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.
BACKGROUND
Patients with metastatic castration-resistant prostate cancer have few treatment options. We investigated the safety and efficacy of lenalidomide, an immunomodulatory agent with anti-angiogenic properties, in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer.


METHODS
In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned chemotherapy-naive patients with progressive metastatic castration-resistant prostate cancer in a 1:1 ratio to receive docetaxel (75 mg/m(2)) on day 1 and prednisone (5 mg twice daily) on days 1-21 and either lenalidomide (25 mg) or placebo once daily on days 1-14 of each 21 day treatment cycle. Permuted block randomisation was done with an interactive voice response system and stratified by Eastern Cooperative Oncology Group performance status, geographic region, and type of disease progression. Clinicians, patients, and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy analysis was by intention to treat. Patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00988208.


RESULTS
1059 patients were enrolled and randomly assigned between Nov 11, 2009, and Nov 23, 2011 (533 to the lenalidomide group and 526 to the control group), and 1046 patients received study treatment (525 in the lenalidomide group and 521 in the placebo group). At data cutoff (Jan 13, 2012) after a median follow-up of 8 months (IQR 5-12), 221 patients had died: 129 in the lenalidomide group and 92 in the placebo group. Median overall survival was 17·7 months (95% CI 14·8-18·8) in the lenalidomide group and not reached in the placebo group (hazard ratio [HR] 1·53, 95% CI 1·17-2·00, p=0·0017). The trial was subsequently closed early due to futility. The number of deaths that occurred during treatment or less than 28 days since the last dose were similar in both groups (18 [3%] of 525 patients in the lenalidomide group vs 13 [2%] of 521 patients). 109 (21%) patients in the lenalidomide group and 78 (15%) in the placebo group died more than 28 days from last dose, mainly due to disease progression. At least one grade 3 or higher adverse event was reported in 381 (73%) of 525 patients receiving lenalidomide and 303 (58%) of 521 patients receiving placebo. Grade 3-4 neutropenia (114 [22%] for lenalidomide vs 85 [16%] for placebo), febrile neutropenia (62 [12%] vs 23 [4%]), diarrhoea (37 [7%] vs 12 [2%]), pneumonia (24 [5%] vs five [1%]), dyspnoea (22 [4%] vs nine [2%]), asthenia (27 [5%] vs 17 [3%]), and pulmonary embolism (32 [6%] vs seven [1%]) occurred more frequently in the lenalidomide group than in the placebo group.


CONCLUSIONS
Overall survival with the combination of lenalidomide, docetaxel, and prednisone was significantly worse than with docetaxel and prednisone for chemotherapy-naive men with metastatic, castration-resistant prostate cancer. Further research with this treatment combination is not warranted.


BACKGROUND
Celgene Corporation.
Yale Cancer Center, Department of Medicine Division of Oncology, New Haven, CT, USA. Electronic address: daniel.petrylak@yale.edu.
Daniel P
DP
Petrylak
US Oncology Research, Houston, TX, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
Nicholas J
NJ
Vogelzang
NSHI Dorozhnaya Clinical Hospital of OAO Russian Railways, Rostov-on-Don, Russia.
Nikolay
N
Budnik
Department of Uro-Oncology, Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie, Warsaw, Poland.
Pawel Jan
PJ
Wiechno
San Camillo and Forlanini Hospitals, Department of Medical Oncology, Rome, Italy.
Cora N
CN
Sternberg
Texas Oncology, Austin, TX, USA.
Kevin
K
Doner
University Hospital del Mar-IMIM, Barcelona, Spain; Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Joaquim
J
Bellmunt
US Oncology Research, Houston, TX, USA; Rocky Mountain Cancer Centers, Aurora, CO, USA.
John M
JM
Burke
Catalan Institute of Oncology, Department of Medical Oncology, Barcelona, Spain.
Maria Ochoa
MO
de Olza
Department of Clinical Oncology, The Christie NHS Foundation Trust and Institute of Cancer Sciences, University of Manchester, Manchester, UK.
Ananya
A
Choudhury
Department of Urology, Rechts der Isar Medical Center, Technische Universität München, München, Germany.
Juergen E
JE
Gschwend
State Institution of Healthcare "Regional Clinical Oncology Dispensary", Omsk, Russia.
Evgeny
E
Kopyltsov
Centre Léon Bérard, Department of Medical Oncology, Lyon, France.
Aude
A
Flechon
Department of Clinical Oncology, Royal Marsden Hospital, London, UK.
Nicolas
N
Van As
Medical Oncology Department, Groupe Hospitalier Universitaire Caremeau Place du Professeur Robert Debré, Nîmes, France.
Nadine
N
Houede
Celgene Corporation, Summit, NJ, USA.
Debora
D
Barton
Celgene Corporation, Summit, NJ, USA.
Abderrahim
A
Fandi
Celgene Corporation, Summit, NJ, USA.
Ulf
U
Jungnelius
Celgene Corporation, Summit, NJ, USA.
Shaoyi
S
Li
ErasmusMC Cancer Institute, Rotterdam, Netherlands.
Ronald
R
de Wit
Institut Gustave Roussy, Department of Cancer Medicine, University of Paris Sud, Villejuif, France.
Karim
K
Fizazi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000077143:Docetaxel; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011241:Prednisone / Q000008:administration & dosage* / Q000009:adverse effects; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
D010919:Placebos; D043823:Taxoids; D000077143:Docetaxel; D013792:Thalidomide; D000077269:Lenalidomide; D011241:Prednisone