LuRa: Efficacy and Safety of Radium-223 Following [177Lu]Lu-PSMA-617 in Patients With Metastatic Castration-Resistant Prostate Cancer - Beyond the Abstract
Radium-223 has an established role in patients with bone-predominant mCRPC. However, most supporting data predate widespread use of PSMA-targeted therapy, leaving uncertainty around its safety and efficacy following [177Lu]Lu-PSMA-617.
To address this gap, we conducted a multi-institutional retrospective study at Mayo Clinic and Dana-Farber Cancer Institute evaluating outcomes with Radium-223 after prior [177Lu]Lu-PSMA-617. Importantly, we aimed not only to assess efficacy but also tolerability in a heavily pre-treated population.
We identified 21 patients with mCRPC who received Radium-223 following [177Lu]Lu-PSMA-617 after a median of five prior systemic therapies. All patients had bone metastases, and the median interval between the radiopharmaceutical therapies was approximately 9 months. This cohort reflects real-world patients who progress after or derive benefit from PSMA-directed therapy and remain candidates for additional anti-cancer treatment.
Our results suggest that Radium-223 remains feasible in carefully selected patients, though clinical activity is modest. Only 19% completed all six planned cycles, with most discontinuations due to disease progression—highlighting the aggressive disease biology in this setting. Consistent with data from prospective trials involving Radium-223, PSA responses were limited, with only one patient achieving a PSA50 response. However, 42% experienced a ≥30% decline in alkaline phosphatase. This distinction is important because PSA is not always a reliable marker of benefit with Radium-223, whereas alkaline phosphatase may better reflect activity in bone-predominant disease.
Median overall survival (OS) from Radium-223 initiation (after [177Lu]Lu-PSMA-617) was 10.6 months. This compares favorably with the ALSYMPCA trial, which reported a median OS of 14.9 months. These outcomes provide useful benchmarks for patient counseling and suggest that Radium-223 may retain activity in select individuals even after PSMA-targeted therapy. While real-world data suggest that patients are most likely to receive a cabazitaxel-based regimen after treatment with [177Lu]Lu-PSMA-617, some patients are not fit for chemotherapy or prefer a chemotherapy-free option.
Safety is a critical consideration. Grade ≥3 anemia and thrombocytopenia occurred in 33% and 19% of patients, respectively. Notably, 38% required red blood cell transfusions, all within 30 days of the final Radium-223 cycle, suggesting cumulative marrow toxicity. No cases of myelodysplastic syndrome or acute leukemia were observed.
Skeletal-related events remain an important concern. Four patients developed new events, and three experienced worsening of pre-existing fractures. These findings underscore the importance of bone health optimization, including the use of bone-protective agents when appropriate, particularly in the context of sequential radiopharmaceutical therapy.
Ideal candidates for Radium-223 after [177Lu]Lu-PSMA-617 should have bone-predominant disease, adequate hematologic reserve, preserved performance status, and sufficient life expectancy to derive benefit. Close monitoring of blood counts is essential, and patients should be counseled regarding risks of cytopenias, transfusion requirements, and early discontinuation.
Beyond Radium-223, these findings have broader implications as additional alpha-emitting therapies, including actinium, enter clinical development. Sequential radiopharmaceutical strategies will become more common, but optimal sequencing, timing, and toxicity mitigation remain undefined.
This study is limited by its retrospective design, small sample size, and heterogeneity in imaging assessment. Nonetheless, it provides timely real-world data addressing a clinically relevant question.
In summary, Radium-223 after [177Lu]Lu-PSMA-617 is feasible in selected patients with bone-predominant mCRPC, with modest efficacy and manageable but notable hematologic toxicity. These results support its continued consideration while emphasizing the need for careful patient selection, monitoring, and prospective validation of sequential radiopharmaceutical approaches.
Written by: Jabra Zarka, MD, Mayo Clinic, Rochester, MN
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