Xofigo (radium Ra-223 dichloride)

P=N/A, N=1474, Active, not recruiting, Bayer | Trial completion date: Feb 2025 --> Oct 2024

P=N/A, N=1, Completed, Pfizer | Trial completion date: Jun 2023 --> Apr 2024 | Trial primary completion date: Jun 2023 --> Apr 2024

P3, N=446, Active, not recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Trial completion date: Dec 2025 --> Dec 2028

Clinical responders possessed lower circulating frequencies of Ki67+ T and myeloid cells at baseline and higher circulating frequencies of TIM-3+ T and myeloid cells by week 9. Although R223+P did not induce T-cell infiltration into the tumor microenvironment, exhaustion of induced peripheral T-cell immune responses may dampen the combination's clinical activity.

P1, N=43, Active, not recruiting, Tufts Medical Center | Recruiting --> Active, not recruiting | N=25 --> 43 | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

As determined by receiver operating characteristic (ROC) curve analysis, tetanus-specific IL-10 spots at baseline had the highest predictive value (p = 0.005) for tumor burden at month 6, with an area under the curve (AUC) of 0.90 (sensitivity 100%, specificity 78%). In conclusion, we observed an additive effect of treatment with 223Ra on immune function and found that IL-10 secretion at baseline predicted tumor burden at month 6 after treatment.

P3, N=806, Completed, Bayer | Active, not recruiting --> Completed

P4, N=255, Completed, Bayer | Active, not recruiting --> Completed

P=N/A, N=1474, Active, not recruiting, Bayer | Trial primary completion date: Nov 2024 --> Aug 2024

Quantitative bone scan assessment with aBSI and CTC analyses are prognostic markers in patients treated with radium-223. AR-V7 expression in CTCs is a particularly promising prognostic biomarker and warrants validation in larger cohorts.

P1/2, N=90, Suspended, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=20, Completed, University of Utah | Active, not recruiting --> Completed | Trial completion date: Aug 2024 --> Aug 2023

P2, N=54, Not yet recruiting, University of California, San Francisco | Initiation date: Dec 2023 --> Apr 2024

P4, N=24, Active, not recruiting, University Health Network, Toronto | Recruiting --> Active, not recruiting | Trial completion date: Dec 2022 --> Jul 2024 | Trial primary completion date: Dec 2022 --> Sep 2023

P1/2; Recruiting --> Suspended

P=N/A; Active, not recruiting --> Completed

The inflammatory cytokine IL-6 and the angiogenic biomarker PlGF at baseline were promising outcome biomarkers after standard Ra223 treatment. In mouse models, Ra223 increased intratumoral CD8 T cell infiltration and proliferation and could improve OS when combined with anti-PD1 ICI.

A total of 29 (72.5%) patients received 233 Ra following abiraterone or enzalutamide treatment while 10 (25%) received 233 Ra post docetaxel. While the number of patients included in our review was small, our analysis suggested that patients with HRD may have a slight improvement in OS after 223Ra treatment. Validation in a prospective dataset is required, and whether HRD status has implications for other radiopharmaceuticals such as lutetium-177 remains to be seen.

In this descriptive analysis of real-world data, patients who received EBRT prior to Ra-223 did not demonstrate an increased incidence of hematological toxicities relative to the overall US subset. Although percent of SPMs and bone fractures seems higher among patients treated with EBRT relative to the overall US subset, the real-world incidence of these events remains low.

Therapies received prior to Ra-223 were androgen receptor pathway inhibitors (75.4%), chemotherapy (32.1%), sipuleucel-T (13.7%) and bone health agents (73.7%). Ra-223 was utilized as a combination therapy by 26.0% of the overall population, predominately with enzalutamide... Nearly half of men completed 5+ cycles of Ra-223 therapy in a large US cohort of relatively young mCRPC men with private health insurance. Advanced disease state with short survival and low comorbidity were key factors associated with lower completion of 5+ cycles. The findings highlight the importance of utilizing Ra-223 early after mCRPC diagnosis, when the probability of >6-month survival is higher, to enhance treatment completion that has been shown to result in better outcomes.

CTC count and AS of cfDNA at baseline and during treatment predict clinical response to radium-223 in patients with mCRPC, warranting future evaluation of their value in treatment guidance.

P1/2; Trial completion date: Nov 2023 --> Nov 2024 | Trial primary completion date: Nov 2023 --> Nov 2024

P2, N=25, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Apr 2025 | Trial primary completion date: Dec 2023 --> Apr 2025

P1/2, N=90, Suspended, National Cancer Institute (NCI) | Phase classification: P2 --> P1/2

P2, N=30, Active, not recruiting, University of Southern California | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2023 --> Nov 2024

P=N/A, N=1, Completed, Pfizer | Recruiting --> Completed | Trial completion date: Nov 2023 --> Jun 2023 | Trial primary completion date: Nov 2023 --> Jun 2023

P2, N=90, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P=N/A, N=1226, Completed, Bayer | Active, not recruiting --> Completed | N=850 --> 1226 | Trial completion date: Jan 2024 --> May 2023 | Trial primary completion date: Dec 2023 --> May 2023

P=N/A, N=103, Completed, Bayer | Recruiting --> Completed | Trial completion date: Feb 2024 --> Nov 2022 | Trial primary completion date: Feb 2024 --> Nov 2022

Mechanically, Ra-induced DNA damage leads to the activation of stimulator of interferon genes (STING)-mediated DNA sensing pathway, which is critical for NLRP3 inflammasome-dependent pyroptosis and subsequent DCs maturation as well as T cell activation. These findings establish an essential role of STING in mediating alpha-emitter Ra-induced antitumor immunity, which provides the basis for the development of novel cancer therapeutic strategies and combinatory therapy.

Changes in physical activity had modest ability to predict moderate to severe symptoms overall. Although participation was suboptimal, daily activity monitoring in older adults with cancer appears feasible and may have other uses such as improving physical activity levels. Further studies are warranted.

In summary, around 20% of mCRPC patients experience Ra223-induced PSA flares, whose outcome is similar to that of men with or without PSA responses. Further studies are needed regarding suitable biochemical surrogate markers of response to Ra223.

Current evidence supporting NAFCIST comes from a pilot study that evaluated alpha particle radium-223 in patients with osteosarcoma. In this review, practical guidance for utilizing NAFCIST in the context of bone tumors is illustrated to aid future studies.

The abiraterone/prednisone treatment decreased radium-223 incorporation into tumor-bearing bone, possibly explaining the lack of additional antitumor efficacy. In conclusion, radium-223/abiraterone/prednisone combination increased bone resorption, which may have been one of the mechanisms leading to an increased fracture risk in patients with mCRPC.

• 18F-sodium fluoride PET baseline SUVmax of castration-resistant prostate cancer bone metastases showed significant association with response to radium-223. • Baseline 18F-sodium fluoride PET can improve patient selection for radium-223 therapy. • Change in whole-body DWI parameters can be used for response correlation with baseline 18F-sodium fluoride PET SUVmax in castration-resistant prostate cancer bone metastases.

Longer OS was observed in the patients with normal baseline tALP, in those with elevated baseline tALP that showed a response to treatment (≥ 10% reduction), and in those who received 5-6 cycles of therapy. The tALP may be used to predict which patients will benefit from treatment with a greater number of cycles of radium-223 therapy and will have longer OS.

Current preclinical experiments are focused on the structural modification of Lu-PSMA-617 and relevant investigational agents to increase tumor targeting and reduce off-target binding and toxicity in healthy organs...In addition, agents carrying the α-particle-emitting radiohalogen, astatine-211 (At), or radiometals, actinium-225 (Ac), lead-212 (Pb), radium-223 (Ra), and thorium-227 (Th), have been increasingly investigated in preclinical research...Here, we review the current developments related to the preclinical radiopharmaceutical therapy of prostate cancer. These are summarized in two major topics: (1) therapeutic radionuclides and (2) tumor-targeting approaches using monoclonal antibodies, small molecules, and peptides.

The CB rate of Ra-223 was 73.7%. No predictive factor for treatment response was obtained from pre-treatment data. The mean percentage changes in ALP, LDH, and PSA levels compared with baseline significantly differed between the CB and PD groups, especially the LDH levels. The CB and PD groups showed different OS, with LDH levels exhibiting the potential to predict OS.

The present study aimed to evaluate the optimal timing of radium-223 chloride (Ra-223) administration among patients with bone metastasis from castration-resistant prostate cancer (BmCRPC)...The timing of Ra-223 administration did not significantly affect the survival of patients from the initiation of treatment. Further studies are thus required to determine the optimal timing for Ra-223 administration.

This study stresses the importance of BMA use in patients with CRPC and bone metastases in Ra-223 treatment.

P=N/A, P3 | "Results The proportions of pts who had completed ≥1 life-prolonging therapy for mCRPC prior to 223Ra were 43%, 52% and 61% in the combined, layered and All pts groups, respectively (30%, 27% and 33% had received prior abiraterone and 17%, 29% and 36% had received prior docetaxel, respectively). Median OS was numerically longer in the combined vs the layered group or All pts. A phase 3 trial (PEACE III, NCT02194842) investigating the combination of enza with 223Ra is ongoing."