Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial

Smith, Matthew R.; Parker, Chris; Saad, Fred; Miller, Kurt; Tombal, Bertrand; Ng, Quan Sing; Boegemann, Martin; Matveev, Vsevolod; Piulats, Josep María; Zucca, Luis Eduardo Rosa; Karyakin, Oleg; Kimura, Go; Matsubara, Nobuaki; Nahas, William Carlos; Nolè, Franco; Rosenbaum, Eli; Heidenreich, Axel; Kakehi, Yoshiyuki; Zhang, Amily; Krissel, Heiko; Teufel, Michael; Shen, Jiayu; Wagner, V.; Higano, Celestia S.

doi:10.1016/s1470-2045(18)30860-x

Cited by 305 publications

(278 citation statements)

References 22 publications

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“…In 2018, the European Medicines Agency (EMA) issued a specific note on the indications for treatment with Ra223 in a review of an ongoing phase 3 trial by the EMA's Pharmacovigilance Risk Assessment Committee, basically moving Ra223 to a third-line of treatment of mCRPC patients (EMA/500948/2018; https://www.ema.europa.eu/en/documents/press-release/ema-restrictsuse-prostate-cancer-medicine-xofigo_en.pdf). The observation of increased the risk of fractures, in the absence of statistically significant survival benefit in patients with <6 bone lesions enrolled in the ERA-223 study, receiving Ra223 in combination with abiraterone acetate plus prednisone/prednisolone, motivated this action [22]. In fact, patients with lower skeletal disease burden might have a larger proportion of Ra223 homing to healthy bone, as compared to patients with extensive bone metastases.…”

Section: Patient's Selection For Ra223mentioning

confidence: 99%

Role of Baseline and Post-Therapy 18F-FDG PET in the Prognostic Stratification of Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated with Radium-223

Bauckneht

Capitanio

Donegani

et al. 2019

Cancers

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Radium-223 dichloride (Ra223) represents the unique bone-directed treatment option that shows an improvement in overall survival (OS) in metastatic castrate resistant prostate cancer (mCRPC). However, there is an urgent need for the identification of reliable biomarkers to non-invasively determine its efficacy (possibly improving patients’ selection or identifying responders’ after therapy completion). 18F-Fluorodeoxyglucose (FDG)-avidity is low in naïve prostate cancer, but it is enhanced in advanced and chemotherapy-refractory mCRPC, providing prognostic insights. Moreover, this tool showed high potential for the evaluation of response in cancer patients with bone involvement. For these reasons, FDG Positron Emission Tomography (FDG-PET) might represent an effective tool that is able to provide prognostic stratification (improving patients selection) at baseline and assessing the treatment response to Ra223. We conducted a retrospective analysis of 28 mCRPC patients that were treated with Ra223 and submitted to bone scan and FDG-PET/CT for prognostic purposes at baseline and within two months after therapy completion. The following parameters were measured: number of bone lesions at bone scan, SUVmax of the hottest bone lesion, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). In patients who underwent post-therapy 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT), (20/28), PET Response Criteria in Solid Tumors (PERCIST), and European Organization for Research and Treatment of Cancer (EORTC) criteria were applied to evaluate the metabolic treatment response. The difference between end of therapy and baseline values was also calculated for Metabolic Tumor Volume (MTV), TLG, prostate-specific antigen (PSA), alkaline phosphatase (AP), and lactate dehydrogenase (LDH) (termed deltaMTV, deltaTLG, deltaPSA, deltaAP and deltaLDH, respectively). Predictive power of baseline and post-therapy PET- and biochemical-derived parameters on OS were assessed by Kaplan–Meier, univariate and multivariate analyses. At baseline, PSA, LDH, and MTV significantly predicted OS. However, MTV (but not PSA nor LDH) was able to identify a subgroup of patients with worse prognosis, even after adjusting for the number of lesions at bone scan (which, in turn, was not an independent predictor of OS). After therapy, PERCIST criteria were able to capture the response to Ra223 by demonstrating longer OS in patients with partial metabolic response. Moreover, the biochemical parameters were outperformed by PERCIST in the post-treatment setting, as their variation after therapy was not informative on long term OS. The present study supports the role of FDG-PET as a tool for patient’s selection and response assessment in mCRPC patients undergoing Ra223 administration.

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Section: Patient's Selection For Ra223mentioning

confidence: 99%

Role of Baseline and Post-Therapy 18F-FDG PET in the Prognostic Stratification of Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated with Radium-223

Bauckneht

Capitanio

Donegani

et al. 2019

Cancers

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“…Neither SSE‐free survival, the primary endpoint, nor overall survival differed significantly between arms. However, the rate of fractures was higher among men treated with concurrent abiraterone and prednisone and radium‐223, compared to men receiving abiraterone and prednisone and placebo regardless of whether they were on bone health agents . Notably, approximately half (44%) of the men in our series received concurrent abiraterone or enzalutamide during radium‐223% and 71% received concurrent bone anti‐resorptive therapies.…”

Section: Discussionmentioning

confidence: 71%

Patterns of response and progression in bone and soft tissue during and after treatment with radium‐223 for metastatic castrate‐resistant prostate cancer

McNamara¹,

Oyekunle²,

Chin

et al. 2019

The Prostate

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Background Radium‐223 improves survival and time to first symptomatic skeletal event in symptomatic bone predominant metastatic castrate‐resistant prostate cancer (mCRPC). The imaging response to radium‐223 has not been well characterized. Methods To describe patterns of response and progression with radium‐223, we performed a retrospective review of all mCPRC patients who received radium‐223 at Duke from 1 June 2013 to 1 June 2015. Radionuclide bone scans obtained at baseline, during, and after treatment were reviewed by two radiologists. The automated bone scan index (aBSI) was generated at each time point using EXINI boneBSI version 2.4. Computed tomography (CT) and magnetic resonance imaging (MRI) clinical radiology reports were reviewed to evaluate for soft tissue, visceral, epidural, and bone progression. Clinical data were abstracted from the electronic health record. Results We identified 61 men who received at least one dose of radium‐223 at Duke during the study period (median, 5 doses; range, 1‐6). Among men with imaging during treatment, 2 of 14 (14.3%) had resolution of greater than or equal to 1 lesion on bone scan, 4 of 14 (28.6%) had zero new bone lesions, 10 of 14 (71.4%) had greater than or equal to 1 new bone lesion, 14 of 26 (53.9%) progressed on CT. After radium‐223, 6 of 39 (15.4%) had resolution of 1 to 4 bone lesions, 15 of 39 (38.5%) demonstrated zero new bone lesions, 24 of 39 (61.5%) progressed on bone scan, 15 of 37 (40.5%) progressed on CT, and 10 of 34 (29.4%) progressed on both bone scan and CT. No men with zero new bone lesions after radium‐223 ultimately progressed in bone alone and only 3 of 15 eventually demonstrated any progression in the bone. aBSI decreased significantly from baseline to after radium‐223 among men with zero new bone lesions (median change in aBSI −0.23 [IQR, −1.5, 0.02]) and increased significantly for men with greater than or equal to 1 new postradium bone lesions (median change in aBSI 1.41 [IQR, −0.05, 3.63] [P = 0.018]). Conclusions Bone and soft tissue progression during and following radium‐223 is common in heavily pretreated men with mCRPC. However, stable disease and responses were observed in a subset of patients and may be associated with durable treatment response in the bone. Prospective studies are needed to further investigate the change in aBSI as a biomarker of bone scan response/stabilization and progression following treatment with radium‐223.

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“…Initial results from the ERA-223 study (NCT02043678) have shown evidence that a higher fracture rate is observed in patients who have been treated with abiraterone acetate þ prednisone/prednisole (AAP) and 223 Ra-Dichloride compared with patients treated with AAP and placebo. 3 This increased rate of fractures in the 223 Ra-Dichloride arm of the study is, to date, not well understood, but the European Medicines Agency has subsequently recommended restrictions on the use of 223 Ra-Dichloride. 35 Fractures appeared to have delayed development with respect to treatment with 223 Ra-Dichloride and AAP.…”

Section: Discussionmentioning

confidence: 99%

“…223 Ra-Dichloride is used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). [1][2][3][4] Skeletalrelated events caused by bone metastases are often serious and can reduce the quality of life of patients. 5 Boneseeking radionuclides such as 32 P-orthophosphate, 89 Srchloride, and 153 Sm-EDTMP have been shown to reduce bone pain and have been used to assist in the treatment of bone metastases.…”

Section: Introductionmentioning

confidence: 99%

Compartmental Model for 223Ra-Dichloride in Patients With Metastatic Bone Disease From Castration-Resistant Prostate Cancer

Taprogge

Murray

Gear

et al. 2019

International Journal of Radiation Oncology*Biology*Physics

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A better understanding of the uptake mechanisms of 223 Ra-Dichloride is essential for patient-tailored treatment planning and to improve understanding of the effects of alpha radiation on bone tissue. The developed compartmental model suggests that 223 Ra-Dichloride locates on the bone surface and is incorporated into the bone matrix. Those findings could have implications for bone marrow dosimetry and can be used to further investigate the effects of alpha Purpose: 223 Ra-Dichloride is used for treatment of patients with metastatic bone disease from castration-resistant prostate cancer. The uptake and mechanism of action of 223 Ra-Dichloride is not well understood. The aim of this work was to develop a compartmental model for 223 Ra-Dichloride in patients to improve understanding of the underlying mechanisms. Methods and Materials: A compartmental model was developed based on activity retention data from 6 patients (2 treatments of 110 kBq/kg 223 Ra-Dichloride) for plasma, bone surfaces, small intestines, large intestines, and excretion data. Rate constants were extracted. Rate constant variability between patients and treatments was assessed. A population model was proposed and compared with the established International Commission on Radiological Protection-67 compartmental model. Results: A single bone compartment cannot accurately describe activity retention in the skeleton. The addition of a second bone compartment improved the fit to skeleton retention data, and the Akaike information criterion decreased. Mean rate constants of 4.

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Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial

Cited by 305 publications

References 22 publications

Role of Baseline and Post-Therapy 18F-FDG PET in the Prognostic Stratification of Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated with Radium-223

Role of Baseline and Post-Therapy 18F-FDG PET in the Prognostic Stratification of Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated with Radium-223

Patterns of response and progression in bone and soft tissue during and after treatment with radium‐223 for metastatic castrate‐resistant prostate cancer

Compartmental Model for 223Ra-Dichloride in Patients With Metastatic Bone Disease From Castration-Resistant Prostate Cancer

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