65 to 3.08) for those with an ECOG status of 2 in LATITUDE (Fizazi et al. 2019). It recognised that age alone would not determine whether a person could have docetaxel, but that age was associated with decreased docetaxel use. It also heard that people with a poor performance status may not get abiraterone. The committee agreed that abiraterone appears less effective among people with characteristics shared by people who cannot or should not have docetaxel based on subgroup data. However, it noted that subgroup data should be interpreted with caution when based on data from a small group of people (40 out of 1,159 people in LATITUDE had a performance status of 2). It also recalled that the subgroups did not specifically reflect the population for whom docetaxel is contraindicated or unsuitable. Overall, the committee concluded it was not possible to say whether abiraterone was equally effective, or less clinically effective for people for whom docetaxel is contraindicated or unsuitable.

The baseline risks from which to estimate the absolute effectiveness of abiraterone in people who cannot have docetaxel are not presented

3.12 Both the relative benefits of treatment with abiraterone compared with ADT alone, and the baseline risks of progression and dying, may differ between populations who can and cannot have docetaxel. The committee recognised that many of the risk factors for not having docetaxel (for example, age and poor performance status) are also risk factors for dying. It concluded that any modelling should take this into account (see section 3.15).

Overall survival estimates from LATITUDE include the effect of follow-on docetaxel, which would not apply to people who cannot have docetaxel

3.13 The company considered that the results of LATITUDE could be generalised to people who cannot or should not have docetaxel in its modelling (see section 3.15). The clinical experts explained that, with some exceptions, people for whom docetaxel is unsuitable during hormone-sensitive disease would not have docetaxel after their cancer progressed to being hormone relapsed. People in LATITUDE and STAMPEDE could go on to have docetaxel after abiraterone in combination or ADT alone, which did not reflect the treatment pathway for people who cannot have docetaxel, and yet was reflected in the trial results. The evidence of clinical effectiveness from LATITUDE does not reflect the treatment pathway for people for whom docetaxel is contraindicated or unsuitable. The committee therefore again agreed that it had not been presented with data on the effectiveness of abiraterone in combination compared with ADT in people for whom docetaxel is contraindicated or unsuitable.

A partitioned survival model is appropriate

3.14 The company provided 2 models. In its original submission, it provided a multistate Markov model. The committee deemed that this did not provide plausible estimates of post-progression or overall survival and did not generate valid estimates of cost effectiveness. In its submission for the third committee meeting, the company provided a partitioned survival model. Both models were split into 2 phases:

There is no modelling reflecting the treatment pathway, costs and benefits for people for whom docetaxel is contraindicated or unsuitable

3.15 For the third committee discussion, the company provided estimates of the cost effectiveness of abiraterone in combination compared with ADT alone for a population it referred to as 'chemo-ineligible' (see section 3.2). The committee noted that the company based these estimates on data for the 'whole population' (from now, meaning people for whom docetaxel may or may not be suitable). The committee recognised that the clinical data used in the model may not be generalisable to the 'chemo-ineligible' group. It also recognised that the modelled treatment pathway did not reflect what treatments people for whom docetaxel is contraindicated or unsuitable would have. Specifically:

The Weibull and log-logistic distributions are plausible for extrapolating progression-free and overall survival respectively in whole population

3.16 The committee agreed with the company that the hazards of progression and death for abiraterone in combination compared with ADT alone from LATITUDE were not proportional. It concluded that it was appropriate to fit curves to each arm separately. During the committee's third meeting, the company presented results using the log-logistic distribution for each modelled treatment arm (which the company considered plausible but optimistic) and the Weibull distribution (which it considered plausible but pessimistic). The committee considered that the Weibull curves were plausible for progression-free survival. It noted that results from STAMPEDE for abiraterone in combination compared with ADT (presented to the committee in its fourth meeting after the appeal) represented an 8-year follow up. It supported using the log-logistic distribution to extrapolate overall survival from LATITUDE (these data cannot be presented here because they are academic in confidence). At the third meeting, the ERG highlighted that a consequence of the model was that the company assumed that the treatment effect is maintained over the long term. However, in clinical practice, it may wane and the ERG provided scenarios to adjust for this at that time. The committee noted that the longer-term data from STAMPEDE could be used to determine the validity of these adjustments. It also acknowledged that the company and other stakeholders had not been able to respond to data presented by BUG after the appeal. The committee concluded that the progression-free survival extrapolation using the Weibull distribution was broadly appropriate for the overall population. However, it did not see evidence of extrapolating outcomes in people for whom docetaxel is contraindicated or unsuitable. The committee recognised that these people, being on average older, may have a different pattern of mortality. It further concluded that the predicted overall survival based on extrapolations using the log-logistic distribution was plausible for the overall trial population. The committee would have preferred to see further extrapolations exploring alternative time points for equalising the hazard using 2 plausible curves: 1 for the whole population, and another for people for whom docetaxel is contraindicated or unsuitable.

The utility estimates should be based on the same measure of quality of life, and from the same source, as the data on effectiveness

3.17 The company considered separately the effects on quality of life of adverse effects and of being on treatment. The sources of these data are in table 1.

The company used different approaches to estimate the effect on quality of life of having abiraterone in combination or ADT alone than it did to estimate the effect with docetaxel in combination. It sourced utility values for being on abiraterone in combination from EQ‑5D results from LATITUDE, and for being on docetaxel in combination from a separate survey of the general public that it had carried out. The NICE methods guide states that EQ‑5D is the preferred measure of health-related quality of life. The committee noted that STAMPEDE collected EQ‑5D data for a UK population randomised to abiraterone in combination, to docetaxel in combination and to ADT alone. In response to consultation and in the third committee meeting, the company confirmed that it did not request or have access to these data. The ERG carried out a scenario using the disutility estimate for docetaxel from the economic evaluation of docetaxel in combination in NICE's guideline for prostate cancer. The ERG derived the disutility value from EQ‑5D data collected in STAMPEDE (whole population and metastatic subgroup). The company stated that the ERG's scenario was consistent with the results from the company's survey. The committee considered that the effectiveness data from the metastatic subgroup from STAMPEDE were generalisable to the higher-risk population under appraisal (see section 3.5). However, the committee considered that it was plausible that the level of risk affects quality of life. It concluded that it was preferable to use EQ‑5D data from the subgroup of people from STAMPEDE with high-risk hormone-sensitive metastatic prostate cancer to assess quality of life. It further noted that comparable data were available for abiraterone in combination, docetaxel in combination and ADT alone. The committee then went on to consider evidence submitted by BUG after the appeal. This showed the results of an as yet unpublished quality of life study from STAMPEDE that focused on people with high-risk metastatic disease. The data were collected using a different measure of quality of life to EQ-5D (these data are academic in confidence so cannot be reported here). The committee concluded that the findings supported the company's modelling that showed a worse quality of life on docetaxel in combination compared with abiraterone in combination. It also concluded that the ERG's estimate was likely to be broadly appropriate.

The company's model includes the costs of follow-on treatments in the NHS, but not the full benefits of these treatments

3.18 In response to the committee's second meeting, the company revised the treatment pathways in the hormone-relapsed state to reflect NHS market shares of treatments for hormone-relapsed disease. It based its estimates of market shares on the opinion of 4 clinicians, which the committee concluded may not reflect the actual market shares in UK clinical practice. The company assumed that:

The company's base case for the whole population covered by abiraterone's license does not reflect the preferred assumptions

3.19 The committee agreed that its preferred approach to modelling would reflect the company's base case with the following assumptions:

The results of the cost-effectiveness analyses should be made transparent

3.20 The prices of abiraterone made by Janssen and technologies made by company's other than Janssen are confidential. This meant that estimates of the ICERs could not be presented in the final appraisal determination that followed the committee's third meeting. This stated that the cost-effectiveness estimates without a commercial arrangement were considerably higher than the range normally considered a cost-effective use of NHS resources. The appeal panel concluded that this was not transparent. The committee addressed this (see section 3.21) by stating a figure above which the ICER lies. It was not possible to publish a narrow range because the ICERs using list prices have been previously published and the company stated that this would allow back calculation of its discount for abiraterone. The committee strongly supported being more transparent in reporting estimates of cost effectiveness.

Abiraterone is not a cost-effective use of NHS resources for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer

3.21 At the time of the fourth committee meeting, the company agreed a confidential discounted price for abiraterone. The committee noted its duty to appraise technologies across their marketing authorisation. At this price, the company's base case with the appraisal committee's preferred modelling assumptions was:

Abiraterone may be associated with benefits unaccounted for in the modelling, and more data and revisions to the assumptions are needed

NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. This means the committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. For the narrower population in the marketing authorisation for abiraterone (that is, people for whom docetaxel is contraindicated or unsuitable), the committee stated that further data from the company were needed to determine the clinical effectiveness of abiraterone in combination compared with ADT alone. It stated that the company also needed to provide a model that was relevant for this group. The committee recognised that there was an unmet need for another treatment option to ADT in this group. It concluded that the benefits of abiraterone being an oral treatment that could be taken at home were not captured in the model.

The recommendations apply to all people with prostate cancer and do not discriminate on the basis of age

3.22 The committee noted that, as in previous NICE technology appraisals of prostate cancer treatments, its recommendations should apply to all people with prostate cancer, including transgender individuals. It also noted that, in clinical practice, older people are less likely to have docetaxel than younger people. This was based on NHS data from appellants presented at the fourth committee meeting. The clinical experts explained that, although docetaxel is more likely to be contraindicated or unsuitable for older people, age itself will not determine whether a person could or should have docetaxel in clinical practice. The committee were aware that making recommendations by age to reflect people who cannot or should not have docetaxel could discriminate against younger people for whom docetaxel is contraindicated or unsuitable. It noted the appeal panel's conclusions that: 'the current reasoning around the failure to define this subgroup does not address the fact that the subgroup will tend to comprise older men'. It also noted that the appeal panel: 'wishes to be clear that although equality legislation requires this subgroup to be more fully considered it does not necessarily follow that in this case, after appropriate consideration, special provision will need to be made for them'.' The committee concluded that the appeal panel's statement needs to be taken into account in its decision making.

The points upheld in appeal are addressed

3.23 The committee noted that the upheld points in the appeal related to transparency (see section 3.21), equality issues (see section 3.23) and defining a population for whom docetaxel is contraindicated or unsuitable. The appeal panel stated that the committee should: