Objectives

This study investigated the cancer-control outcomes of Lutetium-177 prostate-specific membrane antigen radioligand therapy (Lu-177-PSMA) in metastatic castration-resistant prostate cancer (mCRPC) patients who were either pretreated with Radium-223 or were Radium-223-naïve. The core finding is that sequential treatment with Radium-223 prior to Lu-177-PSMA does not significantly affect progression-free survival (PFS) or overall survival (OS) outcomes compared to Radium-223-naïve patients receiving Lu-177-PSMA. This suggests both radiopharmaceuticals can be used sequentially within the mCRPC treatment algorithm without compromising the efficacy of Lu-177-PSMA.

Methodology

This retrospective study utilized data from the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP). Patients with mCRPC treated with Lu-177-PSMA between 2014-2025 were included and stratified based on prior Radium-223 treatment. Statistical analysis involved:

• Descriptive statistics (frequencies, proportions, medians, IQRs).
• Chi-square test, t-test, and Kruskal–Wallis test for comparing baseline characteristics.
• Kaplan-Meier estimates with log-rank tests to compare PFS and OS between the Radium-223 pretreated and naïve groups.
• Univariable and multivariable Cox regression models to assess the influence of Radium-223 pretreatment on PFS and OS, adjusting for covariates such as age, Gleason score, Eastern Cooperative Oncology Group (ECOG) performance status, De novo metastatic hormone-sensitive prostate cancer (mHSPC), CHAARTED high volume mHSPC, specific Lu-177-PSMA treatment line (for PFS), and total number of received mCRPC lines (for OS).

Results

The study included 329 mCRPC patients treated with Lu-177-PSMA, with 64 (19%) pretreated with Radium-223 and 265 (81%) being Radium-223-naïve. Radium-223 pretreated patients had received significantly more prior systemic mCRPC treatments (median 4 vs. 3, p<0.01).

• PFS analysis showed no significant difference: median PFS was 16.0 months for Radium-223 pretreated vs. 11.9 months for Radium-223-naïve patients (Hazard Ratio [HR]: 0.73, 95% Confidence Interval [CI]: 0.52–1.02, p=0.063).
• OS analysis also showed no significant difference: median OS was 17.9 months for Radium-223 pretreated vs. 14.8 months for Radium-223-naïve patients (HR: 0.99, 95% CI: 0.71–1.37, p>0.9).
• Multivariable Cox regression analyses, after adjusting for confounders, confirmed no significant differences in PFS (HR: 0.54, CI: 0.25–1.16, p=0.11) or OS (HR: 0.45, CI: 0.18–1.11, p=0.085) between the groups.

Discussions

This study provides valuable real-world data on the sequential use of Radium-223 and Lu-177-PSMA in mCRPC patients. The finding that prior Radium-223 does not negatively impact subsequent Lu-177-PSMA efficacy is clinically relevant. However, certain limitations should be considered:

• The retrospective nature introduces potential selection bias and confounding. Although multivariable analysis was performed, unmeasured confounders might still exist.
• Significant differences in the number of prior treatment lines between groups (median 4 vs 3) indicate heterogeneity; the Radium-223 pretreated group was more heavily pretreated, which could influence outcomes despite adjustments.
• Selection criteria for each therapy (Radium-223 requiring bone metastases, Lu-177-PSMA requiring PSMA expression) inherently create different patient populations, potentially biasing the comparison.
• The study acknowledges missing data (e.g., exact bone metastasis burden) which could impact endpoints.
• While referencing a prior publication on toxicity, this specific analysis lacks detailed comparative data on adverse events between the two groups, which is crucial when considering sequential radiotherapy. Future research could benefit from prospective studies or propensity score matching analyses to better control for baseline differences and provide more robust evidence on both efficacy and cumulative toxicity.

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Reference: Cancer control outcomes of Radium 223 pretreated lutetium 177 PSMA Radioligand vs Radium 223 na ve mCRPC patients