Background
Metastatic prostate cancer poses a significant clinical challenge—particularly in patients no longer responding to systemic treatment, such as androgen-deprivation therapy or chemotherapy. In these patients, PET can detect whether the metastatic disease expresses prostate-specific membrane antigen (PSMA). Radioligand therapy (RLT) with lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617) delivers beta-particle radiation to PSMA-expressing cells and poses a new treatment option with a good safety profile in such instances.1,2
As the first international multicenter phase III study, the VISION trial3 examined RLT with 177Lu-PSMA-617 and randomized 813 patients with metastatic castration-resistant prostate cancer (mCRPC) and positive 68Ga-PSMA-PET scans. Compared with standard of care (SoC) alone, patients who received 177Lu-PSMA-617 therapy exhibited prolonged progression-free survival (median, 8.7 vs 3.4 months; hazard ratio for progression or death, 0.40) and overall survival (median, 15.3 vs 11.3 months; hazard ratio for death, 0.62). Despite increased adverse events (grade ≥3: 52.7% vs 38.0%), quality of life was not adversely affected.
Before integrating 177Lu-PSMA-617 therapy into routine care, it is important to assess whether the clinical benefits are justified by potential differences in resource use that would be required for its implementation. This study analyzes the long-term cost and outcome implications associated with the use of 177Lu-PSMA-617 therapy in the treatment of patients with mCRPC.
Methods
Model Structure
Our analysis followed recommendations of the CHEERS 2022 reporting guidance on health economic analyses.4 A partitioned survival model was designed using decision-analytic software (TreeAge, Healthcare Pro 2021, TreeAge). SoC and 177Lu-PSMA-617 therapy were analyzed regarding costs and effectiveness over a lifetime horizon, using a cycle length of 1 month. During each cycle, patients could remain in the progression-free state, experience disease progression, or die. The only absorbing state was death.
Model Input Parameters
Initial and Transition Probabilities
All individuals started in the progression-free state. For transition probabilities, overall survival and progression-free survival data were derived from the VISION trial’s3 Kaplan-Meier curves. Parametric survival regressions were fitted using the flexsurv package in R (version 4.1.1, R Foundation for Statistical Computing; supplemental eFigure 1, available with this article at JNCCN.org). Best fitting was evaluated by log likelihood and Akaike information criterion. For improved adjustment, parametric survival of progression-free survival in the SoC group was reproduced as a Weibull distribution in the first 3.6 months and as a lognormal function thereafter. No adjustments for age-related death were made because these were already accounted for by the overall survival trial data. As a time frame for the analysis, a lifetime horizon was chosen in which >99% of simulations entered the death state. Using the calculated fitted parametric survival regressions, the time point was determined to be at 60 months. An overview of the model structure is shown in supplemental eFigure 2.
Costs
Costs for standard care in the 177Lu-PSMA-617 and SoC groups were derived from the VISION trial,3 consisting of various treatment regimens for patients with mCRPC. An offsetting comprising the cost for the used treatments and the percentage of patients receiving standard care in both groups was established (Table 1). The same applied for posttrial treatment after the median follow-up of 20.9 months. Because of missing information concerning treatment in the progression-free state, leuprolide as a maintenance treatment was assumed for both groups.5,6 Due to the lack of precise information on the application time of posttrial one-off therapies, these were accumulated per group and added in the first month after the trial. Costs were estimated using claims data from the Medicare Part B and D programs5; when unavailable, treatment costs were derived from the literature.7,8 Pharmaceutical pricing data from the US Department of Veteran Affairs9 was used as an external validation (see additional scenario analysis, Table 2). The standard dosage of therapies was obtained from public databases.10 Because no information was available on the treatment cost of 177Lu-PSMA-617, we used the price for 177Lu-DOTATATE RLTs as a proxy.11 Five cycles with a radiation dose per cycle of 7.4 GBq were assumed in line with the VISION trial data.3 Additional best supportive care costs were added for patients with progressive disease who had not received any further cancer treatment.12 End-of-life costs were implemented as a single time cost when entering the death state.13
Detailed Model Input Parameters
Additional Scenario Analyses
Frequency and severity information regarding therapy-related adverse events for standard care and for 177Lu-PSMA-617 was obtained from the VISION trial supplementary appendix,3 and costs were extracted from the literature.14 Costs for adverse events from 177Lu-PSMA-617 treatment were added for the median treatment period of 6 months. Costs for adverse events of SoC were added to both groups for the first 20 months and thereafter for posttrial monthly treatment. To identify the impact of the time horizon, adverse events, best supportive care, and end-of-life costs, we performed an additional scenario analysis (Table 2).
Utilities
Therapy effectiveness was measured using quality-adjusted life years (QALYs), calculated by multiplying the years spent in progression-free and postprogression states by assigned utility weights. Utility weights for progression-free and postprogression survival of patients with mCRPC were derived from the literature.15,16 The frequency of disutilities connected to treatment with 177Lu-PSMA-617 and standard care was obtained from the VISION trial.3 Furthermore, the frequency of disutility connected to skeletal pain was deducted from the Brief Pain Inventory–Short Form in the VISION trial appendix and added to both postprogression groups accordingly. Costs were derived from the literature.17,18
An overview of the input parameters is provided in Table 1 and supplemental eTable 1 for costs used in the additional analysis. An annual discount of 3% for costs and utilities was implemented in the analysis. All costs were adjusted to 2021 US dollars according to the US Consumer Price Index.
Cost-Effectiveness Analysis
Treatment strategies were compared in terms of net monetary benefits, incremental costs, incremental effectiveness, and incremental cost-effectiveness ratios (ICERs). The willingness-to-pay (WTP) was set to $50,000, 100,000, and $200,000 per QALY (Figure 1). The net monetary benefit combines costs and effectiveness in one measure: (effectiveness × WTP) − costs.
Threshold analysis for cycle costs of 177Lu-PSMA-617 therapy. Impact of costs per cycle of 177Lu-PSMA-617 on ICER in a one-way deterministic sensitivity analysis. Base case value of $29,320 was associated with an ICER of $200,708/QALY just above the WTP threshold of $200,000/QALY. Costs per cycle of 177Lu-PSMA-617 at WTP threshold of $50,000/QALY and $100,000/QALY are depicted.
Abbreviations: 177Lu-PSMA-617, lutetium Lu 177 vipivotide tetraxetan; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; WTP, willingness-to-pay.
Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7070
Sensitivity Analysis
We used comprehensive deterministic and probabilistic sensitivity analysis to test the robustness of the model. Deterministic one-way sensitivity analysis was performed to identify variables that significantly influence the model outcomes. The ranges for deterministic sensitivity analysis were determined by the 95% confidence interval of the initial probabilities and by ±20% for costs. Moreover, probabilistic sensitivity analysis allowed the simultaneous alteration of multiple model input parameters using distributions according to probability density functions for second-order Monte Carlo simulation runs (n=10,000).19 The model input parameters were assigned appropriate distributions as indicated in Table 1.
Results
Base Case Analysis
In the base case analysis of the total study population over the lifetime horizon, combined treatment using 177Lu-PSMA-617 and SoC led to an increased effectiveness of 0.42 QALYs at increased costs of $83,712; the ICER was $200,708 per QALY (Table 3). Additional scenario analyses were performed to examine the impact of time horizon, discount rate, adverse events, posttrial treatment, costs for best supportive care, and end-of-life costs on the base case results (Table 2). All these scenarios only had minor impacts on the ICER.
Base Case Analysis
Deterministic Sensitivity Analysis
The results of deterministic one-way sensitivity analyses are presented in Figure 2. Parameters for overall survival of patients in the 177Lu-PSMA-617 group and progression-free survival for patients in the SoC and 177Lu-PSMA-617 groups had the strongest impact on ICER. Prolonged overall survival and progression-free survival of the 177Lu-PSMA-617 group supported 177Lu-PSMA-617 treatment, whereas prolonged progression-free survival of the SoC group favored SoC treatment alone. Additional 1-way sensitivity analyses were performed for 177Lu-PSMA-617 treatment to determine cycle costs at the WTP thresholds of $50,000, $100,000, and $200,000 per QALY (Figure 1), with the assumed cycle cost of 177Lu-PSMA-617 treatment only slightly differing from the WTP threshold of $200,000 per QALY ($29,320 vs $29,240).
Tornado diagram for deterministic sensitivity analysis. Survival parameters showed the strongest cumulative impact on ICER followed by the cost of 177Lu-PSMA-617 treatment and utility value for progression-free state. Blue bars indicate changes based on the upper bound of a parameter variation, and orange bars indicate the lower bound of the respective parameter. WTP thresholds of $100,000/QALY and $200,000/QALY are depicted.
Abbreviations: 177Lu-PSMA-617, lutetium Lu 177 vipivotide tetraxetan; ICER, incremental cost-effectiveness ratio; OS, overall survival; PD, progressive disease; PFD, progression-free disease; PFS, progression-free survival; QALY, quality-adjusted life year; SD, standard deviation; SoC, standard of care; WTP, willingness-to-pay.
Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7070
Probabilistic Sensitivity Analysis
At a WTP threshold of $200,000 per QALY, treatment using 177Lu-PSMA-617 remained cost-effective in 37.14% of Monte Carlo simulation runs, with an ICER of $199,829 per QALY during the lifetime horizon. The mean incremental effectiveness was positive, meaning that additional treatment using 177Lu-PSMA-617 on average led to increased QALYs.
Using a different WTP threshold, the portion of cost-effective simulations decreased to 6.2% at $100,000 per QALY and 1.3% at $50,000 per QALY. The results for 10,000 Monte Carlo simulation runs are illustrated on a cost-effectiveness plane in Figure 3.
Probabilistic sensitivity analysis. Cost-effectiveness planes of incremental costs and incremental effectiveness of 177Lu-PSMA-617 therapy versus standard of care are shown for the probabilistic sensitivity analysis. Each dot represents one simulation run. The dashed line indicates a WTP threshold of $200,000/QALY. Dots to the right of this line are considered cost-effective simulation runs.
Abbreviations: 177Lu-PSMA-617, lutetium Lu 177 vipivotide tetraxetan; QALY, quality-adjusted life year; WTP, willingness-to-pay.
Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7070
Discussion
mCRPC still poses a therapeutic challenge. Treatment options have increased considerably over the past decade, yet this has also led to increasing healthcare costs.20 The VISION trial3 is the first phase III trial to indicate survival benefits for 177Lu-PSMA-617 treatment in addition to SoC. Similar results have been shown in the TheraP trial,21 a multicenter phase II study comparing 177Lu-PSMA-617 versus cabazitaxel in mCRPC.
Our analysis indicates that 177Lu-PSMA-617 therapy in addition to SoC yielded 0.42 incremental QALYs and was cost-effective in certain scenarios. The magnitude of the estimated long-term benefit in terms of QALYs reflects the considerable extension of overall survival in the trial. Because of additional costs resulting from 177Lu-PSMA-617 treatment, the ICER amounted to $200,708 per QALY, with assumed cycle costs for 177Lu-PSMA-617 nearly identical to the WTP threshold of $200,000 per QALY.
Deterministic sensitivity analysis indicated the robustness of the results, and only minor alterations of the ICER were noted in the additional scenario analyses. Probabilistic sensitivity analysis exhibited cost-effectiveness in just 37.14% of simulations, underlining the need for future postapproval reduction in treatment costs. There are 2 main findings that contribute to this fact. First, as new therapies enter the market, prices are fairly high. As treatment options become more available with additional generics, prices for treatment decrease, which will benefit the result of cost-effectiveness analysis.22 Second, other more elaborate treatment options for mCRPC also show elevated ICER.23 Third, SoC drugs in both groups during and after the trial duration had mostly been established for a longer period with lower prices compared with newer systemic therapies.
Furthermore, only a small fraction of patients (25% in the 177Lu-PSMA-617 group and 32% in the SoC group) received further treatment after the trial duration, also contributing to the incremental costs for 177Lu-PSMA-617 therapy.
This analysis may inform decision-making for the implementation of 177Lu-PSMA-617 therapy in clinical routine. In light of the recent approval by the FDA for 177Lu-PSMA-617 treatment, and ongoing phase III trials for taxane-naïve patients with mCRPC and patients with metastatic hormone-sensitive prostate cancer, RLT with 177Lu-PSMA-617 may soon become a widespread treatment option. Increasing demands for production, the adaptation of hospital operational and organizational structures, and the associated costs pose a major challenge.24 Therefore, it is important to address the resources and infrastructure needed for future clinical implementation.
The field of theranostics, in which similar molecules are being used for noninvasive imaging and therapy, is gaining importance in other areas as well. Several analyses have shown that RLT is a cost-effective alternative to systemic treatment in other cancers such as neuroendocrine tumors.25–28 In the diagnostic process, the proPSMA trial has shown the superior diagnostic value of 68Ga-PSMA-PET compared with conventional imaging in patients with prostate cancer, and it has also proved to be less costly.29 Besides primary staging, the early detection of metastasis also has a high value in recurrent disease, such as in the setting of oligometastatic disease30 and in differentiating nonmetastatic from metastatic prostate cancer.31
Certain limitations affect our analysis. First, because 177Lu-PSMA-617 was just recently approved by the FDA, exact reimbursement costs are not yet known. Using the costs of 177Lu-DOTATATE as a proxy results in uncertainty for the analysis. Because of similar production and handling of both RLTs, we assume comparable reimbursement costs. Second, although the main composition of standard care and adverse events during and after the trial duration for both groups was provided in the appendix of the VISION trial,3 the exact duration of treatments and adverse events was not accessible. Costs and average treatment durations were derived from claims data from the Medicare Part B and D programs and from the literature; however, some uncertainty remains. For the external validation of costs for SoC treatment, we therefore conducted an additional scenario analysis using cost data from the US Department of Veterans Affairs database, resulting in an ICER of $223,717 per QALY (Table 2).
Third, another potential source of uncertainty relates to the quality-of-life data. Only information on the relative decrease in quality of life for both groups was accessible from the VISION trial.3 We therefore used complementary data from the literature, leaving some uncertainty about the absolute quality of life for the progression-free and postprogression states. For further validation, long-term survival data and additional studies concerning dosage are required to increase the validity of the results. Furthermore, because the systemic treatment options are a moving target, cost analysis should be repeated as soon as updated treatment regimens for patients with mCRPC have been established.
Conclusions
This first economic analysis of 117Lu-PSMA-617 RLT shows notable long-term clinical benefits as measured in QALYs and indicates the cost-effectiveness of this new treatment option in certain scenarios compared with the SoC as used in the VISION trial. This analysis may guide the planning of infrastructure and resources for future implementation into clinical practice.
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