Re-treatment of metastatic castration-resistant prostate cancer patients with radium-223 therapy in daily practice.
Authors: van der Doelen Maarten Johannes , van Riel Joost H.H.M. , Donswijk Maarten L. , Brouwer Christel , Gerritsen Winald R. , Tan-Phan Ha , Thimister Willie , Noordzij Walter , te Beek Erik T. , van Warmerdam Laurence , Bergman Andre M. , van Oort Inge M. , Wyndaele Dirk N.J. 
Published: February 2025

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Background:
Radium-223 is a therapeutic option for metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic bone metastases and consists of up to 6 monthly injections. After the approved 6 radium-223 injections, treatment may be repeated. This study evaluated the safety and efficacy of radium-223 re-treatment in mCRPC patients in routine clinical practice.
Methods:
This multicenter, retrospective cohort study included patients with bone mCRPC who previously received 6 consecutive injections of radium-223 according to standard of care, and received at least one radium-223 re-treatment injection between 2014 and 2024. Patients with visceral metastases were excluded. Primary endpoint was safety (hematological and non-hematological adverse events (AEs), including skeletal-related events (SREs)). Secondary endpoints were the number of administered injections, overall survival, and alkaline phosphatase (ALP) and prostate-specific antigen (PSA) responses. Exploratory analyses intended to find variables associated with ALP response during re-treatment and completion of radium-223 re-treatment.
Results:
Across 7 Dutch medical centers, 61 patients were included. Median age was 75 years, 44% received prior chemotherapy, 87% previously received at least one androgen receptor pathway inhibitor and 51% received concomitant bone health agents. Median number of prior systemic therapies was 3. 81% of patients had an ECOG performance status ≥1. 95% of patients had at least one hematological AE, including 14% grade 3 hematological AEs. In total, 44 (75%) patients experienced at least one non-hematological AE during radium-223 re-treatment. No grade 4-5 AEs occurred. 11 (18%) patients developed a SRE during radium-223 re-treatment, including 2 (3%) patients with spinal cord compression. Time until first SRE was 9.5 months (95% CI, 6.2-12.8). The patients received a median number of 6 radium-223 re-treatment injections (IQR; 4-6). Overall survival was 16.9 months (95% CI, 11.9-21.9) from start of re-treatment. 56% of patients had a ≥30% ALP response and 25% had a ≥30% PSA response. Other than elevated ALP levels at baseline, no variables were associated with ≥30% ALP response during radium-223 re-treatment. High baseline hemoglobin levels, no prior chemotherapy and a PSA response ≥30% during the initial radium-223 therapy were predictors for completion of 6 radium-223 re-treatment injections.
Conclusions:
Radium-223 re-treatment was well tolerated and is therefore deemed safe in selected mCRPC patients. In addition, the high number of administered injections and the high ALP response rates suggest benefit in this cohort of advanced mCRPC patients. Further research should directly compare radium-223 re-treatment and other life-prolonging therapies to determine the position of radium-223 re-treatment within the therapeutic landscape of mCRPC.