Advertisement

Docetaxel and prednisone with or without enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer: CHEIRON, a randomised phase II trial

Published:August 03, 2021DOI:https://doi.org/10.1016/j.ejca.2021.06.016

      Highlights

      • Docetaxel (D) and enzalutamide (E) have different mechanism of action.
      • They are efficacious in metastatic castration-resistant prostate cancer (mCRPC).
      • We compared their combination versus docetaxel alone in first-line mCRPC.
      • This combination increased the 6-month disease control rate by 15.3%.
      • We observed more grade III- toxicities in DE arm than in D arm.

      Abstract

      Background

      Pre-clinical data suggest that docetaxel and enzalutamide interfere with androgen receptor translocation and signalling. The aim of this study is to assess the efficacy of their concurrent administration in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC).

      Methods

      In this open-label, randomised, phase II trial, previously untreated mCRPC patients were randomised 1:1 to receive eight 21-d courses of docetaxel 75 mg/m2, oral prednisone 5 mg twice daily and oral enzalutamide 160 mg/d (arm DE), or the same treatment without enzalutamide (arm D). The primary end-point was the percentage of patients without investigator-assessed disease progression 6 months after the first docetaxel administration.

      Results

      The 246 eligible patients were randomly assigned to receive docetaxel, prednisone and enzalutamide (n = 120) or docetaxel and prednisone (n = 126). The 6-month progression rate was 12.5% (95% confidence interval [CI] 8.1–20.6) in arm DE and 27.8% (95% CI 22.8–39.4) in arm D (chi-squared test 10.01; P = 0.002). The most frequent grade III–IV adverse events were fatigue (12.5% in arm DE versus 5.6% in arm D), febrile neutropenia (9.3% versus 4.0%) and neutropenia (7.6% versus 5.6%).

      Conclusions

      The combination of enzalutamide and docetaxel appears to be more clinically beneficial than docetaxel alone in previously untreated mCRPC patients, although serious adverse events were more frequent. Our findings suggest that first-line treatment with this combination could lead to an additional clinical benefit when prompt and prolonged disease control is simultaneously required. Clearly, these results should be considered cautiously because of the study’s phase II design and the absence of an overall survival benefit.

      Trial registration numbers

      EudraCT 2014-000175-43 – NCT02453009.

      Graphical abstract

      Keywords

      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:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Tannock I.F.
        • de Wit R.
        • Berry W.R.
        • Horti J.
        • Pluzanska A.
        • Chi K.N.
        • et al.
        Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.
        N Engl J Med. 2004; 351: 1502-1512
        • de Bono J.S.
        • Logothetis C.J.
        • Molina A.
        • Fizazi K.
        • North S.
        • Chu L.
        • et al.
        Abiraterone and increased survival in metastatic prostate cancer.
        N Engl J Med. 2011; 364: 1995-2005
        • Ryan C.J.
        • Smith M.R.
        • de Bono J.S.
        • Molina A.
        • Logothetis C.J.
        • de Souza P.
        • et al.
        Abiraterone in metastatic prostate cancer without previous chemotherapy.
        N Engl J Med. 2013; 368: 138-148
        • Scher H.I.
        • Fizazi K.
        • Saad F.
        • Taplin M.E.
        • Sternberg C.N.
        • Miller K.
        • et al.
        Increased survival with enzalutamide in prostate cancer after chemotherapy.
        N Engl J Med. 2012; 367: 1187-1197
        • Beer T.M.
        • Armstrong A.J.
        • Rathkopf D.
        • Loriot Y.
        • Sternberg C.N.
        • Higano C.S.
        • et al.
        Enzalutamide in men with chemotherapy-naive metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study.
        Eur Urol. 2017; 71: 151-154
        • Parker C.
        • Nilsson S.
        • Heinrich D.
        • Helle S.I.
        • O'Sullivan J.M.
        • Fossa S.D.
        • et al.
        Alpha emitter radium-223 and survival in metastatic prostate cancer.
        N Engl J Med. 2013; 369: 213-223
        • Marteau F.
        • Gimonet G.
        • Gabriel S.
        • Dinet J.
        • Flinois A.
        • LE Chleac’h J.Y.
        Epidemiology of patients with metastatic castrate resistant prostate cancer in Europe and Australia.
        Value Health. 2014; 17: A619
        • Tagawa S.T.
        • Posadas E.M.
        • Bruce J.
        • Lim E.A.
        • Petrylak D.P.
        • Peng W.
        • et al.
        Phase 1b study of abiraterone acetate plus prednisone and docetaxel in patients with metastatic castration-resistant prostate cancer.
        Eur Urol. 2016; 70: 718-721
        • Morris M.J.
        • Rathkopf D.E.
        • Novotny W.
        • Gibbons J.A.
        • Peterson A.C.
        • Khondker Z.
        • et al.
        Phase Ib study of enzalutamide in combination with docetaxel in men with metastatic castration-resistant prostate cancer.
        Clin Cancer Res. 2016; 22: 3774-3781
        • Scher H.I.
        • Morris M.J.
        • Basch E.
        • Heller G.
        End points and outcomes in castration-resistant prostate cancer: from clinical trials to clinical practice.
        J Clin Oncol. 2011; 29: 3695-3704
        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • Schwartz L.H.
        • Sargent D.
        • Ford R.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247
        • Petrylak D.P.
        • Tangen C.M.
        • Hussain M.H.
        • Lara Jr., P.N.
        • Jones J.A.
        • Taplin M.E.
        • et al.
        Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.
        N Engl J Med. 2004; 351: 1513-1520
        • Rubinstein L.V.
        • Korn E.L.
        • Freidlin B.
        • Hunsberger S.
        • Ivy S.P.
        • Smith M.A.
        Design issues of randomized phase II trials and a proposal for phase II screening trials.
        J Clin Oncol. 2005; 23: 7199-7206
        • Tannock I.F.
        • Fizazi K.
        • Ivanov S.
        • Karlsson C.T.
        • Flechon A.
        • Skoneczna I.
        • et al.
        Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial.
        Lancet Oncol. 2013; 14: 760-768
        • Petrylak D.P.
        • Vogelzang N.J.
        • Budnik N.
        • Wiechno P.J.
        • Sternberg C.N.
        • Doner K.
        • et al.
        Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial.
        Lancet Oncol. 2015; 16: 417-425
        • Komura K.
        • Jeong S.H.
        • Hinohara K.
        • Qu F.
        • Wang X.
        • Hiraki M.
        • et al.
        Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression.
        Proc Natl Acad Sci U S A. 2016; 113: 6259-6264
        • Xu J.
        • Qiu Y.
        Current opinion and mechanistic interpretation of combination therapy for castration-resistant prostate cancer.
        Asian J Androl. 2019; 21: 270-278
        • Massard C.
        • Mateo J.
        • Loriot Y.
        • Pezaro C.
        • Albiges L.
        • Mehra N.
        • et al.
        Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone.
        Ann Oncol. 2017; 28: 90-95
        • Graff J.N.
        • Cheng H.H.
        • Vuky J.
        • Alumkal J.J.
        • Kreitner D.
        • Petreaca D.
        • et al.
        Phase II study of cabazitaxel (CAB) plus enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC).
        J Clin Oncol. 2020; 38: 86
        • Davis I.D.
        • Martin A.J.
        • Stockler M.R.
        • Begbie S.
        • Chi K.N.
        • Chowdhury S.
        • et al.
        Enzalutamide with standard first-line therapy in metastatic prostate cancer.
        N Engl J Med. 2019; 381: 121-131