Evaluation Of Efficacy,Safety And Economy Of Treatment Regimens For Metastatic Hormone-Sensitive Prostate Cancer

BackgroundProstate cancer is the second most common cancer and the fifth leading cause of cancerrelated death among men in 2020,with an estimated approximately 1.4 million new cases and 375,000 deaths worldwide.The majority of patients with prostate cancer(68%)are diagnosed at an advanced stage and 54%newly diagnosed with metastatic disease.Androgen-deprivation therapy(ADT)-either surgical castration or treatment using luteinizing hormone-releasing hormone agonists or antagonists with or without anti-androgen drugs—is the mainstay of treatment for prostate cancer patients with recurrence after primary management.Metastatic hormone-sensitive prostate cancer(mHSPC)is a stage of metastatic prostate cancer that responds efficaciously to ADT,and after progression,patients will progress to metastatic castration-resistant prostate cancer(mCRPC),a stage with extremely limited survival.Recently,docetaxel,abiraterone acetate,enzalutamide,apalutamide and darolutamide have been approved by the National Medical Products Administration and successfully entered the National Health Insurance Drug List through substantial price reductions in the medical insurance drug access negotiation.Families,clinicians and health systems are confronted with numerous treatment options,and it is crucial to assess the efficacy,safety and cost-effectiveness of multiple treatment alternatives in order to determine the preferred or optimal treatment strategy.ObjectivesThe study was designed to comprehensively investigate the efficacy,safety and affordability of ADT,docetaxel+ ADT+prednisone,abiraterone acetate+ADT+prednisone,enzalutamide+ADT,apalutamide+ADT and darolutamide+docetaxel+ADT in the treatment of patients with mHSPC from the Chinese healthcare system perspective based on Bayesian Network Meta-analysis.Our results could provide references for clinical rational drug use,precision medicine decision-making and dynamic adjustment mechanism of the medical insurance drug catalogue.MethodsFor the evaluation of efficacy and safety,PubMed,Web of Science,Cochrane Library,Scopus,Embase,CNKI,Wanfang Database,VIP,CBM were systematically searched to collect randomized controlled trials associated with mHSPC.Two researchers independently performed literature screening,data extraction,and quality evaluation based on inclusion and exclusion criteria,and the clinical outcome indicators included progression-free survival(PFS),metastasis-free survival,overall survival(OS),incidence of adverse events(AEs)and grade≥3 AEs.The Cochrane risk-of-bias tool was used to evaluate the quality of the included studies,and Stata 15.1 and R software were used to conduct Bayesian Network Meta-analyses.At the same time,subgroup analyses were performed based on the baseline characteristics of mHSPC patients,and the efficacy and safety ranking of different treatment strategies were carried out.For the economic evaluation,a 3-state partitioned survival model(mHSPC,mCRPC,and death)with a 4-week cycle and a 10-year time horizon was constructed from the perspective of Chinese healthcare system based on Bayesian Network Meta-analyses.Survival data were obtained from clinical trials.The PFS and OS related to ADT regimen were used as standard arms,and the other regimens were further determined by constant hazard ratio calculated by Network Meta-analyses.Cost inputs were estimated from the average winning bids in 2022 from YAOZHI database,published literature,and expert consultations.Health state utility values and disutility values were retrieved from clinical trials,published literature,and expert consultations.Primary outcomes were measured in total costs,quality-adjusted life-years(QALYs)and incremental cost-effectiveness ratios(ICER).The willingness-to-pay(WTP)threshold was set as 1 to 3 times per capita gross domestic product(CNY 80,976 to 242,928/QALY)in 2021.Scenario analyses,one-way sensitivity analyses,and probabilistic sensitivity analyses were performed to examine the robustness of the base-case analyses.ResultsThe literature search identified 8,485 publications,and 20 publications involving 20,727 patients with mHSPC in 9 phase Ⅲ randomized controlled trials were finally included through initial and secondary screening.In terms of efficacy,compared with ADT,docetaxel+ ADT,abiraterone+ADT,enzalutamide+ADT,apalutamide+ADT and darolutamide+docetaxel+ADT significantly prolonged PFS and OS in mHSPC patients.As for PFS improvement,darolutamide+docetaxel+ADT>apalutamide+ADT>abiraterone+ADT>enzalutamide+ADT>docetaxel+ADT>ADT.As for OS improvement,darolutamide+docetaxel+ADT>apalutamide+ADT>enzalutamide+ADT>abiraterone+ADT>docetaxel+ADT>ADT.In terms of safety,compared with ADT,docetaxel+ADT,abiraterone+ADT,enzalutamide+ADT,apalutamide+ADT and darolutamide+docetaxel+ADT significantly increased the incidence of grade≥3 AEs,along with increased risk of neutropenia,febrile neutropenia,fatigue,and hypertension.The ranking of the incidence was darolutamide+docetaxel+ADT>docetaxel+ADT>abiraterone+ADT>enzalutamide+ADT>apalutamide+ADT>ADT.In terms of cost-effectiveness,when the WTP threshold was 1 to 3 times per capita gross domestic product in 2021,abiraterone+ADT,enzalutamide+ADT,apalutamide+ADT and darolutamide+docetaxel+ADT were cost-effective compared with ADT and docetaxel+ADT,and enzalutamide+ADT,apalutamide+ADT and darolutamide+docetaxel+ADT were not cost-effective compared with abiraterone+ADT.Scenario analyses demonstrated that enzalutamide+ADT,apalutamide+ADT and darolutamide+docetaxel+ADT would be costeffective when the price reductions were 18%,24%and 20%for enzalutamide,apalutamide and darolutamide,respectively.One-way sensitivity analyses revealed that hazard ratio-related parameters,costs of second-generation androgen receptor inhibitors,discount rate,and health state utility values had greater influence on the base-case analyses.Probabilistic sensitivity analyses indicated that the probabilities of ADT,docetaxel+ADT,abiraterone+ADT,enzalutamide+ADT,apalutamide+ADT,and darolutamide+docetaxel+ ADT being the optimal treatment regimens were 0.00%,1.94%,47.07%,19.69%,14.45%,and 16.85%,respectively.Conclusion and Policy ImplicationsThis was the first study to comprehensively evaluate the efficacy,safety,and economy of multiple regimens for the treatment of mHSPC patients based on Bayesian Network Metaanalysis from the Chinese healthcare system perspective,and represented an important complement to domestic pharmacoeconomic evaluation and health technology assessment.The main conclusions were as follows:(1)Darolutamide+docetaxel+ADT was the optimal treatment regimen for PFS and OS improvement.(2)docetaxel+ADT,abiraterone+ADT,enzalutamide+ADT,apalutamide+ADT and darolutamide+docetaxel+ADT significantly increased the incidence of grade≥3 AEs and discontinuation-related AEs.(3)Neutropenia,febrile neutropenia,fatigue and hypertension were the major AEs during the treatment for mHSPC patients.(4)Abiraterone+ADT was the preferred treatment option for mHSPC patients at current prices and WTP thresholds.Enzalutamide+ADT,apalutamide+ADT and darolutamide+docetaxel+ADT were potential alternatives,which have higher health outcomes and treatment expenditures.Based on the above discussions,the following suggestions of the clinical practice,payment decision-making and health technology assessment can be proposed:(1)The clinical benefit from the triple therapy of darolutamide+docetaxel+ADT is worth recognizing as an important clinical treatment option,which will reshape the treatment landscape of prostate cancer in the future.(2)Survival should not be improved at the cost of increased toxicity.Monitoring the AEs should be strengthened during clinical treatment,and the dose and intensity of medications should be adjusted promptly to reduce the incidence of severe AEs.(3)Triple therapy,domestic generic drugs and innovative drugs continuously enter the Chinese market,and price reductions and patient assistance programmes are important initiatives to maintain the therapeutic advantage of available treatment options.(4)Domestic health state utility values related to prostate cancer are extremely limited.Conducting original studies based on domestic populations and developing cancer-specific WTP thresholds remain priorities for future health technology assessments.