With the rapid aging of the Chinese population, the incidence rate of prostate cancer (PCa) has soared, placing it ninth among male malignant tumors in China (1). In 2022, the incidence rate reached 9.7 per 100,000, while the mortality rate stood at 4.5 per 100,000, ranking seventh among all male malignant tumors (2). Globally, PCa treatment poses a significant financial burden. In 2021, the global age-standardized rates for incidence, mortality, and disability-adjusted life years were 348.8, 177.93 and 2513.84 per 100,100, respectively (3). In the United States, the cost burden attributable to metastatic PCa exceeds $55,000 per person-year among men with employer-sponsored health insurance and $43,000 among those covered by employer-sponsored Medicare supplement plans (4). Similarly, projections indicate that the incidence and mortality of PCa in China are expected to continue increasing over the next decade, reaching an estimated 315,310 new cases and 81,540 deaths by 2030 (5).

Androgen-deprivation therapy (ADT) is the primary treatment option for locally advanced or metastatic PCa. Among the non-surgical ADT options, degarelix and luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin, leuprorelin, and triptorelin, are the most widely used. Although numerous studies (6–8) have investigated the cost-effectiveness of degarelix and LHRH agonists in treating PCa, a comprehensive systematic review of economic evaluations encompassing degarelix and these three LHRH agonists is currently absent. Therefore, it is imperative to conduct a thorough and systematic evaluation and analysis of the existing economic research evidence for degarelix and LHRH agonists. This will enable us to assess their cost-effectiveness for PCa patients and provide valuable insights to support clinical rational drug use and medical insurance decision-making.

This systematic review and meta-analysis adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure a high standard of quality (9, 10). No ethics approval or patient consent was necessary for conducting this analysis. The protocol has been registered on the PROSPERO website (Registration number: CRD420250653923).

In this systematic review, thirteen studies that examined the cost-effectiveness of degarelix and various LHRH agonists-specifically goserelin, leuprorelin, and triptorelin for the treatment of PCa were identified. Primarily conducted in developed countries and focusing on adult patients, these studies collectively suggest that degarelix may be a more cost-effective option for PCa treatment compared to goserelin, leuprorelin, and triptorelin. Among the three LHRH agonists, the 6-month depot formulation of triptorelin may be the cost-effective strategy.

Pca boasts a longer natural survival period compared to other types of malignancies. Endocrine therapy for Pca has been in practice for over 70 years, and despite the advent of newer therapies, ADT continues to be the cornerstone of its treatment. Studies have demonstrated that endocrine therapy is effective in prolonging the survival of patients; notably, one study reported a median survival time of 7.81 years for Pca patients undergoing endocrine therapy (23). This particular study presents the inaugural pharmacoeconomic evaluation of degarelix and three types LHRH agonists, analyzed from the healthcare system's perspective. It addresses a significant research gap in this domain and provides valuable, evidence-based insights that can inform clinical practice and promote the judicious use of medications.

The role of funders in conducting research is essential to guarantee that readers can accurately identify potential biases. Seven studies (13–16, 18–20) in our analysis were funded by pharmaceutical companies. Additionally, two studies (7, 8) did not reveal their funding sources, although some of their authors were employed by pharmaceutical companies. Meanwhile, two studies (6, 17) received support from national institutes. Potential impacts of industry sponsorship may include, for example, study designs that tend to highlight the advantages of the sponsor's product, the selection of outcome measures that may favor the intervention group, or selective analysis and reporting of results. At the same time, it should be objectively noted that not all industry-sponsored studies are inherently biased, as some still adhere to rigorous methodological standards. We have assessed the methodological quality of such studies using systematic evaluation tools (such as the QHES and CHEERS assessment tool). However, due to the limited number of such studies or inconsistent reporting of results, quantitative synthesis was not feasible, and therefore the potential influence of sponsorship-related bias on the overall conclusions cannot be entirely ruled out.

Lu et al. (17) yields a contradictory conclusions for the following reasons: (a) the country/region assessed and its drug pricing. The study explicitly states that if the price of degarelix were reduced by 10%, the ICER would drop sharply from £59,000 to £31,000 per QALY. If the price were reduced by 30%, degarelix would become the more cost-effective option. This highlights the central role of the UK market price in 2011 in the study's conclusion; (b) lower or no consideration of the risk of initial treatment-related adverse events. The model assumes that among patients who experience spinal cord compression, the proportion of severe (paralysis-causing) vs. mild cases is split 50%/50%. This proportion is based entirely on local clinician opinion and lacks data support. Sensitivity analysis shows this parameter is a key driver of the results; (c) use of different comparator regimens (e.g., different LHRHa or antiandrogen drugs).

The study conducted by Rezaee et al. adopts a societal perspective, encompassing not only direct medical costs but also direct non-medical costs and indirect costs. The results indicate that the higher “other costs” and direct non-medical costs in the triptorelin group were the primary drivers of its elevated total cost. This fundamentally differs from many studies that focus solely on the healthcare system perspective, concentrating primarily on drug pricing and hospitalization expenses. The study employs a willingness-to-pay threshold based on Iran's per capita GDP (13,116 international dollars), which is significantly lower than thresholds commonly used by institutions like NICE (e.g., £20,000–£30,000 per QALY). This directly influences the criteria for determining “cost-effectiveness”. Iran's drug pricing system, reimbursement rates, and patient out-of-pocket payment structure differ markedly from those in developed countries. The text mentions that although nearly all patients have health insurance, the high direct treatment costs are still primarily borne by the patients themselves. This highlights that drug pricing and the structure of insurance coverage are key drivers of the cost outcomes.

Although this study employed a qualitative synthesis approach rather than conducting traditional quantitative meta-analysis, this decision was primarily due to significant heterogeneity among the included studies in terms of model structure, cost parameters, and time horizon. The included studies utilized various analytical models, such as cost-effectiveness analysis, cost-minimization analysis, budget impact analysis, or Markov models, with variations in state definitions, transition probabilities, and cycle lengths. The estimation of direct medical costs, direct non-medical costs, and indirect costs across studies relied on localized data from different countries or regions and different years. The time frames of the studies ranged from 1 year to 30 years, affecting the discounting and accumulation of costs and outcomes. Given the heterogeneity described above, conducting direct statistical pooling or effect size aggregation could potentially yield misleading results. Therefore, we make a narrative synthesis to systematically summarize and compare the main findings, key assumptions, and conclusions across the studies.

The majority of studies included in this review were conducted in high-income countries, where the structure of the healthcare system, drug pricing mechanisms, clinical practice norms, willingness-to-pay thresholds (typically $20,000–$30,000 per QALY or higher), and local parameters used in cost-effectiveness assessments are highly context-specific. There are orders-of-magnitude differences between low- and middle-income countries and high-income countries in terms of drug prices, healthcare service costs, per capita income, and official willingness-to-pay thresholds (often based on 1–3 times GDP per capita). Interventions deemed “cost-effective” in high-income countries may impose a disproportionately high economic burden in low- and middle-income countries. Limited healthcare resources, low insurance coverage, high patient out-of-pocket expenses, and varying accessibility to different clinical pathways can significantly alter the actual costs and outcomes of interventions. Variations in disease staging, comorbidities, treatment adherence, and the choice of comparator treatments may affect the comparative efficacy of interventions.

Heterogeneity arises from study perspectives, model types and structures, cost and discounting parameters, and utility values and health state valuations. The included studies adopted varying analytical perspectives, which directly influenced the scope of cost inclusions (such as whether indirect costs or patient out-of-pocket expenses were considered). Studies employed different types of decision-analytic models, with varying assumptions, health state definitions, cycle lengths, and time horizons. The cost data years, currency units, exchange rate conversion methods, and discount rates (ranging from 3% to 5%) differed across studies. The sources of utility values used to calculate QALYs varied (e.g., from clinical trials, literature reviews, or mapping studies), and valuations for similar health states may have differed. Variations existed in the choice of comparator treatments, clinical pathways, and target population characteristics (e.g., disease stage, risk stratification) across studies.

We will explicitly state that precisely due to the significant multidimensional heterogeneity described above, it was neither feasible nor methodologically sound to simply pool numerical results or conduct traditional meta-analyses. The reasons include: Non-Comparability of Outcome Measures: ICERs across studies lacked direct comparability due to differences in cost baselines, effectiveness calculation methods, and threshold criteria. Risk of Misleading Pooled Estimates: Statistically pooling highly heterogeneous studies could produce summary results with limited clinical or policy relevance and potentially obscure important contextual differences. Given these considerations, we opted for a structured descriptive synthesis and qualitative comparison. This approach involved systematically presenting study characteristics, key parameters, and outcomes in tables and narrative form, with a focus on analyzing how heterogeneity sources influence the contextual applicability of conclusions.

This systematic review is not devoid of limitations. Firstly, the inclusion of a limited number of studies and the exclusive focus on published literature may introduce potential publication bias. Secondly, the included cost-effectiveness studies varied widely in terms of country backgrounds and data sources, making it challenging to perform a quantitative synthesis of their results. Thirdly, the findings of the studies in this review were heterogeneous. Fourthly, since most studies were conducted in developed countries, further research is needed to assess the applicability of these findings in low- or middle-income countries. Fifthly, a pooled NPV was not calculated due to variations in the comparator treatments across the groups included in this study. Finally, this study only investigated cost-effectiveness in clinical practice. We should comprehensively consider its efficacy, adverse effects, cost-effectiveness, and overall patient survival in clinical practice. In the future, studies that provide a well-designed, head-to-head cost-effectiveness analyses in diverse settings are necessary, particularly in low- and middle-income country settings.