Impact of Novel Hormonal Agents (Abiraterone, Enzalutamide) on the Development of Visceral and/or Brain Metastases in Patients With Bone-metastatic Castration-resistant Prostate Cancer

Published:April 21, 2022DOI:



      The overall survival (OS) of metastatic castration-resistant prostate cancer (mCRPC) patients has improved since 2011 with the use of novel hormonal agents (NHAs). The incidence of brain metastases (mets) has been reported to increase since 2004 with the use of docetaxel, but not the incidence of visceral mets. Our objective was to study whether the use of NHAs increases the risk of developing visceral or brain mets (VBMs).

      Patients and Methods

      mCRPC patients with mets limited to bone (bmCRPC), treated at Tours University Hospital between 2007 and 2015, were included retrospectively. The primary endpoint was to determine whether treatment with NHAs was associated with an increased incidence of VBMs. Secondary endpoints included the search for putative predictive factors to develop VBMs.


      On 187 bmCRPC patients included, 65 developed VBMs. VBM incidence increased in bmCRPC patients alive after 2011, compared to patients who died before (39.7 vs. 24.6%, P = .04). Meanwhile, their median OS increased from 16.3 months to 28.5 months (P = .01). The longer was the treatment with NHAs, the lower was the risk of VBMs (HR = 0.96, 95% CI [0.94; 0.99]), whereas age < 70 years (HR = 3.33, 95% CI [1.50; 7.40]) and low PSA level at diagnosis (HR = 1.58, 95% CI [1.16; 2.15]) increased this risk.


      Though retrospective, our results showed an increased incidence of VBMs in bmCRPC patients after 2011. However, this was not associated with NHA exposure duration. The role of NHA exposure remains unclear and needs further investigation.



      bmCRPC (Bone metastatic castration resistant prostate cancer), CNIL (« Commission Nationale de l'Informatique et des Libertés »), ISUP (International society of urological pathology), mCRPC (Metastatic castration resistant prostate cancer), mets (Metastases), NHA (Novel hormonal agent), OS (Overall survival), PCWG2 (Prostate cancer clinical trials working group), PSA (Prostate-specific antigen), VBM (Visceral and/or brain metastases), wo (Without)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Genitourinary Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Rawla P.
        Epidemiology of prostate cancer.
        World J Oncol. 2019; 10: 63-89
        • Tannock IF
        • de Wit R
        • Berry WR
        • et al.
        Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.
        N Engl J Med. 2004; 351: 1502-1512
        • Bubendorf L
        • Schöpfer A
        • Wagner U
        • et al.
        Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients.
        Hum Pathol. 2000; 31: 578-583
        • Taplin ME
        • Bubley GJ
        • Shuster TD
        • et al.
        Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer.
        N Engl J Med. 1995; 332: 1393-1398
        • Beer TM
        • Armstrong AJ
        • Rathkopf DE
        • et al.
        Enzalutamide in metastatic prostate cancer before chemotherapy.
        N Engl J Med. 2014; 371: 424-433
        • Ryan CJ
        • Smith MR
        • Fizazi K
        • et al.
        Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study.
        Lancet Oncol. 2015; 16: 152-160
        • Tremont-Lukats IW
        • Bobustuc G
        • Lagos GK
        • Lolas K
        • Kyritsis AP
        • Puduvalli VK.
        Brain metastasis from prostate carcinoma: the M. D. Anderson Cancer Center experience.
        Cancer. 2003; 98: 363-368
        • Gandaglia G
        • Karakiewicz PI
        • Briganti A
        • et al.
        Impact of the site of metastases on survival in patients with metastatic prostate cancer.
        Eur Urol. 2015; 68: 325-334
        • de Bono JS
        • Logothetis CJ
        • Molina A
        • et al.
        Abiraterone and increased survival in metastatic prostate cancer.
        N Engl J Med. 2011; 364: 1995-2005
        • Scher HI
        • Fizazi K
        • Saad F
        • et al.
        Increased survival with enzalutamide in prostate cancer after chemotherapy.
        N Engl J Med. 2012; 367: 1187-1197
        • Caffo O
        • Veccia A
        • Fellin G
        • et al.
        Frequency of brain metastases from prostate cancer: an 18-year single-institution experience.
        J Neurooncol. 2013; 111: 163-167
        • Halabi S
        • Kelly WK
        • Ma H
        • et al.
        Meta-analysis evaluating the impact of site of metastasis on overall survival in men with castration-resistant prostate cancer.
        J Clin Oncol. 2016; 34: 1652-1659
        • Whitney CA
        • Howard LE
        • Posadas EM
        • et al.
        In men with castration-resistant prostate cancer, visceral metastases predict shorter overall survival: what predicts visceral metastases? Results from the SEARCH database.
        Eur Urol Focus. 2017; 3: 480-486
        • Budnik J
        • Suri J
        • Bates JE
        • Bylund KC
        • Milano MT.
        Prognostic significance of sites of visceral metastatic disease in prostate cancer: a population-based study of 12,180 patients.
        Clin Genitourin Cancer. 2019; 17: 260-267
        • Castro E
        • Goh C
        • Olmos D
        • et al.
        Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer.
        J Clin Oncol. 2013; 31: 1748-1757
        • Doctor SM
        • Tsao CK
        • Godbold JH
        • Galsky MD
        • Oh WK.
        Is prostate cancer changing?: evolving patterns of metastatic castration-resistant prostate cancer.
        Cancer. 2014; 120: 833-839
        • Zaffuto E
        • Pompe R
        • Zanaty M
        • et al.
        Contemporary incidence and cancer control outcomes of primary neuroendocrine prostate cancer: a SEER database analysis.
        Clin Genitourin Cancer. 2017; 15: e793-e800
        • Scher HI
        • Halabi S
        • Tannock I
        • et al.
        Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.
        J Clin Oncol. 2008; 26: 1148-1159
        • Nafissi NN
        • Kosiorek HE
        • Butterfield RJ
        • Moore C
        • Ho T
        • Singh P
        • Bryce AH
        Evolving Natural History of Metastatic Prostate Cancer.
        Cureus. 2020; 12 (PMID: 33329980; PMCID: PMC7735525): e11484
        • Akamatsu S
        • Inoue T
        • Ogawa O
        • Gleave ME.
        Clinical and molecular features of treatment-related neuroendocrine prostate cancer.
        Int J Urol. 2018; 25: 345-351
        • Aggarwal R
        • Huang J
        • Alumkal JJ
        • et al.
        Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study.
        J Clin Oncol. 2018; 36: 2492-2503
        • Montironi R
        • Cimadamore A
        • Lopez-Beltran A
        • et al.
        Morphologic, molecular and clinical features of aggressive variant prostate cancer.
        Cells. 2020; 9: 1073
        • Katsogiannou M
        • Ziouziou H
        • Karaki S
        • Andrieu C
        • Henry de Villeneuve M
        • Rocchi P
        The hallmarks of castration-resistant prostate cancers.
        Cancer Treat Rev. 2015; 41: 588-597
        • Rezaei S
        • Mahjoubin Tehran M
        • Sahebkar A
        • Jalili A
        • Aghaee-Bakhtiari SH.
        Androgen receptor-related micro RNAs in prostate cancer and their role in antiandrogen drug resistance.
        J Cell Physiol. 2020; 235: 3222-3234
        • Miao L
        • Yang L
        • Li R
        • et al.
        Disrupting androgen receptor signaling induces snail-mediated epithelial-mesenchymal plasticity in prostate cancer.
        Cancer Res. 2017; 77: 3101-3112
        • Guo L
        • Lin M
        • Cheng Z
        • Chen Y
        • Huang Y
        • Xu K.
        Identification of key genes and multiple molecular pathways of metastatic process in prostate cancer.
        PeerJ. 2019; 7: e7899
        • Lu ZH
        • Kaliberov S
        • Sohn RE
        • et al.
        A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector.
        Oncotarget. 2017; 8: 12272-12289
        • Hatzoglou V
        • Patel GV
        • Morris MJ
        • et al.
        Brain metastases from prostate cancer: an 11-year analysis in the MRI era with emphasis on imaging characteristics, incidence, and prognosis.
        J Neuroimaging. 2014; 24: 161-166
        • Myint ZW
        • Qasrawi AH.
        Prostate adenocarcinoma with brain metastasis: a surveillance, epidemiology, and end results database analysis 2010-2015.
        Med Sci Monit. 2021; 27
        • Lin DW
        • Porter M
        • Montgomery B.
        Treatment and survival outcomes in young men diagnosed with prostate cancer: a Population-based Cohort Study.
        Cancer. 2009; 115: 2863-2871