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Radium-223 for patients with metastatic castration-resistant prostate cancer with asymptomatic bone metastases progressing on first-line abiraterone acetate or enzalutamide: A single-arm phase II trial

Open AccessPublished:August 15, 2022DOI:https://doi.org/10.1016/j.ejca.2022.06.057

      Highlights

      • 223Ra had a promising antitumour activity in patients with metastatic castration-resistant prostate cancer with asymptomatic bone metastases.
      • 223Ra showed an acceptable safety profile similar to that reported in other studies.
      • Overall survival of androgen receptor splice variant 7 (−) patients was significantly higher than androgen receptor splice variant 7 (+) patients.

      Abstract

      Purpose

      The paper aims to evaluate the efficacy and safety of 223Ra in patients who progressed after first-line androgen deprivation therapy.

      Patients and methods

      EXCAAPE (NCT03002220) was a multicentre, single-arm, open-label, non-controlled phase IIa trial in 52 patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases who have progressed on abiraterone acetate or enzalutamide, up to six doses of 223Ra (55 kBq/kg of body weight per month). The primary end-point was radiographic progression-free survival (rPFS). Secondary end-points included rPFS based on androgen receptor splice variant 7 (AR-V7) expression in circulating tumour cells (CTCs), overall survival, and safety.

      Results

      Median rPFS was 5.5 months (95% CI 5.3–5.5). Median rPFS of patients with AR-V7(−) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2–not reached) and was significantly greater for AR-V7(−) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01). 223Ra was well tolerated; anaemia and thrombocytopenia were the most common grade 3/4 adverse events (5.8% and 11.5%, respectively).

      Conclusions

      223Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile.

      Keywords

      1. Introduction

      Prostate cancer is the second most commonly diagnosed cancer worldwide and the fifth leading cause of cancer mortality in men [
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • Laversanne M.
      • Soerjomataram I.
      • Jemal A.
      • et al.
      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ]. Five-year survival rates of prostate cancer are poor when distant metastases are present [
      • Guo Y.
      • Mao S.
      • Zhang A.
      • Wang R.
      • Zhang Z.
      • Zhang J.
      • et al.
      Prognostic significance of young age and non-bone metastasis at diagnosis in patients with metastatic prostate cancer: a SEER population-based data analysis.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021. CA.
      ], being bone the most common metastatic site [
      • Bubendorf L.
      • Schöpfer A.
      • Wagner U.
      • Sauter G.
      • Moch H.
      • Willi N.
      • et al.
      Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients.
      ].
      The mainstay treatment for patients with advanced prostate cancer is conventional androgen deprivation therapy (ADT); however, most patients develop resistance to ADT, classified then as castration-resistant prostate cancer (CRPC) [
      • Zhang T.
      • Karsh L.I.
      • Nissenblatt M.J.
      • Canfield S.E.
      Androgen receptor splice variant, AR-V7, as a biomarker of resistance to androgen axis-targeted therapies in advanced prostate cancer.
      ,
      National Comprehensive Cancer Network
      NCCN guidelines: prostate cancer v2.
      ,
      • Parker C.
      • Castro E.
      • Fizazi K.
      • Heidenreich A.
      • Ost P.
      • Procopio G.
      • et al.
      Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ]. Docetaxel was the only treatment for patients with metastatic CRPC (mCRPC) until 2010; in the past decade, new agents have been approved, including novel hormonal therapy (e.g. abiraterone acetate, enzalutamide), next-generation taxanes (e.g. cabazitaxel), immunotherapy (sipuleucel-T), alpha particle-emitting agents (radium-223 [223Ra]), and poly-ADP-ribose polymerase (PARP) inhibitors [
      • Zhang T.
      • Karsh L.I.
      • Nissenblatt M.J.
      • Canfield S.E.
      Androgen receptor splice variant, AR-V7, as a biomarker of resistance to androgen axis-targeted therapies in advanced prostate cancer.
      ].
      Treatment with the alpha particle-emitting bone-targeted radionuclide 223Ra is recommended for treating bone-symptomatic mCRPC patients without visceral metastases prolonging overall survival (OS) and time to first symptomatic skeletal event, on the basis of the ALSYMPCA trial that led to its approval [
      • Sartor O.
      • Coleman R.
      • Nilsson S.
      • Heinrich D.
      • Helle S.I.
      • O'Sullivan J.M.
      • 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 3, double-blind, randomised trial.
      ]. Moreover, a recent single-arm, phase IIIb trial found that 223Ra with concomitant abiraterone, enzalutamide, or denosumab led to improved survival of patients with mCRPC with bone metastases (BMs); particularly, asymptomatic patients achieved better OS than symptomatic patients [
      • Saad F.
      • Carles J.
      • Gillessen S.
      • Heidenreich A.
      • Heinrich D.
      • Gratt J.
      • et al.
      Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial.
      ,
      • Heidenreich A.
      • Gillessen S.
      • Heinrich D.
      • Keizman D.
      • O'Sullivan J.M.
      • Carles J.
      • et al.
      Radium-223 in asymptomatic patients with castration-resistant prostate cancer and bone metastases treated in an international early access program.
      ]. However, the randomised, phase III ERA 223 trial found that 223Ra combined with abiraterone acetate plus prednisone or prednisolone did not prolong symptomatic skeletal event-free survival but rather led to an increase in the incidence of fractures compared with placebo, plus abiraterone acetate, prednisone, or prednisolone [
      • Smith M.
      • Parker C.
      • Saad F.
      • Miller K.
      • Tombal B.
      • Ng Q.S.
      • 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 randomised, double-blind, placebo-controlled, phase 3 trial.
      ].
      Patients may also develop resistance to novel hormonal therapy, which has been linked to androgen receptor splice variant 7 (AR-V7), among other causes [
      • Zhang T.
      • Karsh L.I.
      • Nissenblatt M.J.
      • Canfield S.E.
      Androgen receptor splice variant, AR-V7, as a biomarker of resistance to androgen axis-targeted therapies in advanced prostate cancer.
      ]. AR-V7 expression is higher in prostate cancer compared to normal prostate tissue and significantly increased with the number of lines of therapy received [
      • Zhang T.
      • Karsh L.I.
      • Nissenblatt M.J.
      • Canfield S.E.
      Androgen receptor splice variant, AR-V7, as a biomarker of resistance to androgen axis-targeted therapies in advanced prostate cancer.
      ,
      • Wadosky K.M.
      • Koochekpour S.
      Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer.
      ]. AR-V7-positive expression in circulating tumour cells (CTCs) represents a strong independent predictor of poor outcome in patients treated with the second- and third-line next-generation hormonal therapies [
      • Sharp A.
      • Coleman I.
      • Yuan W.
      • Sprenger C.
      • Dolling D.
      • Rodrigues D.N.
      • et al.
      Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer.
      ]. Clinical studies showed that patients with AR-V7-positive mCRPC will benefit more from taxane-containing regimens rather than additional hormonal therapies[
      • Antonarakis E.S.
      • Lu C.
      • Luber B.
      • Wang H.
      • Chen Y.
      • Nakazawa M.
      • et al.
      Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer.
      ,
      • Scher H.I.
      • Lu D.
      • Schreiber N.A.
      • Louw J.
      • Graf R.P.
      • Vargas H.A.
      • et al.
      Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer.
      ]. However, no data exist on AR-V7 expression as a predictor of outcomes in patients with mCRPC who received 223Ra.
      Given the paucity of data regarding asymptomatic patients, EXCAAPE study aimed to evaluate the efficacy and safety of 223Ra in patients with mCRPC with asymptomatic BMs who have progressed on first-line abiraterone acetate or enzalutamide, with an interest in assessing its value as an alternative to docetaxel. The association between AR-V7 expression in CTCs and 223Ra efficacy was also evaluated.

      2. Patients and methods

      2.1 Study design and patients

      This multicentre, single-arm, open-label, non-controlled phase IIa was conducted at nine sites in Spain. Patients with mCRPC and asymptomatic BMs who progressed on first-line treatment with abiraterone acetate or enzalutamide were treated with up to six cycles (one every 4 weeks) of intravenous injections of 55 kBq/kg of body weight of 223Ra per month. BMs were defined as asymptomatic when patients reported no pain in the previous 24 h and no use of opiate analgesics for prostate cancer-related pain at screening or in the 2 weeks prior. Adult patients with a histologically confirmed adenocarcinoma of the prostate, BMs, and no visceral metastases; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; who had received treatment with abiraterone acetate or enzalutamide ≥24 weeks and were receiving ADT; or had a bilateral orchiectomy were eligible. Full enrolment criteria can be found in the Supplementary Material.
      The study protocol and all its amendments were approved by Ethics Committee of Clinical Research Parc Taulí (Spain). The trial was done in compliance with the Declaration of Helsinki, and all patients provided written informed consent before enrolment. This study was registered at ClinicalTrials.gov (NCT030022-20).

      2.2 Outcomes

      The primary end-point was radiographic progression-free survival (rPFS) using Prostate Cancer Clinical Trials Working Group 2 criteria. Timing of assessments is shown in Table S1. The secondary end-points included the assessment of AR-V7 expression in CTCs and CTC count at baseline and at disease progression or treatment completion; the analysis of OS based on AR-V7 expression in CTCs, time to first symptomatic skeletal event (SSE), PFS using Response Evaluation Criteria in Solid Tumors version 1.1, time to prostate-specific antigen (PSA) progression using Prostate Cancer Clinical Trials Working Group 2 criteria, PSA response (≥30% or ≥50% reduction from baseline at 12 weeks), and alkaline phosphatase (ALP) level of response using ALSYMPCA study criteria (<220 U per litre) [
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • Helle S.I.
      • O'Sullivan J.M.
      • Fosså S.D.
      • et al.
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      ]; the assessment of adverse events (AEs) using the Common Terminology Criteria for Adverse Events 4.0, vital signs, ECOG status, physical examination, duration and extent of exposure, concomitant medications, Brief Pain Inventory Questionnaire at baseline and quality of life of patients according to the functional assessment of cancer therapy for prostate questionnaire (FACT-P) at baseline, cycle 1 to cycle 6, and end of treatment (EoT).

      2.3 Detection of CTCs

      Blood samples were collected by venipuncture at the baseline and at the EoT when documenting disease progression. CTCs were detected by isolating nucleated cells from blood samples, carrying out immunofluorescence for counting rare cells using the Epic Sciences platform, as previously described [
      • Werner S.L.
      • Graf R.P.
      • Landers M.
      • Valenta D.T.
      • Schroeder M.
      • Greene S.B.
      • et al.
      Analytical validation and capabilities of the epic CTC platform: enrichment-free circulating tumour cell detection and characterization.
      ]. Briefly, nucleated cells from blood samples were fixed onto glass pathology slides and stained for cytokeratin (CK) and CD45 by immunofluorescence. CTCs were identified as DAPI(+), CK(+), CD45(−) cells.

      2.4 Determination of AR-V7 expression in CTCs

      AR-V7 was determined as previously described [
      • Scher H.I.
      • Graf R.P.
      • Schreiber N.A.
      • Jayaram A.
      • Winquist E.
      • McLaughlin B.
      • et al.
      Assessment of the validity of nuclear-localized androgen receptor splice variant 7 in circulating tumor cells as a predictive biomarker for castration-resistant prostate cancer.
      ,
      • Lu D.
      • Krupa R.
      • Harvey M.
      • Graf R.P.
      • Schreiber N.
      • Barnette E.
      • et al.
      Development of an immunofluorescent AR-V7 circulating tumor cell assay – a blood-based test for men with metastatic prostate cancer.
      ]. Briefly, slides with fixed cells from blood samples were stained; candidate DAPI(+), CD45(−), CK(+) CTCs with nuclear expression of AR-V7 (Abcam EP343 clone, Abcam plc, Cambridge, UK) were scored and confirmed by trained technicians. A sample was considered AR-V7-positive if at least one CTC had nuclear AR-V7.

      2.5 Statistical analysis

      Primary analysis was based on a one-arm log-rank test (null hypothesis: rPFS ≤3 months; alternative: rPFS ≥6.3 months) [
      • Jung Sin-Ho
      Randomized phase II cancer clinical trials.
      ]. A sample size of 52 patients was needed to attain 80% power at a nominal one-sided α level of 5%. The efficacy and safety analyses included all treated patients.
      Kaplan–Meier and Clopper–Pearson methods were used to estimate 95% confidence intervals (CIs) for median survival and percentage, respectively. Wilcoxon test and 95% CIs for mean difference were used to analyse change between baseline and EoT for quantitative scores. In subgroup analyses, time-to-event end-points were analysed using the Firth's method for Cox regression model, due to low number of patients and unbalanced cohorts. Binary end-points were analysed using Chi-squared or Fisher's exact tests. Statistical analyses were conducted with R version 4.0.2.

      3. Results

      3.1 Patients and treatment

      Between December 2016 and October 2018, 63 patients were screened. Of these, 52 met the eligibility criteria and were included in this study (Fig. S1; Table S2). Patients had a median age of 76.1 years; 48 (92.3%) had received two prior lines of hormone therapy (plus concomitant ADT), and 35 (87.5%) were negative for AR-V7 (Table 1).
      Table 1Patient demographics.
      CharacteristicAR-V7 [+]

      N = 5
      AR-V7 [-]

      N = 35
      All patients

      N = 52
      Age, median, (IQR), years82.2 (79.0; 82.4)74.7 (66.2; 83.0)76.1 (69.4; 82.3)
      PSA, median (IQR), μg/L35.5 (6.4–317.4)13.7 (0.5–703.3)20.3 (0.04–703.3)
      ALK, median (IQR), μg/L105 (97.0–179)118 (83.8–203)113 (87.5–198)
      Brief Pain Inventory
       Intensity, median (IQR)0 (0–0.75)0 (0–1.25)0 (0–3)
       Interference, median (IQR)0 (0–2.4)0 (0–7.3)0 (0–7.3)
      HRQoL Questionnaire (FACT-P)
       Median (IQR), U/L117.6 (103–145)119.3 (63.7–141.8)120.5 (46.6–148)
      Number of bone lesions, n (%)
       <61 (20)10 (28.6)15 (28.8)
       6–204 (80)24 (68.6)36 (69.2)
       >200 (0)1 (2.8)1 (2)
      Prior lines of hormonal therapy in the castration-resistance setting, n (%)
      Hormonal therapy includes androgen deprivation therapy, abiraterone acetate, or enzalutamide.
       Abiraterone4 (80)24 (68.6)32 (61.5)
       Enzalutamide2 (40)13 (37.1)23 (44.2)
       Abiraterone and enzalutamide
      Patients 02-01, 02–05, 02–09, and 08-01 first received abiraterone and, after having discontinued treatment due to toxicity with no disease progression, they started treatment with enzalutamide.
      1 (20)3 (8.6)4 (7.7)
      Prior docetaxel in the hormone-sensitive setting, n (%)
       No5 (100)32 (91.4)48 (92.3)
       Yes0 (0)3 (8.6)4 (7.7)
      FACT-P: functional assessment of cancer therapy – prostate; HRQoL: health-related quality of life; IQR: interquartile range (percentile 25 to percentile 75).
      a Hormonal therapy includes androgen deprivation therapy, abiraterone acetate, or enzalutamide.
      b Patients 02-01, 02–05, 02–09, and 08-01 first received abiraterone and, after having discontinued treatment due to toxicity with no disease progression, they started treatment with enzalutamide.
      Median duration of treatment was 5.5 months (1.3–6.4), and 40.4% (21/52) of the patients did not complete all six cycles, mainly due to disease progression prior to the sixth cycle – other reasons were withdrawal of consent, discontinuation due to unacceptable toxicity, worsening of ECOG status, or investigator's decision.

      3.2 Radiographic response and survival

      At a median follow-up of 6.6 months (1.3–18.2), median rPFS was 5.5 months (95% CI 5.3–5.5; P = 0.025) meeting the primary end-point. Thirty-one (59,6%) of the 52 patients experienced progression disease or death (Table 2). Median rPFS of patients with AR-V7(−) CTCs was longer than that of patients with AR-V7(+) CTCs; however, the difference was not statistically significant (5.5 versus 2.2 months, respectively; P = 0.398; Fig. 1).
      Table 2Location of disease radiological progression after 223Ra therapy.
      Variable, n (%)N = 52
      Without radiological progression21 (40.4)
      Radiological progression31 (59.6)
      Bone21 (40.4)
      Lymph nodes11 (21.2)
      Lung3 (5.8)
      Liver2 (3.8)
      Bladder1 (1.9)
      Fig. 1
      Fig. 1Radiographic progression-free survival based on AR-V7 expression. Kaplan–Meier curves of radiographic progression-free survival, evaluated using Prostate Cancer Clinical Trials Working Group 2 criteria. Tick marks indicate censored data. Analyses adjusted by age, bone lesions, PSA, and AKT values at baseline. AR-V7: androgen receptor splice variant-7; CI: confidence interval; rPFS: radiographic progression-free survival.

      3.3 Secondary efficacy end-points

      By data cut-off on January 9, 2021, 14 patients (26.9%) had died; median OS was 14.8 months (95%CI 11.2–not reached; Fig. 2). Subgroup analyses showed that OS was significantly longer for patients with AR-V7(−) expression compared to patients with AR-V7(+) expression (14.8 months versus 3.5 months, respectively; P < 0.01; Fig. 3).
      Fig. 2
      Fig. 2Overall survival Kaplan–Meier curve. Kaplan–Meier curve of overall survival. Tick marks indicate censored data. CI: confidence interval; OS: overall survival; NE: not evaluable.
      Fig. 3
      Fig. 3Kaplan–Meier curves of time-to-event end-points subgroup analysis based on AR-V7 expression. (A) Overall survival. (B) Time to the first symptomatic skeletal event (SSE). (C) Progression-free survival evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. (D) Time to prostate-specific antigen (PSA) progression. Tick marks indicate censored data. Analyses adjusted by age, bone lesions, PSA, and AKT values at baseline. SSE was not analysable with adjusted model; unadjusted data are presented.
      PSA levels significantly increased from baseline to EoT (mean difference 73.2; 95%CI 19.6–126.7; P < 0.001). No clinically relevant variation in vital signs was observed.
      At baseline, 27 patients (51.9%) had ECOG 0 status and 25 (48.1%) had ECOG 1. At EoT, the number of patients with ECOG 0 significantly decreased (12; 23.1%, P < 0.01), whereas the number of patients with ECOG 1 remained stable (26; 50%). Moreover, ECOG 2 and ECOG 3 status were recorded (4 patients, 7.7%; and 5 patients, 9.6%, respectively).
      Five patients experienced SSEs (9.6%); median time to first SSE was not reached (Fig. 3)
      There was a confirmed PSA response, defined as a ≥30% or ≥50% reduction in PSA serum levels, in five (9.6%; 95%CI 3.2–21.0) and four patients (7.7%; 95%CI 2.1–18.5), respectively. Use of post-protocol therapy is reported in supplementary data (Table S3).
      There was a confirmed ALP response, defined as ≥30% or ≥50% reduction in ALP serum levels, in 25 (48.1%; 95%CI 34.0–62.4) and 12 patients (23.1%; 95%CI 12.5–36.8), respectively.

      3.4 CTC count before and after treatment

      CTC count changed in some patients over the treatment course. A trend for association with OS can be observed but without statistical significance.
      Baseline and EoT CTC count were available for 21 patients. At baseline, most patient samples (30/40) had <5 CTCs. Of the seven patients with ≥5 CTCs at baseline who also had EoT evaluation, five had <5 CTCs at EoT. Of the 14 patients with <5 CTCs at baseline who also had EoT evaluation, only 1 had ≥5 CTCs at EoT (Table S4).
      Patients who experienced a reduction in the number of CTCs from baseline to the EoT had a longer OS; however, the likelihood ratio test had P = 0.073 (Fig. S2).

      3.5 AR-V7 expression in CTCs before and after treatment

      Baseline AR-V7 expression in CTCs was not determined for 12 patients (23.1%) because of prolonged time between sample collection and processing (over 96 h). Thirty-five (87.5%) of the 40 patients showed no expression of AR-V7 in CTCs at baseline. Evaluation of 20 patients showed that two (10%) were positive for AR-V7 at baseline and switched to negative AR-V7, and only one who was negative at baseline became positive at the EoT (Table S4).
      Patients who experienced a switch from a positive to a negative AR-V7 expression had a longer OS; however, the likelihood ratio test had P = 0.058 (Fig. S3).

      3.6 Correlation between CTC count and AR-V7 expression before and after treatment

      Baseline CTC count was available for 40 patients. Patients with negative AR-V7 expression showed lower CTC count than those with positive AR-V7 expression (1.3 [0.3–4.7] versus median 4.7 [IQR 3.5–7.3]); P = 0.074; Fig. S4).
      EoT CTC count was available for 27 patients. Patients with negative AR-V7 expression showed lower CTC count than those with positive AR-V7 expression (median 0.5 [IQR 0.1–2.1] versus 2.5; Fig. S5).

      3.7 Safety

      Three deaths occurred, none treatment-related. Two patients discontinued treatment due to AEs (Table 3). Overall, 46 patients (88.5%) reported AEs; asthenia (26.9%) and arthralgia (25.0%) were the most common (Table S5). Anaemia and thrombocytopenia were the most common grade 3/4 AEs overall (5.8% and 11.5%, respectively) and possibly treatment-related AEs (3.8% in both cases). Serious AEs were reported by 11 patients (21.2%); the most common was anaemia (5.8%; Table S6).
      Table 3Adverse events possibly related to treatment.
      Adverse eventsAny GradeGrade 1Grade 2Grade 3Grade 4
      Any, n (%)26 (50.0%)15 (28.8%)8 (15.4%)2 (3.8%)1 (1.9%)
      Hematologic
       Anaemia3 (5.8%)01 (1.9%)1 (1.9%)1 (1.9%)
       Thrombocytopenia3 (5.8%)1 (1.9%)02 (3.8%)0
       Leukopenia1 (1.9%)001 (1.9%)0
       Neutropenia1 (1.9%)01 (1.9%)00
      Non-haematologic
       Asthenia13 (25.0%)9 (17.3%)4 (7.7%)00
       Diarrhoea4 (7.7%)2 (3.8%)2 (3.8%)00
       Nausea4 (7.7%)4 (7.7%)000
       Anorexia3 (5.8%)3 (5.8%)000
       Arthralgia3 (5.8%)3 (5.8%)000
       Bone pain3 (5.8%)1 (1.9%)2 (3.8%)00
       Fatigue2 (3.8%)1 (1.9%)1 (1.9%)00
       Fever2 (3.8%)2 (3.8%)000
       Acute kidney injury1 (1.9%)01 (1.9%)00
       Burning1 (1.9%)1 (1.9%)000
       Dizziness1 (1.9%)1 (1.9%)000
       Epistaxis1 (1.9%)1 (1.9%)000
       Flank pain1 (1.9%)1 (1.9%)000
       Gastric discomfort1 (1.9%)1 (1.9%)000
       Pain1 (1.9%)01 (1.9%)00
       Vomiting1 (1.9%)1 (1.9%)000
      N: number of patients experiencing a specific AE treatment possibly related.
      Health-related quality of life deteriorated between baseline and EoT, primarily in relation to patient physical (−3.6; 95%CI -5.8, −1.3; P = 0.005) and functional well-being (−3.0; 95%CI -5.3, −0.7; P = 0.016). Nevertheless, treatment with 223Ra was overall considered safe and tolerable.

      4. Discussion

      We established the efficacy and safety of 223Ra for treating patients with mCRPC and asymptomatic BMs after progressing on first-line therapy. The most common AEs and premature discontinuations were in line with those reported in other studies treating patients with 223Ra [
      • Saad F.
      • Carles J.
      • Gillessen S.
      • Heidenreich A.
      • Heinrich D.
      • Gratt J.
      • et al.
      Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial.
      ,
      • Huynh-Le M.P.
      • Shults R.C.
      • Connor M.J.
      • Hattangadi-Gluth J.A.
      Adverse events associated with radium-223 in metastatic prostate cancer: disproportionality analysis of FDA data reflecting worldwide utilization.
      ,
      • Jadvar H.
      • Challa S.
      • Quinn D.I.
      • Conti P.S.
      One-year postapproval clinical experience with radium-223 dichloride in patients with metastatic castrate-resistant prostate cancer.
      ].
      CTC count >5 at baseline has been associated with worse OS in mCRPC patients treated with 223Ra [
      • Carles J.
      • Castellano D.
      • Méndez-Vidal M.J.
      • Mellado B.
      • Saez M.I.
      • González del Alba A.
      • et al.
      Circulating tumor cells as a biomarker of survival and response to radium-223 therapy: experience in a cohort of patients with metastatic castration-resistant prostate cancer.
      ], docetaxel [
      • Goldkorn A.
      • Ely B.
      • Quinn D.I.
      • Tangen C.M.
      • Fink L.M.
      • Xu T.
      • et al.
      Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer.
      ], or abiraterone acetate [
      • Scher H.I.
      • Heller G.
      • Molina A.
      • Attard G.
      • Danila D.C.
      • Jia X.
      • et al.
      Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer.
      ]. In line with this, we found that patients whose CTC count decreased from ≥5 at baseline to <5 at EoT had a longer OS, suggesting that 223Ra improves patient prognosis; however, the small sample size precluded establishing a definitive conclusion, and statistical significance was not reached.
      AR-V7 in CTCs of patients with mCRPC has been associated with resistance to abiraterone acetate or enzalutamide and with worse prognosis [
      • Antonarakis E.S.
      • Lu C.
      • Wang H.
      • Luber B.
      • Nakazawa M.
      • Roeser J.C.
      • et al.
      AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.
      ,
      • Cattrini C.
      • Rubagotti A.
      • Zinoli L.
      • Cerbone L.
      • Zanardi E.
      • Capaia M.
      • et al.
      Role of circulating tumor cells (CTC), androgen receptor full length (AR-FL) and androgen receptor splice variant 7 (AR-V7) in a prospective cohort of castration-resistant metastatic prostate cancer patients.
      ,
      • Armstrong A.J.
      • Halabi S.
      • Luo J.
      • Nanus D.M.
      • Giannakakou P.
      • Szmulewitz R.Z.
      • et al.
      Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: the PROPHECY study.
      ]. Antonarakis et al. proved that, although AR-V7 status was not predictive of clinical resistance to taxanes, patients with AR-V7(+) mCRPC who were treated with taxanes showed a better outcome than AR-V7(+) patients treated with second-generation anti-androgen drugs abiraterone or enzalutamide [
      • Antonarakis E.S.
      • Lu C.
      • Luber B.
      • Wang H.
      • Chen Y.
      • Nakazawa M.
      • et al.
      Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer.
      ,
      • Antonarakis E.S.
      • Lu C.
      • Wang H.
      • Luber B.
      • Nakazawa M.
      • Roeser J.C.
      • et al.
      AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.
      ]. Here, we investigated whether AR-V7 status would have a differential impact on enzalutamide- or abiraterone-treated men, and we observed that 223Ra increases OS of patients with AR-V7(+) on CTCs compared to AR-V7(−). However, the low number of AR-V7(+) cases limited definitive conclusions on the utility of AR-V7 expression in patients who are treated with 223Ra. Thus, these findings merit further investigations to evaluate the role of AR-V7 as a biomarker with predictive value for treatment with 223Ra.
      In the USA, most patients with mCRPC receive first- and second-line treatment with novel hormonal therapy [
      • George D.J.
      • Sartor O.
      • Miller K.
      • Saad F.
      • Tombal B.
      • Kalinovský J.
      • et al.
      Treatment patterns and outcomes in patients with metastatic castration-resistant prostate cancer in a real-world clinical practice setting in the United States.
      ,
      • Oh W.K.
      • Miao R.
      • Vekeman F.
      • Sung J.
      • Cheng W.Y.
      • Gauthier-Loiselle M.
      • et al.
      Real-world characteristics and outcomes of patients with metastatic castration-resistant prostate cancer receiving chemotherapy versus androgen receptor-targeted therapy after failure of first-line androgen receptor-targeted therapy in the community setting.
      ]; nevertheless, therapy sequence differs in other countries [
      • Okita K.
      • Hatakeyama S.
      • Narita S.
      • Takahashi M.
      • Sakurai T.
      • Kawamura S.
      • et al.
      The effect of treatment sequence on overall survival for men with metastatic castration-resistant prostate cancer: a multicenter retrospective study.
      ,
      • Schmidt A.
      • Anton A.
      • Shapiro J.
      • Wong S.
      • Azad A.
      • Kwan E.
      • et al.
      Treatment outcomes for patients with metastatic castrate-resistant prostate cancer following docetaxel for hormone-sensitive disease.
      ,
      • Kuppen M.C.P.
      • Westgeest H.M.
      • van den Eertwegh A.J.M.
      • van Moorselaar R.J.A.
      • van Oort I.M.
      • Coenen J.L.L.M.
      • et al.
      Real-world outcomes of sequential androgen-receptor targeting therapies with or without interposed life-prolonging drugs in metastatic castration-resistant prostate cancer: results from the Dutch castration-resistant prostate cancer registry.
      ,
      • Chowdhury S.
      • Bjartell A.
      • Lumen N.
      • Maroto P.
      • Paiss T.
      • Gomez-Veiga F.
      • et al.
      Real-World outcomes in first-line treatment of metastatic castration-resistant prostate cancer: the prostate cancer registry.
      ]. For patients with mCRPC, cabazitaxel after docetaxel and novel hormonal therapy was found to achieve a longer median rPFS than that found in our study (8.0 versus 5.5 months, respectively); however, most of the patients in our study (92.3%) had not received docetaxel and, thus, cabazitaxel would not be an option for them [
      • de Wit R.
      • de Bono J.
      • Sternberg C.N.
      • Fizazi K.
      • Tombal B.
      • Wülfing C.
      • et al.
      Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer.
      ]. Additionally, the advanced age of the patient population included in our study (median of 76.1 years) must be considered regarding its safety. 223Ra can be a valuable treatment for patients with mCRPC and asymptomatic BMs who progress on novel hormonal therapy and who are ineligible for or refuse taxane-based therapy. Docetaxel achieved an rPFS of 9.0 months when given concurrently with ADT and 6.0 months when given as monotherapy to chemotherapy-naive patients with mCRPC and BMs [
      • Jang H.S.
      • Koo K.C.
      • Cho K.S.
      • Chung B.H.
      Survival outcomes of concurrent treatment with docetaxel and androgen deprivation therapy in metastatic castration-resistant prostate cancer.
      ]. However, retrospective studies showed a reduced clinical benefit from docetaxel following treatment with abiraterone, indicating a possible cross-resistance effect [
      • Mezynski J.
      • Pezaro C.
      • Bianchini D.
      • Zivi A.
      • Sandhu S.
      • Thompson E.
      • et al.
      Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance?.
      ,
      • Schweizer M.T.
      • Zhou X.C.
      • Wang H.
      • Bassi S.
      • Carducci M.A.
      • Eisenberger M.A.
      • et al.
      The influence of prior abiraterone treatment on the clinical activity of docetaxel in men with metastatic castration-resistant prostate cancer.
      ].
      The pivotal ALSYMPCA trial with 223Ra did not include patients with asymptomatic BMs [
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • Helle S.I.
      • O'Sullivan J.M.
      • Fosså S.D.
      • et al.
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      ]. Our study is the first to evaluate the role of 223Ra specifically in this patient population. Moreover, a 223Ra phase IIIb trial included asymptomatic and symptomatic patients, but only 40% and 8% of the treated patients had received prior abiraterone or enzalutamide, respectively [
      • Saad F.
      • Carles J.
      • Gillessen S.
      • Heidenreich A.
      • Heinrich D.
      • Gratt J.
      • et al.
      Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial.
      ]. Finally, these studies did not evaluate CTCs or AR-V7 expression. Of note, we observed a confirmed ALP response (according to ALP, biochemical response (≥30 and ≥ 50%) in our study was similar to that obtained in the ALSYMPCA trial (48.1% and 23.1% versus 47.1% and 27.4%, respectively).
      Our findings show, for the first time, the clinical benefit of using 223Ra for treating patients with mCRPC and asymptomatic BMs who have progressed on novel hormonal therapy and the role of AR-V7. Approved indications for 223Ra vary from the USA or Australia that do have any limit to a specific line of treatment [
      Xofigo (Radium 223 dichloride)
      ,
      Xofigo (Radium 223 dichloride)
      ] to Europe restricting the 223Ra indication to patients with mCRPC who have had two previous systemic treatments (other than ADT) or who cannot receive other treatments [
      Xofigo (Radium 223 dichloride)
      European Medicines agency SmPC.
      ]. Although this recommendation was based on the results of the ERA 223 trial [
      • Smith M.
      • Parker C.
      • Saad F.
      • Miller K.
      • Tombal B.
      • Ng Q.S.
      • 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 randomised, double-blind, placebo-controlled, phase 3 trial.
      ], many concerns have been raised about the potential missing opportunity to benefit from 223Ra therapy for many patients with mCRPC who are more likely to have developed visceral disease [
      • O'Sullivan J.M.
      • Heinrich D.
      • James N.D.
      • Nilsson S.
      • Ost P.
      • Parker C.C.
      • et al.
      The case against the European Medicines agency's change to the label for radium-223 for the treatment of metastatic castration-resistant prostate cancer.
      ]. We aim for our findings to establish the use of 223Ra in the patient population considered here and to drive development of further studies.
      One of the limitations of this study is the lack of baseline information of AR-V7 expression for 12 patients (23.1%). Another limitation is the small sample size, which precludes establishing an association between AR-V7 expression and survival. Nevertheless, AR-V7(+) patients had higher PSA values and more metastases, highlighting the prognostic value of AR-V7 status. Finally, the single-arm design prevents comparison of findings with patients who did not receive 223Ra. However, this study also presents several strengths. First, the long follow-up time of up to 18 months for some patients allowed to adequately evaluate safety and tolerability of 223Ra. Second, this is the first clinical trial using 223Ra focused on patients with mCRPC and asymptomatic BMs, showing the role that AR-V7 plays in OS.
      In conclusion, 223Ra seems to be a reasonable treatment for patients with mCRPC and asymptomatic BMs who have progressed on abiraterone acetate or enzalutamide. AR-V7 expression in CTCs was significantly associated with OS but not with rPFS although, due to the limited sample size, these findings should be considered as hypothesis-generating and interpreted cautiously. Over the treatment course with 223Ra, some patients experienced a reduction in CTC count and a switch in AR-V7 expression, which should be further explored in larger studies to assess their prognostic value.

      Author contributions

      Joan Carles, Miguel Sampayo-Cordero, and Andrea Malfettone had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
      Study concept and design: Joan Carles.
      Acquisition of data: Miguel Sampayo-Cordero.
      Analysis and interpretation of data: All authors.
      Drafting of the manuscript: All authors.
      Critical revision of the manuscript for important intellectual content: All authors.
      Statistical analysis: Miguel Sampayo-Cordero.
      Obtaining funding: None.
      Administrative, technical, or material support: Andrea Malfettone.
      Supervision: None.
      Other: None.

      Funding support

      The study was conceived and designed by Joan Carles in collaboration with Medica Scientia Innovation Research (MEDSIR). MEDSIR, as legal sponsor of the study, is responsible for compliance with all clinical and regulatory procedures and adherence to the study protocol. MEDSIR had a role in study design, collection, management, analysis, and interpretation of the data and writing of the report. Bayer Inc. funded the study and provided 223Ra. The funder of the study had no role in data collection, management, data analysis, data interpretation, writing of the report, or decision to submit the manuscript for publication. All authors had full access to the data used to prepare the manuscript and participated in writing, editing, and/or critically reviewing the manuscript. The manuscript was written with editorial support from a medical writer, funded by MEDSIR. The corresponding author had final responsibility for the decision to submit for publication.

      Conflict of interest statement

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bayer, Johnson & Johnson, Bristol-Myers Squibb, Astellas Pharma, Pfizer, Sanofi, MSD, Roche, AstraZeneca, Asofarma, Ipsen, AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, Aveo Pharmaceuticals INC, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim España, S.A., , Clovis Oncology INC, Cougar Biotechnology INC, Deciphera Pharmaceuticals LLC, Exelixis INC, F. Hoffmann-La Roche LTD, Genentech INC, GlaxoSmithKline, Incyte Corporation, -Cilag, International NV, Karyopharm Therapeutics INC., EISAI, Merck Serono, Lilly, Novartis Pharmaceutical, S.A, Janssen, Eusa Pharma, Sanofi-Genzyme, Beigene, VCN biotech, and VCN biotech; Leurquin Mediolanum SAS, Pierre Fabre, Rovi, Daiichi Sankyo, Techdow, Leo Pharma, Menarini, Ferrer, Millennium Pharmaceuticals, INC, Medimmune, Nanobiotix SA, S.L.U, Puma Biotechnology, FJ Pharma LTD. II, Teva Pharma S.L.U., MEDSIR.

      Acknowledgements

      The authors wish to thank the patients who kindly participated in our study and their families. The authors also thank all study teams of participating sites and the trial unit staff at MEDSIR and Bayer Inc. The authors thank Angela Rynne Vidal, PhD, of ThePaperMill for providing medical writing support, funded by MEDSIR.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article: Supplementary material related to this article can be found in the online version.

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