The Committee endorsed the recommendations of the EML Cancer Medicine
Working Group with regard to the proposed threshold of four to six months of
overall survival benefit as a guiding principle for prioritizing cancer medicines
for inclusion on the EML, and applied this principle to the consideration of
abiraterone and enzalutamide.
The Committee recommended the addition of abiraterone to the
complementary list of the EML for use in the treatment of metastatic castrationresistant
The Expert Committee acknowledged the significant public health
burden of prostate cancer, which afflicts an increasing number of people in all
countries, irrespective of income. The Committee recalled that the EML currently
includes docetaxel, bicalutamide and leuprorelin for use in the treatment of
metastatic prostate cancer. However, a significant proportion of patients will not
respond to these medicines and patients will ultimately develop resistance.
The Committee noted that abiraterone and enzalutamide have each
been shown to be effective treatments for metastatic castration-resistant prostate
cancer, both in chemotherapy-naive and in pre-treated patients. The Committee
noted that abiraterone had not shown any relevant clinical advantage over
enzalutamide in terms of efficacy outcomes or safety. However, the Committee
recognized the potential advantages offered by abiraterone in terms of emerging
dosing strategies (lower doses may be possible when administered with food),
reduced pill burden potentially improving adherence, wider availability of
generics and potential associated cost savings. Given that metastatic prostate
cancer often requires treatment over longer periods of time (i.e. above one
year) and that low dosing and availability of generics would be associated with
substantial cost savings, the Committee decided not to recommend listing
abiraterone with a square box indicating enzalutamide as an alternative. While
enzalutamide remains an effective therapeutic option for mCRPC, its use
instead of abiraterone could result in considerable additional expenditure at
country level, without additional clinical benefit. The Committee considered
that addition of abiraterone alone on the EML serves to support its use,
promoting competition between brand and generic medicines, and improving
access and affordability.
The application requested the addition of abiraterone and enzalutamide to the
EML for use in the treatment of metastatic castration-resistant prostate cancer.
In 2017, the Committee considered an application requesting inclusion of
enzalutamide on the EML for the treatment of prostate cancer, but did not
recommend inclusion, instead recommending a comprehensive review of prostate
cancer medicines including abiraterone to be considered at its next meeting (1).
Public health relevance
Prostate cancer is the second most common cancer in men and the fourth most
common cancer overall. In 2018, approximately 1.3 million men were diagnosed
with prostate cancer (2). When patients are diagnosed with prostate cancer, if
they are treated early and tumours are localized, the prognosis is often favourable.
However, some patients will relapse, which in nearly all cases, leads to castrationresistant
prostate cancer (CRPC). At the CRPC stage, the disease is no longer
responsive to androgen deprivation therapy (ADT), thus limiting the available
There are currently six treatments being used to treat CRPC. Enzalutamide
and abiraterone acetate have several advantages over the other treatments. Four
of the other treatments are invasive and require IV administration, leukapheresis,
or the use of radiopharmaceuticals. Enzalutamide and abiraterone acetate are
the only daily oral tablets.
The application described the findings of two randomized placebo-controlled
Phase III studies of enzalutamide for treatment of mCRPC.
The AFFIRM trial randomly assigned 1199 men with metastatic CRPC
(mCRPC) who had previously taken docetaxel to 160 mg enzalutamide or placebo
daily (3). Both groups received continuing androgen deprivation therapy. Overall
survival (OS) favoured enzalutamide (18.4 months vs 13.6 months; HR 0.63,
95%CI 0.53 to 0.75; p<0.001). Progression-free survival (PFS) also favoured
enzalutamide (8.3 months vs 2.9 months; HR 0.40, 95%CI 0.35 to 0.47, p<0.001).
54% of enzalutamide-treated patients experienced a 50% or greater decrease in
prostate specific antigen (PSA) levels compared to only 2% in the control arm
The PREVAIL trial investigated enzalutamide in a first-line setting in men
with mCRPC who were chemotherapy naive. 1717 patients were randomized to
receive 160 mg enzalutamide or placebo daily (4). The study was stopped after
a planned interim analysis showed benefit for enzalutamide. Significantly fewer
deaths were reported in the treatment arm compared to placebo (28% vs 35%;
HR 0.71, 95%CI 0.60 to 0.84l p<0.001).
The application described the findings of two randomized placebo-controlled
Phase III studies of abiraterone for treatment of mCRPC.
The COU-AA-301 trial randomly assigned 1195 patients who had
failed prior docetaxel therapy to receive prednisone 5 mg twice daily with
either abiraterone 1000 mg daily or placebo (5). The primary endpoint was
overall survival and was significantly longer in the abiraterone-prednisone arm
compared to the control arm (14.8 months vs 10.9 months; HR 0.65, 95%CI
0.54 to 0.77; p<0.001). Abiraterone was also associated with significant benefit
compared to placebo for the secondary endpoints of time to PSA progression
(10.2 months vs 6.6 months; HR 0.58, 95%CI 0.46 to 0.73; p<0.001), and PFS
(5.6 months vs 3.6 months; HR 0.67, 95%CI 0.59 to 0.78; p<0.001).
The COU-AA-302 trial randomly assigned 1088 chemotherapy naive
patients with prostate cancer to receive abiraterone 1000 mg daily plus prednisone
5 mg twice daily or placebo plus prednisone (6). Median overall survival was
observed to be longer in abiraterone treated patients compared to the placebo
group (34.7 months vs 30.3 months; HR 0.81, 95%CI 0.70 to 0.93; p=0.0033).
Enzalutamide versus abiraterone acetate
The application described the findings of three studies in which enzalutamide
and abiraterone were compared.
A network meta-analysis of eight RCTs involving 8666 patients with
mCRPC compared the efficacy of abiraterone, enzalutamide and orteronel (7).
Pooled hazard ratios for the primary endpoint of overall survival were 0.71 and
0.78 for enzalutamide and abiraterone, respectively compared to control groups.
Enzalutamide also significantly improved PFS (HR 0.36), whereas abiraterone
was not associated with a significant improvement. Enzalutamide and abiraterone
were both associated with significant improvements in time to PSA progression
compared to controls (HR 0.20 and 0.56, respectively). There were no significant
associations for either drug with regard to the development of adverse events.
A retrospective study of patients with mCRPC receiving treatment with
enzalutamide (n=807) or abiraterone (n=2591) compared real-world treatment
patterns and adherence to therapy (8). Abiraterone-treated patients were found
to have higher medication possession ratios (MPRs) than enzalutamide-treated
patients, suggesting greater medication adherence to abiraterone. Abirateronetreated
patients also had lower Kaplan-Meier rates of dose reduction.
A second retrospective study compared the combined duration of
prostate cancer treatments of mCRPC patients initiated on abiraterone
(n=2591) or enzalutamide (n=807) (9). Compared with patients initiated on
enzalutamide, patients initiated on abiraterone had fewer discontinuations of
mCRPC treatments (HR 0.73, p=0.004) or of any prostate cancer treatments
(HR 0.61, p=0.002) at three months and the result was maintained up to 24
months. The median duration of mCRPC treatments was 4.1 months longer for
patients initiated on abiraterone compared with those initiated on enzalutamide
(18.3 vs 14.2 months, p<0.001). Similarly, the median duration of any prostate
cancer treatment was longer for patients initiated on abiraterone compared with
those initiated on enzalutamide (not reached vs 22.2 months, p<0.001).
From the PROSPECT trial in patients with non-metastatic disease, adverse
events of Grade 3 or higher occurred in 31% of enzalutamide-treated patients
compared with 23% receiving placebo. The most commonly reported adverse
events occurring more frequently in the enzalutamide group included fatigue,
hot flush, hypertension, nausea and constipation (10).
From the AFFIRM trial in previously treated patients with mCRPC,
adverse events of Grade 3 or above were reported in 45.3% of patients in the
enzalutamide arm compared to 53.1% of placebo-treated patients. Enzalutamidetreated
patients experienced a higher incidence of any grade fatigue, diarrhoea,
hot flashes, musculoskeletal pain, headache and seizures compared to placebotreated
patients. Adverse events causing death occurred in 3% and 4% of
enzalutamide- and placebo-treated patients, respectively (3).
From the PREVAIL trial in chemotherapy naive patients with mCRPC,
adverse events of Grade 3 or more were reported in 43% of the patients in the
enzalutamide group, and 37% in the placebo group. Common adverse events
occurring at least 2% more frequently in the enzalutamide group included
fatigue, back pain, constipation and arthralgia (4).
In the COU-AA-301 trial, there were more deaths, treatment discontinuations,
and treatment discontinuations due to adverse events in the placebo arm versus
the abiraterone arm. Common adverse events occurring at similar frequency
between treatment groups were fatigue, back pain, nausea, constipation, bone
pain and arthralgia. Urinary tract infection was observed more frequently in
the abiraterone arm (5). The most common Grade 3 or greater adverse events
of special interest reported in the COU-AA-302 trial occurring more frequently
in the abiraterone arm were cardiac disorders (8% vs 4%), increased alanine
aminotransferase (6% vs <1%) and hypertension (5% vs 3%) (6).
A recent prospective randomized Phase II study (n=72) investigated the effect
of the administration of low dose abiraterone (250 mg daily) with a low-fat meal,
compared to standard dose abiraterone (1000 mg daily) administered under
fasting conditions (11). At 12 weeks, a greater effect on PSA was observed in the
low-dose arm compared with the standard dose arm (mean log change −1.59
vs −1.19) meeting the predefined non-inferiority criteria. The PSA response
rate was 58% and 50% in the low-dose and standard-dose arms, respectively.
Median PFS was approximately nine months in both groups. Androgen levels
decreased similarly in both arms. Abiraterone concentrations were higher in the
standard-dose group, yet there was no difference in PSA response or PFS. The
study authors considered these data could have significant pharmacoeconomic
implications and deserve consideration by prescribers, payers and patients.
However, the study also concludes that additional studies are required to
determine the long-term efficacy of this dosing strategy.
Cost / cost effectiveness
Many of the cost-benefit studies have been done using the prices from originator
companies. Both drugs are now also available from generic suppliers, and as
competition among generic suppliers expands, prices should decline considerably.
Before generic entry, some publicly quoted prices for the active
pharmaceutical ingredient enzalutamide were in the range of US$ 6000 to
US$ 13 000 per kg. At US$ 6000 per kg, the cost of the active pharmaceutical
ingredient (API) for one 40 mg capsule of enzalutamide would be US$ 0.24
(US$ 0.006 per mg).
Prices of generic abiraterone acetate vary. One company offers 120 x
250 mg abiraterone acetate tablets for approximately US$ 238.40. The price for a
unit of the API is US$ 7947 per kg and US$ 0.007947 per mg.
It is anticipated that API costs could decline to between US$ 300 and
US$ 900 per kg over time for both products, in line with prices for tamoxifen
(US$ 271 per kg), capecitabine (US$ 393 per kg) and prednisolone (US$ 962
per kg). A decline of that magnitude would result in API costs of US$ 0.012
to US$ 0.036 per 40 mg capsule, or US$ 0.048 to US$ 0.144 per day, for
enzalutamide, and US$ 0.075 to US$ 0.225 per 250 mg tablet or US$ 0.30 to
US$ 0.90 per day for abiraterone acetate (without prednisone).
Technology appraisal guidance issued by the National Institute for
Health and Care Excellence (NICE) for enzalutamide and abiraterone state that
these medicines are recommended treatment options people with metastatic
hormone-relapsed prostate cancer if the manufacturers provide the drugs at
agreed fixed or discounted prices (12, 13). Similarly, the National Centre for
Pharmacoeconomics in Ireland approved reimbursement for enzalutamide and
abiraterone only after price negotiations were conducted.
The application summarized numerous studies that investigated the
cost-effectiveness of enzalutamide and abiraterone, noting that many study
authors were affiliated with the pharmaceutical manufacturers at the time of
publication. The studies cited used the high originator prices and are of limited
use when considering whether these medicines would be cost-effective in
resource-limited settings, when and where the medicines available at lower
prices from generic suppliers.
Enzalutamide and abiraterone acetate have worldwide regulatory approval.
There are many generic versions of abiraterone acetate available, while only a
single generic version of enzalutamide.
Comments on the application were received from the WHO Department of
Management of NCDs, Disability, Violence and Injury Prevention. The technical
unit advised that it did not support the inclusion of abiraterone or enzalutamide
on the EML for management of castration-resistant prostate cancer at this time,
though noting with interest ongoing studies and more mature data that may
demonstrate significant benefit, particularly for overall survival.
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