Economic Evaluation of Lutetium-177 (¹⁷⁷Lu)–PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer in Italy

Simple Summary

Lutetium-177 (¹⁷⁷Lu)–PSMA-617 is a new treatment for patients with advanced prostate cancer whose disease expresses PSMA. Although this treatment can delay disease progression and prolong survival, it is associated with substantial treatment costs. We evaluated the economic value of ¹⁷⁷Lu-PSMA-617 from the perspective of the Italian healthcare system. We compared its treatment costs and clinical benefit with standard care and with other commonly used treatments, using data from randomized clinical trials. We also developed an exploratory model to estimate the additional cost required to gain one quality-adjusted life year (QALY). Our results indicate that ¹⁷⁷Lu-PSMA-617 provides a meaningful clinical benefit, but this benefit is associated with high additional treatment costs. The estimated cost per QALY was approximately €85,000, although this result was influenced by several assumptions, including treatment duration, healthcare costs, and quality-of-life estimates. These findings highlight the importance of considering both clinical benefit and economic sustainability when assessing the use of ¹⁷⁷Lu-PSMA-617 in the Italian healthcare system. Further studies using real-world costs, treatment patterns, and patient-reported quality-of-life data are needed.

Abstract

Introduction: The increasing costs of cancer care have raised the need for economic evaluations that integrate treatment efficacy and resource utilization. This study aimed to assess the economic value of Lutetium-177 (¹⁷⁷Lu)–prostate-specific membrane antigen (PSMA)-617 in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) from an Italian healthcare perspective. Patients and Methods: A cost-effectiveness analysis was performed using clinical efficacy data from randomized controlled trials (RCTs) evaluating ¹⁷⁷Lu-PSMA-617. Two scenarios were considered. Scenario 1 evaluated ¹⁷⁷Lu-PSMA-617 plus standard care (SC) versus SC alone using pivotal phase III trial data. Scenario 2 compared ¹⁷⁷Lu-PSMA-617 with chemotherapy and androgen receptor pathway inhibitors (ARPIs) using phase II and III RCTs. Drug costs were based on Italian ex-factory prices. In addition, an exploratory three-state Markov cost–utility model including progression-free survival (PFS), progressive disease, and death was developed using data from the VISION trial. Results: In Scenario 1, 730 patients were analyzed. The ESMO-MCBS grade was 3, and the incremental cost per month of PFS gained with ¹⁷⁷Lu-PSMA-617 versus SC was €20,906. In Scenario 2, 651 patients were included. The monthly cost per PFS gained with ¹⁷⁷Lu-PSMA-617 was €19,017 versus enzalutamide and €20,565 versus abiraterone. In the exploratory cost–utility model, estimated QALYs were 1.02 with ¹⁷⁷Lu-PSMA-617 and 0.64 with SC, corresponding to an incremental gain of 0.38 QALYs. At an incremental cost of approximately €32,000 per patient, the resulting model-based ICER was approximately €85,000/QALY. Conclusions: ¹⁷⁷Lu-PSMA-617 provides meaningful clinical benefit in appropriately selected patients with PSMA-positive mCRPC, but this benefit is associated with substantial incremental treatment costs. The exploratory model-based ICER was sensitive to treatment duration and other model assumptions. These findings support careful assessment of the clinical value and economic sustainability of ¹⁷⁷Lu-PSMA-617 in the Italian healthcare setting. Further studies incorporating real-world resource utilization, treatment-related costs, post-progression therapies, and prospectively collected quality-of-life data are warranted.

1. Introduction

The rising costs of cancer care are increasingly under scrutiny. Prostate cancer represents a relevant paradigm due to its high prevalence, widespread diagnostic approaches, and the availability of an expanding therapeutic armamentarium, including radioligand therapy.

Recently, Lutetium-177 (¹⁷⁷Lu)–prostate-specific membrane antigen (PSMA)-617, a radioligand therapy delivering beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment, has been approved by the European Medicines Agency (EMA) in combination with androgen deprivation therapy (ADT), with or without an androgen receptor (AR) pathway inhibitor, for adult patients with progressive, PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) previously treated with an AR pathway inhibitor and taxane-based chemotherapy. International EANM/SNMMI recommendations have subsequently provided guidance on patient selection, treatment administration, monitoring, and the management of adverse events associated with ¹⁷⁷Lu-PSMA radioligand therapy [1,2].

The phase III VISION trial evaluated ¹⁷⁷Lu-PSMA-617 in patients with mCRPC who had received at least one AR-pathway inhibitor and one or two taxane regimens. Patients were randomized to receive ¹⁷⁷Lu-PSMA-617 plus protocol-permitted standard care (SC) (n = 529) versus SC alone (n = 201). Excluded treatments included chemotherapy, immunotherapy, radium-223 (²²³Ra), and investigational drugs.

Radioligand therapy with ¹⁷⁷Lu-PSMA-617 significantly prolonged imaging-based progression-free survival (PFS) and overall survival (OS) compared with SC. Median PFS was 8.7 months in the ¹⁷⁷Lu-PSMA-617 arm versus 3.4 months in the SC arm (HR = 0.40, 99.2% CI: 0.29–0.57, p < 0.001), while median OS was 15.3 months versus 11.3 months (HR = 0.62, 95% CI: 0.52–0.74, p < 0.001). The incidence of grade ≥ 3 adverse events was higher with ¹⁷⁷Lu-PSMA-617 than with SC (52.7% vs. 38.0%), but quality of life was not adversely affected (Sartor O el al. 2021) [3]. Subsequent analyses of VISION further characterized health-related quality of life and pain outcomes, supporting the clinical benefit of ¹⁷⁷Lu-PSMA-617 beyond conventional survival endpoints [4].

Given this background, the EMA-approved indication, and the significant budgetary impact of new therapies [3], we conducted a cost-effectiveness analysis comparing ¹⁷⁷Lu-PSMA-617 versus SC in patients with PSMA-positive mCRPC. The objectives of this study were to assess the economic value of ¹⁷⁷Lu-PSMA-617 in the Italian healthcare context by combining a PFS-based drug cost analysis with a model-based cost–utility analysis and to explore the effect of treatment duration on the resulting ICER.

2. Patients and Methods

The analysis was conducted in three sequential steps: (1) definition of outcomes, (2) search strategy, and (3) trial selection criteria and data extraction. In addition, a model-based cost–utility analysis was performed using a three-state Markov model.

2.1. Outcome Definition

The objective of this analysis was to evaluate the effect of ¹⁷⁷Lu-PSMA-617 in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) on progression-free survival (PFS). Two scenarios were considered:

• Scenario 1: Evaluation of pivotal phase III RCTs of ¹⁷⁷Lu-PSMA-617 versus standard care (SC) [3].
• Scenario 2: Comparison of ¹⁷⁷Lu-PSMA-617 versus SC and other therapies (chemotherapy or androgen receptor pathway inhibitors [ARPIs]) in phase II and III RCTs [5,6].

The economic analyses comprised two complementary components. First, an incremental cost per month of PFS gained was calculated for the available randomized comparisons. Second, a cost–utility analysis was conducted using a three-state Markov model to estimate QALYs and the corresponding ICER. The distinction between cost–consequence measures and formal cost–utility analysis is consistent with established principles for economic evaluation in healthcare [7,8,9]. Previous economic evaluations in mCRPC have used different approaches to relate treatment costs to survival, progression-free survival, life years, and QALYs, highlighting the impact of methodological assumptions on the resulting estimates [10]. These two analyses were considered complementary rather than interchangeable economic endpoints. For the PFS-based analysis, the incremental cost per month of PFS gained was calculated as the difference in treatment costs between the intervention and comparator groups divided by the corresponding difference in median PFS: incremental cost per month of PFS gained = (cost of ¹⁷⁷Lu-PSMA-617 − cost of comparator)/(median PFS with ¹⁷⁷Lu-PSMA-617 − median PFS with comparator). This metric represents the additional treatment cost associated with one additional month of median PFS and was distinguished from the model-based ICER expressed as €/QALY.

Drug costs were ex-factory prices obtained from AIFA public determinations, and they are expressed herein in euros (€). Dosages were based on those reported in the respective RCTs [3,5,6]. Specifically, we assumed the following costs (VAT excluded):

• ¹⁷⁷Lu-PSMA-617, 1000 MBq/mL solution for injection (7.5–12.5 mL vial): €22,160.66 per vial (Italian Medicines Agency [AIFA] 2025) [11];
• Cabazitaxel, 20 mg/mL concentrate for infusion (6 mL vial, 60 mg total): €3005.20 per vial (Italian Medicines Agency [AIFA] 2021) [12];
• Enzalutamide, 112-tablet packs (60 mg each): €3773.00 (Italian Medicines Agency [AIFA] 2024) [13];
• Abiraterone, 56-tablet packs (500 mg each): €1915.34 (Italian Medicines Agency [AIFA] 2025) [11].

Clinical benefit was evaluated using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) [14,15].

Grades range from 1 to 5, with adjustments (upgrade or downgrade) based on quality of life (QoL) or grade 3–4 toxicities affecting daily functioning.

Risk of bias was assessed using the Cochrane Collaboration tool for randomized trials [16]. The assessment considered the seven pre-specified domains of the Cochrane Risk of Bias tool, including sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other potential sources of bias. Rather than interpreting the assessment as a global numerical score, the risk of bias was evaluated at the domain level.

2.2. Markov Cost–Utility Model

A three-state Markov model was developed to provide an exploratory estimate of the cost-effectiveness of ¹⁷⁷Lu-PSMA-617 versus standard care (SC), using clinical inputs from the VISION trial [3]. The model included three health states: progression-free survival (PFS), progressive disease (PD), and death. Patients could remain in the same health state or transition from PFS to PD or death, and from PD to death.

The model used a 1-month cycle length and a 60-month time horizon. Transition probabilities were estimated from the available survival data assuming constant hazards over each model cycle. Hazard rates were converted into monthly transition probabilities using the relationship p = 1 − exp(−λt), where λ represents the hazard rate and t the cycle duration. Drug costs were applied during the PFS state for a maximum of six treatment cycles. Additional medical costs were estimated at €500 per month for PFS follow-up and €1000 per month for PD management.

QALYs were estimated by applying health-state utility weights to the modeled time spent in the PFS and PD states, with death assigned a utility of 0. The utility assumptions were applied consistently to both treatment groups. Because the original utility source used in the exploratory model could not be independently verified retrospectively, the QALY estimates should be considered exploratory and interpreted with caution. Given the simplified model structure and the uncertainty surrounding the utility assumptions, the resulting QALYs and ICER were considered model-based exploratory estimates rather than direct measurements from the VISION trial.

No discounting of costs or health outcomes was applied because this was designed as a simplified exploratory analysis over a 60-month time horizon. No formal deterministic or probabilistic sensitivity analysis was performed. Accordingly, the results should be interpreted in light of uncertainty surrounding the model assumptions, particularly health-state utilities, treatment duration, and disease-management costs.

2.3. Search Strategy

The literature search included full reports and updates of phase II and III RCTs published or presented up to 28 February 2025. Sources included Medline (PubMed), ASCO (www.asco.org, accessed on 1 April 2025), and ESMO (www.esmo.org, accessed on 1 April 2025). The keywords were as follows: advanced mCRPC, ¹⁷⁷Lu-PSMA-617, phase II, phase III, randomized. In addition, the reference lists of review and original articles were manually screened to identify any missing trials.

2.4. Trial Selection Criteria and Data Extraction

All phase II and III RCTs in which patients with mCRPC were prospectively randomized to receive ¹⁷⁷Lu-PSMA-617 versus SC were eligible. Data extraction was performed for each trial’s most recent update. Two investigators (J.G. and F.F.) independently reviewed and extracted the data to ensure accuracy. Discrepancies between investigators were resolved by discussion and consensus. Extracted data included sample size, treatment regimen, PFS, overall survival (when available), comparator treatment, treatment duration, and drug dosage/cost parameters.

3. Results

In Scenario 1 (

Table 1. Pharmacological costs and difference in PFS with ¹⁷⁷Lu-PSMA-617 in patients with advanced PSMA-positive mCRPC.

Trial	Comparative Regimens	Total N Patients	Primary Endpoint	Median PFS (Months)	PFS Gain (Months)	Mean Duration of Treatment (Months)	Costs of Therapy (€)	Difference in Costs (€)	Cost/PFS Month Gained (€)
VISION1	177Lu-PSMA-617 plus standard care	529	PFS, OS	8.7	5.3	6.9	110,803 + X	110,803	20,906
	Standard care	201		3.4		2.1	X

Legend: N = number; PFS = progression-free survival; OS = overall survival.

), 730 patients were considered. The ESMO-MCBS reached grade 3. The risk-of-bias assessment was conducted across the seven domains of the Cochrane Collaboration tool, and it is reported by individual domain in Table 1, rather than as an aggregate numerical score. The incremental treatment cost was €110,803, with an incremental median PFS of 5.3 months (8.7 vs. 3.4 months), corresponding to an incremental cost of €20,906 per month of median PFS gained with ¹⁷⁷Lu-PSMA-617 versus standard care (SC) (Table 1).

In Scenario 2 (

Table 2. Pharmacological costs and difference in PFS with ¹⁷⁷Lu-PSMA-617 vs. cabazitaxel and AR-pathway inhibitor in patients with advanced PSMA-positive mCRPC.

Trial	Comparative Regimens	Total N Patients	Primary Endpoint	Median PFS (Months)	PFS Gain (Months)	Mean Duration of Treatment (Cycles)	Costs of Therapy (€)	Difference in Costs (€)	Cost/PFS Month Gained (€)
TheraP3	177Lu-PSMA-617	98	PSA response	5.1	0.0	5	110,803	86,761	NA
	cabazitaxel	85		5.1		8	24,042
PSMAfore4	177Lu-PSMA-617	234	PFS	11.6	6.0	6	132,964	114,099 c 123,388 d	19,017 c 20,565 d
	ARPI-change	234		5.6		5	18,865 a 9576.2 b

Legend: N = number; PFS = progression-free survival; PSA = prostate-specific antigen; ARPI = androgen receptor pathway inhibitor; ^a = enzalutamide; ^b = abiraterone; ^c = towards enzalutamide; ^d = towards abiraterone.

), 651 patients were included across the TheraP and PSMAfore trials. The ESMO-MCBS reached grade 3 for the TheraP trial [5] and grade 4 for the PSMAfore trial [6]. The risk-of-bias assessment was performed using the same seven Cochrane domains for both trials and is reported by individual domain in Table 2 rather than as an aggregate numerical score. In TheraP, median PFS was 5.1 months in both treatment groups; therefore, no incremental PFS gain was observed, and the incremental cost per month of PFS gained was not calculable. In PSMAfore, median PFS was 11.6 months with ¹⁷⁷Lu-PSMA-617 versus 5.6 months with the comparator, corresponding to an incremental PFS gain of 6.0 months. The incremental cost per month of PFS gained with ¹⁷⁷Lu-PSMA-617 was €19,017 versus enzalutamide and €20,565 versus abiraterone (Table 2).

The PFS-based results represent the incremental treatment cost per additional month of PFS and should therefore be distinguished from the model-based ICER expressed as €/QALY.

In the exploratory cost–utility analysis, total quality-adjusted life years (QALYs) were estimated at 1.02 for ¹⁷⁷Lu-PSMA-617 and 0.64 for SC, corresponding to an incremental gain of 0.38 QALYs. QALYs were estimated by applying health-state utility assumptions to the time spent in the PFS and PD states over the 60-month model horizon. The model estimated 1.02 QALYs with ¹⁷⁷Lu-PSMA-617 versus 0.64 with SC, corresponding to an incremental gain of 0.38 QALYs. This estimate should be interpreted as an exploratory model-based result and is dependent on the assumptions underlying the health-state utilities, treatment costs, and survival estimates.

4. Discussion

Although health professionals often avoid explicitly valuing life, the limited availability of healthcare resources necessitates societal decisions regarding what constitutes a clinical benefit, how costs should influence these decisions, and who should participate in the deliberation process. The introduction of high-cost oncology drugs underscores the need to evaluate clinical gains, in terms of months of life, relative to the costs incurred [17].

Treatment efficacy is primarily determined by results from RCTs, which reflect specific inclusion criteria but may not fully represent routine clinical practice [18] This issue is particularly relevant for ¹⁷⁷Lu-PSMA-617, for which treatment eligibility depends on adequate PSMA expression and appropriate imaging-based patient selection [1,2]. Previous economic evaluations of mCRPC have similarly shown that treatment acquisition costs, treatment duration, and survival assumptions can substantially influence the estimated economic value of systemic therapies [19,20,21]. Drug price represents a second critical variable, as pharmacy costs vary across countries. This economic factor can create a form of “cost resistance,” potentially limiting access to novel oncological treatments independent of biological considerations. In this analysis, we focused on direct drug costs, while the exploratory model-based analysis additionally incorporated selected disease-management costs. Administration costs, PSMA-PET/CT imaging, adverse-event management, and other forms of healthcare resource utilization were not included in the base case because of limitations in the availability and consistency of Italian resource-use estimates. These exclusions may affect the absolute ICER and represent an important source of uncertainty. No formal deterministic or probabilistic sensitivity analysis was performed.

Using progression-free survival (PFS) rather than overall survival (OS) for the trial-based economic comparison allowed for a timely assessment of effectiveness, given that subsequent therapies may influence OS. The complementary cost–utility analysis incorporated survival transitions through the PFS–PD–death Markov structure. Consequently, the model-based results depend on the assumptions used to estimate transition probabilities and extrapolate survival over the 60-month time horizon. Importantly, patient-reported outcomes from VISION provide additional evidence regarding health-related quality of life and pain, which are relevant when translating clinical benefit into economic value [4].

Previous Italian studies on mCRPC (not specific to ¹⁷⁷Lu-PSMA-617) have shown that drug therapy is the main cost driver in advanced prostate cancer, with annual direct costs to the national health system reaching hundreds of millions of euros [22]. Our findings should be considered in the context of previous economic evaluations of ¹⁷⁷Lu-PSMA-617. In particular, Mehrens et al. [23] developed a partitioned survival cost-effectiveness model based on the VISION trial from a US healthcare-system perspective, reporting an incremental gain of approximately 0.42 QALYs and an ICER of approximately $200,708/QALY. More broadly, previous economic evaluations of systemic treatments for mCRPC have reported substantial variation in ICERs according to treatment sequence, drug acquisition costs, survival assumptions, and the perspective adopted [20,21]. More recently, Brinkmann et al. developed a cost–utility model from the German healthcare perspective using data from VISION and TheraP [24]. Their analysis estimated an incremental gain of 0.39 QALYs and an ICER of €69,418/QALY for ¹⁷⁷Lu-PSMA-617 plus standard care versus standard care alone. Our analysis differs from this previous work in several respects, including its focus on the Italian healthcare context, the use of Italian ex-factory drug prices, the complementary PFS-based cost analysis, and the inclusion of alternative randomized comparisons. Therefore, rather than representing the first cost-effectiveness analysis of ¹⁷⁷Lu-PSMA-617, our study provides an additional country-specific economic assessment using Italian cost inputs and a complementary methodological approach.

The annual treatment cost of ¹⁷⁷Lu-PSMA-617 (€250,872 in Scenario 1) appears higher than previously reported literature ranges (€56,962–153,752) [25]. However, these values are based on ex-factory prices, and confidential discounts of up to 40% could reduce real costs to approximately €150,528 (Regione Toscana 2025) [26], aligning with literature estimates [27]. Thus, negotiated discounts and outcome-based reimbursement agreements may play an important role in determining the affordability and sustainability of radioligand therapy.

Despite national reimbursement, access to ¹⁷⁷Lu-PSMA-617 may vary regionally due to administrative procedures, availability of nuclear medicine centers, and PSMA-PET diagnostic capacity, potentially creating territorial inequities. At the EU level, harmonized health technology assessments (e.g., EUnetHTA) and transparent pricing policies may help reduce cost variability and encourage joint purchasing or risk-sharing agreements. However, willingness-to-pay thresholds differ across healthcare systems, and Italy does not have a single universally applicable formal willingness-to-pay threshold for cost per QALY.

Accordingly, the estimated ICER of approximately €85,000/QALY should not be interpreted as establishing that ¹⁷⁷Lu-PSMA-617 is definitively cost-effective or not cost-effective on the basis of a fixed national threshold. Rather, this estimate should be interpreted in the context of disease severity, unmet clinical need, opportunity costs, and the uncertainty surrounding the model assumptions.

Some limitations of our analysis relate to the interpretation of the VISION trial, where the standard care (SC) arm included heterogeneous treatments. The principal demographic and disease-related baseline characteristics reported in the VISION trial, including age, ECOG performance status, PSA levels, metastatic sites, Gleason score, and prior prostatectomy, were broadly similar between treatment groups, supporting the comparability of the randomized cohorts. However, the distribution of protocol-permitted standard care treatments was not identical between arms. Specifically, enzalutamide was used in 29.7% of patients in the experimental arm compared with 42.4% in the SC arm, while abiraterone was used in 25.0% versus 35.1%, respectively. These differences may influence treatment costs and should therefore be considered when interpreting the economic comparison.

Radioligand therapy requires careful patient selection using PSMA-PET, as well as possibly FDG-PET, to identify eligible metastatic lesions. Economic evaluations have also shown that PSMA-PET/CT may have favorable cost-effectiveness compared with conventional imaging, although its economic impact depends on the clinical setting and diagnostic pathway [26]. Current international recommendations emphasize the importance of appropriate molecular imaging and patient selection before ¹⁷⁷Lu-PSMA radioligand therapy [1,2]. The costs of diagnostic procedures, such as PSMA PET-CT, add to the overall economic impact and should be considered in future analyses. Similarly, administration costs, adverse-event management, and other forms of healthcare resource utilization were not incorporated into the base-case analysis and may influence the overall economic results.

To facilitate direct comparisons with other therapies, we considered two additional RCTs (Scenario 2): TheraP [5] and PSMAfore [6]. These trials were considered as complementary evidence rather than as a pooled homogeneous comparator population because they differed in study design, treatment setting, and comparator therapy. Longer-term follow-up of TheraP provided additional overall survival data and further characterization of the clinical outcomes of ¹⁷⁷Lu-PSMA-617 compared with cabazitaxel [2]. TheraP showed no difference in median PFS between treatment groups and therefore did not allow for the calculation of an incremental cost per additional month of PFS. In contrast, PSMAfore provided a quantifiable PFS difference and was therefore used for the PFS-based economic comparison with enzalutamide and abiraterone. Additional analyses of PSMAfore have also evaluated health-related quality of life, pain, and symptomatic skeletal events, providing further context for the clinical value of ¹⁷⁷Lu-PSMA-617 in taxane-naive patients [4]. The incremental cost per month of PFS gained was €19,017 compared with enzalutamide and €20,565 compared with abiraterone. These estimates represent treatment-cost comparisons and should not be interpreted as formal cost-effectiveness estimates in €/QALY.

The magnitude of clinical benefit may support a careful price-value assessment rather than automatically establishing cost-effectiveness. In VISION, ¹⁷⁷Lu-PSMA-617 improved both PFS and OS compared with SC, providing a clinically relevant benefit in a heavily pretreated population. However, the economic value of this benefit depends on the relationship between the additional clinical benefit and the associated treatment costs. Therefore, the clinical benefit should be considered jointly with treatment price, duration, toxicity, resource use, and patient quality of life when assessing value.

The comparison with cabazitaxel should be interpreted cautiously. Previous economic analyses of cabazitaxel in patients with mCRPC previously treated with docetaxel and androgen-signaling-targeted inhibitors have also highlighted the importance of treatment costs and subsequent therapy assumptions when comparing systemic treatment strategies [28,29]. TheraP demonstrated clinically meaningful activity of ¹⁷⁷Lu-PSMA-617, but median PFS was identical between treatment groups in the data considered in our analysis. Consequently, no incremental cost per additional month of PFS could be calculated for this comparison. Our results should therefore not be interpreted as demonstrating that ¹⁷⁷Lu-PSMA-617 is unequivocally more cost-effective than cabazitaxel.

The QALY gain observed in our model reflects the survival estimates incorporated from the VISION trial [3]. However, because the cost–utility analysis was based on a simplified exploratory Markov model and the utility assumptions could not be independently verified retrospectively, the estimated QALYs and ICER should be interpreted cautiously. The estimated ICER of approximately €85,000/QALY represents a model-based estimate rather than a direct measurement from the VISION trial, and its interpretation should take into account the uncertainty surrounding health-state utilities, treatment costs, disease-management costs, and survival assumptions.

The number of administered treatment cycles is also an important determinant of treatment acquisition costs. In the randomized trials included in our analysis, treatment duration differed between treatment groups and studies. However, because no formal sensitivity analysis of alternative treatment durations was performed, our data do not allow us to quantify the effect of reducing treatment to a specific number of cycles on the ICER. Treatment duration should therefore be considered an important area for future real-world and prospective economic evaluation rather than as a basis for recommending a specific treatment duration.

Finally, indirect costs, including productivity losses and caregiver burden, were not considered, potentially underestimating the societal value of ¹⁷⁷Lu-PSMA-617. Real-world cost heterogeneity may also arise from differences in nuclear medicine infrastructure and service delivery across centers. Future studies incorporating real-world resource utilization, administration and imaging costs, adverse-event management, patient-reported quality of life, and alternative treatment-duration strategies may provide a more comprehensive assessment of the economic value of ¹⁷⁷Lu-PSMA-617 in the Italian healthcare setting.

5. Conclusions

Our analysis indicates that ¹⁷⁷Lu-PSMA-617 provides a meaningful clinical benefit in patients with PSMA-positive mCRPC, but this benefit is associated with a substantial incremental treatment cost. The cost-effectiveness findings should be interpreted as exploratory model-based estimates and in light of the uncertainty surrounding treatment duration, disease-management costs, health-state utility assumptions, and survival estimates.

Rather than supporting a specific treatment duration, our findings suggest that the number of administered cycles is an important determinant of treatment acquisition costs and warrants further investigation in real-world clinical practice.

Future Italian cost-effectiveness analyses should incorporate real-world resource utilization, diagnostic and administration costs, adverse-event management, post-progression treatments, and prospectively collected health-related quality-of-life data. Such analyses may provide a more comprehensive assessment of the value and economic sustainability of ¹⁷⁷Lu-PSMA-617 within the Italian healthcare system.