Bone Metastatic Castration-resistant Prostate Research Articles

Radium-223 treatment in castration resistant bone metastatic prostate cancer. Should be the primary tumor always treated?

IntroductionRadium-223 (223Ra) improves symptoms and survival in patients with bone metastatic castration-resistant prostate cancer (mCRPC). Study aimTo evaluate the impact of a previous radical prostatectomy (RP) on the outcome of 223Ra therapy in mCRPC patients. The primary prostate tumor left untreated could progress during 223Ra treatment. Materials and methodsmCRPC symptomatic patients treated with 223Ra were enrolled. Luteinizing Hormone-Releasing Hormone analogue was maintained. No other anticancer therapy was given. 223Ra was administered i.v. at the dose of 55 kBq/kg every 4 weeks for 6 cycles. Patients were stratified according to previous RP or not. Hematological toxicity was monitored. Statistical analysis of 223Ra discontinuations, progressions, and deaths were performed. ResultsForty-four patients were enrolled, 16 (36.4%) previously received RP, 5 (11.3%) prostate radiotherapy and 23 (52.3%) maintained the primary prostate tumor after local treatment. All patients presented only bone metastases, 24 patients (54.5%) had more than 20. Twenty-six (59.1%) patients were treated after first or second line systemic chemotherapy. Treatment interruptions occurred in 14 patients (50%) with prostate and in 4 (25%) without (P = 0.04). After a median follow-up of 18 months (6–30 months), 15 (53.6%), and 7 (43.7%) progressions (P = 0.34) and 13 and 1 (6.2%) deaths (P = 0.04) occurred in patients with and without prostate respectively. ConclusionThe presence of the primary prostate tumor seems to play a detrimental role in mCRPC patients undergoing 223Ra treatment in absence of other concomitant anticancer therapy. On the other hand a previous RP might play a protective role.

SC177 - Radium-223 in bone metastatic castration resistant prostate cancer. Should we always treat the prostate primary tumour?

SC177 - Radium-223 in bone metastatic castration resistant prostate cancer. Should we always treat the prostate primary tumour?

Population-Based Analysis Of The Use Of Radium-223 For Bone-Metastatic Castration-Resistant Prostate Cancer In Ontario, And Of Factors Associated With Treatment Completion And Outcome.

IntroductionRadium-223 (Ra223) prolongs the survival and improves the quality of life of men with metastatic, castration-resistant prostate cancer (mCRPC) to bones. However, compared to other mCRPC therapies, using Ra223 comes with its unique challenges. Hence, we aimed to identify Ra223 utilization patterns under real-world conditions, as well as factors predicting treatment completion and outcome.MethodsIn this retrospective chart analysis, 198 mCRPC patients were identified that had received Ra223 outside of clinical trials or access programs from January 2015 to October 2016 at four cancer centres in Ontario. The main outcomes studied were Ra223 completion rate, reasons for early treatment discontinuation, overall survival, and survival differences in patients completing Ra223 therapy versus patients receiving <6 cycles of Ra223. In addition, patient and disease characteristics were analysed to identify predictors of treatment completion and survival.ResultsIn this cohort of patients mostly pretreated with abiraterone and/or enzalutamide (92.4%), almost half of which had also received docetaxel (48.5%), the Ra223 completion rate was 46.5%, and the actuarial median survival was 13.3 months. The main reason for early Ra223 discontinuation was disease progression, and Ra223 non-completion was associated with poorer outcome (median survival 8.1 months [6.0–12.2] versus 18.7 months [15.3–22.3] in men completing Ra223, p<0.0001). Lymph node metastases and a high baseline prostate-specific antigen (PSA) were independent predictors of early treatment discontinuation. Multivariable Cox proportional hazards models revealed early Ra223 discontinuation, baseline anemia, high PSA, prior skeletal-related events, visceral metastases, and being referred to another centre for Ra223 therapy as predictors of worse outcome.ConclusionDespite a lower completion rate than observed under clinical trial conditions, the real-world results achieved with Ra223 are encouraging. If prospectively validated, predictive patient and disease characteristics identified in our cohort might become instrumental to identify mCRPC patients likely to complete and to most benefit from Ra223 therapy.

Correlation between Automated Bone Scan Index Change after Cabazitaxel and Survival among Men with Castration-Resistant Prostate Cancer

Background: Automated bone scan index (aBSI) change (ΔBSI) after treatment and survival in men with prostate cancer remains unclear. We evaluated the correlation between ΔBSI after cabazitaxel and overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (CRPC). Methods: We retrospectively enrolled 32 men with bone metastatic CRPC who had received cabazitaxel. The correlation between ΔBSI from baseline to 16 weeks after starting cabazitaxel and OS was analyzed by multivariate analysis. Results: Median age and time to CRPC were 70.7 years and 9.5 months, respectively. The median cycles of docetaxel before cabazitaxel were eight. Ten (31.2%) patients had visceral metastases at baseline. Median baseline prostate-specific antigen (PSA) was 123.0 ng/mL. The median aBSIs at baseline and 16 weeks after cabazitaxel were 3.2 and 4.4%, respectively. Improvements in aBSI and PSA after 16 weeks of cabazitaxel occurred in 7 (21.9%) and 12 patients (37.5%), respectively. There were no correlations between ΔBSI and OS (p = 0.55), but PSA change was significantly correlated with OS (p = 0.03) by multivariate analysis. Conclusions: This study demonstrated that ΔBSI from baseline to16 weeks after starting cabazitaxel was not correlated with OS among men with bone metastatic CRPC. Further prospective studies may be warranted to confirm the limited utility of aBSI in this setting.

Advances in targeted alpha therapy for prostate cancer.

Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.

Abstract 934: γδ CAR T-cell therapy significantly mitigates bone metastatic castrate-resistant prostate cancer

Abstract Bone metastasis is a frequent complication in advanced prostate cancer, with the resultant lesions significantly contributing to patient morbidity and mortality. While next generation hormone ablation therapies and bone protecting bisphosphonates alleviate these symptoms, the disease remains incurable, and new therapeutic approaches are of urgent need. In this regard, we have focused on tapping the tumor-seeking potential of chimeric antigen receptor (CAR) T cells. CAR T cells have shown remarkable anti-tumor responses in hematologic malignancies, but unique physical and biological challenges have hindered their activity in solid tumors. Interestingly, patients treated with bisphosphonates such as zoledronate exhibit enhanced recruitment and activation of the γδ subset of T cells in bone due intracellular accumulation of isopentenyl pyrophosphate (IPP) phosphoantigen. Whereas conventional CAR T cell therapies utilize αβ T cells, we posit that designing γδ CAR T cells could improve homing to bone metastases when administered with bisphosphonates. First, to test the impact of prostate specific stem cell antigen (PSCA)-specific γδ CAR T cells against bone metastatic prostate cancer in vivo, NSG mice (n=10) were intratibially injected with PSCA/luciferase-expressing C4-2B (2x105) castrate resistant prostate cancer cells. Tumors were allowed to establish for 10 days and then randomized into control or γδ CAR T (1.5x107 via tail vein) groups. Subsequent bioluminescent imaging indicated a rapid and significant (p=0.0006) regression of tumors in the γδ CAR T cell group, leading to increased overall survival (5/5 γδ CAR T vs. 0/5 control after 68 days, p=0.0002). Ex vivo bone morphometry analysis also demonstrated the significant protective effect of γδ CAR T associated bone disease. To determine whether bisphosphonates could further enhance the homing of γδ CAR T to bone, NSG mice (n=30) were intratibially injected with C4-2B (2x105), and randomized into control and zoledronate (30µg/kg) groups. After 10 days, mice received γδ T cells (3x106). Subsets were sacrificed at 1, 3, and 5 days post-T cell administration, and peripheral blood, tibia bone marrow, and spleens isolated. CD3-Vδ2 flow cytometry indicated increased γδ T cells in the tibia bone marrow from zoledronate groups (Day 1=61%, Day 3=32%, and Day 5=57%). Furthermore, decreased tumor growth rates were observed in the zoledronate group, suggesting that increased homing of γδ T cells induced anti-tumor effects. Our data to date demonstrate that γδ CAR T cells significantly mitigate bone metastatic prostate cancer and associated bone disease. Further, bisphosphonates (already used in the clinical setting) enhance the homing of γδ CAR T cells to the tumor-bone microenvironment. We posit that γδ CAR T will be an effective immunotherapy approach for the treatment of men with incurable bone metastatic prostate cancer. Citation Format: Jeremy Steven Frieling, Maria Cecilia Ramello, Ismahene Benzaid, Emiliano Roselli, Chen Hao Lo, Conor C. Lynch, Daniel Abate-Daga. γδ CAR T-cell therapy significantly mitigates bone metastatic castrate-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 934.

Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) recurs after androgen deprivation therapy (ADT) and is incurable. Reactivation of androgen receptor (AR) signaling in the low androgen environment of ADT drives CRPC. This AR activity occurs through a variety of mechanisms, including up-regulation of AR coactivators such as VAV3 and expression of constitutively active AR variants such as the clinically relevant AR-V7. AR-V7 lacks a ligand-binding domain and is linked to poor prognosis. We previously showed that VAV3 enhances AR-V7 activity to drive CRPC progression. Gene expression profiling after depletion of either VAV3 or AR-V7 in CRPC cells revealed arginine vasopressin receptor 1a (AVPR1A) as the most commonly down-regulated gene, indicating that this G protein-coupled receptor may be critical for CRPC. Analysis of publicly available human PC datasets showed that AVPR1A has a higher copy number and increased amounts of mRNA in advanced PC. Depletion of AVPR1A in CRPC cells resulted in decreased cell proliferation and reduced cyclin A. In contrast, androgen-dependent PC, AR-negative PC, or nontumorigenic prostate epithelial cells, which have undetectable AVPR1A mRNA, were minimally affected by AVPR1A depletion. Ectopic expression of AVPR1A in androgen-dependent PC cells conferred castration resistance in vitro and in vivo. Furthermore, treatment of CRPC cells with the AVPR1A ligand, arginine vasopressin (AVP), activated ERK and CREB, known promoters of PC progression. A clinically safe and selective AVPR1A antagonist, relcovaptan, prevented CRPC emergence and decreased CRPC orthotopic and bone metastatic growth in mouse models. Based on these preclinical findings, repurposing AVPR1A antagonists is a promising therapeutic approach for CRPC.

Interlesional response assessment with 18F-sodium fluoride (18F-NaF) PET/CT in men with chemotherapy-naive bone metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZA).

5036 Background: 18F-NaF PET/CT provides spatial and quantitative information on osteoblastic activity in men with bone mCRPC; thus, it can be used to assess interlesional response heterogeneity, a critical clinical issue. Here we assess the proportion of men treated with ENZA with responding lesions by 18F-NaF PET/CT at the time of prostate-specific antigen (PSA), standard radiographic, or clinical progression. Methods: Men with progressive mCRPC with ≥ 2 lesions on bone scintigraphy were enrolled and treated with ENZA 160 mg daily at 3 US sites. 18F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of PSA progression (increase of ≥ 25% and ≥ 2.0 ng/mL above nadir), standard radiographic or clinical progression, or at 2 years without progression (PET3) using Quantitative Total Bone Imaging (QTBI). The primary endpoint was the proportion of men with ≥ 1 responding bone lesion (defined as a lesion with a total NaF standardized uptake value [SUV] less than baseline) on PET3. Evaluable men had scans at PET1 and PET3. Results: A total of 23 men (median age, 72 years [range, 51-93]; median PSA, 20.5 ng/mL [range, 3.9-133.6]) were enrolled. The study met its primary objective; 22 of 22 (100%) evaluable men had ≥ 1 responding bone lesion on QTBI at PET3. Total disease burden changed from a mean baseline SUV of 5700 (range, 507-22,850) to 5590 (range, 213-17,090) at PET2 and 6020 (range, 118-16,650) at PET3. The proportion of progressive lesions increased from a mean 7.8% (range, 0-29) at PET2 to 9.4% (range, 0-32) at PET3. Conclusions: Although PSA response with ENZA is high, many men experience a mixed response to treatment. While overall functional disease burden improves during treatment, an eventual increase in global burden is seen at the time of progression as measured by 18F-NaF PET/CT. At the primary endpoint analysis the proportion of progressing lesions is low, supporting both the hypothesis that a substantial number of lesions continue to benefit from treatment and the concept of treating beyond progression and selectively targeting nonresponding lesions while keeping patients on ENZA. Clinical trial information: NCT02384382.

Enzalutamide in Combination with Abiraterone Acetate in Bone Metastatic Castration-resistant Prostate Cancer Patients

BackgroundIt is hypothesised that cotargeting the androgen receptor (AR) and paracrine androgen biosynthesis with enzalutamide and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) will dissipate adaptive feedback loops observed with either agent alone. ObjectiveTo assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC). Design, setting, and participantsThis open-label, single-centre interventional study was conducted in bmCRPC patients. InterventionEnzalutamide 160mg and abiraterone acetate 1000mg once daily; prednisone 5mg twice daily. Outcome measurements and statistical analysisAdverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and Cmin plasma concentrations were evaluated. Results and limitationsSixty patients were enrolled. Common AEs independent of grade/causality included fatigue (72%), hyperglycaemia (67%), alkaline phosphatase (ALP) elevation (53%), and hot flush (43%). Grade 3 AEs included hypertension (17%), alanine aminotransferase elevation (12%), ALP elevation (5%), and arthralgia (5%). No treatment-related grade 4 AEs or deaths were reported. Median treatment-discontinuation time was 312d (95% confidence interval [CI] 196.0–483.0). Maximal PSA decline ≥50% and ≥90% occurred in 46 (77%) and 29 (48%) patients, respectively. Median PFS was 251d (95% CI 147–337). At week 9, median tumour microenvironment androgens, precursors, and nuclear AR expression decreased (p<0.001). The baseline tumour AR C/N terminal ratio of ≥80% was associated with treatment benefit. At enzalutamide steady state, abiraterone acetate Cmin was ∼23% lower (range 14.05–200.5ng/ml) than when given alone. ConclusionsEnzalutamide combined with abiraterone acetate has a manageable safety profile, without a meaningful DDI. Both agents are pharmacodynamically active with no feedback. Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC. Patient summaryThis is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe.

Interim analysis of the REASSURE (Radium-223 alpha Emitter Agent in non-intervention Safety Study in mCRPC popUlation for long-teRm Evaluation) study: patient characteristics and safety according to prior use of chemotherapy in routine clinical practice

PurposeREASSURE is a global, prospective, non-interventional study to assess long-term safety of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Here we report an interim analysis of patients according to previous use of chemotherapy.MethodsRadium-223 was administered in routine clinical practice. Interim safety analysis was planned after enrolment of the first 600 patients. Patient characteristics and safety data by previous administration of chemotherapy (docetaxel and/or cabazitaxel) were investigated.ResultsThis interim analysis included 583 patients. Median duration of observation was 7 months (range, 0–20). Nineteen patients treated with concomitant chemotherapy were excluded, 564 (97%) were eligible for exploratory analysis according to prior use of chemotherapy; 190 (34%) had previously received and completed chemotherapy, and 374 (66%) had not. In the prior versus no prior chemotherapy group, a higher proportion of patients had an Eastern Cooperative Oncology Group performance status of ≥2 (22% vs 11%) and > 20 metastatic lesions (26% vs 15%), median alkaline phosphatase (162.0 vs 115.0 U/L) and prostate-specific antigen (132.0 vs 40.2 ng/mL) levels were higher, and a lower proportion completed 6 radium-223 injections (45% vs 63%). Drug-related treatment-emergent adverse events (TEAEs) occurred in 63 and 48%, and haematological drug-related TEAEs in 21 and 9% of patients who had or had not previously received chemotherapy. Four drug-related deaths were reported, all in the prior chemotherapy group.ConclusionsThe short-term safety profile of radium-223 in routine clinical practice was comparable to other clinical studies, irrespective of prior chemotherapy use. Haematological TEAEs occurred more frequently in the prior chemotherapy group, presumably due to decreased bone marrow function as a consequence of more advanced disease and prior exposure to cytotoxic therapy. Patients who had not previously received chemotherapy appeared to have a lower burden of disease at baseline, and a lower proportion discontinued radium-223 treatment.

Patient Selection for Radium-223 Therapy in Patients With Bone Metastatic Castration-Resistant Prostate Cancer: New Recommendations and Future Perspectives.

Radium-223 therapy was registered in 2013 as a new life-prolonging therapeutic option for patients with symptomatic bone metastatic castration-resistant prostate cancer after the phase 3 ALSYMPCA study. Postregistration reports on the use of radium-223 in real-world populations demonstrate that appropriate selection of patients for radium-223 therapy is challenging. While primarily retrospective and post hoc studies identified prognostic variables associated with overall survival, validated predictive biomarkers are still lacking. Important pretherapeutic prognostic variables include the number of prior therapies, baseline Eastern Cooperative Oncology Group performance status, baseline extent of bone metastatic disease, and baseline alkaline phosphatase, prostate-specific antigen, and lactate dehydrogenase levels. We reviewed the currently available literature to provide recommendations on patient selection for radium-223 therapy in patients with bone metastatic castration-resistant prostate cancer. In addition, the recent evidence from the report of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee regarding the restricted use of radium-223 after interim data analysis of the ERA-223 trial has been incorporated into our recommendations. Future perspectives are also discussed, including radium-223 re-treatment, the use of concomitant therapies, and the implementation of pretherapeutic molecular analysis for treatment stratification.

Efficacy of Radium-223 in Bone-metastatic Castration-resistant Prostate Cancer with and Without Homologous Repair Gene Defects

BackgroundPathogenic mutations in genes mediating homologous recombination (HR) DNA repair are present in 20–30% of men with metastatic castrate-resistant prostate cancer (mCRPC). Radium-223 is a bone-seeking α-emitter that induces double-strand DNA breaks, thereby killing cancer cells in the bone microenvironment. ObjectiveTo evaluate the potential impact of germline or somatic HR-deficiency (HRD) mutations on radium-223 efficacy in mCRPC with bone metastasis. Design, setting, and participantsThis is a retrospective single-institution study. Medical records of 190 mCRPC patients for whom germline and/or somatic DNA sequencing data were available were reviewed. Of these patients, 28 had received standard-of-care radium-223 at Johns Hopkins between February 2013 and February 2018. Outcome measurements and statistical analysisAlkaline phosphatase (ALP) responses and time-to-ALP-progression were the coprimary endpoints. Prostate-specific antigen (PSA) responses, overall survival (OS), and time to next systemic therapy were also evaluated. Results and limitationsOf the 28 patients included, 10 men (35.7%) had a germline/somatic HRD mutation (three in BRCA2, and one each in ATM, ATR, CHEK2, FANCG, FANCI, FANCL, and PALB2) and 18 (64.3%) did not. Men with HRD mutations (HRD+) had numerically lower ages (66 vs 73yr, p=0.25), more soft-tissue metastases (50% vs 38%, p=0.43), and higher baseline ALP levels (130 vs 108 U/l, p=0.84). Compared with HRD(–) men, HRD(+) patients showed greater ALP responses (80% vs 39%, p=0.04), longer time to ALP progression (median10.4 vs 5.8mo, hazard ratio [HR] 6.4, p=0.005), and a trend toward longer OS (median 36.9 vs 19.0mo, HR 3.3, p=0.11). PSA responses (0% vs 0%, p>0.99) and time to next systemic therapy (HR 1.5, p=0.39) were similar between the two groups. Results are limited by the retrospective nature of the analysis and the small sample size. ConclusionsIn this exploratory study, bone-metastatic CRPC patients with inactivating HRD mutations demonstrated significantly improved ALP responses and time to ALP progression. These results should motivate prospective validation of the “synthetic lethality” hypothesis between HRD mutations and radium-223 activity. Patient summaryIn this report, we retrospectively examined outcomes to metastatic prostate cancer in patients with and without DNA repair mutations who received radium-223, a therapy that kills cancer cells by causing direct DNA damage. Our study suggested that patients who have inherited or acquired DNA repair gene mutations derived greater benefit from radium-223 when compared with patients without these mutations. We concluded that radium-223 might have an important role in this setting; however, prospective studies are needed to confirm whether DNA repair mutations truly make radium-223 work better or not.

Biological issues with cabozantinib in bone metastatic renal cell carcinoma and castration-resistant prostate cancer.

Biological issues with cabozantinib in bone metastatic renal cell carcinoma and castration-resistant prostate cancer.

Abstract 838: Synergistic in vivo activity of the ATR inhibitor BAY 1895344 in combination with the targeted alpha therapy radium-223 dichloride in a preclinical tumor model mimicking bone metastatic castration-resistant prostate cancer (mCRPC)

Abstract The integrity of the genome in eukaryotic cells is secured by complex signalling pathways, known collectively as DNA damage response (DDR). Recognition of DNA damage activates DDR pathways resulting in cell cycle arrest, suppression of general translation, induction of DNA repair, cell survival, or even cell death. Proteins that directly recognize aberrant DNA structures recruit and activate kinases of the DDR pathway, such as ATR (ataxia telangiectasia and Rad3-related). The ATR kinase is activated by a broad spectrum of DNA damages, including double-strand breaks (DSBs) and lesions derived from interference with DNA replication as well as increased replication stress. Therefore, inhibition of ATR kinase activity could be the basis for a novel anti-cancer therapy in cancers characterized by increased DNA damage, deficiency in DNA damage repair or replication stress. Radium-223 dichloride (Xofigo®) is the first approved targeted alpha therapy. It is indicated for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease, based on improvement of overall survival. It is a calcium-mimetics that selectively binds to hydroxyapatite targeting areas of high bone turnover such as bone metastases, thereby exhibiting strong cytotoxic effects on adjacent cells via induction of DNA DSBs. We assessed the anti-tumor efficacy of combination treatment with ATR inhibitor (ATRi) BAY 1895344 and radium-223 dichloride in an intratibially injected prostate cancer model mimicking CRPC with bone metastases. In vivo analyses addressed the optimization of the dosing schedule as well as dose-response of BAY 1895344 in radium-223 combination setting. Levels of intra-tumor DNA damage (P-H2AX) were assessed to demonstrate the proposed mode-of-action. Here, we show that combination treatment with ATRi BAY 1895344 and radium-223 exhibits synergistic anti-tumor activity in the intratibial LNCaP xenograft model of mCRPC, achieving best efficacy when BAY 1895344 is applied 24 hours after treatment with radium-223, as indicated by direct reduction of tumor burden in the bone, lower serum tumor marker (PSA), and smaller areas of tumor-induced changes in bone. With this optimized schedule, a very low dose of BAY 1895344 (3% of single-agent MTD) was effective in combination with radium-223. Our findings strongly suggest that the combination of DNA damage induction by radium-223 with DDR inhibition by ATRi BAY 1895344 creates a potential new treatment option for CRPC patients with bone metastases. BAY 1895344 is currently under clinical investigation in patients with advanced solid tumors and lymphomas (NCT03188965). Citation Format: Antje Margret Wengner, Gerhard Siemeister, Ulrich Luecking, Julien Lefranc, Arne Scholz, Mari Suominen, Kirstin Meyer, Eleni Lagkadinou, Dominik Mumberg. Synergistic in vivo activity of the ATR inhibitor BAY 1895344 in combination with the targeted alpha therapy radium-223 dichloride in a preclinical tumor model mimicking bone metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 838.

A randomized phase 2 study investigating 3 dosing regimens of radium-223 dichloride (Ra-223) in bone metastatic castration-resistant prostate cancer (mCRPC).

5008Background: Ra-223, standard dose (SD) 55 kBq/kg q4w for 6 cycles improved overall survival (OS) and delayed time to symptomatic skeletal events (SSEs) in patients (pts) with mCRPC and bone met...

The impact of age on radium-223 distribution and an evaluation of molecular imaging surrogates

IntroductionRadium-223 dichloride is the first alpha-particle emitting therapeutic agent approved by FDA and EMA for bone metastatic castration-resistant prostate cancer. We studied its age-dependent biodistribution in mice, and compared it with [99mTc]Tc-MDP and [18F]NaF aiming to identify a potential imaging surrogate to predict [223Ra]RaCl2 whole-body localization. MethodsMale C57Bl/6 mice dosed with [223Ra]RaCl2 were sacrificed at different time points to explore [223Ra]RaCl2 whole-body distribution. In another experiment, mice at different ages were dosed with [223Ra]RaCl2 to evaluate the aging impact. Finally, [99mTc]Tc-MDP and [18F]NaF were administered to mice, and we compared their biodistributions with [223Ra]RaCl2. Detailed micro-localization of each tracer was visualized using autoradiography and histochemical staining. Results[223Ra]RaCl2 uptake in bone was rapid and stable. We observed persistent localization at bone epiphyses, as well as the red pulp of the spleen, while its uptake in most soft tissues cleared within 24 h. [223Ra]RaCl2 distribution in soft tissues is similar in all age groups tested, while bone activity significantly decreased with aging. Although the diagnostic tracers cleared much faster from soft tissues than the therapeutic radionuclide, [99mTc]Tc-MDP and [18F]NaF both co-localized with [223Ra]RaCl2 in the skeletal compartment. ConclusionsRadium-223 localization to the bone is dependent on age-varying factors, which implies that radium-223 dosimetry should take patient age into account. [99mTc]Tc-MDP shows a different biodistribution from [223Ra]RaCl2, both in soft tissues and in bone. [18F]NaF presents a high similarity with [223Ra]RaCl2 in skeletal uptake, which validates the potential of [18F]NaF as an imaging surrogate to predict radium-223 radiotherapeutic distribution in bone.

Molecular profiling of liquid biopsies from patients (pts) with bone metastatic castration-resistant prostate cancer (BM-CRPC) treated with radium-223 (RA-223) to reveal differential enrichment for markers that correlate with overall survival (OS).

259 Introduction: RA-223 prolongs OS in BM-CRPC pts but predictive markers are lacking. We hypothesized that molecular profiling of plasma-derived extracellular vesicles (EVs) from BM-CRPC pts treated with RA-223 would predict efficacy and inform development of combinations. Methods: Paired baseline (BL) and end of treatment (EoT) blood samples were collected from 25 pts treated with RA-223. Pts were stratified by median OS into 3 groups: 1) 6.3 months (range 3.3-8.5, n=5 pts, UnFav OS), 2) 18.2 months (range 12.6-19.4, n=7 pts, Middle OS) and 3) 27.6 months (range 23.1-33.8, n=13 pts, Fav OS). EVs were isolated from plasma and analyzed for specific proteins and RNA transcripts. Marker profiles by domain and analytic method were determined in pts from the stratified OS groups. Results: At EoT, there is enrichment of RNA transcripts and proteins involved in regulating immune responses, DNA Damage Response (DDR) and bone metabolism (Table). By benchmarking molecular signatures in pts with UnFav Os and Fav OS, we could analyze the molecular profiles of pts in the Middle OS group and stratify them to UnFav OS or Fav OS groups. Conclusion: Plasma-based molecular markers are predictive for RA-223 efficacy. An association between OS and immune and DDR profiles in men with BM-CRPC may indicate mechanism of action and identify subsets most likely to benefit. These preliminary results provide rationale for combination therapy with RA-223 and immune-checkpoint blockade or PARP inhibition. Clinical trial information: NCT02135484. [Table: see text]

Value of bone scan index for predicting overall survival among patients treated with radium-223 for bone metastatic castration-resistant prostate cancer.

216 Background: The objective of this study was to evaluate the bone scan index (BSI) as a prognostic biomarker for overall survival (OS) among patients treated with radium-223 (Ra-223) for bone metastatic castration-resistant prostate cancer (mCRPC). Methods: We retrospectively identified 42 men who had been treated with Ra-223 for bone metastatic CRPC between 2012 and 2017 and investigated correlations between the baseline clinical factors of age, time to CRPC, previous use of docetaxel, PSA, Gleason score, alkaline phosphatase (ALP), and BSI and OS by multivariate analysis using the Cox proportional hazard model. We also analyzed the correlations between OS and absolute BSI value or BSI change from baseline after 12 weeks of treatment. Continuous variables were classified as dichotomous. Results: The median age, PSA, and time to CRPC were 75.5 years, 42.8 ng/mL, and 11.2 months, respectively. The median observation period was 11.7 months. Twenty-five (59.5 %) of the 42 patients had completed six cycles of Ra-223 treatment. Twenty-two patients (52.4 %) had died, including 20 (47.6 %) of cancer, by the time of analysis. The median OS in the entire cohort was 20.7 months. Multivariate analysis also showed that only BSI (≥1.5 vs. &lt; 1.5, HR 3.72, 95% CI 1.17–11.79, p = 0.026) was significantly correlated with OS. The BSI had decreased in 16 (51.6%) of the 31 patients who had undergone bone scans after 12 weeks of treatment . Multivariate analysis showed that absolute BSI value after 12 weeks treatment was significantly correlated with OS (BSI (≥2.0 vs. &lt; 2.0%, HR 13.07, 95% CI 2.61–65.53, p = 0.002). No correlation was found between BSI change from baseline after 12 weeks and OS. Conclusions: According to multivariate analysis, both baseline BSI and PSA were significant prognostic factors for OS among men treated with Ra-223. Absolute BSI value after 12 weeks of Ra-223 treatment was also found to be an independent prognostic factor for OS.

P049 - Real world lessons for optimal selection of patients with bone metastatic castration-resistant prostate cancer for radium-223 therapy

P049 - Real world lessons for optimal selection of patients with bone metastatic castration-resistant prostate cancer for radium-223 therapy

223Ra-dichloride therapy in an elderly bone metastatic castration-resistant prostate cancer patient: a case report presentation and comparison with existing literature.

223Ra-dichloride therapy in an elderly bone metastatic castration-resistant prostate cancer patient: a case report presentation and comparison with existing literature.