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Real World Outcomes in Patients With Metastatic, Castration-Resistant Prostate Cancer Treated With Radium-223 in Routine Clinical Practice in Sweden

Open AccessPublished:September 08, 2022DOI:https://doi.org/10.1016/j.clgc.2022.09.002

      Highlights

      • Radium-223 is a treatment for symptomatic bone metastases in prostate cancer.
      • In a clinical trial, its combination with abiraterone was associated with fractures.
      • We used real world data from Swedish registries to evaluate the risk of fractures.
      • The risk of fractures associated its use as monotherapy was small, if any.

      Abstract

      Aim

      Estimate the effect of Radium-223 (Ra-223) on the incidence of bone fractures, prostate cancer death, and all-cause death compared with other standard treatments for metastatic, castration-resistant prostate cancer (mCRPC).

      Methods

      Using a cohort design, we estimated the effect of Ra-223 on the risk of bone fractures, all-cause and prostate cancer–specific mortality across different lines of treatment for mCRPC using Prostate Cancer data Base Sweden (2013-2018). The comparator group comprised other standard treatments for mCRPC. We used 36-month risk differences and hazard ratios (HRs) as effect estimates.

      Results

      The number of eligible individuals was 635, 453, 262, and 84 for the first-, second-, third-, and fourth-line cohorts, respectively. When compared Ra-223 to other standard treatments, the difference in the 36-month risk of fracture was 6% (95% confidence interval [CI], −7% to 18%) in the first-line cohort (n = 635) and 8% (95% CI, −7% to 18%) in the second-line cohort (n = 453). The number of fractures in the third-/fourth-line cohorts was too small for an adjusted comparison. The difference in 36-month mortality was higher in the first-line cohort 13% (95% CI, −3% to 31%), but lower in the second- and third-/fourth-line cohorts−8% (95% CI, −23% to 7%) and −14% (95% CI, −21% to 16%) respectively. Most deaths were due to prostate cancer.

      Conclusion

      Results suggest that the difference in the risk of fractures is small, if any. A difference in the risk of mortality may be present in first-line treatment, but a decreased risk of mortality was observed in second and later lines of treatment. The results on mortality need to be considered in the context of potential unmeasured or residual confounding.

      Keywords

      Introduction

      Radium-223 (Ra-223) is a life-prolonging, systemic, targeted alpha therapy indicated for adults with metastatic castration-resistant prostate cancer (mCRPC) who have symptomatic bone metastases and no visceral metastases. In the pivotal ALSYMPCA clinical trial, Ra-223 prolonged overall survival (OS) and time to first symptomatic skeletal event, increased quality of life or delayed its decline, and had a good safety profile.
      • Parker C
      • Nilsson S
      • Heinrich D
      • et al.
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      • Sartor O
      • Coleman R
      • Nilsson S
      • et al.
      Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase III, double-blind, randomized trial.
      • Parker C
      • Heidenreich A
      • Nilsson S
      • Shore N.
      Current approaches to incorporation of radium-223 in clinical practice.
      In the subsequent ERA 223 trial, Ra-223 in combination with abiraterone acetate plus prednisone and/or prednisolone (AAP) was found to increase the risk of bone fractures (29% of patients treated with Ra-223 plus AAP compared with 11% who received placebo plus AAP and deaths in the treatment arm, leading to unblinding.
      • Bayer
      Phase III trial of radium-223 dichloride in combination with abiraterone acetate and prednisone/prednisolone for patients with metastatic castration-resistant prostate cancer unblinded early.
      ,
      • Smith M
      • Parker C
      • Saad F
      • et al.
      Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomized, double-blind, placebo-controlled, phase III trial.
      An adjusted analysis of OS yielded a hazard ratio (HR) of 1.06 (95% confidence interval [CI], 0.84-1.35).
      • Smith M
      • Parker C
      • Saad F
      • et al.
      Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomized, double-blind, placebo-controlled, phase III trial.
      This safety signal triggered a regulatory procedure by the European Medicines Agency (EMA) that included a change to the label in the European Union (by adding a contraindication for the combination with AAP and a restriction to patients who had progressed to at least two prior treatments for mCRPC or were ineligible for systemic mCRPC treatment). The aim of this post-authorisation safety study
      • European Medicines Agency
      EMA restricts use of prostate cancer medicine Xofigo [press release].
      was to estimate the effect of Ra-223 on the incidence of fractures and death compared with the standard of care in a real-world setting, which we report here. As recommended by the EMA,
      • European Medicines Agency
      Guideline on good pharmacovigilance practices (GVP). Module VIII – Post-authorization safety studies (EMA/813938/2011 Rev 3).
      the study and its protocol and report are posted in the EU PAS register (EUPAS33448).

      European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. EU PAS Register Number: EUPAS33448. Amsterdam, Netherlands, February 5, 2020. Available at: https://www.encepp.eu/encepp/viewResource.htm?id=42249.

      Methods

      Study setting

      We analysed data (November 2013-December 2018) from Prostate Cancer data Base Sweden (PCBaSe), a database linking the National Prostate Cancer Register of Sweden, including the Patient-overview Prostate Cancer, with other health care registries
      • Van Hemelrijck M
      • Wigertz A
      • Sandin F
      • et al.
      Cohort profile: the National Prostate Cancer Register of Sweden and Prostate Cancer data Base Sweden 2.0.
      ,
      • Franck Lissbrant I
      • Hjälm Eriksson M
      • Lambe M
      • Törnblom M
      • Stattin P
      Set-up and preliminary results from the Patient-overview Prostate Cancer. Longitudinal registration of treatment of advanced prostate cancer in the National Prostate Cancer Register of Sweden.
      (Supplementary Methods). This study was approved by the Research Ethics Board in Uppsala, Sweden.

      Eligibility criteria

      Eligibility criteria included a diagnosis of adenocarcinoma of the prostate, initiation of any systemic treatment for mCRPC after progressing to luteinising hormone-releasing hormone (LHRH) analogues (procedures to identify the use of docetaxel and abiraterone for mCRPC as opposed to their use for castration-sensitive prostate cancer are described in Supplementary Methods), and presence of bone metastasis. Patients with prior use of Ra-223 or without complete information on baseline variables were excluded (Supplementary Methods)

      Study design

      We designed this observational study to emulate a target trial
      • Hernan MA
      • Robins JM.
      Using big data to emulate a target trial when a randomized trial is not available.
      (Supplementary Table S1) that would compare two treatment strategies: (1) initiation of Ra-223 as monotherapy for less than or equal to 6 cycles, with early cessation if clinically indicated, and (2) initiation of any of the following comparator drugs (docetaxel, cabazitaxel, enzalutamide, abiraterone, or others [cisplatin, cyclophosphamide, doxorubicin, estramustine, etoposide, gemcitabine, carboplatin, methotrexate, mitoxantrone]), with cessation if clinically indicated. Under both treatment strategies, patients would be allowed to receive first-generation antiandrogens and/or LHRH analogues and continue subsequent treatment with a different drug other than Ra-223. These treatment strategies were operationalised by classifying patients into study groups according to their baseline data (ie, beginning of treatment line) and by artificially censoring patients in the comparator group when they started Ra-223. Artificial censoring was not applied in the Ra-223 group because none received other mCRPC treatment concomitantly. The primary outcome was bone fractures requiring admission to a hospital or treatment in an outpatient setting. The secondary outcomes were death due to all causes and death due to prostate cancer.
      Because all study drugs could be used for any treatment line for mCRPC (Supplementary Figure S1), we first emulated a trial for first-line treatment in which eligible patients were classified into treatment strategies the day they initiated a first-line treatment. They were followed until the artificial censoring, occurrence of the outcome of interest, or the administrative end of follow-up. We repeated this process for the four lines of treatment (later lines of treatment were scarcely represented in the data), creating four cohorts. Patients could contribute eligible individuals in multiple line-of-treatment–specific cohorts if they remained eligible
      • Garcia-Albeniz X
      • Hsu J
      • Hernan MA.
      The value of explicitly emulating a target trial when using real world evidence: an application to colorectal cancer screening.
      • Hernan MA
      • Alonso A
      • Logan R
      • et al.
      Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease.
      • Hernan MA
      • Robins JM
      • Garcia Rodriguez L.
      Discussion on “Statistical Issues in the Women's Health Initiative.
      (Supplementary Methods). For both fractures and survival, we evaluated the homogeneity of the 12-month adjusted risk difference estimates across line-of-treatment cohorts using the I2 statistic
      • Higgins JP
      • Thompson SG.
      Quantifying heterogeneity in a meta-analysis.
      and established a priori that if I2 was ≤50%, we would pool the cohorts. Several sensitivity analyses (Supplementary Table S2) and a negative control outcome (Supplementary Methods and Supplementary Figure S2) were run.

      Statistical analysis

      We estimated the hazard ratios of the three outcomes for Ra-223 versus comparator drug via a weighted pooled logistic model
      • Hernan MA
      • Robins JM.
      Causal survival analysis. In: Causal inference.
      ,
      • Thompson WA
      On the treatment of grouped observations in life studies.
      that included the indicator for the treatment strategy and a flexible function of time (restricted cubic splines to estimate the baseline hazard). The model was weighted using stabilised weights where the denominator indicated the probability that a patient would initiate a treatment strategy conditional on the following baseline variables: age, calendar year, time from prostate cancer diagnosis, history of skeletal-related events, TNM (tumour [T], nodes [N], and metastases [M]) stage, tumour grade, Eastern Cooperative Oncology Group (ECOG) performance status (PS), prostate-specific antigen (PSA), haemoglobin, total alkaline phosphatase, Charlson Comorbidity Index, site of metastasis (visceral, bone, lymph node), prior spinal cord compression, bone-health agent (zoledronate, denosumab) use, steroid use, time on androgen deprivation therapy (ADT), prior radiation therapy, prior mCRPC drugs, and current treatment line. The numerator indicated the corresponding marginal probability. To adjust for the potential selection bias introduced because of the artificial censoring applied to the comparator group, we used a second set of weights that were a function of the time-varying probability of initiating Ra-223 conditional on the following time-varying variables: ECOG PS, PSA, haemoglobin, total alkaline phosphatase, Charlson Comorbidity Index, metastasis site, prior spinal cord compression, bone-health agent use, steroid use, treatment line, and prior mCRPC drugs. Missing values in baseline variables were addressed by applying weights to the complete case population.
      • Toh S
      • Garcia Rodriguez LA
      • Hernan MA
      Analyzing partially missing confounder information in comparative effectiveness and safety research of therapeutics.
      Weights were truncated at percentile 99 to avoid undue influence of outliers.
      • Cain LE
      • Logan R
      • Robins JM
      • et al.
      When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.
      ,
      • Cole SR
      • Hernán MA.
      Constructing inverse probability weights for marginal structural models.
      To estimate cumulative incidence probabilities and survival under both strategies, we fit a weighted outcome model like the one above including product terms for treatment strategy and time. The model's predicted values were used to estimate the cumulative incidence and survival at 6-month intervals up to 36 months. We computed percentile-based 95% CIs via bootstrapping (500 resamplings).

      Results

      There were 1771 patients diagnosed with mCRPC registered in PCBaSe between November 2013 and December 2018. Of these, 635 individuals were eligible for the first-line cohort (Ra-223, n = 203; comparator, n = 432), 453 for the second-line cohort (Ra-223, n = 239; comparator, n = 214), 262 for the third-line cohort (Ra-223, n = 180; comparator, n = 82), and 84 for the fourth-line cohort (Ra-223, n = 59; comparator, n = 25); ie, 1434 individuals participated in the four treatment-line–specific cohorts (1203 unique patients) (Supplementary Table S3).
      The variables age, ECOG PS, and Charlson Comorbidity Index score were balanced, considering all lines of treatment together. Patients receiving Ra-223 as first-line treatment were more likely to have experienced a bone fracture before baseline than patients receiving a comparator. Enzalutamide was the most frequently used baseline drug in the comparator group in the first two lines of treatment and cabazitaxel in the third and fourth lines of treatment (Table 1). Supplementary Table S4 contains the treatments received after the baseline treatment strategy and Supplementary Table S5 describes the follow-up, censoring reasons, and outcomes in the overall study population and by treatment line.
      Table 1Baseline Characteristics, by Group and Treatment Line, PCBaSe, 2013-2018
      Characteristic
      Each individual may contribute to more than one line of treatment.
      Comparator armRadium-223 arm
      All (n = 753)Line 1 (n = 432)Line 2 n = 214)Line 3 (n = 82)Line 4 (n = 25)All (n = 681)Line 1 (n = 203)Line 2 (n = 239)Line 3 (n = 180)Line 4 (n = 59)
      Age, mean (SD), y74 (8)75 (8)73 (7)72 (7)70 (7)74 (7)75 (8)74 (8)73 (6)72 (7)
      Calendar year at cohort entry, n (%)
       Nov 2013-20144 (1)3 (1)1 (0)0011 (2)1 (0)4 (2)3 (2)3 (5)
       201564 (9)28 (6)25 (12)9 (11)2 (8)143 (21)39 (19)38 (16)43 (24)23 (39)
       2016157 (21)98 (23)38 (18)16 (20)5 (20)182 (27)43 (21)70 (29)51 (28)18 (31)
       2017248 (33)144 (33)69 (32)27 (33)8 (32)214 (31)81 (40)76 (32)49 (27)8 (14)
       2018280 (37)159 (37)81 (38)30 (37)10 (40)131 (19)39 (19)51 (21)34 (19)7 (12)
      Months from prostate cancer diagnosis to baseline, mean (SD)71 (53)66 (56)75 (51)83 (47)71 (37)76(55)61 (55)76 (56)88 (49)97 (50)
      Skeletal-related events before baseline,
      Includes bone fracture, spinal cord compression and bone-targeted radiotherapy.
      n (%)
      308 (41)138 (32)103 (48)51 (62)16 (64)350 (51)85 (42)118 (49)109 (61)38 (64)
      History of fractures, n (%)129 (17)62 (14)38 (18)22 (27)7 (28)133 (20)46 (23)35 (15)38 (21)14 (24)
      T stage, n (%)
       T1146 (19)88 (20)35 (16)18 (22)5 (20)131 (19)35 (17)51 (21)35 (19)10 (17)
       T2236 (31)131 (30)74 (35)25 (30)6 (24)202 (30)67 (33)76 (32)48 (27)11 (19)
       T3315 (42)183 (42)87 (41)34 (41)11 (44)286 (42)83 (41)93 (39)76 (42)34 (58)
       T456 (7)30 (7)18 (8)5 (6)3 (12)62 (9)18 (9)19 (8)21 (12)4 (7)
      N stage, n (%)
       N0161 (21)101 (23)46 (22)12 (15)2 (8)155 (23)55 (27)55 (23)34 (19)11 (19)
       N1142 (19)73 (17)41 (19)17 (21)11 (44)91 (13)29 (14)30 (13)29 (16)3 (5)
       NX450 (60)258 (60)127 (59)53 (65)12 (48)435 (64)119 (59)154 (64)117 (65)45 (76)
      M stage, n (%)
       M0475 (63)260 (60)143 (67)57 (70)15 (60)385 (57)104 (51)129 (54)114 (63)38 (64)
       M1278 (37)172 (40)71 (33)25 (30)10 (40)296 (43)99 (49)110 (46)66 (37)21 (36)
      Grade, n (%)
      Gleason ≤6
      Gleason score 6 included 6 (3%) cancers graded as WHO grade I
      111 (15)64 (15)28 (13)14 (17)5 (20)80 (12)14 (7)39 (16)18 (10)9 (15)
      Gleason = 7
      Gleason score 7 included 18 (4%) cancers graded as WHO grade II
      255 (34)143 (33)77 (36)30 (37)5(20)208 (31)56 (28)70 (29)62 (34)20 (34)
      Gleason >7
      Gleason score >7 included 15 (2%) cancers graded as WHO grade III
      387 (51)225 (52)109 (51)38 (46)15 (60)393 (58)133 (66)130 (54)100 (56)30 (51)
      ECOG PS, n (%)
       0318 (42)205 (47)80 (37)26 (32)7 (28)269 (40)97 (48)82 (34)72 (40)18 (31)
       1300 (40)155 (36)100 (47)38 (46)7 (28)305 (45)77 (38)115 (48)80 (44)33 (56)
       2124 (16)69 (16)29 (14)16 (20)10 (40)100 (15)25 (13)41 (17)26 (14)8 (14)
       311 (1)3 (1)5 (2)2 (2)1 (4)7 (1)4 (2)1 (0)2 (1)0
      Prostate-specific antigen, mean (SD)191 (446)160 (354)203 (494)267 (672)367 (465)268 (828)160 (336)348 (1280)288 (501)249 (280)
      Haemoglobin, mean (SD), g/L126 (15)127 (15)125 (14)125 (15)114 (11)125 (15)125 (15)124 (15)126 (16)123 (15)
      Alkaline phosphatase, mean (SD), µkat/L4 (4)4 (5)3 (3)3 (3)4 (4)5 (7)5 (6)5 (8)5 (9)4 (3)
      Osteoporosis diagnosis, n (%)1 (0)1 (0)0004 (1)2 (1)01 (1)1 (2)
      Charlson Comorbidity Index, n (%)
       0463 (61)265 (61)131 (61)50 (61)17 (68)424 (62)122 (60)142 (59)122 (68)38 (64)
       1135 (18)76 (18)37 (17)17 (21)5 (20)138 (20)46 (23)48 (20)31 (17)13 (22)
       287 (12)48 (11)26 (12)12 (15)1 (4)66 (10)20 (10)28 (12)12 (7)6 (10)
       3+68 (9)43 (10)20 (9)3 (4)2 (8)53 (8)15 (7)21 (9)15 (8)2 (3)
      Visceral metastasis, n (%)105 (14)41 (9)33 (15)22 (27)9 (36)28 (4)5 (2)11 (5)7 (4)5 (8)
      Lymph node metastasis, n (%)323 (43)158 (37)102 (48)48 (59)15 (60)176 (26)36 (18)64 (27)59 (33)17 (29)
      Other site of metastasis, n (%)43 (6)18 (4)15 (7)8 (10)2 (8)22 (3)3 (1)12 (5)5 (3)2 (3)
      Prior diagnosis of other cancer, n (%)39 (5)24 (6)11 (5)3 (4)1 (4)27 (4)11 (5)11 (5)4 (2)1 (2)
      History of spinal cord compression, n (%)10 (1)4 (1)6 (3)0011 (2)2 (1)3 (1)4 (2)2 (3)
      Concomitant use of bone-health agents, n (%)130 (17)54 (13)42 (20)29 (35)5 (20)230 (34)52 (26)76 (32)72 (40)30 (51)
      Current use of steroids, n (%)408 (54)171 (40)153 (72)64 (78)20 (80)207 (30)25 (12)70 (29)77 (43)35 (59)
      Months on androgen deprivation therapy
      Includes both surgical and chemical castration.
       Mean (SD)32 (28)28 (29)35 (27)39 (22)47 (18)38 (30)26 (27)37 (27)49 (32)54 (26)
      Prior radiation therapy, n (%)384 (51)171 (40)135 (63)57 (70)21 (84)406 (60)96 (47)142 (59)125 (69)43 (73)
      Prior systemic therapy
      Percentages are computed over the number of patients starting a second, third, or fourth line of treatment.
      , n (%)
       Docetaxel156 (49)076 (36)62 (76)18 (72)250 (52)062 (26)132 (73)56 (95)
       Cabazitaxel22 (7)02 (1)7 (9)13 (52)60 (13)01 (0)20 (11)39 (66)
       Abiraterone111 (35)048 (22)43 (52)20 (80)181 (38)050 (21)85 (47)46 (78)
       Enzalutamide151 (47)082 (38)47 (57)22 (88)262 (55)0121 (51)110 (61)31 (53)
       Others13 (4)06 (3)5 (6)2 (8)22 (5)05 (2)12 (7)5 (8)
      Baseline systemic therapy, n (%)
       Docetaxel102 (14)66 (15)33 (15)3 (4)0
       Cabazitaxel60 (8)3 (1)24 (11)25 (30)8 (32)
       Abiraterone186 (25)120 (28)51 (24)12 (15)3 (12)
       Enzalutamide343 (46)240 (56)81 (38)20 (24)2 (8)
       Others62 (8)3 (1)25 (12)22 (27)12 (48)
      Abbreviations: ECOG = Eastern Cooperative Oncology Group; NA = not applicable; PCBaSe = Prostate Cancer data Base Sweden; PS = performance status; Q1 = first quartile; Q3 = third quartile; SD = standard deviation; WHO = World Health Organization.
      a Each individual may contribute to more than one line of treatment.
      b Includes bone fracture, spinal cord compression and bone-targeted radiotherapy.
      c Gleason score 6 included 6 (3%) cancers graded as WHO grade I
      d Gleason score 7 included 18 (4%) cancers graded as WHO grade II
      e Gleason score >7 included 15 (2%) cancers graded as WHO grade III
      f Includes both surgical and chemical castration.
      g Percentages are computed over the number of patients starting a second, third, or fourth line of treatment.

      Risk of bone fractures

      Overall, 62 fractures (9%) occurred in the Ra-223 group and 36 (5%) in the comparator group. The most common fractures were factures of the femoral neck and pertrochanteric and subtrochanteric femur (Supplementary Table S6). In the first-line cohort, the estimated adjusted 36-month risk of fracture (95% CI) was 18% (8%-32%) in the Ra-223 group and 12% (7%-22%) in the comparator group, corresponding to a difference in 36-month risk of 6 % (95% CI, −7% to 18%). In the second-line cohort, the estimated adjusted 36-month risk of fracture was 16% (9%-24%) in the Ra-223 group and 9% (1%-21%) in the comparator group, corresponding to a difference in 36-month risk of 8 % (95% CI, −7% to 18%). Table 2 indicates the corresponding HRs. In the third and fourth lines of treatment cohorts, there was only one fracture in the comparator groups, precluding an informative adjusted analysis.
      Table 2Bone Fractures and Survival Analyses for Ra-223 Versus Comparator Drug, by Group and Treatment Line in the Prostate Cancer data Base Sweden, 2013-2018
      Risk is expressed in number of cases per 100 persons.
      First lineSecond lineThird/fourth linePooled
      ComparatorRa-223ComparatorRa-223ComparatorRa-223ComparatorRa-223
      Fractures
       36-month risk (95% CI)12 (7 to 22)18 (8 to 32)9 (1 to 21)16 (9 to 24)NENE10 (5 to 17)19 (13 to 26)
       Difference in 36-month risk (95% CI)Ref.6 (−7 to 18)Ref.8 (−7 to 18)Ref.NERef.9 (0 to 17)
       Hazard ratio (95% CI)Ref.1.14 (0.50 to 2.15)Ref.1.86 (0.62 to 10.93)Ref.NERef.1.61 (0.96 to 3.02)
      Death
       36-month risk (95% CI)73 (56 to 87)86 (76 to 94)94 (80 to 100)87 (75 to 94)100 (71 to 100)86 (78 to 92)NENE
       Difference in 36-month risk (95% CI)Ref.13 (−3 to 31)Ref.−8 (−23 to 7)Ref.−14 (−21 to 16)Ref.NE
       Hazard ratio (95% CI)Ref.1.63 (1.27 to 2.16)Ref.0.91 (0.60 to 1.23)Ref.0.72 (0.41 to 1.19)Ref.NE
      Prostate cancer death
       36-month risk (95% CI)68 (51 to 84)83 (72 to 93)92 (73 to 100)85 (72 to 94)100 (71 to 100)83 (75 to 91)NENE
       Difference in 36-month risk (95% CI)Ref.15 (−4 to 34)Ref.−7 (−23 to 14)Ref.−17 (−24 to 13)Ref.NE
       Hazard ratio (95% CI)Ref.1.83 (1.38 to 2.48)Ref.0.92 (0.59 to 1.29)Ref.0.72 (0.42 to 1.20)Ref.NE
      Abbreviations: CI = confidence interval; NE = not estimable; Ref. = reference.
      a Risk is expressed in number of cases per 100 persons.
      The evaluation of the heterogeneity of the effect of Ra-223 versus the comparator on the risk of fracture by treatment line yielded an I2 of 19% (although the few events in the third-/fourth-line cohorts may have impeded a correct estimation of heterogeneity), and the four cohorts were therefore pooled. When pooling the four treatment-line–specific cohorts, the estimated adjusted 36-month risk of fracture (95% CI) was 19% (13%-26%) in the Ra-223 group and 10% (5%-17%) in the comparator group, corresponding to a difference in 36-month risk of 9% (95% CI, 0%-17%) (Figure 1).
      Figure 1
      Figure 1Standardised cumulative incidence curves for bone fractures, by treatment group, first and second lines, and all lines of treatment-specific cohorts. CI = confidence interval; Ra-223 = radium-223.

      All-cause mortality

      In the first-line treatment cohort, the 36-month mortality (95% CI) was 86% (76%-94%) in the Ra-223 group and 73% (56%-87%) in the comparator group; the risk difference was 13% (−3% to 31%). In the second-line treatment cohort, the 36-month mortality was 87% (75%-94%) in the Ra-223 group and 94% (80%-100%) in the comparator group; the risk difference was −8% (−23% to 7%). In the third-/fourth-line treatment cohorts, the 36-month mortality was 86% (78%-92%) in the Ra-223 group and 100% (71%-100%) in the comparator group; the risk difference was −14% (−21% to 16%) (Table 2). The I2 was 63%, and thus pooling was not considered appropriate.

      Prostate cancer–specific mortality

      In the first-line treatment cohort, the 36-month prostate cancer mortality (95% CI) was 83% (72%-93%) in the Ra-223 group and 68% (51%-84%) in the comparator group; the risk difference was 15% (−4% to 34%). In the second-line treatment cohort, the 36-month mortality was 85% (72%-94%) in the Ra-223 group and 92% (73%-100%) in the comparator group; the risk difference was −7% (−23% to 14%). In the third-/fourth-line treatment cohorts, the 36-month mortality was 83% (75%-91%) in the Ra-223 group and 100% (71%-100%) in the comparator group; the risk difference was −17% (−24% to 13%) (Table 2).
      Sensitivity analyses that analysed patients with recorded bone metastasis, those that included a potential follow-up of 18 months, and those that that did not censor patients in the comparator group when they started Ra-223 during the follow-up yielded consistent results (Supplementary Table S6).

      Bone-health agents use at baseline

      There were 230 (34%) individuals in the Ra-223 group and 130 (17%) individuals in the comparator group receiving bone-health agents at baseline (Table 1). In the Ra-223 group, the unadjusted 36-month risk of fracture was 15% (95% CI, 6%-27%) in those receiving bone-health agents at baseline and 19% (95% CI, 14%-25%) in those who did not. In the comparator group, the unadjusted 36-month risk of fracture was 5% (95% CI, 1%-11%) in those receiving bone-health agents at baseline and 12% (95% CI, 6%-24%) in those who did not.

      Discussion

      The effect estimates of Ra-223 on the 36-month risk of bone fractures compared with other standard of care in first- and second-line treatments were of small magnitude, with 95% CIs that were compatible with both a slightly protective and a mildly deleterious effect.
      Our estimations of fracture risk among Ra-223 users were in line with other studies of Ra-223 monotherapy: 9% after 9-month median follow-up in ALSYMPCA (Procedure No.: EMEA/H/A-20/1459/C/002653/0028. Xofigo [BAY 88–8223)]/Radium-223 dichloride Castration-Resistant Prostate Cancer [CRPC] Bayer Response to List of Outstanding Issues), 5% after 6-month median follow-up in REASSURE,
      • Higano CS
      • Saad F
      • Sartor AO
      • et al.
      Clinical outcomes and patient (pt) profiles in REASSURE: an observational study of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC).
      and a substantially lower percentage than in ERA 223 (26% after 21-month median follow-up
      • Smith M
      • Parker C
      • Saad F
      • et al.
      Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomized, double-blind, placebo-controlled, phase III trial.
      ). We found that patients in the Ra-223 group using bone-health agents at baseline had a lower risk of fracture than those not using them, a finding previously reported by ERA 223
      • Smith M
      • Parker C
      • Saad F
      • et al.
      Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomized, double-blind, placebo-controlled, phase III trial.
      and PEACE-III.
      • Gillessen S
      • Choudhury A
      • Rodriguez-Vida A
      • et al.
      Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: an updated safety analysis.
      In contrast, our estimations of fracture risk in the comparator group were lower than the risk reported in a study using SEER-Medicare data, which reported a 12% risk of fractures in patients treated with drugs other than Ra-223 for mCRPC after a mean follow-up of 11 months,
      • Kawai AT
      • Martinez D
      • Saltus CW
      • Vassilev ZP
      • Soriano-Gabarró M
      • Kaye JA.
      Incidence of skeletal-related events in patients with castration-resistant prostate cancer: an observational retrospective cohort study in the US.
      and lower than the risk of fractures for the control group in PEACE-III (enzalutamide without bone-health agents), which was reported to be 16% after 12-month follow-up.
      • Gillessen S
      • Choudhury A
      • Rodriguez-Vida A
      • et al.
      Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: an updated safety analysis.
      Patients in the Ra-223 group had characteristics indicating worse bone health (prior fractures, bone-health agent use, high alkaline phosphatase levels) than the comparator group, which were measured and adjusted for via inverse-probability weighting for both baseline and time-varying confounding. Nevertheless, if these variables were mismeasured (eg, capture of bone-health agents may be differential between study groups because reporting their use was mandatory only for patients receiving Ra-223, and zoledronate administration is not captured in PCBaSe if administered in hospital), if the models used were misspecified, if unmeasured confounders existed (eg, the number of bone metastases, metastatic volume, bone density), or if patients in the Ra-223 group received more imaging surveillance, the estimates may not correspond to the true causal effect. In the Swedish National Patient Register, fractures have been validated in the inpatient
      • Bergstrom MF
      • Byberg L
      • Melhus H
      • Michaelsson K
      • Gedeborg R.
      Extent and consequences of misclassified injury diagnoses in a national hospital discharge registry.
      but not in the outpatient setting. Given the almost complete coverage of national healthcare registries, it is safe to assume that all symptomatic fractures requiring medical care were captured. These limitations and the small risk of fracture in the comparator groups need to be considered when interpreting the results.
      The effect estimates of Ra-223 on the 36-month OS compared with other standard of care in first-line treatment corresponded to a 13% difference in risk, with a 95% CI compatible with both a slightly protective effect and a harmful effect (−3% to 31%). The corresponding HR was 1.63 (95% CI, 1.27-2.16). Decreases in overall survival associated with Ra-223 use were not found in later lines of treatment. Ra-223 as monotherapy for first line versus standard of care in fit patients has not been addressed in clinical trials, probably because it is not considered to meet equipoise. In clinical practice during the study period, Ra-223 as first-line monotherapy was probably used in patients not eligible for other systemic mCRPC treatments, maybe because of frailty (unmeasured in our study setting). A real-world analysis of 285 patients treated with Ra-223 in the Netherlands reported that 10% received it as a first-line monotherapy.
      • Kuppen MC
      • Westgeest HM
      • van der Doelen MJ
      • et al.
      Real-world outcomes of radium-223 dichloride for metastatic castration resistant prostate cancer.
      Although the PCBaSe has information on relevant prognostic factors (eg, haemoglobin, alkaline phosphatase, PSA, ECOG PS,
      • Frantellizzi V
      • Monari F
      • Mascia M
      • et al.
      Validation of the 3-variable prognostic score (3-PS) in mCRPC patients treated with (223)Radium-dichloride: a national multicenter study.
      and treatment line
      • Yamamoto Y
      • Okuda Y
      • Kanaki T
      • et al.
      Clinical indicators for predicting prognosis after radium-223 administration in castration-resistant prostate cancer with bone metastases.
      ), these factors may not sufficiently surrogate frailty. To characterise the presence of unmeasured confounding, an analysis of a composite cardiovascular outcome as a negative control was performed, which mapped the results of survival (Supplementary Methods and Supplementary Figure S2), thus supporting the presence of residual confounding. Because the confounders for cardiovascular events and death (eg, overweight, hypertension, hyperlipidaemia) are likely different from those for fractures (eg, time on ADT, steroids, history of prior fractures), this negative control outcome analysis does not inform the bone fractures results. Drugs used in this study for mCRPC (docetaxel, abiraterone, enzalutamide) have subsequently been approved for treatment of castration-sensitive prostate cancer in recent years, meaning that in the future, a larger proportion of men treated for mCRPC (either with Ra-223 or with other drugs) will have received them earlier than the men in our study. Therefore, this rapidly changing treatment landscape needs to be considered when interpreting the results. We provide results for patients receiving second and later lines of treatment for mCRPC, although admittedly these estimates were imprecise.
      In conclusion, real-world data indicated that the risk of fractures in patients receiving Ra-223 was similar to that in previous observational studies and clinical trials, and the effect estimates for fractures do not point to a large increase and were compatible with a small, if any, increase in the risk associated with Ra-223 use versus a comparator in first- and second-line treatment. In the first-line cohort, Ra-223 use was associated with moderately increased risks of all-cause and prostate cancer–specific mortality. In the second- and third-/fourth-line cohorts, ie, in the lines during which Ra-223 was predominantly used in clinical practice, Ra-223 use was associated with a decreased risk of mortality. The observed associations in survival need to be interpreted with caution because of the likelihood of unmeasured confounding.

      Clinical Practice Points

      • In the ALSYMPCA trial, Ra-223 for the treatment of metastatic castration-resistant prostate cancer (mCRPC) demonstrated prolonged overall survival and time to first symptomatic skeletal event, as well as improvements to quality of life. However, in the subsequent ERA 223 trial Ra-223 combined with abiraterone acetate plus prednisone and/or prednisolone (APP) increased the risk of bone fractures compared to placebo plus APP. This report caused the European Medicines Agency to issue a label contraindication against the combination of Ra-223 with APP and a restriction for Ra-223 to patients who had progressed after two or more prior treatments for mCRPC or who were ineligible for other mCRPC treatment.
      • The aim of this real-world study was to estimate the effect of Ra-223 on the incidence of fractures and death compared with standard of care. Data on 1434 men who underwent treatment for mCRPC from Swedish registries were analyzed.
      • Our findings on bone fractures were imprecise and compatible with both a slightly protective and a mildly deleterious effect of Ra-223 both as first- and as second-line treatment. Patients in the Ra-223 group using concomitant bone-health agents had a lower risk of fracture than those not using them. Our study found moderately increased mortality risk in patients treated with Ra-223 in the first line, which was not observed in later lines of treatment. This result should be interpreted with caution since residual confounding is plausible, eg, patients receiving Ra-223 as first-line monotherapy were likely ineligible for other treatments, possibly due to frailty.

      Funding

      Bayer US contributed to the study design, interpretation of the results and writing of the report. Bayer US was not involved in the collection, analysis of the data, or in the decision to submit the article for publication.

      Disclosure

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Region Uppsala has, on behalf of NPCR, made agreements on subscriptions for quarterly reports from Patient-overview Prostate Cancer with Astellas, Sanofi, Janssen, and Bayer, as well as research projects with Astellas, Bayer, and Janssen. IFL has received speaker's honoraria from Astra Zeneca. AU received a grant from Bayer in 2016 for IIR to support the study; Retrospective evaluation of ALP kinetics as a pharmacodynamic marker in radium-223 treated mCRPC patients – A 10-year single center experience of Radium-223 treatment in 100+ patients. ZV and PS are employees of Bayer US. They have no other financial interests or personal relationships relevant to the PRECISE study. RW, DM, and XGA are employees of RTI Health Solutions, which was contracted to perform work on the study and manuscript, funded by Bayer AG.

      Acknowledgments

      This project was made possible by the continuous work of the National Prostate Cancer Register of Sweden (NPCR) steering group: Pär Stattin (chairman), Ingela Franck Lissbrant (co-chair), Camilla Thellenberg-Karlsson, Johan Styrke, Hampus Nugin, Eva Johansson, Magnus Törnblom, Stefan Carlsson, David Robinson, Mats Andén, Olof Ståhl, Thomas Jiborn, Hans Joelsson, Gert Malmberg, Olof Akre, Johan Stranne, Jonas Hugosson, Maria Nyberg, Per Fransson, Fredrik Jäderling, Fredrik Sandin and Karin Hellström. Susana Perez-Gutthann (RTI Health Solutions) provided scientific input and senior advising to the study and manuscript. We thank John Forbes at RTI Health Solutions for providing editorial assistance.

      CRediT authorship contribution statement

      Pär Stattin: Data curation, Supervision, Writing – review & editing. Marcus Westerberg: Writing – review & editing, Formal analysis, Data curation. Ingela Franck Lissbrant: Data curation, Writing – review & editing. Marie Hjälm Eriksson: Data curation, Writing – review & editing. Anders Kjellman: Data curation, Writing – review & editing. Anders Ullén: Data curation, Writing – review & editing. Zdravko Vassilev: Writing – review & editing. Per Sandstrom: Writing – review & editing. Rachel Weinrib: Writing – review & editing, Project administration. David Martinez: Writing – review & editing, Methodology. Xabier Garcia-Albeniz: Writing – original draft, Methodology, Conceptualization.

      Appendix. Supplementary materials

      References

        • Parker C
        • Nilsson S
        • Heinrich D
        • et al.
        Alpha emitter radium-223 and survival in metastatic prostate cancer.
        N Engl J Med. 2013; 369 (Jul 18): 213-223https://doi.org/10.1056/NEJMoa1213755
        • Sartor O
        • Coleman R
        • Nilsson S
        • et al.
        Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase III, double-blind, randomized trial.
        Lancet Oncol. 2014; 15 (Jun): 738-746https://doi.org/10.1016/s1470-2045(14)70183-4
        • Parker C
        • Heidenreich A
        • Nilsson S
        • Shore N.
        Current approaches to incorporation of radium-223 in clinical practice.
        Prostate Cancer Prostatic Dis. 2018; 21 (2018/04/01): 37-47https://doi.org/10.1038/s41391-017-0020-y
        • Bayer
        Phase III trial of radium-223 dichloride in combination with abiraterone acetate and prednisone/prednisolone for patients with metastatic castration-resistant prostate cancer unblinded early.
        Berlin, Germany2017 (Available at:) (Accessed 03 Jan 2022)
        • Smith M
        • Parker C
        • Saad F
        • et al.
        Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomized, double-blind, placebo-controlled, phase III trial.
        Lancet Oncol. 2019; 20: 408-419https://doi.org/10.1016/S1470-2045(18)30860-X
        • European Medicines Agency
        EMA restricts use of prostate cancer medicine Xofigo [press release].
        London, UK2018 (26 Jul 2018. Available at:) (Accessed 03 Jan 2022)
        • European Medicines Agency
        Guideline on good pharmacovigilance practices (GVP). Module VIII – Post-authorization safety studies (EMA/813938/2011 Rev 3).
        London, UK2017 (09 October. Available at:) (Accessed 09 October 2018)
      1. European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. EU PAS Register Number: EUPAS33448. Amsterdam, Netherlands, February 5, 2020. Available at: https://www.encepp.eu/encepp/viewResource.htm?id=42249.

        • Van Hemelrijck M
        • Wigertz A
        • Sandin F
        • et al.
        Cohort profile: the National Prostate Cancer Register of Sweden and Prostate Cancer data Base Sweden 2.0.
        Int J Epidemiol. 2013; 42 (Aug): 956-967https://doi.org/10.1093/ije/dys068
        • Franck Lissbrant I
        • Hjälm Eriksson M
        • Lambe M
        • Törnblom M
        • Stattin P
        Set-up and preliminary results from the Patient-overview Prostate Cancer. Longitudinal registration of treatment of advanced prostate cancer in the National Prostate Cancer Register of Sweden.
        Scand J Urol. 2020; 54 (Jun): 227-234https://doi.org/10.1080/21681805.2020.1756402
        • Hernan MA
        • Robins JM.
        Using big data to emulate a target trial when a randomized trial is not available.
        Am J Epidemiol. 2016; 183 (Apr 15): 758-764https://doi.org/10.1093/aje/kwv254
        • Garcia-Albeniz X
        • Hsu J
        • Hernan MA.
        The value of explicitly emulating a target trial when using real world evidence: an application to colorectal cancer screening.
        Eur J Epidemiol. 2017; 32 (Jun): 495-500https://doi.org/10.1007/s10654-017-0287-2
        • Hernan MA
        • Alonso A
        • Logan R
        • et al.
        Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease.
        Epidemiology. 2008; 19 (Nov): 766-779https://doi.org/10.1097/EDE.0b013e3181875e61
        • Hernan MA
        • Robins JM
        • Garcia Rodriguez L.
        Discussion on “Statistical Issues in the Women's Health Initiative.
        Biometrics. 2005; 61: 922-930
        • Higgins JP
        • Thompson SG.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558https://doi.org/10.1002/sim.1186
        • Hernan MA
        • Robins JM.
        Causal survival analysis. In: Causal inference.
        Chapman & Hall/CRC, Boca Raton, Florida2020 (Available at:) (Accessed 13 Aug 2018)
        • Thompson WA
        On the treatment of grouped observations in life studies.
        Biometrics. 1977; 33 (Sep): 463-470
        • Toh S
        • Garcia Rodriguez LA
        • Hernan MA
        Analyzing partially missing confounder information in comparative effectiveness and safety research of therapeutics.
        Pharmacoepidemiol Drug Saf. 2012; 21 (May): 13-20https://doi.org/10.1002/pds.3248
        • Cain LE
        • Logan R
        • Robins JM
        • et al.
        When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.
        Ann Intern Med. 2011; 154 (Apr 19): 509-515https://doi.org/10.7326/0003-4819-154-8-201104190-00001
        • Cole SR
        • Hernán MA.
        Constructing inverse probability weights for marginal structural models.
        Am J Epidemiol. 2008; 168 (Sep 15): 656-664https://doi.org/10.1093/aje/kwn164
        • Higano CS
        • Saad F
        • Sartor AO
        • et al.
        Clinical outcomes and patient (pt) profiles in REASSURE: an observational study of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC).
        J Clin Oncol. 2020; 38: 32https://doi.org/10.1200/JCO.2020.38.6_suppl.32
        • Gillessen S
        • Choudhury A
        • Rodriguez-Vida A
        • et al.
        Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: an updated safety analysis.
        J Clin Oncol. 2021; 39 (abstr): 5002
        • Kawai AT
        • Martinez D
        • Saltus CW
        • Vassilev ZP
        • Soriano-Gabarró M
        • Kaye JA.
        Incidence of skeletal-related events in patients with castration-resistant prostate cancer: an observational retrospective cohort study in the US.
        Prostate Cancer. 2019; 20195971615https://doi.org/10.1155/2019/5971615
        • Bergstrom MF
        • Byberg L
        • Melhus H
        • Michaelsson K
        • Gedeborg R.
        Extent and consequences of misclassified injury diagnoses in a national hospital discharge registry.
        Inj Prev. 2011; 17 (Apr): 108-113https://doi.org/10.1136/ip.2010.028951
        • Kuppen MC
        • Westgeest HM
        • van der Doelen MJ
        • et al.
        Real-world outcomes of radium-223 dichloride for metastatic castration resistant prostate cancer.
        Future Oncol. 2020; 16 (Jul): 1371-1384https://doi.org/10.2217/fon-2020-0039
        • Frantellizzi V
        • Monari F
        • Mascia M
        • et al.
        Validation of the 3-variable prognostic score (3-PS) in mCRPC patients treated with (223)Radium-dichloride: a national multicenter study.
        Ann Nucl Med. 2020; 34 (Oct): 772-780https://doi.org/10.1007/s12149-020-01501-7
        • Yamamoto Y
        • Okuda Y
        • Kanaki T
        • et al.
        Clinical indicators for predicting prognosis after radium-223 administration in castration-resistant prostate cancer with bone metastases.
        Int J Clin Oncol. 2021; 26 (Jan): 192-198https://doi.org/10.1007/s10147-020-01776-w