Impact of Prior Chemotherapy on Response to Second-line Pembrolizumab in Urothelial Cancer: Exploratory Analysis of the Phase 3 KEYNOTE-045 Trial.

BACKGROUND AND OBJECTIVE: Until recently, the standard first-line treatment for advanced urothelial carcinoma (UC) was platinum-based combination chemotherapy followed by avelumab maintenance therapy for patients without progressive disease (PD). For patients with advanced UC who experience PD or recurrence, standard-of-care treatment is pembrolizumab monotherapy based on the phase 3 KEYNOTE-045 study. This post hoc analysis of the KEYNOTE-045 study evaluated the efficacy of pembrolizumab compared with chemotherapy by the best response to prior platinum-based chemotherapy. METHODS: Patients with advanced UC that progressed or recurred after first-line platinum-based chemotherapy were randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 wk (Q3W) for ≤2 yr or investigator's choice of chemotherapy (paclitaxel [175 mg/m2], docetaxel [75 mg/m2], or vinflunine [320 mg/m2], each Q3W). Endpoints included overall survival (OS) from the initiation of the last treatment prior to death, objective response rate (ORR), and duration of response (DOR) as per Response Evaluation Criteria in Solid Tumors version 1.1 from the date of the first response. KEY FINDINGS AND LIMITATIONS: An objective response to pembrolizumab was observed in all groups in terms of a prior response to first-line platinum-based chemotherapy. Median OS, ORR, and median DOR were numerically greater with pembrolizumab than with chemotherapy across subgroups. Patients with PD as the best response to prior platinum-based chemotherapy had the poorest OS outcomes. Limitations include a lack of formal hypothesis testing. CONCLUSIONS AND CLINICAL IMPLICATIONS: When compared with chemotherapy, prolonged OS and durable responses to second-line pembrolizumab were observed independently of the response to or type of prior platinum-based chemotherapy. These findings further support pembrolizumab as second-line treatment for advanced UC.

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab for advanced urothelial carcinoma: results from the randomized phase III ECHO-303/KEYNOTE-698 study.

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%. METHODS: ECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Target enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35-48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67-29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent. CONCLUSIONS: Epacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03374488. Registered 12/15/2017.

Enfortumab vedotin and pembrolizumab combination as a relevant game changer in urothelial carcinoma: What is left behind?

The EV-302 study1 marks a pivotal leap in the management of advanced urothelial carcinoma, setting a new benchmark for frontline therapy. Enfortumab vedotin plus pembrolizumab is the first combination therapy that has ever outperformed standard chemotherapy. The degree of benefit and the reported safety profile should make this combination a first-choice option for most patients with advanced-stage urothelial carcinoma.

Dual mTOR1/2 Inhibitor Sapanisertib (FTH-003/TAK-228) in Combination With Weekly Paclitaxel in Patients With Previously Treated Metastatic Urothelial Carcinoma: A Phase II Open-Label Study.

BACKGROUND: The PI3K/AKT/mTOR pathway is frequently altered at genomic level in metastatic urothelial carcinoma (mUC). Since mTOR is the last protein in the PI3K signaling cascade, it may have the largest impact on the pathway and has been a focus of targeted therapies. Sapanisertib (FTH-003/TAK-228) is an oral highly selective mTOR1 and mTOR2 inhibitor. NFE2L2 mutations have been described as predictive biomarkers of response in patients with advanced squamous cell lung cancer treated with sapanisertib. PATIENTS AND METHODS: This was an open-label, investigator-initiated phase II study evaluating safety and efficacy of sapanisertib plus paclitaxel in patients with mUC who had progressed to prior platinum therapy, and the correlation with NFE2L2 mutations in responders. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Patients were treated with weekly paclitaxel at dose of 80 mg/m2 on days 1, 8, and 15 in combination with sapanisertib 4 mg administered orally 3 days per week on days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle. NFE2L2 mutations were analyzed by Sanger sequencing in responders. RESULTS: 22 patients were enrolled from May 2018 to April 2020; the trial was halted early due to slow accrual and the COVID-19 pandemic. ORR was 18.2% (n = 4). Disease control rate was 50% (7 SD and 4 PR). Median PFS was 3.4 months (95% CI: 1.8-6.1) and median OS was 6.1 months (95% CI: 1.8-13.4). Adverse events (AE) of grade 3-4 were seen in 86% of patients, but no patients discontinued treatment due to AEs. NFE2L2 mutations were not found in responders. CONCLUSIONS: Although the primary endpoint was no met, sapanisertib and paclitaxel combination demonstrated clinical activity in a heavily pretreated population of mUC. This trial generates insight for future combination of sapaniserib with immunotherapy and/or antibody drug conjugates.

Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients.

BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Analysis from JAVELIN Bladder 100 by Duration of First-line Chemotherapy and Interval Before Maintenance.

BACKGROUND: In the JAVELIN Bladder 100 phase 3 trial, avelumab first-line maintenance + best supportive care (BSC) prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (advanced UC) without progression after first-line platinum-based chemotherapy. OBJECTIVE: To report post hoc analyses of subgroups defined by the duration of first-line chemotherapy and interval before maintenance. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced UC without progression after four to six cycles of platinum-based chemotherapy and a 4-10-wk interval after chemotherapy (n = 700) were randomized to receive avelumab + BSC or BSC alone. Subgroups were defined by duration (quartile [Q]) and estimated number of cycles of chemotherapy, and interval between chemotherapy and maintenance. The median follow-up was >19 mo in both arms. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS (primary endpoint), PFS, and safety were assessed. RESULTS AND LIMITATIONS: Hazard ratios (95% confidence interval) for OS with avelumab + BSC versus BSC alone were as follows: by chemotherapy duration-Q3: 0.63 (0.39-1.00); by number of cycles-four cycles: 0.69 (0.48-1.00), five cycles: 0.98 (0.57-1.71), and six cycles: 0.66 (0.47-0.92); and by interval-4-<6 wk: 0.75 (0.54-1.04), 6-<8 wk: 0.67 (0.43-1.06), and 8-10 wk: 0.69 (0.47-1.02). Results were similar for PFS. Safety was similar across subgroups. All analyses were exploratory. CONCLUSIONS: Post hoc analyses of OS and PFS in subgroups defined by first-line chemotherapy duration and interval before maintenance were generally consistent with the results in the overall population, with similar safety findings. Prospective trials are warranted to confirm these findings. PATIENT SUMMARY: Avelumab maintenance treatment helped patients with advanced urothelial cancer without disease progression after at least four cycles of prior chemotherapy, and who started maintenance treatment at least 4 wk after chemotherapy, to live longer.

Progress in systemic therapy for advanced-stage urothelial carcinoma.

Despite recent advances, advanced-stage urothelial carcinoma (aUC) remains incurable, with 5-year survival rates of approximately 10%. Platinum-based chemotherapy has a major role as first-line therapy for most patients with aUC. The approval of the anti-PD-L1 antibody avelumab as maintenance therapy for patients without initial disease progression on platinum-based chemotherapy is an important development that has improved the survival outcomes of patients with this disease. Otherwise, the use of first-line immune-checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 has been restricted to patients who are ineligible for platinum-containing chemotherapy regimens. Other important developments include the FDA-accelerated approval of first-line enfortumab vedotin plus pembrolizumab for patients ineligible to receive cisplatin and the availability of FGFR inhibitors, enfortumab vedotin and sacituzumab govitecan for subsequent lines of therapy. Several research questions remain unaddressed including the lack of adequate biomarkers, how to assign priority to the different treatment options for individual patients and which agents can be effective as monotherapies. The future is promising with the emergence of modalities such as antibody-drug conjugate-like drugs, next-generation ICIs, bispecific antibodies and cellular therapies. In this Review, we summarize the evolution of systemic therapy for patients with aUC and provide insights into the unmet needs.

Updated Overall Survival by Circulating Tumor DNA Status from the Phase 3 IMvigor010 Trial: Adjuvant Atezolizumab Versus Observation in Muscle-invasive Urothelial Carcinoma.

BACKGROUND: Interim results from IMvigor010 showed an overall survival (OS) benefit for adjuvant atezolizumab (anti-PD-L1) versus observation in patients with circulating tumor DNA (ctDNA)-positive muscle-invasive urothelial carcinoma (MIUC). OBJECTIVE: To report updated OS and safety by ctDNA status. DESIGN, SETTING, AND PARTICIPANTS: This ad hoc analysis from a global, open-label, randomized, phase 3 trial (NCT02450331) included intention-to-treat (ITT) population with evaluable cycle 1 day 1 (C1D1) ctDNA samples. INTERVENTION: Atezolizumab (1200 mg every 3 wk) or observation for ≤1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS, relapse rates, and safety by ctDNA status were assessed. RESULTS AND LIMITATIONS: Among 581 of 809 ITT patients included, 214 (37%) were ctDNA positive. Atezolizumab did not improve OS versus observation in ITT patients (hazard ratio [HR] 0.91 [95% confidence interval {CI} 0.73-1.13]; median follow-up 46.8 mo [interquartile range, 36.1-53.6]). In the observation arm, ctDNA positivity versus negativity was associated with shorter OS (HR 6.3 [95% CI 4.3-9.3]). The ctDNA positivity identified patients with an OS benefit favoring atezolizumab versus observation (HR 0.59 [95% CI 0.42-0.83]). A greater reduction in ctDNA levels with atezolizumab (C3D1) was associated with longer OS (100% clearance, 60.0 mo [95% CI 35.5-not estimable]; 50-99% reduction, 34.3 mo [95% CI 15.2-not estimable]; <50% reduction, 19.9 mo [95% CI 16.4-32.2]). The ctDNA positivity at C1D1 + C3D1 was associated with relapse with greater sensitivity than C1D1 alone (68% vs 57%). Adverse events were more frequent with atezolizumab than with observation, regardless of ctDNA status. A study limitation was its exploratory design. CONCLUSIONS: Evidence suggests that ctDNA positivity in MIUC predicts a benefit with atezolizumab. An in-progress prospective study will further evaluate these findings. PATIENT SUMMARY: Among patients with urothelial cancer after surgery, survival was poorer if tumor-derived DNA was detected in their bloodstream; these patients' survival was longer with atezolizumab versus observation. Bloodstream tumor-derived DNA may identify patients who benefit from atezolizumab.

Bone targeting agents, but not radiation therapy, improves survival in patients with bone metastases from advanced urothelial carcinoma receiving pembrolizumab: results from the ARON-2 study.

The ARON-2 study (NCT05290038) aimed to assess the real-world efficacy of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. This retrospective analysis reports the outcomes of urothelial carcinoma (UC) patients with bone metastases (BM). Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were reviewed from60 institutions in 20 countries. Patients were assessed for Overall Response Rate (ORR), Progression-Free Survival (PFS), and Overall Survival (OS). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. 881 patients were included; of them, 263 (30%) presented BM. Median follow-up time was 22.7 months. Patients with BM showed both shorter median OS (5.9 months vs 13.1 months, p < 0.001) and PFS (3.5 months, vs 7.3 months, p < 0.001) compared to patients without BM. Patients who received bone targeted agents (BTAs) showed a significantly longer median OS (8.5 months vs 4.6 months, p = 0.003) and PFS (6.1 months vs 3.2 months, p = 0.003), while no survival benefits were observed among patients who received radiation therapy for BM during pembrolizumab treatment compared to those who did not. In multivariate analysis, performance status, concomitant liver metastases, and the lack of use of BTAs were significantly associated with worse OS and PFS. Bone involvement in UC patients treated with pembrolizumab predicts inferior survival. Poor performance status and liver metastases may further worsen outcomes, while the use of BTAs is associated with improved outcomes.

Immunohistochemical markers as predictors of prognosis in multifocal prostate cancer.

The impact of tumor focality on prostate cancer (PCa) prognosis has been addressed in several studies with conflicting results. Tumor foci from multifocal (MF) PCa can show highly heterogeneous molecular features. Our aim was to analyze the protein expression of PTEN, SPOP, SLC45A3, ETV1, ERG and the "triple hit" (ERG overexpression, PTEN plus SLC45A3 loss) in unifocal (UF) and MF PCa, to evaluate their value as prognostic markers according to focality, and the role of tumor heterogeneity in MF disease. PTEN, SPOP, SLC45A3, ETV1 and ERG immunohistochemical expression was evaluated in 185 PCa from 9 TMAs, 51 UF and 134 MF. In a subset of 69 MF cases, the dominant and secondary foci (DF and SF) were compared. Heterogeneity was considered when both tumor foci presented different expression patterns. Relationship with clinicopathological features was also analyzed. MF PCa was diagnosed in significantly younger patients when compared to UF ones (p = 0.007). ETV1 overexpression was associated with UF disease (p = 0.028). A shorter time to PSA recurrence was related to SLC45A3 wt expression in UF PCa (p = 0.052), and to SPOP expression loss (p = 0.043) or "triple hit" phenotype in MF PCa (p = 0.041). In MF cases, PTEN loss, SLC45A3 loss and "triple hit" phenotype were associated with the DF and had significant heterogeneity. In conclusion, our results indicate that UF and MF PCa have relevant and consistent molecular differences. The analysis of an immunohistochemical panel, composed by PTEN, SPOP, SLC45A3, ETV1 and ERG, could be useful to predict outcome in MF cases.

The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and can result in complete remissions even at advanced stages of the disease. However, only a small fraction of patients respond to the treatment. To better understand which factors drive clinical benefit, we have generated whole exome and RNA sequencing data from 27 advanced urothelial carcinoma patients treated with anti-PD-(L)1 monoclonal antibodies. We assessed the influence on the response of non-synonymous mutations (tumor mutational burden or TMB), clonal and subclonal mutations, neoantigen load and various gene expression markers. We found that although TMB is significantly associated with response, this effect can be mostly explained by clonal mutations, present in all cancer cells. This trend was validated in an additional cohort. Additionally, we found that responders with few clonal mutations had abnormally high levels of T and B cell immune markers, suggesting that a high immune cell infiltration signature could be a better predictive biomarker for this subset of patients. Our results support the idea that highly clonal cancers are more likely to respond to ICI and suggest that non-additive effects of different signatures should be considered for predictive models.

A Plea for the Use of Video-recorded Cystoscopy for Blinded Independent Central Review of Tumor Response in Open-label Non-muscle invasive Bladder Cancer Trials.

Given that most of non-muscle invasive bladder cancer trials available in the literature share the same limitation of an open-label design, they are likely prone to detection bias. Indeed, tumor response is currently assessed by unblinded investigators, mainly via follow-up cystoscopy, which has well-known intraobserver and interobserver variability. Thus, we believe that the use of video-recorded cystoscopy for blinded independent central review of tumor response could help to minimize detection bias in open-label NMIBC trials.

Conditional survival following radical cystectomy for urothelial carcinoma of the bladder.

INTRODUCTION: Traditional surveillance protocols do not adequately account for the decreasing risk of mortality over time in aggressive malignancies, such as bladder cancer. Rather, the risk of death depends on both the baseline risk of mortality and the time survived since treatment. We therefore evaluated the conditional survival of patients diagnosed with urothelial carcinoma of the bladder (UCB) following radical cystectomy (RC). PATIENTS AND METHODS: We identified patients aged 18 to 75 with Charlson 0-1 and pTany pN0-3 cM0 UCB diagnosed from 2006 to 2015 in the National Cancer Database and treated with RC. The 2- and 5-year conditional overall survival (COS)-i.e., the probability of surviving an additional 2- or 5-years given a specified time survived since treatment-was estimated using the Kaplan-Meier method. Multivariable Cox regression models with landmark time analysis were used to evaluate the associations of baseline characteristics with OS over time. RESULTS: A total of 15,594 patients were included in the study. Median follow-up was 27.8 months. The 2- and 5-year COS for the overall cohort increased through 36 months follow-up and then plateaued. When stratified by pT and pN stage, the COS gain increased with higher pT and pN stage, demonstrating the greatest increase over time for patients with pTany N1-3 disease (5-year COS of 23% at baseline, 58% at 36-months, and 71% at 60-months). In multivariable Cox regression modeling, pT and pN stage were significantly associated with higher all-cause mortality at baseline (HR 3.27 for pT4, HR 2.57 for pT3 vs. ≤pT2; HR 2.26 for pN2-3, HR 1.77 for pN1 vs. pN0), but these associations were attenuated in magnitude with increasing landmark times of 36- and 60-months (HR 1.63 for pT4, HR 1.35 for pT3 vs. ≤pT2; HR 1.34 for pN2-3, HR 1.27 for pN1 vs. pN0). Our study is limited by the retrospective design and the lack of cancer-specific survival data. CONCLUSIONS: Risk of death after RC varies with time elapsed since treatment and disease stage. Accordingly, stage-specific COS may be used to improve prognostication and surveillance protocols.

Evaluating Real-World Characteristics of Patients With Advanced Urothelial Carcinoma Eligible for Avelumab Maintenance Therapy: A Multicountry Retrospective Medical Chart Review.

INTRODUCTION: Urothelial carcinoma (UC) is a malignancy of the urothelium that encompasses the renal pelvis, bladder, and urethra. Current treatment guidelines for advanced (ie, locally advanced or metastatic) UC recommend using avelumab maintenance therapy in patients with nonprogressive disease following first-line platinum-based chemotherapy. This study aimed to assess the representativeness of the patient population in the JAVELIN Bladder 100 (JB-100) trial, which examined the efficacy and safety of avelumab first-line maintenance, vs. real-world patients with advanced UC that had not progressed with first-line platinum-based chemotherapy treated between 2015 and 2018 by reviewing demographic and clinical characteristics. PATIENTS AND METHODS: A medical chart review (MCR) study collected demographics and treatment characteristics for patients with advanced UC in the United States, the United Kingdom, and France. Data were analyzed descriptively for review with data collected from patients enrolled in JB-100. RESULTS: Clinical characteristics were consistent between JB-100 and the MCR. Most patients were male, received 4 to 6 cycles of platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All patients in the MCR had either stable disease or a response with platinum-based chemotherapy (∼75% achieved a complete or partial response). Fewer than half (42.5%) of all patients in the MCR received subsequent therapy. CONCLUSION: Patient demographics, clinical characteristics, and treatment patterns from a MCR of patients with advanced UC that had not progressed following first-line platinum-based chemotherapy appeared similar to data from patients enrolled in JB-100. Future studies should examine whether real-world outcomes are consistent with findings from JB-100. GOV IDENTIFIER: NCT02603432.

Clinical outcomes and treatment patterns in REASSURE: planned interim analysis of a real-world observational study of radium-223 in metastatic castration-resistant prostate cancer.

Background: Radium-223, a targeted alpha therapy, is approved to treat bone-dominant metastatic castration-resistant prostate cancer (mCRPC), based on significantly prolonged overall survival versus placebo and a favourable safety profile in the phase 3 ALSYMPCA study. ALSYMPCA was conducted when few other treatment options were available, and prospectively collected data are limited on the use of radium-223 in the current mCRPC treatment landscape. We sought to understand long-term safety and treatment patterns in men who received radium-223 in real-world clinical practice. Methods: REASSURE (NCT02141438) is a global, prospective, observational study of radium-223 in men with mCRPC. Primary outcomes are adverse events (AEs), including treatment-emergent serious AEs (SAEs) and drug-related AEs during and ≤30 days after radium-223 completion, grade 3/4 haematological toxicities ≤6 months after last radium-223 dose, drug-related SAEs after radium-223 therapy completion, and second primary malignancies. Findings: Data collection commenced on Aug 20, 2014, and the data cutoff date for this prespecified interim analysis was Mar 20, 2019 (median follow-up 11.5 months [interquartile range 6.0-18.6]), 1465 patients were evaluable. For second primary malignancies, 1470 patients were evaluable, 21 (1%) of whom had a total of 23 events. During radium-223 therapy, 311 (21%) of 1465 patients had treatment-emergent SAEs, and 510 (35%) had drug-related AEs. In the 6 months after completion of radium-223 therapy, 214 (15%) patients had grade 3/4 haematological toxicities. Eighty patients (5%) had post-treatment drug-related SAEs. Median overall survival was 15.6 months (95% confidence interval 14.6-16.5) from radium-223 initiation. Patient-reported pain scores declined or stabilised. Seventy (5%) patients had fractures. Interpretation: REASSURE offers insight into radium-223 use in global real-world clinical practice with currently available therapies. At this interim analysis, with a median follow-up of almost 1 year, 1% of patients had second primary malignancies, and safety and overall survival findings were consistent with clinical trial experience. Final analysis of REASSURE is due in 2024. Funding: Bayer HealthCare.