Radium-223 Treatment Research Articles

The impact of genetic aberrations on response to radium-223 treatment for castration-resistant prostate cancer with bone metastases.

Radium (Ra)-223 is an established treatment option for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease. Studies have indicated genetic aberrations that regulate DNA damage response (DDR) in prostate cancer can increase susceptibility to treatments such as poly ADP-ribose polymerase inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota) and Tulane Cancer Center. Patient demographics, genetic aberrations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were ALP and PSA response. Secondary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. One hundred and twenty-seven mCRPC patients treated with Ra-223 had germline and/or somatic genetic sequencing. The median age at time of diagnosis and Ra-223 treatment was 61.0 and 68.6 years, respectively. Seventy-nine (62.2%) had Gleason score ≥ 8 at time of diagnosis. 50.4% received prior docetaxel, and 12.6% received prior cabazitaxel. Notable alterations include TP53 (51.7%), BRCA 1/2 (15.0%), PTEN (13.4%), ATM (11.7%), TMPRSS2-ERG (8.2%), RB deletion (3.4%), and CDK12 (1.9%). There was no significant difference in ALP or PSA response among the different genetic aberrations. Patients with a TMPRSS2-ERG mutation exhibited a trend toward lower OS 15.4 months (95% confidence interval [CI] 10.0-NR) versus 26.8 months (95% CI 20.9-35.1). Patients with an RB deletion had a lower PFS 6.0 months (95% CI 1.28-NR) versus 9.0 months (95% CI 7.3-11.1) and a lower OS 13.9 months (95% CI 5.2-NR) versus 26.5 months (95% CI 19.8-33.8). Among mCRPC patients treated with Ra-223 at Mayo Clinic and Tulane Cancer Center, we did not find any clear negative predictors of biochemical response or survival to treatment. TMPRSS2-ERG and RB mutations were associated with a worse OS. Prospective studies and larger sample sizes are needed to determine the impact of genetic aberrations in response to Ra-223.

Radium-223 in mCPRC patients: a large real-life Italian multicenter study.

Radium-223 is a targeted alpha-particles therapy approved for the treatment of mCRPC patients with symptomatic bone metastases. To our knowledge we account for the largest cohort of mCRPC patients subjected to Radium-223 treatment in our country. We aim to describe in a real-life setting the largest cohort of mCRPC patients treated with Radium-223 ever taken into consideration. Four hundred and thirty consecutive mCRPC patients were enrolled. Clinical data have been collected at baseline and at the end of the Radium-223 treatment. Furthermore, the overall survival(OS) of our population has been provided. One hundred fifty-seven patients (36.5%) were still alive at the time of data analysis. A mean number of 4.95±1.6 cycles of Radium-223 was reached by our cohort. 265 patients (61.6%) completed the whole six cycles regimen. The mean follow-up period from the first cycle of Radium-223 to the date of the analysis was 12.7 months. The analysis of patients Annual Incidence Rate (AIR) in relation to the number of Radium-223 cycles received depicting a clear advantage for those patients who completed the whole six administrations planned, with an AIR (AIR=0.32) of much lesser value compared to those that have performed five cycles (AIR =0.98). 165 patients (38.4%) dropped out of treatment for death or disease progression. This study offers a cross-section of the clinical performance of Radium-223 treatment in a real-world context, confirming on a large scale the effectiveness of Radium-223 in improving the OS and quality of life, along with the preservation of an excellent safety profile.

Real-world patient characteristics associated with survival of 2 years or more after radium-223 treatment for metastatic castration-resistant prostate cancer (EPIX study)

BackgroundThe real-world EPIX study was conducted to gather information about the characteristics of patients with metastatic castration-resistant prostate cancer (mCRPC) who survived ≥2 years after treatment with the alpha-emitter radium-223.MethodsThis retrospective study of electronic health records in the US Flatiron database (NCT04516161) included patients with mCRPC treated with radium-223 between January 2013 and June 2019. Median overall survival (OS) and prostate-specific antigen (PSA) response (≥50% reduction) from start of radium-223 treatment were the primary and secondary endpoints, respectively. Patient characteristics were compared between those who survived ≥2 years versus <2 years, including a subgroup who survived <6 months.ResultsIn the 1180 patients identified, median OS was 12.9 months (95% CI: 12.1–13.7), and 13% of patients with data at 6 months had a PSA response. The survival groups included 775 patients (65.7%) who survived <2 years (including 264 (22.4%) who survived <6 months) and 185 patients (15.7%) who survived ≥2 years; 220 patients (18.6%) had incomplete follow-up data and were censored. On multivariate analysis, age >75 years, Eastern Cooperative Oncology Group performance status (ECOG PS) 2–4, visceral metastases, prior symptomatic skeletal events (SSEs), and prior chemotherapy were independently prognostic of reduced OS. For patients with survival ≥2 years versus <2 years, median age was 71 versus 75 years, 4% versus 14% had ECOG PS 2–4, 4% versus 10% had visceral metastases, 38% versus 44% had prior SSEs, and 16% versus 32% had prior chemotherapy.ConclusionsIn this study of men with mCRPC treated in real-world clinical practice, median OS was consistent with that seen in the phase 3 ALSYMPCA trial. Patients who survived ≥2 years after the start of radium-223 were younger and had better ECOG PS, lower disease burden, and less use of prior chemotherapy than those who survived <2 years.

Radium-223 in patients with prostate specific antigen (PSA) progression and without clinical metastases following maximal local therapy: A pilot study.

Despite the curative intent of radical prostatectomy (RP) (+/- radiotherapy (RT)), 30% of the clinically localized prostate cancer (CaP) patients will develop rising PSA (prostate specific antigen). In absence of clinical recurrence, there is a lack of effective treatment strategies in order to control the disease at its earliest (micro)metastatic stage. The aim of this study was to assess safety, tolerability, and biochemical response of off-label Radium-223 (Xofigo) treatment in CaP patients with PSA relapse following maximal local therapy. We conducted a prospective, single arm, single center open-label, pilot study with Radium-223 in CaP patients with rising PSA (>0.2 ng/ml) following RP + adjuvant/salvage RT. Negative staging with 68Ga-PSMA-11 PET/CT and whole-body MRI was mandatory at time of inclusion. Patients were eligible if they exhibited adverse clinico-pathological features predictive of significant recurrence. Safety, tolerability, biochemical progression (defined as PSA increase >50% from PSA nadir) and clinical recurrence were assessed. In total, 23 patients were screened of whom 8 patients were included is the study. Radium-223 treatment was safe with no serious treatment related adverse events. One patient developed grade 3 lymphopenia. All patients rapidly developed PSA progression (median PSA progression-free survival: 5.5 months). Eventually all patients experienced clinical recurrence (median clinical recurrence-free survival 11.0 months) of whom only 2 patients developed skeletal recurrence. Radium-223 in patients with PSA relapse following maximal local treatment without clinical metastases is safe. However, the clinical benefit of Ra-223 in this setting is doubtful as significant oncological benefit is lacking.

Treatment outcome of radium-223 treatment for castration-resistant prostate cancer and bone metastases at a single university hospital

Treatment outcome of radium-223 treatment for castration-resistant prostate cancer and bone metastases at a single university hospital

A qualitative research study in Japan investigating patients' experience with metastatic castration-resistant prostate cancer: from diagnosis to decision for Ra-223 treatment.

Aim: This qualitative study aimed to reveal symptoms and impacts among bone metastatic castration-resistant prostate cancer (or mCRPC) Japanese patients, prior to Radium-223 (Ra-223) treatment. Materials & Methods: Twenty-three mCRPC patients designated to receive Ra-223 and three treating physicians (Ra-223 prescribers) in Japan, were interviewed. All interview data were assessed for concept frequency, themes and saturation. Results: Forty-five percent of the patients (mean age: 75.8years) were symptomatic at the time of enrollment. Interviews with all patients revealed 47 mCRPC symptoms, including back pain and bone-specific pain, and 45 life impacts, including worry about disease progression and the impact on daily, physical activities. Conclusion: The symptoms and impacts of living with mCRPC and the associated burden of bone metastasis and skeletal-related symptoms are varied and are important considerations for treatment.

Radium-223 Treatment in mCRPC Patient with Polycythemia Vera

There have been several studies on the clinical outcomes of Radium-223 treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) who may have an increased risk of hematologic comorbidities. To the best of our knowledge, this is the first study to explore the potential bone marrow adverse effects (AEs) of Radium-223 administered with specific drugs used for hematologic conditions, such as polycythemia vera (PV). We report the case of a patient with mCRPC who was administered a combined treatment of Radium-223 and hydroxyurea for PV, aiming to support clinicians in predicting eventual AEs.

Radium-223 Treatment of Patients with Metastatic Castration Resistant Prostate Cancer: Biomarkers for Stratification and Response Evaluation.

Simple SummaryRadium-223 dichloride ([223Ra]RaCl2; Ra-223) is an alpha-emitting radiopharmaceutical treatment for patients with metastatic castration resistant prostate cancer (mCRPC) with predominantly bone metastases. While responses to chemotherapeutic and antihormonal mCRPC treatments can be assessed by serum PSA levels, a decrease of serum PSA levels is not expected during Ra-223 therapy. Moreover, radiographic evaluation of bone metastases response is challenging. Therefore, novel biomarkers to select patients for Ra-223 treatment and monitoring response are urgently needed. In this review, we discuss the currently used and exploratory biomarkers for this purpose, including soluble and cellular factors detected in the peripheral blood, genetic defects and radiographic assessments. We conclude that some biomarkers, including metabolic products of collagen degradation and novel PET scan techniques, might hold promise as predictors of response to Ra-223 treatment. However, these biomarkers have not been extensively studied. Consequently, currently, no biomarker has established a place in patient stratification and response evaluation.Radium-223 dichloride ([223Ra]RaCl2; Ra-223) is a targeted alpha-emitting radiopharmaceutical which results in an overall survival and health related quality of life (HRQoL) benefit in symptomatic patients with metastatic castration resistant prostate cancer (mCRPC) and predominantly bone metastasis. Although effective, options to select patients who will derive treatment benefit and to monitor and predict treatment outcomes are limited. PSA response and radiographic evaluation are commonly used in mCRPC treatment assessment but are not informative in Ra-223 treated patients. Consequently, there is a clear need for predictive and prognostic tools. In this review, we discuss the physiology of bone metastases and the mechanism of action and efficacy of Ra-223 treatment, as well as offering an outline of current innovative prognostic and predictive biomarkers.

Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model.

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor–bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease.

Predicting benefit of radium 223 based on biochemical response and site of metastasis: A real life multicenter UK study.

e17034 Background: Studies have shown an improvement in overall survival (OS) and symptom control in metastatic castration-resistant prostate cancer (mCRPC) with Radium-223 treatment. However, there is little information about predicting outcomes using either PSA or Alkaline Phosphatase (ALP) response or comparing bone only disease to bone and lymph node (LN) involvement. Methods: 335 patients receiving Radium 223 at 6 UK centres between March 2014 and June 2020 were included. The primary endpoint was overall survival, secondary endpoints were toxicity, symptomatic benefit and skeletal-related events(SRE) Results: The median age was 75, with 71% having bone only metastases and 29% also having lymph node involvement. Those with PSA response (30%) had a statistically significant improvement in OS, compared to non-responders (18.2 vs 13.8 months, p = 0.026). They also showed highest rate of imaging response/stable disease (54% vs 34%). ALP response was seen in 82%. This did not translate to significantly improved OS, but did correlate with better symptomatic benefit (40% vs 29%). Those with bone only disease showed a survival benefit compared to those with LN involvement (19.4 vs 11.4 months, p = 0.046). Other than anaemia (23.5%), Grade 2 or above toxicities were uncommon including thrombocytopenia and neutropenia(5.5 and 6.2% respectively ) . 14% patients required at-least one blood transfusion. SRE were seen in 24% overall, but lower of in PSA responders(18%). Conclusions: Real life multicentre data suggests that PSA response and bone only disease could be predictors for better survival following Radium-223, whereas ALP response correlates better with symptomatic benefit.

Serial ctDNA profiling in patients with metastatic prostate cancer undergoing treatment with radium-223.

e17018 Background: Assessment of the anti-tumor response to radium-223 (Ra-223) treatment is difficult in individuals. PSA levels seldom fall and imaging of existing bone metastases is imprecise. Circulating tumor DNA (ctDNA) is a non-invasive marker of prostate tumor DNA, with static measurements demonstrating high concordance rates with tumor DNA. Serial monitoring of ctDNA levels may provide insights into therapy response, targetable mutations, and progression of disease. We report changes in ctDNA profiles and clinical associations of 10 patients who had serial ctDNA profiles during Ra-223 treatment. Methods: Serial ctDNA analyses of mutations (73 genes) and amplifications (18 genes) were performed via a commercial provider (Guardant 360; Guardant Health). Assays were performed before treatment, after the third Ra-223 dose, and after the final Ra-223 dose. ctDNA data (minor allele frequencies for mutations, copy number for amplifications) were reviewed to identify clonal mutations with at least 50% change in highest allelic frequency or 30% change in copy number during treatment. Clinical data (performance status (PS), PSA, pain score, prescribed oral morphine equivalents (OME), imaging, progression free survival (PFS), and overall survival) were gathered via chart review. Clinical progression was defined by an increase in at least 2 bone lesions on bone scan, progression of soft tissue disease by RECIST, worsening PS, or at least 20% increase in OME. Results: Three of 10 patients had a reduction in the proportion of mutated or amplified tumor DNA as measured by ctDNA profiling, after receiving Ra-223 (response group). Median PFS defined by time to PSA rise of at least 25% in this group was 120 days (95% CI 83 to 237) compared to 29 days (95% CI 21 to 145) in the group without a reduction (no response group). Median clinical PFS defined as above was 266 days (95% CI 109 to 291) in the response group compared to 83 days (95% CI 33 to 182) in the no response group. There was no difference in baseline pain score between the two groups, though median baseline PSA was higher in the no-response group (97.14 compared to 20.05). Reductions in allelic frequency were noted in several mutated genes, including AR, ARID1A, CDK12, and TP53(G245C), during Ra-223 therapy of subjects in the response group. Decreases in copy number were also seen in several amplified genes, including AR, CCNE1, CDK6, FGFR1. In the no-response group, 4/7 patients had an increase in AR amplification; 3/7 patients had an increase in variant allele fraction of TP53 mutations. In the response group of 3 patients who had a reduction in clonal mutations, none had an increase in the AR amplification. Conclusions: A reduction in proportion of clonal mutations or gene amplification measured in ctDNA may be associated with a longer PFS in patients treated with Ra-223. Mutations in the TP53 gene and amplification of AR gene were associated with shorter PFS.

Radium-223 Treatment Increases Immune Checkpoint Expression in Extracellular Vesicles from the Metastatic Prostate Cancer Bone Microenvironment.

Radium-223 prolongs survival in a fraction of men with bone metastatic prostate cancer (PCa). However, there are no markers for monitoring response and resistance to Radium-223 treatment. Exosomes are mediators of intercellular communication and may reflect response of the bone microenvironment to Radium-223 treatment. We performed molecular profiling of exosomes and compared the molecular profile in patients with favorable and unfavorable overall survival. We performed exosomal transcriptome analysis in plasma derived from our preclinical models (MDA-PCa 118b tumors, TRAMP-C2/BMP4 PCa) and from the plasma of 25 patients (paired baseline and end of treatment) treated with Radium-223. All samples were run in duplicate, and array data analyzed with fold changes +2 to -2 and P < 0.05. We utilized the preclinical models to establish that genes derived from the tumor and the tumor-associated bone microenvironment (bTME) are differentially enriched in plasma exosomes upon Radium-223 treatment. The mouse transcriptome analysis revealed changes in bone-related and DNA damage repair-related pathways. Similar findings were observed in plasma-derived exosomes from patients treated with Radium-223 detected changes. In addition, exosomal transcripts detected immune-suppressors (e.g., PD-L1) that were associated with shorter survival to Radium-223. Treatment of the Myc-CaP mouse model with a combination of Radium-223 and immune checkpoint therapy (ICT) resulted in greater efficacy than monotherapy. These clinical and coclinical analyses showed that RNA profiling of plasma exosomes may be used for monitoring the bTME in response to treatment and that ICT may be used to increase the efficacy of Radium-223.

A novel prediction model for the completion of six cycles of radium-223 treatment and survival in patients with metastatic castration-resistant prostate cancer

PurposeWe evaluated the predictive factors for completion of all six cycles of radium-223 (Ra-223) treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). We also developed a novel prediction model for Ra-223 treatment completion using these predictors.MethodsWe retrospectively reviewed data from 122 patients with mCRPC who were treated with Ra-223. The predictive factors for the completion of six cycles of Ra-223 treatment were evaluated. Statistically significant predictive factors were then used to develop a prediction model for treatment completion. Finally, using this prediction model, we classified the overall survival (OS) of the entire cohort into three groups.ResultsWe identified three significant variables as the predictive factors for treatment completion: baseline alkaline phosphatase (ALP) level, baseline hemoglobin (Hb) level, and baseline pain. The three groups generated using the prediction model were: group 1 (patients with three predictive factors, i.e., ALP < median, Hb ≥ median, and no pain), group 2 (patients with one to two predictive factors), and group 3 (patients without any predictive factors). The treatment completion rates differed between the three groups significantly. Furthermore, the OS also differed among the groups significantly.ConclusionOur study suggested that the baseline ALP level, baseline Hb level, and baseline pain were the predictive factors of completion of all six cycles of Ra-223 treatment in patients with mCRPC. Our prediction model consisting of these factors could predict not only the completion of Ra-223 treatment, but also the post-treatment survival. This model can thus be useful for selection of patients for Ra-223 treatment.

Real-world clinical outcomes study of sequential novel antihormonal therapy (NAH) or radium-223 (Ra-223) treatment of metastatic castration-resistant prostate cancer (mCRPC) that progressed after first-line NAH.

48 Background: We assessed real-life clinical outcomes in patients with mCRPC treated in the USA who received sequential first-line (1L)/second-line (2L) NAH (abiraterone/enzalutamide or enzalutamide/abiraterone) or switched to a different mechanism of action (alpha-emitter Ra-223) after progression on 1L NAH. Methods: This was a retrospective study (PHENIX, NCT03896984) of the Flatiron electronic health record database in patients with mCRPC that progressed on 1L NAH and started 2L monotherapy with Ra-223 (n=120) or NAH (n=226) between Jan 2013 and Dec 2018. Patient characteristics, overall survival (OS) from 2L start, and symptomatic skeletal events (SSEs) were analyzed descriptively. Results: The two cohorts were generally similar at 2L start, including similar rates of bone-health agent (BHA) use, but the Ra-223 cohort had a higher incidence of bone-only metastases, shorter duration of 1L NAH, and higher rate of prior SSEs than the 2L NAH cohort (Table). Median treatment duration was 5.6 mo (median 4.5 doses) for Ra-223 and 4.7 mo for 2L NAH. Median OS from 2L start was 10.8 mo for Ra-223 and 11.2 mo for 2L NAH, with 49% and 39%, respectively, receiving subsequent therapy. Among those who received subsequent therapy, the proportion who received subsequent taxane was lower in the Ra-223 cohort (47%) than in the 2L NAH cohort (76%). SSEs were observed after 2L start in 32 patients (27%) on Ra-223 and 49 (22%) on 2L NAH. Conclusions: OS from start of 2L mCRPC treatment was similar for patients who received Ra-223 or alternative NAH in 2L. Slightly more patients received subsequent therapy in the Ra-223 cohort than in the 2L NAH cohort. Patients who received subsequent therapy were more likely to receive chemotherapy in the 2L NAH cohort, which is unsurprising as 2L NAH after 1L NAH is not highly active. Although the prior SSE rate before 2L start was higher in the Ra-223 cohort than in the 2L NAH cohort, and the two cohorts had similar rates of BHA use at 2L start, the rate of SSEs after 2L start was similar in both cohorts. Clinical trial information: NCT03896984. [Table: see text]

Real-world safety and effectiveness of radium-223 in Japanese patients with castration-resistant prostate cancer (CRPC) and bone metastasis: exploratory analysis, based on the results of post-marketing surveillance, according to prior chemotherapy status and in patients without concomitant use of second-generation androgen-receptor axis-targeted agents

BackgroundBased on results from Japanese post-marketing surveillance, exploratory analyses were performed to investigate real-world outcomes of radium-223 for metastatic CRPC (mCRPC) according to patient characteristics.MethodsThis non-interventional, prospective study enrolled mCRPC patients selected for radium-223 treatment in clinical practice. Six-month safety and effectiveness were evaluated in subgroups who had/had not received prior chemotherapy (prior-chemo/no prior-chemo groups), and a subgroup who had not received concomitant androgen-receptor axis-targeted agents (ARATs).ResultsIn the overall population (n = 296), the prior-chemo group (n = 126) tended to have more bone metastases, more analgesic use, and higher prostate-specific antigen values than the no prior-chemo group (n = 170). Incidences of treatment-emergent adverse events (TEAEs), drug-related TEAEs, and ≥ grade 3 drug-related hematological TEAEs were 47% vs. 53%, 25% vs. 29%, and 4% vs. 7% in the no prior-chemo and prior-chemo groups, respectively. Incidences of TEAEs (61%), drug-related TEAEs (36%), and ≥ grade 3 drug-related hematological events (12%) were numerically higher in 33 patients who had received two lines of prior chemotherapy. Multivariate analysis showed that two lines of prior chemotherapy, and hemoglobin, platelet, and lactate dehydrogenase values were baseline factors significantly related to ≥ grade 2 platelet count decreased. Safety and effectiveness in patients without concomitant ARATs (n = 201) were similar to those in the overall population.ConclusionIn a real-life setting, radium-223 was well tolerated irrespective of prior chemotherapy, but relatively higher incidences of TEAEs and hematotoxicities were suggested in patients with two lines of prior chemotherapy, possibly reflecting more advanced disease. Radium-223 safety and effectiveness in patients without concomitant ARATs were favorable.

Influence of prostate cancer status on the prevalence of medication-related osteonecrosis of the jaw

The aim of this study was to evaluate the risk of osteonecrosis of the jaw (ONJ) in patients with prostate cancer, particularly the relationship between prostate cancer progression and ONJ development. This single-center, retrospective, observational study included 113 patients who received zoledronic acid or denosumab for prostate cancer with bone metastasis between January 2012 and March 2020. The risk of ONJ was evaluated regarding age; antiresorptive drugs; duration of antiresorptive treatment; prostate cancer status, including castration-resistant prostate cancer (CRPC) and prostate-specific antigen level; chemotherapy; radium-223 treatment; corticosteroid treatment; diabetes mellitus; and dental extractions. Overall, 28 patients had ONJ; 10 patients received zoledronic acid and 18 patients received denosumab. Multiple logistic regression analysis demonstrated that CRPC (odds ratio=6.01; 95% confidence interval, 1.76-20.05; P=.004) and dental extractions (odds ratio=12.40; 95% confidence interval, 3.42-44.70; P < .001) were significantly associated with ONJ. In addition, antiresorptive treatment lasting more than 1 year partially mediated between CRPC and development of ONJ. CRPC and dental extraction are risk factors for developing ONJ, and antiresorptive treatment lasting more than 1 year is a partial mediator between CRPC and ONJ.

Overall survival in mCPRC patients treated with Radium-223 in association with bone health agents: a national multicenter study

Purpose Radium-223 has demonstrated efficacy in improving overall survival (OS) and in delaying symptomatic skeletal-related events (SREs). Bone Health Agents (BHA), i.e. RANK ligand inhibitor (Denosumab) and bisphosphonate such as zoledronic acid, are indicated to prevent SREs without a clear survival benefit. SREs on patient health have a high impact and it is, therefore, important to consider the role of new therapies with BHA to better understand the involvement of combination therapy. The primary aim of this multicentric study is to assess OS in mCRPC patients treated with Radium-223 in combination with BHA. Materials and methods 430 consecutive patients treated with Radium-223 alone or in combination with BHA, affected by mCRPC, from January 2015 to July 2019 in six Italian Nuclear Medicine Units, were included. Furthermore, data were collected at baseline, after every Radium-223 administration, and during follow-up, at 3 and 6 months and 1 year after the 6th cycle. Clinical data have been evaluated before starting treatment with Radium-223 and at the end of treatment and/or at progression. Patients who received target bone therapy with BHA before Radium-223 treatment together with patients who did not receive this therapy at all (NO BHA GROUP), were compared to patients treated with concomitant Radium-223 and BHA (BHA GROUP). Results In univariate models (p < .05) several clinical aspects have an impact on OS: concomitant BHA (p = .018), BMI (p .001), ECOG PS (p = .000), Baseline Hb (p = .000), Baseline PSA (p = .000), Baseline tALP (p = .000), Baseline LDH (p = .000), and Baseline neutrophils (p = .009). Baseline Hb, Baseline tALP, and Baseline LDH have been confirmed as statistically significant parameters in multivariate models. Indeed, concomitant BHA has not a significant impact on OS (p = .244) in multivariate models. Conclusions At univariate analysis, our data showed that NO BHA GROUP and BHA GROUP differ in OS by 7 months (95%CI: (1–16.4), p = .02). This is not confirmed at multivariate analysis where after adjusting for other baseline factors, BHA is not significant anymore. This is clearly explained as bias by indication: patients with the same levels of tALP, Hb, and LDH receiving or not receiving BHA are expected to have a similar survival. Our results support and confirm the role of Radium-223 therapy on OS and, furthermore, appear to confirm that BHA treatment has not a survival benefit.

Treatment of metastatic castration resistant prostate cancer with radium-223: a retrospective study at a US tertiary oncology center

BackgroundGuidelines for optimal sequencing of radium-223 and chemotherapy for metastatic castration resistant prostate cancer (mCRPC) do not exist. This study evaluated treatment patterns and overall survival (OS) among patients with mCRPC treated with radium-223 in an academic clinical setting.MethodsA retrospective study was conducted of bone metastases-predominant mCRPC patients treated with radium-223. Treatment patterns from 2013 to 2018 were evaluated in patients treated with radium-223 pre- vs. post-chemotherapy. OS was examined using Kaplan–Meier medians and 95% confidence intervals.ResultsIn total, 220 patients were treated with radium-223 (64 pre-chemotherapy, 83 post-chemotherapy, 73 no chemotherapy). Mean radium-223 injections per patient was 5.3 and 4.3 in the pre- vs. post-chemotherapy cohorts, respectively (p < 0.001). The number of chemotherapy cycles was similar for chemotherapy given pre- or post-radium-223. Mean line of mCRPC therapy of radium-223 was 3rd and 5th when given pre- and post-chemotherapy, respectively (p < 0.001). 41.8% patients were treated with radium-223 in combination with another mCRPC therapy, commonly abiraterone acetate (43.5%) or enzalutamide (52.2%). The majority received combination therapy for the duration of radium-223 treatment; 20.7% started another agent after radium-223 initiation; 20.7% initiated radium-223 while on established therapy. Median OS from first mCRPC treatment was 39.4 months (95% CI 33.0, 48.8) for patients with radium-223 pre-chemotherapy vs. 37.4 months (95% CI 32.0, 43.5) post-chemotherapy (and 35.2 months [95% CI 27.9, 43.3] vs. 32.0 months [95% CI 26.9, 36.0] for patients with radium-223 combination vs. monotherapy).ConclusionsThis retrospective analysis of patients treated with radium-223 demonstrates that administration of radium-223 pre-chemotherapy increased likelihood of completion of radium-223 treatment. Radium-223 given pre- or post-chemotherapy and with or without combination therapy did not result in significant differences in OS. Additional studies are needed to determine the optimal sequencing strategy of mCRPC in the modern era.

Radium-223 in mCPRC patients: a large real-life Italian multicenter study

Radium-223 is a targeted alpha-particles therapy approved for the treatment of mCRPC patients with symptomatic bone metastases. To our knowledge we account for the largest cohort of mCRPC patients subjected to Radium-223 treatment in our country. We aim to describe in a real-life setting the largest cohort of mCRPC patients treated with Radium-223 ever taken into consideration. Four hundred and thirty consecutive mCRPC patients were enrolled. Clinical data have been collected at baseline and at the end of the Radium-223 treatment. Furthermore, the overall survival(OS) of our population has been provided. One hundred fifty-seven patients (36.5%) were still alive at the time of data analysis. A mean number of 4.95±1.6 cycles of Radium-223 was reached by our cohort. 265 patients (61.6%) completed the whole six cycles regimen. The mean follow-up period from the first cycle of Radium-223 to the date of the analysis was 12.7 months. The analysis of patients Annual Incidence Rate (AIR) in relation to the number of Radium-223 cycles received depicting a clear advantage for those patients who completed the whole six administrations planned, with an AIR (AIR=0.32) of much lesser value compared to those that have performed five cycles (AIR =0.98). 165 patients (38.4%) dropped out of treatment for death or disease progression. This study offers a cross-section of the clinical performance of Radium-223 treatment in a real-world context, confirming on a large scale the effectiveness of Radium-223 in improving the OS and quality of life, along with the preservation of an excellent safety profile.

Fracture risk and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) sequentially treated with abiraterone acetate (AA) and radium-223 (RA223).

e17593 Background: The increased incidence of bone fractures found in pts who received the AA-RA223 combination compared to those treated with AA alone in the ERA223 trial led to restrictive recommendations by the European Medicines Agency which limited the use of RA223 to pts who have received at least two previous treatments for mCRPC or who cannot receive any other treatment. Moreover, clinicians started to debate the risk of RA223-related fractures associated with the sequential administration of AA and RA223. The aim of this retrospective study was to assess the safety of administering RA223 to pts who have progressed during AA treatment mainly in terms of the rate of skeletal fractures. Methods: We retrospectively reviewed the records of mCRPC pts who received RA223 after progressing during an AA treatment line in everyday clinical practice in ten Italian Hospitals. Results: We reviewed data of a consecutive series of 94 mCRPC pts. Most of the pts (85.1%) received RA223 as second- or third-line treatment and had a Soloway score 2 or 3 (90%). RA223 treatment was well-tolerated: there were only four cases of grade 3 anemia, two case of grade 3 leukopenia, and one case of grade 3 neutropenia. The overall fracture rate of 2.1%: one fracture was recorded during the course of RA223 treatment, and one was recorded one month after its end. The fractures both occurred at metastatic sites in pts who were not treated with antiresorptive agents. Median overall survival (OS) from RA223 start was more than 14 mos and the pts who received Ra223 in second line (which is not allowed today in Europe) had the same median OS as those who received this agent in later lines. Conclusions: The findings of this study showed that the treatment with RA223 as subsequent treatment line after AA was active and safe with a very low risk of a fracture. The OS outcomes indicated that the administration of RA223 in early treatment lines is not detrimental, even after AA. Thus the present observational report makes a valuable contribution to the current debate concerning the risks and benefits of including RA223 in the therapeutic algorithm.