Effect of Adding Docetaxel to Androgen-Deprivation Therapy in Patients With High-Risk Prostate Cancer With Rising Prostate-Specific Antigen Levels After Primary Local Therapy: A Randomized Clinical Trial | Cancer Biomarkers | JAMA Oncology | JAMA Network
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Pound  CR, Partin  AW, Eisenberger  MA, Chan  DW, Pearson  JD, Walsh  PC.  Natural history of progression after PSA elevation following radical prostatectomy.  JAMA. 1999;281(17):1591-1597. doi:10.1001/jama.281.17.1591PubMedGoogle ScholarCrossref
Ward  JF, Blute  ML, Slezak  J, Bergstralh  EJ, Zincke  H.  The long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy.  J Urol. 2003;170(5):1872-1876. doi:10.1097/01.ju.0000091876.13656.2ePubMedGoogle ScholarCrossref
Antonarakis  ES, Feng  Z, Trock  BJ,  et al.  The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up.  BJU Int. 2012;109(1):32-39. doi:10.1111/j.1464-410X.2011.10422.xPubMedGoogle ScholarCrossref
Albertsen  PC, Hanley  JA, Penson  DF,  et al.  Validation of increasing prostate specific antigen as a predictor of PC death after treatment of localized PC with surgery or radiation.  J Urol. 2004;171(6, pt 1):2221-2225.PubMedGoogle ScholarCrossref
Jhaveri  FM, Klein  EA.  How to explore the patient with a rising PSA after radical prostatectomy: defining local versus systemic failure.  Semin Urol Oncol. 1999;17(3):130-134.PubMedGoogle Scholar
Zhou  P, Chen  MH, McLeod  D, Carroll  PR, Moul  JW, D’Amico  AV.  Predictors of prostate cancer-specific mortality after radical prostatectomy or radiation therapy.  J Clin Oncol. 2005;23(28):6992-6998. doi:10.1200/JCO.2005.01.2906PubMedGoogle ScholarCrossref
Freedland  SJ, Humphreys  EB, Mangold  LA,  et al.  Death in patients with recurrent prostate cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their associated contributions to all-cause mortality.  J Clin Oncol. 2007;25(13):1765-1771. doi:10.1200/JCO.2006.08.0572PubMedGoogle ScholarCrossref
Scher  HI, Eisenberger  M, D’Amico  AV,  et al.  Eligibility and outcomes reporting guidelines for clinical trials for patients in the state of a rising prostate-specific antigen: recommendations from the Prostate-Specific Antigen Working Group.  J Clin Oncol. 2004;22(3):537-556. doi:10.1200/JCO.2004.07.099PubMedGoogle ScholarCrossref
van den Bergh  RC, van Casteren  NJ, van den Broeck  T,  et al.  Role of hormonal treatment in prostate cancer patients with nonmetastatic disease recurrence after local curative treatment: a systematic review.  Eur Urol. 2016;69(5):802-820. doi:10.1016/j.eururo.2015.11.023PubMedGoogle ScholarCrossref
Moul  JW, Wu  H, Sun  L,  et al.  Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy.  J Urol. 2004;171(3):1141-1147. doi:10.1097/01.ju.0000113794.34810.d0PubMedGoogle ScholarCrossref
Shipley  WU, Desilvio  M, Pilepich  MV,  et al.  Early initiation of salvage hormone therapy influences survival in patients who failed initial radiation for locally advanced prostate cancer: a secondary analysis of RTOG protocol 86-10.  Int J Radiat Oncol Biol Phys. 2006;64(4):1162-1167. doi:10.1016/j.ijrobp.2005.09.039PubMedGoogle ScholarCrossref
Duchesne  GM, Woo  HH, Bassett  JK,  et al.  Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial.  Lancet Oncol. 2016;17(6):727-737. doi:10.1016/S1470-2045(16)00107-8PubMedGoogle ScholarCrossref
Graff  JN, Alumkal  JJ, Beer  TM.  Should chemotherapy be used in nonmetastatic PC?  JAMA Oncol. 2017;3(1):11-12. doi:10.1001/jamaoncol.2016.3623PubMedGoogle ScholarCrossref
Yu  EY, Lin  DW.  Avoiding undertreatment of aggressive prostate cancer by early use of chemotherapy.  JAMA Oncol. 2017;3(1):13-14. doi:10.1001/jamaoncol.2016.3634PubMedGoogle ScholarCrossref
Gravis  G, Fizazi  K, Joly  F,  et al.  Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial.  Lancet Oncol. 2013;14(2):149-158. doi:10.1016/S1470-2045(12)70560-0PubMedGoogle ScholarCrossref
Sweeney  CJ, Chen  YH, Carducci  M,  et al.  Chemohormonal therapy in metastatic hormone-sensitive PC.  N Engl J Med. 2015;373(8):737-746. doi:10.1056/NEJMoa1503747PubMedGoogle ScholarCrossref
James  ND, Sydes  MR, Clarke  NW,  et al; STAMPEDE investigators.  Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.  Lancet. 2016;387(10024):1163-1177. doi:10.1016/S0140-6736(15)01037-5PubMedGoogle ScholarCrossref
Vale  CL, Burdett  S, Rydzewska  LHM,  et al; STOpCaP Steering Group.  Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data.  Lancet Oncol. 2016;17(2):243-256. doi:10.1016/S1470-2045(15)00489-1PubMedGoogle ScholarCrossref
Botrel  TE, Clark  O, Lima Pompeo  AC,  et al.  Efficacy and safety of combined androgen deprivation therapy (ADT) and docetaxel compared with ADT alone for metastatic hormone-naive PC: a systematic review and meta-analysis.  PLoS One. 2016;11(6):e0157660. doi:10.1371/journal.pone.0157660PubMedGoogle ScholarCrossref
Hussain  A, Dawson  N, Amin  P,  et al.  Docetaxel followed by hormone therapy in men experiencing prostate-specific antigen after primary local treatments for PC.  J Clin Oncol. 2005;23(12):2789-2796. doi:10.1200/JCO.2005.07.152PubMedGoogle ScholarCrossref
Goodin  S, Medina  P, Capanna  T,  et al.  Effect of docetaxel in patients with hormone-dependent prostate-specific antigen progression after local therapy for prostate cancer.  J Clin Oncol. 2005;23(15):3352-3357. doi:10.1200/JCO.2005.11.111PubMedGoogle ScholarCrossref
Taplin  ME, Xie  W, Bubley  GJ,  et al.  Docetaxel, estramustine, and 15-month androgen deprivation for men with prostate-specific antigen progression after definitive local therapy for prostate cancer.  J Clin Oncol. 2006;24(34):5408-5413. doi:10.1200/JCO.2006.06.6589PubMedGoogle ScholarCrossref
Hainsworth  JD, Meluch  AA, Spigel  DR, Yost  K, Meng  C, Greco  FA.  Weekly docetaxel/estramustine phosphate in patients with increasing serum prostate-specific antigen levels after primary treatment for prostate cancer: a phase II trial of the Minnie Pearl Cancer Research Network.  Clin Genitourin Cancer. 2006;4(4):287-292. doi:10.3816/CGC.2006.n.009PubMedGoogle ScholarCrossref
Fizazi  K, Faivre  L, Lesaunier  F,  et al.  Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial.  Lancet Oncol. 2015;16(7):787-794. doi:10.1016/S1470-2045(15)00011-XPubMedGoogle ScholarCrossref
Sandler  HM, Hu  C, Rosenthal  SA,  et al.  A phase III protocol of androgen suppression (AS) and 3DCRT/IMRT versus AS and 3DCRT/IMRT followed by chemotherapy (CT) with docetaxel and prednisone for localized, high-risk PC (RTOG 0521)  [abstract].  J Clin Oncol. 2015;33(suppl):LBA5002.Google ScholarCrossref
Schweizer  MT, Huang  P, Kattan  MW,  et al.  Adjuvant leuprolide with or without docetaxel in patients with high-risk prostate cancer after radical prostatectomy (TAX-3501): important lessons for future trials.  Cancer. 2013;119(20):3610-3618. doi:10.1002/cncr.28270PubMedGoogle ScholarCrossref
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
Anderson  JR, Cain  KC, Gelber  RD.  Analysis of survival by tumor response.  J Clin Oncol. 1983;1(11):710-719. doi:10.1200/JCO.1983.1.11.710PubMedGoogle ScholarCrossref
Antonarakis  ES, Chen  Y, Elsamanoudi  SI,  et al.  Long-term overall survival and metastasis-free survival for men with prostate-specific antigen-recurrent prostate cancer after prostatectomy: analysis of the Center for Prostate Disease Research National Database.  BJU Int. 2011;108(3):378-385. doi:10.1111/j.1464-410X.2010.09878.xPubMedGoogle ScholarCrossref
Harshman  LC, Chen  YH, Liu  G,  et al; ECOG-ACRIN 3805 Investigators.  Seven-month prostate-specific antigen is prognostic in metastatic hormone-sensitive PC treated with androgen deprivation with or without docetaxel.  J Clin Oncol. 2018;36(4):376-382. doi:10.1200/JCO.2017.75.3921PubMedGoogle ScholarCrossref
Morris  MJ, Hilden  P, Gleave  M,  et al.  Efficacy analysis of a phase III study of androgen deprivation therapy (ADT) +/− docetaxel (D) for men with biochemical relapse (BCR) after prostatectomy  [abstract].  J Clin Oncol. 2015;33(15)(suppl):5011.Google ScholarCrossref
Eymard  JC, Priou  F, Zannetti  A,  et al.  Randomized phase II study of docetaxel plus estramustine and single-agent docetaxel in patients with metastatic hormone-refractory prostate cancer.  Ann Oncol. 2007;18(6):1064-1070. doi:10.1093/annonc/mdm083PubMedGoogle ScholarCrossref
Tannock  IF, de Wit  R, Berry  WR,  et al; TAX 327 Investigators.  Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.  N Engl J Med. 2004;351(15):1502-1512.PubMedGoogle ScholarCrossref
Franke  RM, Carducci  MA, Rudek  MA, Baker  SD, Sparreboom  A.  Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer.  J Clin Oncol. 2010;28(30):4562-4567. doi:10.1200/JCO.2010.30.7025PubMedGoogle ScholarCrossref
Sweeney  C, Nakabayashi  M, Regan  M,  et al; ICECaP Working Group.  The development of intermediate clinical endpoints in cancer of the prostate (ICECaP).  J Natl Cancer Inst. 2015;107(12):djv261.PubMedGoogle Scholar
Xie  W, Regan  MM, Buyse  M,  et al; ICECaP Working Group.  Metastasis-free survival is a strong surrogate of overall survival in localized PC.  J Clin Oncol. 2017;35(27):3097-3104. doi:10.1200/JCO.2017.73.9987PubMedGoogle ScholarCrossref
Gilson  C, Chowdhury  S, Parmar  MKB, Sydes  MR; STAMPEDE Investigators.  Incorporating biomarker stratification into STAMPEDE: an adaptive multi-arm, multi-stage trial platform.  Clin Oncol (R Coll Radiol). 2017;29(12):778-786. doi:10.1016/j.clon.2017.10.004PubMedGoogle ScholarCrossref
Terada  N, Akamatsu  S, Kobayashi  T, Inoue  T, Ogawa  O, Antonarakis  ES.  Prognostic and predictive biomarkers in prostate cancer: latest evidence and clinical implications.  Ther Adv Med Oncol. 2017;9(8):565-573. doi:10.1177/1758834017719215PubMedGoogle ScholarCrossref
Crawford  ED, Schellhammer  PF, McLeod  DG,  et al.  Androgen receptor–targeted treatments for prostate cancer: 35 years’ progress with antiandrogens.  J Urol. 2018;200(5):956-966.PubMedGoogle ScholarCrossref
Original Investigation
January 31, 2019

Effect of Adding Docetaxel to Androgen-Deprivation Therapy in Patients With High-Risk Prostate Cancer With Rising Prostate-Specific Antigen Levels After Primary Local Therapy: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Medical Oncology, Hôpital Européen Georges Pompidou, Paris, France
  • 2Department of Oncology Radiotherapy, Clinique Pasteur, Toulouse, France
  • 3Department of Medical Oncology, Centre Galilée, Hôpital Privé la Louvière, Lille, France
  • 4Department of Oncology Radiotherapy, Centre Hospitalier Privé St Grégoire, Rennes, France
  • 5Department of Medical Oncology, Centre François Baclesse, Caen, France
  • 6Department of Medical Oncology, Hôpital Privé des Côtes d'Armor, Plérin, France
  • 7Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Angers, France
  • 8Department of Medical Oncology, Institut de Cancérologie de l'Ouest, St Herblain, France
  • 9Department of Medical Oncology, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
  • 10Department of Medical Oncology, Centre Hospitalier de Vendée, La Roche sur Yon, France
  • 11Department of Medical Oncology, Institut Curie, Paris, France
  • 12Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
  • 13Department of Medical Oncology, Centre Hospitalier Bretonneau, Tours, France
  • 14Department of Oncology Radiotherapy, Centre Joliot Curie, Rouen, France
  • 15Department of Medical Oncology, Clinique Victor Hugo, Institut Inter-régional de Cancérologie, Le Mans, France
  • 16Department of Oncology Radiotherapy, Hôpital de la Timone, Marseille, France
  • 17Department of Medical Oncology, Centre Hospitalier Versailles André Mignot, Le Chesnay, France
  • 18Department of Medical Oncology, Cancer Institute Ion Chiricuta, Cluj-Napoca, Romania
  • 19Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France
  • 20Department of Medical Oncology, Hôpital St Andre, Bordeaux, France
  • 21Department of Medical Oncology, Centre Alexis Vautrin, Vandoeuvre Les Nancy, France
  • 22Department of Medical Oncology, Hôpital Henri Mondor, Creteil, France
  • 23Department of Medical Oncology, Fondation Hopital St Joseph, Paris, France
  • 24Department of Medical Oncology, Centre Hospitalier de Compiegne, Compiegne, France
  • 25Department of Medical Oncology, Hôpital Foch, Suresnes, France
  • 26Department of Medical Oncology, Institut Bergonie, Bordeaux, France
  • 27Department of Medical Oncology, Hôpital St Louis, Paris, France
  • 28Association pour la Recherche sur les Thérapeutiques Innovantes en Cancérologie, Paris, France
JAMA Oncol. 2019;5(5):623-632. doi:10.1001/jamaoncol.2018.6607
Key Points

Question  Is the combination of androgen-deprivation therapy plus docetaxel superior to androgen-deprivation therapy alone in the treatment of nonmetastatic prostate cancer in patients with increasing prostate-specific antigen levels after primary local therapy?

Findings  In this phase 3 randomized clinical trial including 254 patients, there was no significant difference between treatments for the primary outcome measure, prostate-specific antigen progression-free survival (median follow-up, 30.0 months). In addition, no significant difference was noted in the secondary outcome measures of radiologic progression-free survival and overall survival (median follow-up, 10.5 years).

Meaning  Addition of docetaxel to androgen-deprivation therapy seems to be unwarranted in patients with high-risk prostate cancer without metastases in the absence of better predictors of risk for metastatic disease.


Importance  Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer setting.

Objective  To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease.

Design, Setting, and Participants  This open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (≤6 vs >6 months), and intention-to-treat analysis was used.

Interventions  Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2 (every 3 weeks [6 cycles]), or ADT alone (1 year).

Main Outcomes and Measures  The primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life.

Results  Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio [HR], 0.85; 95% CI, 0.62-1.16; P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43; P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients [48.0%]), febrile neutropenia (10 [8.0%]), and thrombocytopenia (4 [3.0%]). There was no significant between-arm difference in overall quality of life.

Conclusions and Relevance  Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease.

Trial Registration  French Health Products Safety Agency identifier: 030591; ClinicalTrials.gov identifier: NCT00764166