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Lancet Oncol. 2015 Mar;16(3):338-48. doi: 10.1016/S1470-2045(15)70027-6. Epub 2015 Feb 18.

Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial.

Collaborators (313)

Troon S, Underhill C, Dittrich C, Krainer M, Kramer G, Loidl W, Pummer K, Belyakovskiy V, Polyakov S, Goeminne JC, Hoekx L, Luyten D, Van Poppel H, Werbrouck P, Azambuja A, Barrios C, Brust L, Cabral Filho S, Carcano F, Cruz F, Damião R, Delgado G, Diógenes Â, Dzik C, Faccio A, de Faria G, Faulhaber A, Fernandes H, Ferreira U, Filho R, Franke F, Girotto G, Koff W, Kussumoto C, Malzyner A, de Moraes A, Padílha S, de Pádua C, Pinto L, Portella M, Reiriz A, da Silva Teixeira V, Vieiralves L, Dimitrov B, Dudov A, Micheva R, Petrov P, Taskova V, Carmel M, Casey R, Chin J, Jacobson A, Jansz G, Kapoor A, Kinahan T, Love W, Martin AG, Saad F, Trachtenberg J, Webster T, Acevedo Gaete A, Arén Frontera O, Leyton Naranjo R, Miranda Benabarre A, Pastor Arroyo P, Neira Reyes L, Ramirez Pinto G, Restrepo Molina J, Grgic M, Babjuk M, Domes L, Jansa J, Lukes M, Pavlik I, Zachoval R, Kahu J, Tamm T, Marttila T, Tammela T, Vaarala M, Vitanen J, Bompas E, Colombel M, Delva R, Deplanque G, Fizazi K, Flechon A, Giroux J, Joly F, Lechevallier E, Mottet Auselo N, Priou F, Roubaud G, Roupret M, Spaeth D, De La Taille A, Tourani JM, Feyerabend S, De Geeter P, Geiges G, Gleißner J, Hammerer P, Klotz T, Kuczyk M, Marin J, Schrader A, Stenzl A, Steuber T, Wirth M, Efstathiou E, Georgoulias V, Hatzimouratidis K, Kalofonos H, Papandreou C, Thanos A, Leung KC, Ng C, Farkas L, Pintér J, McDermott R, Sullivan F, Berger R, Gabizon A, Gez E, Rosenbaum E, Sella A, Semenisty V, Tavdy E, Alabiso O, Ciuffreda L, Fratino L, Sternberg C, Tubaro A, Akakura K, Arai Y, Egawa S, Fujimoto H, Ichikawa T, Kakehi Y, Kitamura H, Maniwa A, Miyanaga N, Mizokami A, Nakatani T, Nishimura K, Niwakawa M, Sato F, Sugiyama T, Suzuki H, Suzuki K, Takahashi S, Tomita Y, Ueda T, Uemura H, Yamaguchi R, Yokomizo A, Yoshimura K, Brize A, Litavnience D, Vjaters E, Jankevicius F, Jievaltas M, Jocys G, Ulys A, Calvo Domínguez D, González Perez J, de Leon Jaen S, Pérez O, Rodriguez Rivera J, Valdés A, Blaisse R, Hamberg A, Loosveld O, Los M, Van Oort I, de la Rosette J, De Vries P, Vrijhof H, de Wit R, Costello S, Davidson P, Fong C, Gilling P, Neill M, Abrill Mendoza G, Cano Rivera J, Garcia Ahumada S, Huaringa Leiva R, Pazos Franco A, Jablonska Z, Kmieciak R, Coelho J, Sousa N, Bucuras C, Cebotaru C, Ciuleanu T, Jinga V, Anatolyevich I, Yurievich P, Hiang T, Sing N, Balaz V, Brezovsky M, Kliment J, Mikulas J, Mincik I, Sokol R, Botha M, Hart G, Kraus P, Landers G, Malan J, Bellmunt J, Castellano D, Climent Duran M, Veiga F, González B, Pérez Gracia J, Valderrama B, Provencio M, Damber JE, Häggman M, Nyman C, Berthold D, Fischer N, Popescu R, Stenner F, Chang YH, Ou YC, Tsai YC, Wu HC, Wu TL, Bondarenko I, Ivashchenko P, Kobets V, Pasiechnikov S, Semenukha V, Sernyak Y, Stus V, Bahl A, Birtle A, Chowdhury S, Crabb S, Dixit S, Elliott P, Hoskin P, Jones R, Khoo V, MacDonald A, Malik Z, O'Sullivan J, Simms M, Stockdale A, Agarwal N, Alter R, Anderson TC, Bailen J, Berry W, Bidair M, Clark W, Cohn AL, Crawford E, DiSimone C, Feliciano L, Fleming MT, Forero L, Friday B, Fruehauf JP, Gelmann E, George D, Gignac G, Given R, Gullo J, Hainsworth J, Hajdenberg J, Haluschak JJ, Hamid O, Hammers H, Hart LL, Hussain A, Hutson TE, Ibrahim E, Jain SK, Khojasteh A, Kohli M, Lara PN Jr, Lilly M, Lipton A, Mackey DW, Mao SS, Mehta AR, Modiano MR, Morris M, Muscato JJ, Nordquist LT, Richards DA, Ryan C, Sartor AO, Schnadig ID, Sieber PR, Singal R, Smith F, Somer B, Srkalovic G, Tagawa S, Tan W, Twardowski P, Van Veldhuizen PJ, Vogelzang N, Watkins DL, Wertheim M, Wong YN, Zhang J.

Author information

1
Centre Hospitalier de l'Université de Montréal/CRCHUM, Montréal, QC, Canada. Electronic address: fred.saad@umontreal.ca.
2
Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
3
Universitatea de Medicina si Farmacie, Bucharest, Romania.
4
University of Athens Medical School, Athens, Greece.
5
Auckland City Hospital, Auckland, New Zealand.
6
Florida Cancer Specialists, Fort Myers, FL, USA.
7
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
8
The Adelaide and Meath Hospital, Incorporating the National Children's Hospital, Dublin, Ireland.
9
University Hospital Carl Gustav Carus Dresden, Dresden, Germany.
10
Gunma University Graduate School of Medicine, Gunma, Japan.
11
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
12
The University of Tokyo Research Center for Advanced Science and Technology, Tokyo, Japan.
13
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
14
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
15
Cleveland Clinic, Cleveland, OH, USA.
16
Millennium Pharmaceuticals, Inc, Cambridge, MA, USA.
17
Erasmus University Medical Center, Rotterdam, Netherlands.

Abstract

BACKGROUND:

Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer.

METHODS:

In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244.

FINDINGS:

From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone.

INTERPRETATION:

In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer.

FUNDING:

Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

PMID:
25701170
DOI:
10.1016/S1470-2045(15)70027-6
[Indexed for MEDLINE]

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