Susanna Bianchi1, Alessandra Mosca2, Alberto Dalla Volta1, Veronica Prati3, Cinzia Ortega3, Consuelo Buttigliero4, Elena Fea5, Paola Vanella5, Francesca Valcamonico1, Manuel Zamparini1, Zuzana Sirotova6, Isabella Chiappino7, Orietta Dal Canton8, Cristina Masini9, Cosimo Sacco10, Domenico Amoroso11, Francesco Montagnani12, Alessandro Comandone8, Andrea R Bellissimo13, Giovannino Ciccone13, Susanne Baier14, Alessandra Gennari15, Marcello Tucci16, Alfredo Berruti17. 1. Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, ASST-Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy. 2. Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy. 3. Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy; Department of Medical Oncology, Ospedale S. Lazzaro Azienda Sanitaria Locale CN2, Alba-Bra, Cuneo, Italy. 4. Department of Medical Oncology, University of Torino, San Luigi Gonzaga Hospital, Orbassano, Italy. 5. Department of Medical Oncology, S Croce and Carle Teaching Hospital, Cuneo, Italy. 6. Unit of Medical Oncology, Aosta Regional Hospital, Aosta, Italy. 7. Medical Oncology Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, Italy. 8. Medical Oncology Unit, Humanitas Gradenigo Hospital, Turin, Italy; Department of Medical Oncology, Azienda Sanitaria Locale Città di Torino, Turin, Italy. 9. Medical Oncology Unit, Clinical Cancer Center, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy. 10. Department of Oncology, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy. 11. Medical Oncology Unit, Azienda USL Toscana Nord-Ovest, Ospedale Versilia, Lido di Camaiore, Italy. 12. Medical Oncology Unit, Azienda Sanitaria Locale Biella, Biella, Italy. 13. Unit of Clinical Epidemiology, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza di Torino and Centro di Prevenzione Oncologica Piemonte, Torino, Italy. 14. Medical Oncology Unit, Ospedale Centrale di Bolzano, 39100 Bolzano, Italy. 15. Division of Oncology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy. 16. Department of Medical Oncology, Cardinal Massaia Hospital, Asti, Italy. 17. Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, ASST-Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy. Electronic address: alfredo.berruti@unibs.it.
Abstract
BACKGROUND: This study was designed to demonstrate the non-inferiority (NI) in overall survival (OS) of suspension of androgen deprivation therapy (ADT) versus maintenance and intermittent versus continuous docetaxel administration in metastatic castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: mCRPC patients were randomised to first-line docetaxel with maintenance or suspension of ADT. Patients attaining a prostate-specific antigen (PSA) response after four chemotherapy cycles underwent second randomisation to receive continuous or intermittent docetaxel therapy. Six hundred patients were to be randomised to achieve 80% statistical power to demonstrate an NI hazard ratio (HR) of 1.25 of interruption versus maintenance of ADT. RESULTS: The trial was prematurely closed when 198 participants were randomised. OS was similar in patients who continued (N = 96) versus those who interrupted (n = 102) ADT during docetaxel therapy (HR 0.98, 95% confidence interval [CI] 0.72-1.33] and those on a continuous (N = 35) versus an intermittent (N = 42) docetaxel schedule (HR 0.86, 95% CI 0.55-1.43). No difference in radiological progression-free survival, PSA response, or toxicity was observed between the study arms. The actual NI hazard margins of OS in Arms A and B patients were 1.33 and 1.43, respectively. CONCLUSIONS: This trial enrolled one-third of the planned patients; this main weakness dramatically limits the interpretation of the results. ADT discontinuation and switching to an intermittent schedule did not seem to affect docetaxel efficacy. The absence of testosterone recovery in the majority of patients could have been a contributory factor. In men with mCRPC, ADT discontinuation should only be done with regular biochemical and clinical monitoring, with the option of quickly restarting ADT at disease progression.
BACKGROUND: This study was designed to demonstrate the non-inferiority (NI) in overall survival (OS) of suspension of androgen deprivation therapy (ADT) versus maintenance and intermittent versus continuous docetaxel administration in metastatic castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: mCRPC patients were randomised to first-line docetaxel with maintenance or suspension of ADT. Patients attaining a prostate-specific antigen (PSA) response after four chemotherapy cycles underwent second randomisation to receive continuous or intermittent docetaxel therapy. Six hundred patients were to be randomised to achieve 80% statistical power to demonstrate an NI hazard ratio (HR) of 1.25 of interruption versus maintenance of ADT. RESULTS: The trial was prematurely closed when 198 participants were randomised. OS was similar in patients who continued (N = 96) versus those who interrupted (n = 102) ADT during docetaxel therapy (HR 0.98, 95% confidence interval [CI] 0.72-1.33] and those on a continuous (N = 35) versus an intermittent (N = 42) docetaxel schedule (HR 0.86, 95% CI 0.55-1.43). No difference in radiological progression-free survival, PSA response, or toxicity was observed between the study arms. The actual NI hazard margins of OS in Arms A and B patients were 1.33 and 1.43, respectively. CONCLUSIONS: This trial enrolled one-third of the planned patients; this main weakness dramatically limits the interpretation of the results. ADT discontinuation and switching to an intermittent schedule did not seem to affect docetaxel efficacy. The absence of testosterone recovery in the majority of patients could have been a contributory factor. In men with mCRPC, ADT discontinuation should only be done with regular biochemical and clinical monitoring, with the option of quickly restarting ADT at disease progression.