In this study, we evaluated real-world data on radium-223 plus abiraterone/prednisone or enzalutamide. Previously, the ERA 223 trial (NCT02043678) demonstrated increased fracture risk with concurrent treatment with radium-223 and abiraterone plus prednisone/prednisolone in patients with metastatic castration-resistant prostate cancer (mCRPC). We used the Flatiron Health database to perform a retrospective study of patients with mCRPC treated with radium-223. Treatment with radium-223 plus abiraterone/prednisone or enzalutamide was defined as concurrent if both drugs started within 30 days of one another, or layered when the second drug started ≥30 days after the first. The index date was defined as the day of the first radium-223 dose. Outcome measures included symptomatic skeletal events (SSEs), overall survival (OS), and patterns of treatments received. Of the 625 patients treated with radium-223, 22% received it together with abiraterone/prednisone and 27% with enzalutamide. When these agents were combined, they were often initiated in a layered fashion (73% layered, 23% concurrent). Prior or concomitant bone health agents (BHAs) were received by 67% and 55% of patients, respectively. Median follow-up was 9 months. Overall, incidence rates for SSEs and pathologic fractures were 0.35 and 0.11 patients per person-year, respectively. Median OS from mCRPC diagnosis was 28.1 months. In this real-world setting, combination treatments with radium-223 and abiraterone/prednisone or enzalutamide were common. These agents were more commonly given in a layered than a concurrent fashion. Incidence rates for SSEs were reduced when BHAs were used; however, BHAs were underutilized.

/pdf/concurrent-or-layered-treatment-with-radium-223-and-4nd6qdqtme.pdf

Concurrent or layered treatment with radium-223 and enzalutamide or abiraterone/prednisone: real-world clinical outcomes in patients with metastatic castration-resistant prostate cancer.

Radium-223 Within the Evolving Treatment Options for Metastatic Castration-resistant Prostate Cancer: Recommendations from a European Expert Working Group.

Radium-223 is a life-prolonging therapy for castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases. However, validated biomarkers for response monitoring are lacking. The study aim was to investigate whether early alkaline phosphatase (ALP) dynamics after the first radium-223 injection can act as surrogate marker for overall survival (OS). This retrospective multicenter study included consecutive CRPC patients treated with radium-223. Patients were divided into four subgroups based on baseline ALP level (normal/elevated) and early ALP response, defined as ≥10% ALP decrease after the first radium-223 injection. Primary endpoint was OS among the subgroups. Secondary endpoints included time to first skeletal-related event, time to ALP progression, and treatment completion rate. A total of 180 patients were included for analysis. Median OS was 13.5 months (95% confidence interval 11.5–15.5). Patients with elevated baseline ALP without ALP response after the first injection had significantly worse OS when compared to all other patients (median OS 7.9 months versus 15.7 months, hazard ratio 2.56, 95% confidence interval 1.73–3.80, P < 0.001). Multivariate analysis demonstrated that elevated baseline ALP without ALP response after the first injection, the number of prior systemic therapies, baseline LDH level, and baseline ECOG performance status were prognostic factors of OS. Patients with elevated baseline ALP without ALP response after the first injection had significantly shorter times to ALP progression and first skeletal-related event, and more frequently discontinued radium-223 therapy when compared to other patients. Early treatment–induced changes in ALP after one radium-223 injection were associated with OS in metastatic CRPC patients.

/pdf/early-alkaline-phosphatase-dynamics-as-biomarker-of-survival-4bxmevjunf.pdf

Early alkaline phosphatase dynamics as biomarker of survival in metastatic castration-resistant prostate cancer patients treated with radium-223

Background Skeletal-related events cause significant morbidity in patients with metastatic castration-resistant prostate cancer. In the ALSYMPCA study, radium-223 (Ra223) was found to provide pain palliation in addition to prolonged survival and reduced skeletal-related events (SREs). Given previous evidence that bisphosphonates impacted pain relief from the radiopharmaceutical samarium-153, we evaluated whether the timing of bone supportive therapy (BST) such as zoledronic acid or denosumab affected pain palliation from Ra223. Methods We identified patients who received Ra223 at University of Southern California or Mayo Clinic Arizona. Patients were evaluable for pain response if they had baseline pain score > 0 and at least 1 pain score documented after Ra223 with pain medication use data. Patients were evaluable for pain flare if they had known baseline pain score and at least 2 pain scores documented after Ra223. Pain response was defined as > 2 point decrease in pain on a 10-point scale; flare was defined as > 2 point increase followed by return to baseline or lower. Results Of 65 patients, 22 (34%) received BST. Median number of doses Ra223 was 5 (range 2–6). Fourteen patients were evaluable for pain response and 34 for pain flare. Eighteen patients received concurrent abiraterone (abi) or enzalutamide (enza), and 16 did not. Pain response occurred in 6/6 (100%) patients who received BST within 1 month prior to first Ra223 dose and 4/8 (50%) patients who did not receive BST. Pain flare occurred in 6/21 patients (29%) without BST and 2/13 (15%) with BST (p = 0.44). 6/10 (60%) patients with pain response had a decline in alkaline phosphatase (ALP) level, but there was no consistent pattern of ALP changes in patients with flare. 8/8 patients with pain response had no PSA decline. 6/8 (75%) and 2/18 (11%) patients on abi/enza had pain response and flare respectively, and 4/6 (67%) and 6/16 (38%) patients without concurrent abi/enza had response/flare. Conclusions BST within 1 month prior to first Ra223 dose was associated with increased likelihood of pain palliation and might prevent pain flare. Concurrent use of abi/enza was not associated with increased likelihood of pain response but was associated with decreased likelihood of pain flare.

Impact of timing of administration of bone supportive therapy on pain palliation from radium-223.

The objective: is to determine the current role of radium-223 in the emergence of new options in the treatment of patients with metastatic castration-resistant prostate cancer.
Materials and methods. Studies of ERA-223 and ALSYMPCA have identified the role of radium-223 in the treatment of prostate cancer and its impact on human health.
Results. In one such study, ERA-223, it was shown that the combination of abiraterone with radium-223 did not increase survival without symptomatic skeletal events compared with abiraterone plus placebo. In addition, a higher incidence of bone fractures was observed with the combination of abiraterone and radium-223, especially in patients not receiving osteomodulators (denosumab or zoledronic acid). These results have led to some changes in the indications for the use of radium-223 in Europe and more careful attention to the state of bone structure in patients with prostate cancer.
An overview of expert recommendations for the prevention and treatment of bone events, as well as the consequences of prolonged targeted therapy in patients with metastatic prostate cancer, which may improve the results of general and cancer-specific survival. Radium-223 has been shown to be an important option for patients with castration-resistant prostate cancer with bone metastases, and monitoring and maintaining bone health is an important factor in prostate cancer patients. It is established that the treatment of this category of patients should begin with androge n deprivation therapy.
Conclusions. A review of the recommendations of urologists, oncologists and radiation oncologists in Europe, who specialize in the treatment of patients with advanced prostate cancer, to maintain bone health, treatment consequences and the role of radium-223 in the treatment of prostate cancer. Based on the analysis of the use of radium-223 in the current treatment of CRPD, preventive measures to maintain bone health are recommended, as well as side effects based on clinical experience.

/pdf/radii-223-u-suchasnomu-likuvanni-metastatichnogo-abplshek0k.pdf

Радій-223 у сучасному лікуванні метастатичного кастраційно-резистентного раку передміхурової залози

Use of bone health agents (BHAs) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (Ra-223) after abiraterone (Abi): An interim review of REASSURE

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Use of bone health agents (BHAs) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (Ra-223) after abiraterone (Abi): An interim review of REASSURE