Cost-effectiveness analysis of 7 treatments in metastatic hormone-sensitive prostate cancer: a public-payer perspective

Abstract

Background

Recently, several new treatment regimens have been approved for treating metastatic hormone-sensitive prostate cancer, building on androgen deprivation therapy alone. These include docetaxel androgen deprivation therapy, abiraterone acetate-prednisone androgen deprivation therapy, apalutamide androgen deprivation therapy, enzalutamide androgen deprivation therapy, darolutamide-docetaxel androgen deprivation therapy, and abiraterone-prednisone androgen deprivation therapy with docetaxel. There are no validated predictive biomarkers for choosing a specific regimen. The goal of this study was to conduct a health economic outcome evaluation to determine the optimal treatment from the US public sector (Veterans Affairs).

Methods

We developed a partitioned survival model in which metastatic hormone-sensitive prostate cancer patients transitioned between 3 health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan–Meier curves using a Bayesian network meta-analysis of 7 clinical trials (7208 patients). The effectiveness outcome in our model was quality-adjusted life-years (QALYs). Cost input parameters included initial and subsequent treatment costs and costs for terminal care and for managing grade 3 or higher drug-related adverse events and were obtained from the Federal Supply Schedule and published literature.

Results

Average 10-year costs ranged from $34 349 (androgen deprivation therapy) to $658 928 (darolutamide-docetaxel androgen deprivation therapy) and mean QALYs ranged from 3.25 (androgen deprivation therapy) to 4.57 (enzalutamide androgen deprivation therapy). Treatment strategies docetaxel androgen deprivation therapy, enzalutamide androgen deprivation therapy docetaxel, apalutamide androgen deprivation therapy, and darolutamide-docetaxel androgen deprivation therapy were eliminated because of dominance (ie, they were more costly and less effective than other strategies). Of the remaining strategies, abiraterone acetate-prednisone androgen deprivation therapy was the most cost-effective strategy at a willingness-to-pay threshold of $100 000/QALY (incremental cost-effectiveness ratios = $21 247/QALY).

Conclusions

Our simulation model found abiraterone acetate-prednisone androgen deprivation therapy to be an optimal first-line treatment for metastatic hormone-sensitive prostate cancer from a public (Veterans Affairs) payer perspective.

Prostate cancer accounted for more than 34 000 deaths in US males (1) and 325 000 deaths world-wide (2) in 2021. Since 2015, substantial progress has been made in the therapeutic landscape of metastatic hormone-sensitive prostate cancer starting with the publication of the ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) study results (3). This trial’s results re-established a new standard of care for treating metastatic hormone-sensitive prostate cancer after decades of androgen deprivation therapy alone. Combination docetaxel chemotherapy and androgen deprivation therapy in CHAARTED improved overall survival and slowed progression to metastatic castrate-resistant prostate cancer, a cancer progressive state that occurs after metastatic hormone-sensitive prostate cancer. Subsequent studies using combinations of novel hormonal therapeutic drugs with androgen deprivation therapy in metastatic hormone-sensitive prostate cancer have reported similar benefit for prolonging survival and slowing down progression to metastatic castrate-resistant prostate cancer state for combination strategies compared with androgen deprivation therapy alone. Clinical outcomes for abiraterone acetate-prednisone with androgen deprivation therapy (4-6), apalutamide with androgen deprivation therapy (7), and enzalutamide with androgen deprivation therapy (8) compared with androgen deprivation therapy alone have consistently favored combination therapies. Recently, triple combinations of darolutamide with androgen deprivation therapy and docetaxel chemotherapy compared with androgen deprivation therapy alone (9), abiraterone acetate-prednisone with docetaxel chemotherapy and androgen deprivation therapy compared with androgen deprivation therapy alone (10) and enzalutamide with docetaxel and androgen deprivation therapy compared with androgen deprivation therapy (11) have shown similar benefits for combination therapies. Combination drug therapies are now the preferred interventions over androgen deprivation therapy alone in metastatic hormone-sensitive prostate cancer (12,13).

Despite emergence of combination treatment regimens, there is inevitable universal progression to metastatic castrate-resistant prostate cancer and death (14). Combination treatments also increase drug-related adverse events and toxicities compared with androgen deprivation therapy alone. There are also no validated predictive biomarkers to choose a particular combination for preferential use over the other.

We conducted a cost-effectiveness analysis of all currently approved drug combinations in metastatic hormone-sensitive prostate cancer using data from randomized clinical trials to determine which current treatment regimen is the optimal approach to enhance quality of life without compromising on longevity of life. All randomized trials used in this analysis combined androgen deprivation therapy with either novel hormonal agents or with docetaxel or combined all 3 drug therapeutics. The comparator study arm was androgen deprivation therapy alone, except in 1 study (Prostate Cancer Consortium in Europe-1 [PEACE-1] study) (10) in which the triplet of novel hormonal drug agent abiraterone acetate-prednisone was combined with androgen deprivation therapy and docetaxel and was compared with abiraterone acetate-prednisone plus androgen deprivation therapy. Based on the overwhelming use of androgen deprivation therapy alone as the comparator arm, we used androgen deprivation therapy as a reference for conducting the cost-effectiveness analysis.

Methods

Study design overview

A decision analytic model was developed to illustrate the treatment option of patients diagnosed with metastatic hormone-sensitive prostate cancer using costs from the Department of Veterans Affairs (VA) taking a US public perspective. We estimated the cost and effectiveness of the 7 approved treatment strategies used for metastatic hormone-sensitive prostate cancer management: 1) docetaxel with androgen deprivation therapy (3); 2) abiraterone acetate-prednisone with androgen deprivation therapy (4,5); 3) apalutamide with androgen deprivation therapy (7); 4) enzalutamide with androgen deprivation therapy (8); 5) darolutamide with androgen deprivation therapy and docetaxel (9,15); 6) enzalutamide with androgen deprivation therapy and docetaxel (11); and 7) androgen deprivation therapy alone (see Table 1). The effectiveness measure was quality-adjusted life-years (QALYs), a measure that represents the degree to which a treatment extends life and improves quality of life. Costs included the direct costs of the drug and administration, monitoring and end-of-life, and a set of adverse drug events for each treatment. The time horizon of the study was 10 years with a cycle of 4 weeks, as the life expectancy of patients with metastatic hormone-sensitive prostate cancer rarely marks 10 years. Incremental cost-effectiveness ratios were calculated by dividing the difference in cost by the difference in effectiveness between nondominated treatment strategies. A half-cycle correction and a 3% annual discount rate were applied for both costs and effectiveness outcomes. The model was programmed in Tree-Age Pro 2023 (TreeAge Software, Williamstown, MA, USA), and Bayesian network meta-analyses were performed in R: The R Project for Statistical Computing (r-project.org).

Table 1.

List of treatment strategies in published randomized clinical trials^a

Treatment (trial)	No. of patients	Median PFS, mo	Median OS, mo
Docetaxel with androgen deprivation therapy (CHAARTED, ENZAMET)	646	25.6	61.0
Abiraterone acetate-prednisone with androgen deprivation therapy (LATITUDE, STAMPEDE, PEACE)	1452	38.2	58.8
Apalutamide with androgen deprivation therapy (TITAN)	525	37.0	81.5
Enzalutamide with androgen deprivation therapy (ARCHES, ENZAMET)	883	59.5	73.9
Darolutamide with androgen deprivation therapy and docetaxel (ARANSENS)	651	59.2	68.0
Enzalutamide with androgen deprivation therapy and docetaxel (ENZAMET)	254	43.4	63.3
Androgen deprivation therapy (previous SOC)	3922	23.4	48.9

^aOS = overall survival; PFS = progression-free survival.

Model structure

We constructed a decision analytic model to perform a partitioned survival analysis, which is a commonly used approach for cost-effectiveness analyses in oncology (16-18). The model included 3 health states: a progression-free, progression to metastatic castrate-resistant prostate cancer, and death (see Figure 1). The partitioned survival analysis simulates the probability that a patient is in each health state at each point in time, derived from the progression-free survival (PFS) and the overall survival (OS) curves from published clinical trials (see Table 2). All patients continued with the metastatic hormone-sensitive prostate cancer treatment strategy until disease progression to metastatic castrate-resistant prostate cancer or death. Our model performs cost analysis calculations for patients in the metastatic hormone-sensitive prostate cancer state until progression occurs based on the PFS curve estimated from the meta-analysis using published randomized clinical trials. On progression of the disease to the metastatic castrate-resistant prostate cancer state, we assumed patients would receive standard of care subsequent treatments with docetaxel (19,20), cabazitaxel (21), olaparib (22,23), lutetium-177 (24), and mitoxantrone (19,20) following the transition probabilities estimated using each of the PFS and OS curves. The duration for each metastatic castrate-resistant prostate cancer treatment was assumed to follow the median PFS of each treatment as published in the reported clinical trials that led to drug approvals in metastatic castrate-resistant prostate cancer: docetaxel for 6.3 months, cabazitaxel for 8 months, olaparib for 7.4 months, lutetium for 8.7 months, and 3.2 months for mitoxantrone.

Figure 1.

Health states with arrows depicting allowable transitions. *Input parameters including all costs, effectiveness, and utility scores are list in Table 3 and Supplementary Tables 2 and 3 (available online). mCRPC = metastatic castrate-resistant prostate cancer; mHSPC = metastatic hormone-sensitive prostate cancer.

Table 2.

Estimated parameters for Weibull distribution from network meta-analysis

Treatment (trial)	PFSa		OSa
	Shape	Scale	Shape	Scale
Docetaxel with androgen deprivation therapy (CHAARTED, ENZAMET)	1.64	76.25	1.23	34.45
Abiraterone Acetate-Prednisone with androgen deprivation therapy (LATITUDE, STAMPEDE, PEACE)	1.40	76.47	1.26	51.13
Apalutamide with androgen deprivation therapy (TITAN)	1.27	108.66	1.46	47.65
Enzalutamide with androgen deprivation therapy (ARCHES, ENZAMET)	1.60	92.85	1.16	81.70
Darolutamide with androgen deprivation therapy and docetaxel (ARANSENS)	1.40	88.41	1.06	83.56
Enzalutamide with androgen deprivation therapy and docetaxel (ENZAMET)	1.92	76.67	1.72	53.78
Androgen deprivation therapy (previous SOC)	1.52	62.28	1.15	32.18

^aOS = overall survival; PFS = progression-free survival.

Drug effectiveness: model survival and progression risk estimates

Kaplan–Meier curves for OS and radiographic PFS by intervention arm were extracted using WebPlotDigitizer (25). If data on radiographic PFS were not available, then data on clinical PFS or PFS were used as a proxy. The extracted survival curves, along with corresponding numbers of events and numbers at risk over follow-up, were converted into individual patient outcome data using an approach by Guyot et al. (26). Weibull survival models (26) were fit by maximum likelihood to OS and PFS data by intervention arm, using a fixed effect maximum likelihood approach to meta-analysis (27). The fixed effect approach was used given the limited replication of treatment comparisons across included studies.

Drug toxicities

We included adverse drug events for each treatment that were grade 3 or higher reported in clinical trials. Total treatment costs for adverse drug events were obtained from published literature (2,28-37) and were applied in the first cycle of the decision model. The total treatment cost of adverse drug events reflecting frequencies for each treatment strategy is summarized in Table 3, and a full list of adverse drug events and their frequencies included are attached in Supplementary Table 1 (available online).

Table 3.

Estimated input parameters: monthly costs and utility scores

Treatment strategy (trial)	Total cost			Annual utility weight
	Monthly FSS costa	Monthly average wholesale price costa	Total costs for adverse event (Reference)	Progression free (Reference)	Progressive (Reference)
Metastatic hormone-sensitive prostate cancer state
Docetaxel with androgen deprivation therapy (CHAARTED)	$506	$1305	$1745	0.830	0.725
			(34,36,37)	(38)	(39)
Abiraterone Acetate-Prednisone with androgen deprivation therapy (LATITUDE)	$562	$6591	$2923	0.830	0.725
			(2,32-35,37)	(38)	(39)
Apalutamide with androgen deprivation therapy (TITAN)	$11 504	$16 773	$1755	0.800	0.630
			(33-36)	(40)	(40)
Enzalutamide with androgen deprivation therapy (ARCHES)	$8063	$16 142	$5204	0.839	0.754
			(31,33-35,37)	(41)	(41)
Darolutamide with androgen deprivation therapy and docetaxel (ARASENS)	$10 953	$16 008	$2538	0.830	0.725
			(28,30-32,34,35,37)	(42)	(42)
Enzalutamide with androgen deprivation therapy and docetaxel (ENZAMET)	$8415	$16 905	$3124	0.830	0.725
			(2,28-37)	(41)	(41)
Androgen deprivation therapy (Reference arm)	$154	$542	$6965	0.830	0.600
			(2,28-37)	(41)	(43)
Castrate-resistant prostate cancer state treatments
Docetaxel (TAX327)	$352
Cabazitaxel (TROPIC)	$13 910
Olaparib (PROFOUND)	$20 147
Lutetium (VISION)	$23 459
Mitoxantrone (TAX327)	$400

^aCalculations based on 90.63 kg patient. FFS = Federal Supply Schedule.

Utility inputs

QALYs were calculated in the model by weighting the time spent in health states by a utility value, a health-related quality of life that ranges from 0 (death) to 1 (perfect health). Utility scores for each treatment strategy were derived from published literature that established these treatment strategies (38-43). Among the treatment strategies, the utility values ranged from 0.800 for apalutamide with androgen deprivation therapy (40) to 0.839 for enzalutamide with androgen deprivation therapy (41) for the progression-free health state and 0.600 for androgen deprivation therapy alone (43) to 0.754 for enzalutamide with androgen deprivation therapy (41) for the progression to metastatic castrate-resistant prostate cancer health state (Table 3).

Direct drug cost

Direct drug costs of the treatment strategies for metastatic hormone-sensitive prostate cancer and metastatic castrate-resistant prostate cancer were derived from the Federal Supply Schedule (FSS) pharmaceutical pricing data. FSS provides negotiated prices between drug companies and the VA, one of the largest consumers of pharmaceuticals in the United States. Drug costs from FSS would capture the actual burden of the treatments better than the list price of the drug. All direct drug costs were estimated on the basis of a 90.63 kg patient weight. Average administration costs of $208, derived from the Center of Medicare and Medicaid Services physician fee schedule, were added to the total direct costs for parenterally administered drugs. Monthly direct costs of each treatment are summarized in Table 3, and the unit costs and dosages of each drug for the 7 treatments are summarized in Supplementary Table 2 (available online).

Monitoring, postprogression, and end-of-life costs

Costs included costs for monthly monitoring of disease state, costs for administration of parenterally administered therapies and oral therapies (44), costs for performing bone scintigraphy studies and computed tomography scans of the abdomen and pelvis with contrast, and serial prostate-specific antigen tests. Costs for mitoxantrone were also included for patients who had progression of the disease following a series of metastatic castrate-resistant prostate cancer treatments, and the cost of the final month of life was assigned at death (45). Monitoring, postprogression, and end-of-life costs are summarized in Supplementary Table 3 (available online). All costs were adjusted to 2021 US dollars using the Personal Consumption Expenditures Price Index for health-care services.

Sensitivity analyses

The primary partitioned survival analysis was conducted using the point estimates for each input parameter. To examine the sensitivity of these results to drug costs, we also analyzed our model using drug costs obtained from the average wholesale price. We also performed a one-way sensitivity analysis on the drug cost parameter to identify the threshold at which treatments that are more effective at higher costs would become cost-effective at a willingness-to-pay threshold of US$100 000/QALY. Probabilistic sensitivity analysis was performed to assess the impact of uncertainty in drug, adverse drug events, and maintenance treatment costs and utilities. Utility scores were assumed to follow a beta distribution, and cost estimates were assumed to follow a gamma distribution, each with 50% variation (46).

Results

A total of 7208 patients were included from the network meta-analysis for which the cost-effectiveness analysis was performed. Estimated median OS and PFS rates, as well as estimated Weibull parameters from the meta-analysis, are provided in Tables 1 and 2. The results from the primary partitioned survival analysis using transition probabilities determined by the estimated survival functions showed that the estimated 10-year total costs ranged from $34 349 (androgen deprivation therapy) to $658 928 (darolutamide with androgen deprivation therapy and docetaxel) (Table 4). Estimated 10-year QALYs were highest for enzalutamide with androgen deprivation therapy (QALY = 4.57) and the lowest for androgen deprivation therapy (QALY = 3.25). Docetaxel with androgen deprivation therapy, enzalutamide with androgen deprivation therapy and docetaxel, apalutamide with androgen deprivation therapy, and darolutamide with androgen deprivation therapy and docetaxel were eliminated from consideration because they were less effective and more costly than either androgen deprivation therapy, abiraterone acetate-prednisone with androgen deprivation therapy, or enzalutamide with androgen deprivation therapy (dominance) or their linear combination (extended dominance). The incremental cost-effectiveness ratio for abiraterone acetate-prednisone with androgen deprivation therapy compared with androgen deprivation therapy was $21 247/QALY, and hence, abiraterone acetate-prednisone with androgen deprivation therapy was the most cost-effective treatment strategy for metastatic hormone-sensitive prostate cancer at a willingness-to-pay threshold of $100 000/QALY.

Table 4.

Results of base case cost-effectiveness analyses stratified by perspective

Treatment strategy	Cost (2021 US$)	Effectiveness (QALYs)	Incremental cost-effectiveness ratios (US$/QALY)
Veterans Affairs perspective
Androgen deprivation therapy alone	34 349	3.25
Abiraterone acetate-prednisone with androgen deprivation therapy	46 560	3.83	21 247
Enzalutamide with androgen deprivation therapy	488 445	4.57	597 089
Docetaxel with androgen deprivation therapy	48 471	3.79	Dominateda
Enzalutamide with androgen deprivation therapy and docetaxel	402 930	3.99	Dominatedb
Apalutamide with androgen deprivation therapy	483 540	4.16	Dominatedb
Darolutamide with androgen deprivation therapy and docetaxel	658 928	4.29	Dominateda
Average wholesale price perspective
Androgen deprivation therapy alone	45 439	3.25
Docetaxel with androgen deprivation therapy	72 471	3.79	50 389
Enzalutamide with androgen deprivation therapy	955 785	4.57	1 134 913
Abiraterone acetate-prednisone with androgen deprivation therapy	301 030	3.83	Dominatedb
Apalutamide with androgen deprivation therapy	692 614	4.16	Dominatedb
Enzalutamide with androgen deprivation therapy and docetaxel	777 484	3.99	Dominateda
Darolutamide with androgen deprivation therapy and docetaxel	950 169	4.29	Dominatedb

^aThis treatment strategy is more costly and less effective than another treatment strategy (ie, absolute dominance). QALYs = quality-adjusted life-years.

^bThis treatment strategy is more costly and less effective than a linear combination of other treatment strategies (ie, extended dominance).

One-way sensitivity analysis on the drug cost for enzalutamide showed that enzalutamide with androgen deprivation therapy became the most cost-effective treatment strategy at willingness-to-pay of $100 000/QALY if its monthly price is reduced from $7909 to $1550 (Supplementary Figure 1.1, available online). Docetaxel with androgen deprivation therapy was eliminated from consideration because its 10-year total QALY (3.79) was lower at a higher cost ($48 471) than abiraterone acetate-prednisone with androgen deprivation therapy (QALY = 3.83; $46 560), however, docetaxel with androgen deprivation therapy could become a cost-effective option if the drug and administration cost for docetaxel decreased from $352 to $161 while all other input parameters remained the same (Supplementary Figure 1.2, available online). Finally, when considering a range of costs for androgen deprivation therapy ($0-$1500), docetaxel with androgen deprivation therapy becomes the most cost-effective treatment strategy at a willingness-to-pay of $100 000/QALY if the drug cost of androgen deprivation therapy is $626, which is considerably higher than its baseline value ($154) (Supplementary Figure 1.3, available online).

In models using average wholesale price for drug costs, docetaxel with androgen deprivation therapy was the most cost-effective strategy with an incremental cost-effectiveness ratio of $50 389/QALY compared with androgen deprivation therapy (Table 4). All other treatment strategies including abiraterone acetate-prednisone with androgen deprivation therapy were eliminated from consideration because they were less effective and more costly than androgen deprivation therapy, docetaxel with androgen deprivation therapy, enzalutamide with androgen deprivation therapy, or their linear combination. In one-way sensitivity analyses, the monthly cost of abiraterone acetate-prednisone would need to decrease from $6049 to $724 for abiraterone acetate-prednisone with androgen deprivation therapy to be the most cost-effective treatment strategy compared with androgen deprivation therapy (Supplementary Figure 2, available online).

Results from our probabilistic sensitivity analysis are presented in cost-effectiveness acceptability curves (Figures 2, A and B). These results show that abiraterone acetate-prednisone with androgen deprivation therapy was most frequently the cost-effective treatment strategy for willingness-to-pay thresholds of $100 000/QALY (in 26% of the iterations) and $200 000/QALY (in 33% of the iterations), followed closely by docetaxel with androgen deprivation therapy (Figure 2, A). Probabilistic sensitivity analysis from the model using the average wholesale price shows that docetaxel with androgen deprivation therapy was most frequently the cost-effective treatment strategy (in 36%-45% of the iterations) for willingness-to-pay thresholds of $100 000/QALY and $200 000/QALY (Figure 2, B).

Figure 2.

A) Cost-effectiveness acceptability curve from probabilistic sensitivity analysis (Veterans Affairs Federal Supply Schedule costing). B) Cost-effectiveness acceptability curve from probabilistic sensitivity analysis (average wholesale price costing). AAP = abiraterone acetate-prednisone with androgen deprivation therapy; AAT = apalutamide with androgen deprivation therapy; ADT = androgen deprivation therapy; DA = docetaxel with androgen deprivation therapy; DAD = darolutamide with androgen deprivation therapy and docetaxel; EAD = enzalutamide with androgen deprivation therapy and docetaxel; ET = enzalutamide with androgen deprivation therapy.

Discussion

The treatment landscape for metastatic hormone-sensitive prostate cancer with androgen deprivation therapy alone in 2015 has rapidly evolved to combination androgen deprivation therapy–based treatment with several novel hormonal therapies and/or chemotherapy doublets or triplet combinations. This evolution pace has been rapid between 2015 and 2022, and at the same time, none of the treatment regimens have been compared head-to-head for superiority in a structured randomized controlled trial. There are also no validated predictive molecular biomarkers for choosing a specific treatment regimen. In this environment, providers have no other option but to base treatment decisions on empiric clinical judgements and expert opinions. Because several of these new combinations are costly and have associated treatment toxicity, our goal was to quantify these trade-offs to identify the optimal combination that preserves quality of life without compromising longevity of life. Although there are some differences in the inclusion criteria among the published metastatic hormone-sensitive prostate cancer state trials, with some trials having a higher percentage of high-volume metastatic hormone-sensitive prostate cancer patients, clinical practice for treating metastatic hormone-sensitive prostate cancer is based on the National Comprehensive Cancer Network guidelines. These guidelines include as category 1 (prostate.pdf [nccn.org]), all of the listed combinations that were analyzed in our cost-effectiveness analysis. Our analyses thus assumes that the decision to use any of the systemic combination therapy choices at present in an individual patient will be in line with the guidelines considered to be standard of care. We used a public payer perspective in the United States and found that the combination abiraterone acetate-prednisone with androgen deprivation therapy was the most cost-effective treatment strategy in this trade-off with the highest QALY and the most optimum incremental cost-effectiveness ratio (dollars per QALY). However, we also observed that in a probabilistic sensitivity analysis at a willingness-to-pay of $100 000/QALY to $200 000/QALY apart from abiraterone acetate-prednisone with androgen deprivation therapy combination, other combinations including androgen deprivation therapy combinations with docetaxel could also be a candidate for optimal cost-effective treatment strategies.

Of note, these results differ to some extent from other published studies investigating cost effectiveness in metastatic hormone-sensitive prostate cancer state performed with a 30-year time horizon in other countries including Canada and Europe. In a cost effectiveness study conducted in Europe on metastatic hormone-sensitive prostate cancer treatments, which took into account doublets with docetaxel, abiraterone, apalutamide, or enzalutamide and also costs for only 1-2 metastatic castrate-resistant prostate cancer state downstream treatments (47), different results were observed. This study found that the combination of androgen deprivation therapy with abiraterone-acetate and prednisone to be most cost-effective, although the input parameters in this study for reaching the derived cost effectiveness differs from our study when we use average wholesale price costs and also from the perspective of costs and number of downstream treatments. Yet, we do find similarities in conclusions when we consider using VA-FSS costs with this published report, which includes only 1-2 lines of downstream metastatic castrate-resistant prostate cancer treatment costs, while we considered more numbers of sequential metastatic castrate-resistant prostate cancer treatments in our analysis. In another cost effectiveness study, using a cost analysis with the Canadian health-care system comparing only androgen deprivation therapy with apalutamide with androgen deprivation therapy in metastatic hormone-sensitive prostate cancer, androgen deprivation therapy alone was found to be more cost effective at a willingness-to-pay $100 000, unless there were substantial cost reductions in the price for apalutamide (40). We also observe that in a study conducted in the United States with VA-FSS cost structures, a different conclusion from ours was observed after analyzing cost-effectiveness for only 5 doublets in metastatic hormone-sensitive prostate cancer, which had been published at the time of that analysis. This study concluded that the most cost-effective treatment was docetaxel with androgen deprivation therapy when using a willingness-to-pay threshold of $50 000/QALY and abiraterone acetate with androgen deprivation therapy when using a willingness-to-pay threshold of $200 000/QALY (48), although this is likely because metastatic castrate-resistant prostate cancer treatment inputs were not considered as extensively as in our study. In our study, we purposefully included metastatic castrate-resistant prostate cancer drug costs of subsequent antineoplastic standard of care treatments that are now widely available and used, because most metastatic castrate-resistant prostate cancer patients undergo treatment intensification with sequential drug regimens (49,50).

In fact, the variation in input parameters as well as differences in the configurations of treatment combination studied may explain the differences in results across these and other cost-effectiveness approaches. Our study is the largest cost effectiveness analysis in metastatic hormone-sensitive prostate cancer state and includes all available and recent drug combinations approved to treat metastatic hormone-sensitive prostate cancer, including triplet combinations (6,9,15). We also include costs of multiple downstream treatments following progression to castrate-resistant prostate cancer state including recently approved Lu-177 (24) and poly(adenosine diphosphate-ribose) polymerase inhibitor (22) regimens along with costs of monitoring treatment effects and end-of-life care. Many of these input variables were lacking in previous reports (40,47,48). Finally, additional factors to consider in cost effectiveness analyses is the price disparities in different countries and insurer and/or payment systems, not only for drug acquisition costs but also for the management of toxicities, and the number of downstream castrate-resistant prostate cancer treatments, which can impact effectiveness results.

A limitation of our study is that drug costs vary substantially across payers in the United States, particularly between private and public payers, therefore, the results of these analyses are not generalizable across the United States and are largely restricted to VA-FSS. Although this study did not consider the private payer perspective, the drug cost estimates from VA-FSS reflects actual burden in public sector better than the average wholesale price, which is the most commonly used data source for drug costs in cost-effectiveness analyses in oncology. The optimal combination can indeed be different while applying nonpublic payer systems, which in the United States is difficult to estimate as multiple private payer systems exist, and cost figures are not always available for analyses.

Nevertheless, economic evaluation is a critical decision-making tool in the management of cancer therapeutics when multiple therapeutic options are available and no biomarkers exist for choosing a regimen and provide better guidance than clinical estimates alone or if head-to-head trials between treatment strategies are missing. In that context, our results may aid in deciding how to choose individualized treatments without compromising standards of care established for treatment metastatic hormone-sensitive prostate cancer state.

Data availability

All data are incorporated into the article and its online supplementary material (available online).

Author contributions

Minkyoung Yoo, PhD (Data curation; Formal analysis; Funding acquisition; Investigation; Writing—original draft; Writing—review & editing), Richard E. Nelson, PhD (Data curation; Formal analysis; Investigation; Methodology; Project administration; Writing—review & editing), Benjamin Haaland, PhD (Formal analysis; Investigation; Methodology; Writing—review & editing), Maura Doughtery, BS (Formal analysis; Investigation; Writing—review & editing), Zachary Cutshall, BS (Data curation; Investigation; Writing—review & editing), Rhea Kohli, MPH (Data curation; Formal analysis; Writing—review & editing), Rylee Beckstead, BS (Data curation; Formal analysis; Investigation; Writing—review & editing), and Manish Kohli, MD (Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Supervision; Writing—original draft; Writing—review & editing).

Funding

This work was supported by the University of Utah Matheson Center for Health Care Studies and the University of Utah Clinical & Translational Science Institute with funding from the National Cancer Institute/National Center for Advancing Translational Sciences (NCATS) (grant number 1UM1TR004409-01).

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

No funder/agency played a role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.