Ra-223 Treatment Research Articles

Abstract C160: Baseline characteristics, safety, and efficacy of Radium-223 in metastatic castration resistant prostate cancer by race: Insights from the REASSURE US subset

Abstract Background: REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of Ra-223 use in patients with mCRPC with bone metastases within routine clinical settings. Using data from the second planned interim analysis, we compared baseline characteristics, survival, and safety outcomes among White, Black, and Asian patients treated with Ra-223 in the US subset of REASSURE. Methods: In this descriptive analysis (data collection 8-20-2014 to 3-20-2019), we examined baseline characteristics, OS, and safety outcomes for the US subset enrolled into REASSURE stratified by race (White, Black, Asian). Results: Of the 498 men in the US subset, 414 (83.1%) reported as White, 58 (11.7%) as Black, and 10 (2.0%) as Asian; race was not reported for 16 (3.2%) patients. Median age at study entry was 74.0, 69.5, and 71.0 years for White, Black, and Asian men, respectively. The proportion of patients whose prostate cancer was American Joint Committee on Cancer (AJCC) 7th edition stage III or IV at initial diagnosis was 45.2%, 58.6%, and 60.0% for White, Black, and Asian patients, respectively. The proportion of patients who completed 6 Ra-223 injections was similar across groups. Median duration of observation from the start of Ra-223 treatment was 11.3 months (range 0.4-41.3 months) for White patients, 14.9 months (range 0.7-39.1 months) for Black patients, and 20.5 months (range 4-27.7 months) for Asian patients. Median OS for White, Black, and Asian patients was 17.3 months (95% CI, 15.2-19.2 months), 19.5 months (95% CI, 12.9-27.1 months), and 21.8 months (95% CI, 3.58 months-not applicable), respectively. Any treatment-emergent drug related AE, treatment-emergent SAE, or drug-related SAE occurred in 45.2%, 41.4%, and 10.0% of White, Black, and Asian patients, respectively. Any-grade and grade ≥3 drug-related hematological TEAEs occurred in 8.4% and 5.3% of White patients, respectively, 15.5% and 12.1% of Black patients, respectively, and were not observed in Asian patients. Incidence of bone fractures was 4.1%, 3.4%, and 0% in White, Black and Asian patients respectively. Conclusions: This descriptive analysis of REASSURE found that Black patients were younger and presented with later-stage disease at diagnosis compared with White patients. A trend toward longer OS was seen in Black and Asian patients compared with White patients. AEs occurred at similar rates among groups. Drug-related hematological TEAEs, which have been reported with Ra-223 treatment, were more common in Black patients compared with White and Asian patients. Given the very small number of Asian patients enrolled in REASSURE, comparisons with this group should be interpreted with caution. Citation Format: Peter S. Conti, Oliver Sartor, Mary-Ellen Taplin, Daniel Y. Song, Saby George, Jeffrey Tomaszewski, John Sylvester, Constantine Mantz, Robert W. Given, Robert Brookland, Jeff Meltzer, Matthew J. Korn, Richard Andres, Svetlana Babajanyan, Celestia Higano. Baseline characteristics, safety, and efficacy of Radium-223 in metastatic castration resistant prostate cancer by race: Insights from the REASSURE US subset [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C160.

Radium-223 Treatment Produces Prolonged Suppression of Resident Osteoblasts and Decreased Bone Mineral Density in Trabecular Bone in Osteoblast Reporter Mice.

Radium 223 (Ra-223) is an α-emitting bone-homing radiopharmaceutical that targets tumor-induced osteoblasts and is used to reduce bone pain and prolong overall survival in men with bone-metastatic, castrate-resistant prostate cancer. However, increased fracture risk in skeletal sites with no bone metastasis has been observed in patients treated with Ra-223. Both luciferase- or green fluorescence protein (GFP)-labeled osteoblast reporter mice were used to monitor the effect of Ra-223 on resident osteoblasts and normal bone structure. Upon Ra-223 treatment, 70% of resident osteoblasts were reduced within 2 days, and the osteoblast reduction lasted for at least 18 weeks without detectable recovery, as measured by in vivo bioluminescent imaging. In GFP-labeled osteoblast reporter mice, Ra-223 mainly reduced osteoblasts localized in the trabecular bone areas; the osteoblasts in the growth plates were less affected. Micro-computed tomography analyses showed that Ra-223 significantly reduced bone mineral density and bone microstructure in the trabecular area of femurs but not in the cortical bone. Tumor-induced bone was generated by inoculating osteogenic TRAMP-BMP4 prostate cancer cells into the mouse femurs; Ra-223 treatment significantly reduced tumor-induced osteoblasts. Our study shows that Ra-223 affects bone structures that are not involved in bone metastasis. Strategies that improve bone health may reduce fracture risk in patients receiving Ra-223.

Survival outcomes of radium-223 therapy for metastatic castration-resistant prostate cancer following national health insurance reimbursement in Taiwan.

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. 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. 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. 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.

Increase of prostate-specific antigen doubling time predicts survival in metastatic castration-resistant prostate cancer patients undergoing radium therapy.

Radium-223 (Ra-223) is an important treatment modality for bone-dominant metastatic castration-resistant prostate cancer (mCRPC). However, there is currently a lack of effective markers to monitor treatment response during treatment. We aim to investigate the response in prostate-specific antigen doubling time (PSADT) as a potential marker for assessing Ra-223 treatment in mCRPC patients. We retrospectively collected data from mCRPC patients who underwent radium treatment at our institution between August 2020 and June 2023. Prostate-specific antigen (PSA) measurements prior to treatment and during treatment were collected. Baseline PSADT was calculated from PSA measurements prior to Ra-223 treatment; interim PSADT was calculated from PSA measurements before Ra-223 treatment and prior to the fourth course injection. Overall survival was calculated from the start of treatment to the date of death. Univariable and multivariable analysis using the Cox proportional hazards model were performed to examine the association of factors with overall survival. We included 35 patients from our institution, with a median overall survival of 13.3months. Eighteen (51.4%) completed all six courses of treatment. PSA dynamic response (interim PSADT > baseline PSADT or decreased PSA) was observed in 20 patients. Overall survival was associated with a PSA dynamic response (HR = 0.318, 95% CI 0.133-0.762, p = 0.010) when compared to patients without response. Dynamic changes in PSADT were associated with survival in mCRPC patients receiving radium therapy. Comparing interim and baseline PSADT could serve as a valuable marker for determining treatment benefits.

Metastatic castration resistant prostate cancer patients' experience with Radium-223 treatment in Japan.

Aim: We aimed to determine Japanese metastatic castration resistant prostate cancer (CRPC) patients' Ra-223 treatment experience. Patients & methods: Patients answered the Cancer Therapy Satisfaction Questionnaire (CTSQ domains: Satisfaction with Therapy [SWT], Expectations of Therapy [ET], Feelings about Side Effects [FSE]), the Memorial Anxiety Scale for Prostate Cancer (MAX-PC) and the FACT-Bone Pain (FACT-BP) Questionnaire at baseline, during (vists 3 and 5) and after treatment (end of observation;EOO). Results: Data from 72 patients were included. Baseline median CTSQ scores SWT: 66.1 (IQR19.7), ET: 75.0 (IQR45), and FSE 68.8 (IQR 34.4) were unchanged during vists 3 and 5, but the SWT (-3.57 [IQR17.9])and ET (-5.0 [IQR30])decreased while FSE was unchanged (0.0 [IQR31.25])at EOO. The median MAX-PC (18.0 [IQR 49])score was unchanged (0.0, IQR 6) while the median FACT BP (54.0 [IQR13])score decreased by -1.0 (IQR 8) at EOO. Conclusion: Japanese metastatic castration resistant prostate cancerpatients' experience is stable during Ra-223 treatment.

The radiopharmaceutical radium-223 has immunomodulatory effects in patients and facilitates anti-programmed death receptor-1 therapy in murine models of bone metastatic prostate cancer

Background & purposeRadium-223 (Ra223) improves survival in metastatic prostate cancer (mPC), but its impact on systemic immunity is unclear, and biomarkers of response are lacking. We examined markers of immunomodulatory activity during standard clinical Ra223 and studied the impact of Ra223 on response to immune checkpoint inhibition (ICI) in preclinical models. Materials & methodsWe conducted a single-arm biomarker study of Ra223 in 22 bone mPC patients. We measured circulating immune cell subsets and a panel of cytokines before and during Ra223 therapy and correlated them with overall survival (OS). Using two murine mPC models—orthotopic PtenSmad4-null and TRAMP-C1 grafts in syngeneic immunocompetent mice—we tested the efficacy of combining Ra223 with ICI. ResultsAbove-median level of IL-6 at baseline was associated with a median OS of 358 versus 947 days for below levels; p = 0.044, from the log-rank test. Baseline PlGF and PSA inversely correlated with OS (p = 0.018 and p = 0.037, respectively, from the Cox model). Ra223 treatment was associated with a mild decrease in some peripheral immune cell populations and a shift in the proportion of MDSCs from granulocytic to myeloid. In mice, Ra223 increased the proliferation of CD8+ and CD4+ helper T cells without leading to CD8+ T cell exhaustion in the mPC lesions. In one of the models, combining Ra223 and anti-PD-1 antibody significantly prolonged survival, which correlated with increased CD8+ T cell infiltration in tumor tissue. ConclusionThe 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-PD-1 ICI.

Prevalence and Prognostic Implications of PSA Flares during Radium-223 Treatment among Men with Metastatic Castration Resistant Prostate Cancer.

Radium-223 (Ra233) prolongs the survival of men with symptomatic bone-predominant metastatic castration-resistant prostate cancer (mCRPC). However, prostate-specific antigen (PSA) response patterns are not closely associated with Ra223 therapy outcomes. Herein, we sought to analyze the impact of Ra223-induced PSA flares on patient outcome. Using a retrospective cohort study of Ra223 treatment in four Ontario/Canada cancer centres, we identified 134 patients grouped into sub-cohorts according to distinct PSA response patterns: (i) initial PSA flare followed by eventual PSA decline; (ii) PSA response (≥30% PSA decrease within 12 weeks of treatment); and (iii) PSA non-response. We analyzed patient characteristics and outcome measures, including overall survival (OS), using the Kaplan-Meier method and log-rank testing. PSA flares were observed in 27 (20.2%), PSA responses in 11 (8.2%), and PSA non-responses in 96 (71.6%) patients. Amongst PSA flare patients, 12 presented with post-flare PSA decreases below baseline and 15 with PSA decreases below the flare peak but above baseline. Although only six flare patients achieved ≥30% PSA decreases below baseline, the median OS of all flare patients (16.8 months, 95% CI 14.9-18.7) was comparable to that of PSA responders and non-responders (p = 0.349). 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.

Biomarcadores pronósticos en el uso del radio-223 en pacientes con cáncer de próstata metastásico resistente a la castración

ObjectivesEstablish basal biomarkers in patients with bone metastatic castration-resistant prostate cancer (mCRPC) treated with Ra-223 that predicted a better overall survival (OS), assess hematology toxicity and treatment response. Materials and methodsRetrospective multicenter study in 151 patients with mCRPC between 2013 and 2020. OS was assessed according to basal hemoglobin (Hb), PSA, alkaline phosphatase (AP), WHO pain scale, Eastern Cooperative Oncology Group (ECOG), number of metastatic lesions on bone scan (BS), use of protective bone agents and received. Hematological toxicities were evaluated. Treatment response was based on changes in FA and pain. ResultsMedian OS was 24months (95%CI: 16.5-31). OS in 70% of patients who received complete Ra-223 treatment (5-6 doses) was 34.9m vs. 5.8m in patients with incomplete treatment (1-4 doses). OS was longer in patients with lower PSA and AP, Hb>13g/dL, lesser bone metastasis on GO and ECOG 0-1. 52/151 patients (34%) died during follow-up. Nearly 70% of patients experienced decrease in pain and 66% reduction on AP. Half of patients had mild hematological adverse effects and only 5% had severe. ConclusionsmCRPC patients treated with Ra-223 who had Hb>13g/mL, ECOG 0-1, low AP, PSA<20ng/ml and lesser bone metastasis on BS shown a better OS with adequate safety profile.

Bone-modifying agents are protective for symptomatic skeletal events in Radium-223 treatment.

Radium-223 (Ra-223) dichloride therapy increases overall survival and delays time to the first symptomatic skeletal event (SSE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Bone-modifying agents (BMA) reduce SSE in patients with bone metastasis, but there is little information on their use with Ra-223. This study aimed to investigate the effect of BMA on SSE in patients with bone metastatic CRPC treated with Ra-223 in real-world practice. We included 73 patients treated with Ra-223 from 10 institutions in Japan. Time to the first SSE was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. We used univariate analysis to ascertain the association between variables and SSE. During a median follow-up of 12.7 months (interquartile range, 7-21.7), 12 (16.4%) patients presented SSE. Age and BMA use were different between men with and without SSE. The 1-year SSE-free survival rate from Ra-223 treatment initiation was 82.4% (95% CI, 69.4%-90.2%). BMA use was associated with favorable SSE-free survival (hazard risk, 0.23; 95% confidence interval, 0.061-0.85; p = 0.027). Two (4.7%) and seven (23.3%) patients presented symptomatic pathological bone fracture in groups with and without BMA use, respectively (p = 0.017). This study stresses the importance of BMA use in patients with CRPC and bone metastases in Ra-223 treatment.

Treatment outcomes of radium-223 in patients with metastatic castration-resistant prostate cancer: An experience before National Health Insurance reimbursement in Taiwan.

Radium-223 (Ra-223), an α-particle-emitting isotope, inhibits bony metastases and prevents patients from skeletal-related events in metastatic castration-resistant prostate cancer (mCRPC). We retrospectively reviewed the treatment response, predictive factors, and adverse events (AEs) of Ra-223 before the National Health Insurance reimbursement in a Taiwanese tertiary institute. Patients treated with Ra-223 before January 2019 were enrolled and categorized into progressive disease (PD) and clinical benefits (CB) groups. Laboratory data before and after the treatment were collected, and spider plots concerning percentage changes of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and prostate-specific antigen (PSA) were prepared and calculated statistically. CB/PD, baseline ALP, LDH, and PSA levels were also adopted as stratification factors for overall survival (OS). Among 19 patients included, 5 (26.3%) and 14 (73.4%) belonged to the PD and CB groups, respectively, with no significant difference observed in the baseline laboratory data. The percentage changes in ALP, LDH, and PSA levels after Ra-223 treatment were statistically significant among the two groups (ALP: CB 54.3 ± 21.4% vs PD 77.6 ± 11.8%, p = 0.044; LDH: CB 88.2 ± 22.8% vs PD 138.3 ± 49.0%, p = 0.046; PSA: CB 97.8 ± 61.7% vs PD 277.0 ± 101.1%, p = 0.002). The trends of LDH between the two groups in spider plot were separated significantly. There were no differences in the AEs between the two groups. CB had a longer median OS than the PD group (20.50 months vs 9.43 months, p = 0.009). Patients with LDH <250 U/L at baseline tended to have longer OS but without significance. The CB rate of Ra-223 was 73.7%. No predictive factor for treatment response was obtained from pretreatment 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.

Complete Cycles of Radium-223 Improve Overall Survival in Patients With Metastatic Castration-resistant Prostate Cancer: A Retrospective Study.

The aim of this study was to investigate whether complete cycles of Radium-223 (Ra-223) improved survival in patients with metastatic castration resistant prostate cancer (mCRPC). We retrospectively analyzed mCRPC patients treated with Ra-223 at Taichung Veterans General hospital. Patient and disease characteristics, laboratory results, number of bone metastases, mCRPC treatment sequence, Ra-223 treatment cycles and survival outcomes were collected. Overall survival and progression-free survival (PFS) were analyzed with Kaplan-Meier analysis. Uni- and multivariate analysis was used to identify clinical-radiologic factors that influence outcomes. From October 2016 to December 2020, 42 patients with mCRPC were enrolled. Twenty-three patients received <4 cycles of Ra-223 for mCRPC and 19 patients received 5-6 cycles. The median PSA progression free survival was 2.07 months in the <4 cycles group, compared to 3.93 months in the 5-6 cycles group (log rank p=0.006). The median overall survival was 3.93 months in the <4 cycles group, compared to 28.5 months in the 5-6 cycles group (log rank p<0.001). In the multivariate model, the course number of Ra-223 and pre-treatment alkaline phosphatase (ALP) levels were independent risk factors for overall survival. Patients who complete 5-6 cycles of Ra-223 had significantly better overall survival than those who didn't. Patients with a lower pre-treatment ALP were more likely to benefit from Ra-223 treatment.

Impact of pre-existing anemia and/or packed red blood cell transfusion prior to Radium-223 administration on oncologic outcomes.

67 Background: Radium-223 (Ra-223), a targeted alpha-emitting radiopharmaceutical approved for the treatment of metastatic prostate cancer (mPC), can cause myelosuppression. In the ALSYMPCA trial 30% of patients developed cytopenias, including 13% with grade 3/4 anemia. Therefore, it is recommended that only men with a hemoglobin ≥10 g/dL, platelet count ≥100,000/mm3, and ANC ≥1,500/mm3 be considered for Ra-223. Since the FDA approval of Ra-223 in 2013, several new treatments have been approved for men with mPC. With the changing therapeutic landscape, we anticipate more patients (pts) will have preexisting cytopenia prior to Ra-223 consideration. Hence, clinicians are increasingly likely to face the dilemma of whether it is safe and efficacious to administer Ra-223 in the setting of Hgb ≤10 with/without RBC transfusion support. Methods: We retrospectively identified pts with mPC treated with Ra-223, including a subset of men with Hgb &lt;10g/dl at the Medical College of Wisconsin and Tulane Cancer Center from 2014 – 2019. Clinical data including demographics, prior cancer treatments, laboratory data, blood product transfusion data, and oncologic outcomes were collected. Survival was estimated using Kaplan-Meier method and statistical analysis was conducted using student’s t-test. Results: Sixty-two pts were identified. Median age at the time of Ra-223 was 75.3 years. Of these, nearly 20% (n=12) had a Hgb &lt;10 g/dL and/or received RBC transfusions to meet “eligibility criteria” prior to beginning Ra-223 treatments. Compared to men who had Hgb &gt;10g/dL, men with Hgb &lt;10g/dL required more RBC transfusions both during and after Ra-223 treatment and had significantly worse oncologic outcomes. No patients experienced treatment delays of more than 1 week. There were no significant differences in the median number of treatments prior to Ra-223, median number of Ra-223 treatments received, platelet count nadir, or ANC nadir. Conclusions: Pre-existing Hgb &lt; 10 g/dl and/or RBC transfusions prior to Ra-223 therapy is associated with worse oncologic outcomes in mPC, suggesting that the benefit of Ra-223 is limited in this subset. A larger sample size is needed to further validate our findings. Multivariable analysis is planned. [Table: see text]

Patient characteristics and safety of radium-223 dichloride in Taiwan: Analysis of real-world clinical practice.

119 Background: Bone metastases commonly develop in patients with metastatic castration-resistant prostate cancer (mCRPC), leading to poor clinical outcomes. Radium-223 (Ra-223) is a bone-targeting radiopharmaceutical that has been shown to improve the overall survival of these patients. Here, we present data on the safety and effectiveness of Ra-223 in patients with mCRPC and symptomatic bone metastases under routine clinical practice in Taiwan. Methods: This prospective, multicenter, single-arm, non-interventional observational study enrolled patients with mCRPC and symptomatic bone metastases. A total of 224 patients were included from July 2020 to January 2022. The patients received Ra-223 (55 kBq/kg of body weight) once every 4 weeks for a maximum of 6 intravenous injections. An exploratory subgroup analysis was conducted in patients who received Ra-223 either as a first-line, second-line or third-line. This first interim analysis of the study assessed the clinical outcomes observed during 6 months of Ra-223 treatment and 1 month after the final or last tolerated injection. Results: The dataset up until September 2021 (n = 104) was available for analysis. Of the 104 patients, 69 (66.3%) received 5–6 injections of Ra-223 while 35 (33.7%) received 1–4 injections. Sixty percent of enrolled patients were chemotherapy-naive. Furthermore, 22 (21.2%), 43 (41.3%) and 39 (37.5%) patients received Ra-223 as a first-, second- or third-line therapy, respectively; 16 (72.7%), 27 (62.8%) and 26 (66.7%) patients in these subgroups received 5–6 injections of Ra-223, respectively. The incidence of any study drug-related treatment-emergent adverse events (TEAEs), hematologic TEAEs and all fracture events were 10.6%, 9.6% and 1.9%, respectively. When compared with the other subgroups, patients on first-line Ra-223 therapy had lower incidences of any drug-related AEs and discontinuation of therapy owing to AEs. In addition, there was a trend observed that better PSA control occurred in patient population using Ra-223 as mCRPC first-line treatment. Conclusions: The study data showed that under routine clinical practice in Taiwan, the rate of Ra-223-associated AEs were low and no new safety concerns were identified with this therapy. First-line Ra-223 therapy was more likely associated with fewer TEAEs and higher rates of completion with the 6-injection course of therapy. A follow-up observation of up to 2 years after the initial injection is on-going. Clinical trial information: NCT04232761 .

Circulating tumor DNA and homologous recombination deficiency in bone-predominant mCRPC prior to radium-223 therapy.

203 Background: Radium-223 (Ra-223) is a bone-seeking alpha emitter that induces double-stranded DNA breaks, and the homologous recombination (HR) pathway is critical for repairing these breaks. While prior studies suggested that metastatic castrate-resistant prostate cancers (mCRPC) patients (pts) with HR-deficient (HRD+) tumors may be more likely to benefit from Ra-223, obtaining tissue for next generation sequencing to identify HRD+ is challenging in pts with bone-predominant disease. We hypothesized that circulating tumor DNA (ctDNA) would allow for broader identification of HRD+ to assess association with clinical outcomes in a real-world cohort. Methods: We identified 135 mCRPC pts treated with Ra-223 at our institution between 2013 and 2021. Pts who initiated another anti-tumor therapy within 60 days of Ra-223 treatment were excluded; pts continuing hormonal agents initiated &gt;60 days prior were included. ctDNA isolated from pre-treatment plasma underwent ultra-low-pass whole genome sequencing to estimate tumor fraction (TF). Additionally, targeted panel sequencing using an institutional prostate cancer-specific panel of 319 genes with duplex sequencing (utilizing unique molecular identifiers) for error suppression was used to identify germline or somatic deleterious alterations in HR pathway genes. The primary outcome was association between HRD status and completion of fewer than 6 cycles (as a proxy for early clinical progression), assessed using logistic regression. Results: The median age was 61 (IQR, 56-67) years, median pretreatment prostate-specific antigen (PSA) level was 26.2 (IQR, 8.1-84.1) ng/mL, and median TF was 4% (IQR, 3-6%). 97% of pts (n=131) previously received a novel antiandrogen, and 63% (n=85) received prior taxane. 17% (n=23) were HRD+, and 59% (n=80) completed 6 cycles of Ra-223. On multivariable analysis, HRD+ was associated with decreased likelihood of completing 6 cycles compared to HRD- (adjusted odds ratio [AOR] 0.16, 95% confidence interval [CI] 0.05-0.48, P=0.001). 22% (n=5) of HRD+ pts completed 6 cycles compared to 67% (n=75) of HRD- pts. Additional factors associated with decreased likelihood of completing 6 cycles included a higher pretreatment TF (AOR 0.69, 95% CI, 0.48-0.97, P=0.034) and prior taxane use (AOR 0.41, 95% CI, 0.18-0.91, P=0.028), but not pretreatment PSA ( P=0.574). Conclusions: Targeted panel sequencing with error suppression from ctDNA identified HRD+ in mCRPC pts with bone-predominant disease and low median TF at a similar frequency as reported from tissue. In our cohort, HRD+ was prognostic of early clinical progression with Ra-223. Further work is in progress to understand the association of other ctDNA-derived features, including assessment of genomic signatures and transcriptional binding sites, in the setting of Ra-223 therapy. DF/HCC IRB protocol 18-135.

Optimization of Radium-223 Treatment of Castration-resistant Prostate Cancer Based on the Burden of Skeletal Metastasis and Clinical Parameters.

Radium-223 dichloride (Ra-223) is now frequently used to treat prostate cancer that has metastasized to bone, although patient selection continues to be suboptimal for determining who will benefit most from this novel treatment modality. Seventy-nine patients with metastatic castration-resistant prostate cancer (mCRPC) were treated with Ra-223 from 2012 to 2016. The burden of skeletal metastasis was determined for each using the Bone Scan Index (BSI) as a ratio of diseased to normal bone. Clinical, laboratory, and survival data were collected and examined for associations with BSI, and treatment tolerability was assessed. Chemotherapy-naïve patients were significantly more likely to complete the full course of treatment. Median follow-up was 31 months (range 0.7-38.8 months) and median overall survival was 15.4 months (range 9.5-20.6 months). Overall survival was significantly associated with findings on bone scans (P < .05). Patients with higher BSI tended toward poorer outcomes. Nearly half the patients with low baseline BSI survived 3 years or more following Ra-223 treatment. By contrast, only 20% of the patients with high baseline BSI lived for 1 year, and none lived for an additional 3. Baseline BSI was significantly associated with decreased hemoglobin, higher serum PSA and alkaline phosphatase levels, and treatment-associated reductions in platelet and absolute neutrophil counts. Our results suggest better outcomes to Ra-223 therapy for patients who are chemotherapy-naïve and who undergo treatment earlier in the course of their disease as reflected by low BSI and concordant laboratory parameters.

Prostate-specific antigen doubling time following radium-223 treatment as a predictor of the clinical course in patients with metastatic castration-resistant prostate cancer.

To identify useful biomarkers by reviewing laboratory data for a predictor of the clinical course following treatment with radium-223 dichloride (Ra-223) in patients with metastatic castration-resistant prostate cancer. Eighteen metastatic castration-resistant prostate cancer patients who were administered Ra-223 at our hospital were retrospectively enrolled in this study. Prostate-specific antigen doubling times before and after the administration of Ra-223 were evaluated as prognostic factors for metastatic castration-resistant prostate cancer patients treated with Ra-223 using the Kaplan-Meier method and Log-rank test. Four patients failed to complete the planned six-time Ra-223 treatments with the exacerbation of their condition. In the 14 patients who completed the planned Ra-223 treatment, before the Ra-223 treatment, no significant differences were observed in overall survival between patients with prostate-specific antigen doubling time of 6 months or less and those with prostate-specific antigen doubling time of more than 6 months or stable (p = 0.642). Following the completion of the Ra-223 treatment, overall survival was significantly shorter in patients with prostate-specific antigen doubling time of 6 months or less than in those with prostate-specific antigen doubling time of more than 6 months or stable (p = 0.007). Prostate-specific antigen doubling time after the Ra-223 treatment is a useful predictor of the clinical course following treatment in metastatic castration-resistant prostate cancer patients.

Clinical significance of completion of radium-223 treatment and acute adverse events in patients with metastatic castration-resistant prostate cancer.

In the treatment of castration-resistant prostate cancer (CRPC) with bone metastases, radium-223 dichloride (Ra-223) is the only bone-targeted drug that shows survival benefits. Completing six courses of Ra-223 treatment is thought to be associated with better patient survival, but this treatment has a relatively high rate of acute adverse events. This retrospective study included 85 patients from 12 institutions in Japan to investigate the clinical significance of the completion of Ra-223 treatment and acute adverse events in CRPC patients. Six courses of Ra-223 treatment were completed in 65.9% of the patients. Grade 3 or higher acute adverse events were observed in 27.1% of patients. The prostate specific antigen and alkaline phosphatase declined at 26.9% and 87.9%, respectively. The overall survival rates at 12 and 24 months were 80.7% and 63.2%, respectively. Both completion of six courses of Ra-223 treatment and absence of grade 3 or higher acute adverse events were associated with longer overall survival. In univariate analysis, factors related to the history of treatment (five or more hormone therapy agents and cytotoxic chemotherapy) and hematological parameters (Prostate specific antigen (PSA) doubling time, alkaline phosphatase, hemoglobin, albumin, and serum calcium) were associated with completing six courses of Ra-223 treatment without experiencing grade 3 or higher acute adverse events. Multivariate analysis showed that a history of chemotherapy, PSA doubling time, hemoglobin, and serum calcium showed statistical significance. We built a predictive score by these four factors. Patients with lower scores showed higher rates of treatment success (p<0.001) and longer overall survival (p<0.001) with statistical significance. Accomplishing six courses of Ra-223 treatment without grade 3 or higher acute adverse events was a prognostic factor in patients with mCRPC treated with Ra-223. We built a predictive score of treatment success and need future external validation.

Investigation into the Optimal Strategy of Radium-223 Therapy for Metastatic Castration-Resistant Prostate Cancer

The optimal sequence and combination of radium-223 therapy (Ra-223) for castration-resistant prostate cancer with bone metastasis (mCRPC) remain unclear. This study aimed to explore the prognostic factors after Ra-223 administration and to determine the optimal treatment strategy. We enrolled 64 patients with mCRPC who underwent Ra-223 therapy from June 2016 to July 2022 at a single institution in Japan. Overall survival (OS) and pain progression-free survival (p-PFS), which was proposed as a measure of quality of life (QOL), were analyzed using Cox proportional hazards models and log-rank tests, and between-factor analysis was performed with the Mann–Whitney U (MWU) test. Univariable and multivariable analyses revealed prognostic factors; specifically, early treatment (≤third line), completion of six treatment cycles, low bone scan index (BSI) (&lt;0.61), alkaline phosphatase (ALP) (&lt;140 U/L), prostate-specific antigen (PSA; &lt;22.9 ng/mL), lactate dehydrogenase (LDH; &lt;240 U/L), high hemoglobin (Hb) (≥11.4 g/dL), and prior denosumab use significantly prolonged OS. Low BSI, low ALP, and early Ra-223 treatment also prolonged p-PFS in the log-rank tests. The MWU test showed that high BSI (≥0.61) was associated with high PSA and high ALP and a tendency for Hb to decrease. Late Ra-223 treatment (≥fourth line) was significantly associated with low Hb and high PSA. Early Ra-223 treatment was significantly associated with improved OS, and administering Ra-223 before novel hormonal or anticancer agents may be meaningful.

Appropriate Patient Status for Ra-223 Treatment in the Treatment Sequence for Castration-resistant Prostate Cancer.

Radium (Ra)-223 is widely used for treating castration-resistant prostate cancer (CRPC) with bone metastasis based on evidence of increased survival and decreased skeletal-related events. However, the timing of Ra-223 use in the treatment sequence of CRPC remains controversial. Therefore, this study aimed to explore the appropriate patient status for Ra-223 use in the CRPC treatment sequence by examining patients treated with Ra-223 from the time of CRPC diagnosis until death. The medical records of 67 CRPC patients with bone metastasis who were treated with Ra-223 at two institutes were retrospectively analysed. The impact of 13 factors from the time of CRPC diagnosis until death was analysed using univariate and multivariate Cox hazard ratio models to evaluate the appropriate patient status for Ra-223 treatment. The median survival time following CRPC diagnosis for all the patient groups was 3.82 years. Univariate analysis identified a higher-than-normal alkaline phosphatase (ALP) level, bone scan indexes ≥2, and prostate-specific antigen (PSA) doubling time <3 months before Ra-223 treatment as predominant adverse prognostic factors. Ra-223 therapy discontinuation was not a significant factor. The survival of CRPC patients with these factors was significantly worse than that of patients without these factors. In the multivariate analysis, a higher-than-normal ALP level at the start of treatment was identified as a poor prognostic factor for mortality. The appropriate patient status for Ra-223 use includes low bone metastasis burden and well-controlled PSA levels.

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.