Radium [Ra-223] dichloride 6.6MBq/6ml solution for injection vials

BACKGROUND: In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment. OBJECTIVE: To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection. DESIGN, SETTING, AND PARTICIPANTS: Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics. RESULTS AND LIMITATIONS: During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary non-treatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up. CONCLUSIONS: Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns. PATIENT SUMMARY: Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection.

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PURPOSE Randomized clinical trials (RCTs) have shown progression-free survival (PFS) benefits of metastasis-directed therapy (MDT) without androgen deprivation therapy for oligometastatic castration-sensitive prostate cancer (omCSPC). Most patients with bone metastatic (BM) omCSPC recur with additional bone disease after MDT. We hypothesized the BM-targeting alpha-emitter radium-223 dichloride (Ra223) could target subclinical bone disease and delay progression. METHODS This is an investigator-initiated, multicenter, open-label phase II RCT. Eligible men with recurrent omCSPC with ≥one bone metastasis (≤three on conventional imaging and/or ≤five on molecular imaging) were randomly assigned (1:1) to stereotactic ablative radiation (SABR) MDT alone or SABR MDT with Ra223 (six cycles). Primary end point was composite PFS. RESULTS From August 9, 2019, to March 2, 2023, 64 patients were randomly assigned, 33 to SABR MDT and 31 to SABR MDT/Ra223 balancing for key covariates. Most SABR MDT/Ra223 patients (87%) received six cycles of Ra223. The median PFS was 11.8 months with SABR MDT and 10.5 months with SABR MDT/Ra223 (adjusted hazard ratio [aHR], 1.42 [95% CI, 0.79 to 2.56]; P = .24). Seven patients (11%) experienced grade 3 treatment-related adverse events (no grade 4 or 5), 2 of 33 (6%) with SABR and 5 of 30 (17%) with SABR MDT/Ra223. Patients with high-risk (HiRi) pathogenic mutations in ATM , BRCA1/2 , RB1 , or TP53 had worse PFS (HR, 5.95 [95% CI, 1.83 to 19.3]; P = .003). Greater T-cell receptor (TCR) unique productive rearrangements were prognostic for improved PFS independent of the treatment arm (aHR, 0.45 [95% CI, 0.21 to 0.96]; P = .04). CONCLUSION Adding Ra223 to SABR MDT in BM omCSPC does not delay progression of disease. We provide evidence for an HiRi mutational signature and TCR repertoire as prognostic biomarkers in omCSPC treated with SABR MDT, highlighting the importance of collecting biological correlates in RCTs for omCSPC.

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BACKGROUND: The treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) has evolved since radium-223 (Ra-223) was approved in the United States (2013). We examined treatment patterns and real-world overall survival (rwOS) of men with mCRPC treated with Ra-223 in the modern treatment era. METHODS: A retrospective cohort of men treated with Ra-223 was derived using private insurance data from the Komodo Health dataset from January 1, 2017 to June 30, 2022. Cox-regression analyses examined associations between Ra-223 use and rwOS with adjustment for covariates. RESULTS: Of 1376 men, the median age was 68 years, 51% were White, and 89% had bone-only metastases. Overall, 17%, 35%, and 25% of men received Ra-223 as first-line, second-line, or third-line treatment for mCRPC, respectively. Thirty-six percent received Ra-223 as combination/layered therapy, mainly with enzalutamide, and 46% completed ≥5 cycles. Overall, median rwOS was 22.9 months. Median rwOS was longer in men who completed ≥5 Ra-223 cycles versus 1-4 cycles (30.3 versus 15.3 months) and combination/layered therapy versus monotherapy (26.6 versus 20.5 months). Combination/layered therapy and completion of ≥5 Ra-223 cycles were associated with 22% and 55% reductions in risk of death in adjusted analyses, respectively. Limitations include some clinical information not captured by claims databases. CONCLUSIONS: Significant rwOS benefits were identified in men who received Ra-223 as an earlier line of therapy, received Ra-223 in combination with another therapy, and completed ≥5 Ra-223 cycles, underscoring the importance of Ra-223 in the current treatment landscape.

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BACKGROUND: A post-marketing surveillance (PMS) study was conducted in Japan to assess real-world outcomes with radium-223 treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Results from the treatment period showed that radium-223 was generally well tolerated. Follow-up was subsequently extended to 3 years to collect data on fracture events. Results of the extended follow-up are now reported. METHODS: This prospective, non-interventional, multicenter, single-cohort PMS study enrolled men with CRPC and bone metastases treated with radium-223 under clinical practice. Extended follow-up lasted until 3 years after the first administration of radium-223. Data on clinical fractures and survival were collected. RESULTS: A total of 334 patients were enrolled, with a median follow-up of 15.3 months (range 1-50). The overall incidence proportion of fractures reported as adverse events was 7.76% (95% confidence interval [CI] 5.09-11.25%), with a fracture incidence rate of 5.22 patients [with fracture]/100 person-years (PY). Patients who received bone-modifying agents (BMAs) had a numerically lower incidence of fractures (5.85%; 3.46/100PY vs 9.93%; 7.92/100PY). Median overall survival was 26.32 months (95% CI 21.65-not reached). CONCLUSION: Compared with existing reference data, there was no obvious increase in the incidence of clinical fractures in Japanese patients with mCRPC who were treated with radium-223 under clinical practice. As is already well known for androgen deprivation, BMAs may also be useful in reducing bone fracture after radium-223.

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Abstract Several life‐prolonging therapies for metastatic castration‐resistant prostate cancer (mCRPC) are available, including radium‐223 dichloride ( 223 Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real‐world evidence for 223 Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223 Ra was prescribed as part of routine practice by investigators. Patients with prior 223 Ra treatment were excluded. The primary objective was to assess 223 Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223 Ra was first‐ or second‐line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5–6 223 Ra cycles was 68.8%; this proportion was greater with first‐line use (84.3%) than second‐ (65.7%) or third‐/fourth‐line use (64.1%). More chemotherapy‐naïve patients (61.9%) completed the 6‐cycle 223 Ra treatment than chemotherapy‐exposed patients (56.7%). Any‐grade treatment‐emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223 Ra‐related adverse events. Median OS was 15.7 months (95% confidence interval 12.13–19.51); patients receiving 5–6 223 Ra injections and earlier 223 Ra use had longer OS than those receiving fewer injections and later 223 Ra use. 223 Ra provides a well‐tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases.

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BACKGROUND: Radium-223 dichloride (Ra-223) prolongs overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) with symptomatic bone metastases. However, there is considerable variation in outcomes among individuals. We aimed to evaluate the prognostic determinants associated with patient survival following National Health Insurance (NHI) reimbursement for Ra-223 therapy in Taiwan. METHODS: Patients with mCRPC who underwent Ra-223 treatment at Taipei Veterans General Hospital were retrospectively enrolled. Each intravenous Ra-223 dose was administered at 55 kBq/kg at 4-week intervals. Clinical outcomes were obtained from medical records; potential prognostic factors for survival were assessed. Kaplan-Meier analysis was used to generate cumulative survival curves; between-group differences were evaluated using the Chi-squared test. Statistical significance was set at p < 0.05. RESULTS: Seventy-six patients underwent Ra-223 therapy; 62 patients received NHI reimbursement and the remainder self-paid. Fifty patients (65.8%) completed six cycles of treatment; 26 (34.2%) received 1 to 5 cycles. Mortality occurred in 47 patients. Factors significantly associated with survival included ≤five bone metastases ( p = 0.0018), baseline prostate-specific antigen (PSA) ≤36 ng/mL ( p = 0.0004), baseline alkaline phosphate (ALP) <115 U/L ( p = 0.0007), and baseline hemoglobin (Hb) >12 g/dL ( p = 0.0029). Patients who completed six cycles of treatment achieved significantly higher OS compared to those who did not ( p < 0.0001). There has been a 4.4-fold increase in the number of patients since reimbursement began; there was no significant difference in OS between patients who received NHI reimbursement and those who self-paid. CONCLUSION: Administration of Ra-223 demonstrates considerable potential to extend the survival of patients with mCRPC. Survival outcomes may be influenced by various prognostic factors. However, no significant difference in OS was observed subsequent to reimbursement of Ra-223 therapy for mCRPC through the NHI system in Taiwan.

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Abstract Targeted alpha therapy (TαT) employs alpha particle-emitting radioisotopes conjugated to tumour-specific carriers to precisely irradiate tumour cells. Monte-carlo techniques have been used to accurately simulate absorbed dose and DNA damage for the four promising TαT radionuclides, Actinium-225 ( 225 Ac), Radium-223, ( 223 Ra), Lead-212 ( 212 Pb) and Astatine-211, ( 211 At). TOPAS and TOPAS-nBio, based on the Geant4 and Geant4-DNA monte-carlo codes respectively, were used to model the radioactive decay and alpha particle transport within a simplified spherical cell model. Four different sites within the cell model were used for the initial radionuclide distributions: the cell membrane layer, within the cytoplasm volume, on the nucleus surface, and within the nucleus volume. Results indicate higher absorbed doses to the nucleus per decay when radionuclides are initially located on the nucleus wall or within the nucleus volume. 225 Ac and 223 Ra, with longer decay chains and higher alpha yields, exhibit higher doses to the nucleus per decay compared to 212 Pb and 211 At. Notably, 211 At, particularly when initially distributed within the nucleus volume or at its surface, demonstrates high relative efficacy, indicated by the absorbed dose to the nucleus per decay and number of single and double-strand breaks. These findings suggest that tumour-specific molecules should ideally target the nucleus to optimize efficacy.

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