Critical Appraisal of Economic Evaluation study by

Sung et al., (2021) titled: “A Cost-Effectiveness

Analysis of Systemic Therapy for Metastatic
Hormone-Sensitive Prostate Cancer”

By

Emmanuel Ikechukwu Emesowum

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Health Economics
UPGPBHM05-38986

9th July, 2022.

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Introduction
In 2016, prostate cancer was the most prevalent cancer among men worldwide, with 1.4 million
patients and 381 000 deaths (Fitzmaurice et al., 2018, p. 1553). In 2021, prostate cancer is
projected to be the leading cause of cancer and the second most common cause of cancer-
related deaths among men in the United States, accounting for 26 percent and 11 percent of all
tumor sites, respectively (Siegel et al., 2021, p.7). Patients can present with de novo metastatic
prostate cancer, despite the fact that most men are diagnosed with localized, curable disease
(Pelloux-Prayer et al., 2022). Treatment for localized prostate cancer may cause recurrence or
metastasis in some men. Patients with metastatic hormone-sensitive prostate cancer (mHSPC)
are those who have metastasized but are still responding to hormone therapy (Sung, et al., 2021,
p.627083). Androgen deprivation therapy (ADT) was the only treatment option available to
these patients until recently.
Men are diagnosed with prostate cancer at a rate of one out of every five in the United States,
making it the most commonly diagnosed and deadliest form of cancer in men (Siegel et al.,
2021, p.7). Although the prevalence of prostate cancer is declining, the prevalence of metastatic
prostate cancer is rising (Weiner et al., 2016, p. 395). The 5-year survival rate for patients with
metastatic prostate cancer is 30.5% (NIH, 2020). While androgen deprivation therapy remains
the cornerstone treatment for metastatic hormone-sensitive prostate cancer, new evidence
supports the addition of novel agents such as chemotherapy or inhibitors of the androgen
receptor pathway (Sung, et al; 2021, p.627083).
Over the past six years, a number of studies have shown that patients with metastatic hormone-
sensitive prostate cancer benefit from intensifying androgen deprivation therapy with
additional treatment. Docetaxel (James et al., 2016, p.1163), abiraterone acetate plus
prednisone (Fizazi et al; 2017, p.352), and enzalutamide (Davis et al., 2019, p.13) have been
demonstrated to improve overall survival in mHSPC setting (Chi et al., 2019, p.381).

Thus, the availability of these innovative but costly treatments has significantly altered the
management of hormone-sensitive metastatic prostate cancer, thereby increasing the economic
burden of prostate cancer (Beer et al., 2014, p. 424). While this evolution in treatment is
essential from the patient's perspective, it suggests that clinicians now have more options for
treatment selection and treatment sequences (Pelloux-Prayer et al., 2022). Treatment choices
must now be individualized based on indirect comparisons of efficacy data from multiple
studies, taking into account the disease, the treatment's expected impact, and the cost
reimbursement within the healthcare setting (Schnipper et al., 2015, p. 2563).

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There are no direct comparisons of different agents, and a randomized controlled trial
comparing all agents is unlikely to be feasible (Sung, et al., 2021, p.627083). Castration-naive
patients now have additional treatment options, which has complicated the search for the most
effective regimen for metastatic hormone-sensitive prostate cancer (Sung, et al., 2021,
p.627083). To date, network meta-analyses have not provided a definitive answer. According
to Sathianathen et al., (2020, p. 365), different combination strategies are statistically
equivalent, with none being notably superior.

In the context of rational decision-making in healthcare, which is an integral component of

health technology assessment, the economic evaluation of healthcare products has evolved into
a necessity. Economic Evaluations are becoming more influential in decision-making and the
reimbursement of new medications in many countries, including Australia, Canada, and the
United Kingdom. (Greenberg et al., 2010, p.82).

Consequently, the purpose of this study was to critically appraise the quality of Sung et al.,
(2021, p.627083). Economic Evaluation regarding the treatment of hormone-sensitive
metastatic prostate cancer. The title of their study is "A Cost-Effectiveness Analysis of
Systemic Therapy for Hormone-Sensitive Metastatic Prostate Cancer." A greater knowledge
of these treatments and improved and efficient utilization of scarce healthcare resources will
be made possible thanks to the findings of this critical appraisal.

Discussion
Recent years have seen a significant shift in the allocation of healthcare resources based on the
results of economic evaluations and their outcomes. The availability of cutting-edge but costly
treatments in metastatic prostate cancer, particularly in HSPC, is linked to both higher costs
and new therapeutic opportunities (Pelloux-Prayer et al., 2020). In order to provide relevant
results for everyday practices and informed decisions, this study allowed the authors to identify
and perform full Economic Evaluations (Cost-Effectiveness Analysis) of high quality (Sung et
al., 2021), which is recommended by many institutions regardless of whether health-related
quality of life is identified as a significant health effect of interventions (Department of
Economics and Public Health Assessment, 2012) and CADTH (2020).
There were three independent reviewers who assessed the quality of the study using the same
criteria, with perfect agreement and a final score based on consensus in Sung et al. study.
Economic Evaluation of Sung et al found that androgen deprivation therapy + enzalutamide
was less cost-effective than androgen deprivation therapy + abiraterone acetate or androgen
deprivation therapy + docetaxel at the Willingness - to - pay threshold (€83 423.7/QALY), with
an incremental cost-utility ratio of €425 304.9/QALY and €163 843.8/QALY, respectively.

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Moreso, androgen deprivation therapy + apalutamide is more cost-effective than androgen
deprivation therapy + enzalutamide, according to Sung et al, with an incremental cost-utility
ratio of €67 223.7/QALY at the Willingness - to - pay threshold of €83 423.7/QALY.

Table 1 below shows the overall quality of the Economic Evaluation by Sung et al. (2020)
study to be high, with a median Drummond "yes" score of 8.6 (86%). With a quality rating of
between 7 and 10, the evidence from the Economic Evaluation certainly qualifies as having
high quality. This can be attributed to the recent publication of this Economic Evaluation, as
well as the improved dissemination and adoption of methodological guidelines. Nevertheless,
despite the fact that the methods and results sections did not address all of the questions on the
Drummond checklist, the results are consistent with those of other Economic Evaluations. The
evaluation of the methodological quality of health Economic Evaluations can be challenging
due to the possibility of subjectivity and the reviewer's influence.
Table 1: Percentage of “Yes” and "No" for each of the 10 questions of the Drummond’s checklist

Drummond Question Yes No Comments

The study examined both costs and effects of the treatment options and
Q1 Was a well-defined question posed in answerable form 100% 0% compared all alternatives. When evaluating the costs and health effects
of treating mHSPC, a Markov state-transition model was developed.
Q2 Was a comprehensive description of the competing alternatives given ? 100% 0% Yes, very comprehensively
Q3 Was the effectiveness established ? 100% 0% Very well established
Q4 Were all the important and relevant costs and consequences for each alternatives
identified ? 86% 14% To a large extent

Q5 Were costs and consequences measured accurately in appropriate physical units ? 86% 14% To a large extent

Q6 Were the costs and consequences valued credibly ? 100% 0% The valuation of consequences were appropriate for the question posed
Q7 Were costs and consequences adjusted for differential timing ? 71% 29% The justification given for the discount rate used was not convincing
Q8 Was an incremental analysis of costs and consequences of alternatives performed
? 71% 29% To some extent
Insufficient justification applied for the sensitivity analysis provided for
Q9 Was allowance made for uncertainty in the estimates of costs and consequences ? 43% 67% the range of values
Q10 Did the presentation and discussion of study results include all issues of concern The study did not sufficiently discuss the generalisability of the results to
to users ? 71% 29% other settings and patient groups
Median Score 86% 14%

As a result of the introduction of second-generation anti-androgens for metastatic hormone-

sensitive prostate cancer to Europe in 2020, Sung et al. published the Economic Evaluation in
2021. For the first-line treatment of metastatic hormone-sensitive prostate cancer, this is in line

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with the European label market's indications, which only recently indicated apalutamide and
enzalutamide (in 2020 and 2021, respectively).

Androgen deprivation therapy + docetaxel appears to be the most cost-effective strategy for
the first-line treatment of patients with metastatic hormone-sensitive prostate cancer at the
WTP threshold of 30 to 50 000 €/LY or QALY. According to the Economic Evaluations
conducted by Sung et al (2021, p.627083), Chiang et al., (2020, p.108) and Aguiar et al., (2020,
p.627083), only a price reduction of abiraterone acetate, enzalutamide, or apalutamide will
change this conclusion (2019, p.17). In the near future, generic versions of AA, enzalutamide,
and apalutamide are expected to be introduced in Europe, which will result in a price reduction
of 70%, according to Pelloux-Prayer et al., (2022).

Except for androgen deprivation therapy + docetaxel or androgen deprivation therapy alone
(the standard treatment), androgen deprivation therapy + abiraterone acetate appears to be the
most cost-effective innovative treatment. According to the Economic Evaluation conducted by
Sung et al., this is the most cost-effective option. The results of their sensitivity analysis
confirmed this, showing that androgen deprivation therapy + abiraterone acetate was the most
preferred option across credible ranges of parameters at a Willing-to-Pay threshold of €83
423.7/QALY gained (Sung, Choi et al., 2021, p.627083). The modern perspective of this
Economic Evaluation, as noted by Pelloux-Prayer et al., (2022) explains these outcomes.
Recent declines in the cost of anti-amyloidosis and new data from Randomized Clinical Trials
permit more accurate extrapolation of efficacy data and costs compared to other Economic
Evaluations.

In this published Economic Evaluation, the focus was solely on metastatic hormone-sensitive
prostate cancer (mHSPC) treatment, or first- or second-line treatment for metastatic castrate-
resistant prostate cancer. None have been based on a treatment progression from first-line to
subsequent lines. According to Pelloux-Prayer et al., (2022), the future will be characterized
by increased availability of second-generation antiandrogens at higher prices. This
diversification will enable the development of novel therapeutic strategies, with successive
treatment lines constituting a therapeutic sequence. Nevertheless, new expenses must also be
considered. To be more useful to practitioners, it is necessary to determine the most cost-
effective and efficient therapeutic sequence. For patients with metastatic hormone-sensitive
prostate cancer who have progressed to metastatic castration-resistant prostate cancer only one
Economic Evaluation has been published (Pelloux-Prayer, Schiele et al., 2021, pp. e326).

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The economic evaluation by Sung et al is limited in several ways. Initially, outcome data were
extracted from randomized controlled trials and a network meta-analysis. The patient selection
criteria used in these trials may limit the applicability of the results to clinical practice in the
real world. Second, drug prices differ across health care systems and are anticipated to fluctuate
over time. For example, the introduction of generic abiraterone has clearly resulted in a lower
incremental cost per QALY gained, making it a cost-effective treatment choice (Pelloux-
Prayer, Schiele et al., 2021, pp. e326). In addition, the model's drug costs were derived from
the VA, whose costs are generally lower and more accurately reflect the drug's actual economic
value, whereas prices paid by private payers and Medicare tend to be inflated. The authors
conducted sensitivity analyses to account for the wide cost value variation. Thirdly, the authors
omitted radiotherapy from their comparison despite its demonstrated value in low-volume
disease (Sathianathen et al., 2020, p. 372). Furthermore, the future availability of new first-line
drugs like darolutamide and the results of RCTs like ENZAMET, ARCHES, and TITAN
(enzalutamide and apalutamide) will undoubtedly be connected to new therapeutic strategies,
novel therapeutic sequences, and additional costs for metastatic hormone-sensitive prostate
cancer. (Armstrong et al., 2019, p. 2974).

In addition, all Economic Evaluations of this study evaluated the effects of androgen
deprivation THERAPY alone, the conventional dual therapy androgen deprivation therapy +
docetaxel, and second-generation antiandrogens. There is still a lack of data on overall survival
for the androgen deprivation therapy + docetaxel + AA triple therapy, but preliminary results
show a significant increase in radiological progression-free survival (Fizazi, Maldonado et al.,
2021, p. 2021).

Androgen deprivation therapy + docetaxel + darolutamide results are also expected to be

published within the next two years, as well (NIH, 2021). If both trials are successful in terms
of overall survival, the economic burden will undoubtedly increase. It would be advantageous
to conduct additional Economic Evaluations to examine the cost-effectiveness or cost-utility
of these treatment lines, not only for a single treatment line but also in terms of treatment
sequences. This would allow for the determination of the most cost-effective strategy for
treating metastatic prostate cancer. In light of the availability and coverage of these new
treatments for metastatic hormone-sensitive prostate cancer, this evaluation will also need to
be revised.

At a Willingness-to-Pay threshold of $100,000 per QALY gained, abiraterone plus androgen

deprivation therapy is the preferred treatment based on the results of the economic evaluation

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Conclusions
In conclusion, first-line treatment with abiraterone and androgen deprivation therapy costs US
$38,897 per QALY gained, and abiraterone plus androgen deprivation therapy is favoured by
US payers at a Willingness - to - pay threshold of US$100,000 per QALY gained (Sung et al.,
2021). The overall high quality of the economic evaluation is demonstrated by the median
Drummond score of 8.6 (86 percent), which corroborates the evidence presented above.

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