Background: Radioligand therapy with [¹⁷⁷Lu]Lu-PSMA-617 represents an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). Its clinical positioning relative to standard therapies remains under discussion. Objective: To compare overall survival (OS), radiographic progression-free survival (rPFS), PSA response, and treatment burden across randomised trials evaluating [¹⁷⁷Lu]Lu-PSMA-617 versus androgen receptor pathway inhibitors (ARTA), Cabazitaxel, or standard of care (SOC). Evidence Acquisition: We conducted a meta-analysis of five randomised controlled trials, including 2073 patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). We assessed survival endpoints, baseline comparability, and treatment intensity. Evidence Synthesis: [¹⁷⁷Lu]Lu-PSMA-617 significantly improved rPFS and PSA response. While modest overall, the OS benefit was more pronounced in taxane-naïve populations. Compared with Cabazitaxel, [¹⁷⁷Lu]Lu-PSMA-617 was associated with similar or better survival despite shorter treatment duration and potentially lower cumulative toxicity and cost. Economic modelling suggests it could offer a more sustainable therapeutic option under typical willingness-to-pay thresholds. Conclusions: [¹⁷⁷Lu]Lu-PSMA-617 shows clinical effectiveness and economic value in mCRPC, with potential advantages over Cabazitaxel and ARTA. Its use could be prioritised in early treatment lines. Patient Summary: This study suggests that PSMA-targeted radioligand therapy is at least as effective as other treatments for advanced prostate cancer, with potential benefits in terms of toxicity, duration, and overall cost.

Introduction: Metastasis-directed therapy (MDT) alone may be effective in preventing disease progression and positively affecting overall survival (OS) in oligometastatic prostate cancer (OMPC). Objective: We systematically reviewed the current literature to analyse the biological rationale for integrating MDT into treatment strategies for OMPC and investigate the current evidence on its role in OMPC. Evidence acquisition: MEDLINE/PUBMED and the EMBASE Database were systematically searched to identify eligible reports published up to January 2024. The proceedings of the European Society for Radiotherapy and Oncology, European Society of Medical Oncology, American Society for Radiation Oncology, American Society of Clinical Oncology, European Uro-Oncology Group, and American Urological Association annual meetings were analysed. Results: Eighteen studies published between 2014 and 2024 were selected for the analysis. The studies included 1058 patients treated with metastasis-directed radiotherapy. No statistically significant differences were found in terms of treatment-escalation-free survival between hormone-naïve patients treated with MDT alone and those treated with MDT and hormonal manipulation. By contrast, the combination treatment significantly increased both 2 year and 4 year disease-progression-free survival (DPFS) rates (p-values < 0.00001 and 0.006, respectively). In patients with castration-sensitive disease treated with MDT alone, the estimated 2 year and 4 year OS rates were 96.4% (95% confidence interval [CI], 92.9–100%) and 89.1% (95% CI, 82.3–96.5%), respectively. The estimated 2 year and 4 year overall survival rates in the combination treatment group were 86.1% (95% CI 79.2–93.7%) and 74.8% (95% CI 64.6.3–86.5%), respectively. Conclusions: MDT alone is associated with promising outcomes in OMPC and represents a valuable, valid, and often preferable strategy. Combined with ADT improves significantly disease-progression-free survival, but its impact on overall survival remains uncertain. Given these findings, the decision to incorporate ADT should be tailored to individual patient characteristics and clinical context. Future research should integrate biomarker-based approaches to optimise MDT use and select the best candidates for a multimodal approach.

Objectives: To evaluate and indirectly compare overall survival (OS) and safety of regorafenib, fruquintinib, and trifluridine/tipiracil (TAS-102) monotherapy in refractory metastatic colorectal cancer (mCRC) beyond the third line. Methods: A systematic review and meta-analysis of phase II/III randomized controlled trials was conducted according to PRISMA guidelines. PubMed/MEDLINE, Embase, and Cochrane CENTRAL were searched from inception. Eligible studies included patients with mCRC previously treated with standard chemotherapy and biologic agents, receiving regorafenib, fruquintinib, or TAS-102 as monotherapy in the fourth line or later. OS data were reconstructed from published Kaplan–Meier curves. Pooled median and mean OS were estimated using a random-effects model, and heterogeneity was assessed using the I² statistic. Safety outcomes were descriptively summarized. Results: Four RCTs were included. The pooled median OS was 7.83 months (95% CI: 6.98–8.80), and the pooled mean OS was 8.90 months (95% CI: 8.00–9.81), with no heterogeneity (I² = 0%). Survival gains versus placebo ranged from 1.4 to 2.6 months. Survival curves largely overlapped, with differences below one month. Safety was consistent with known profiles. Conclusions: These agents provide comparable efficacy with modest survival benefit in late-line mCRC, highlighting the need for improved strategies and better treatment sequencing.

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.