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N Engl J Med. 2019 Mar 28;380(13):1235-1246. doi: 10.1056/NEJMoa1815671. Epub 2019 Feb 14.

Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.

Collaborators (360)

Metrebian S, Montes de Oca LF, Richardet M, Dowling A, Hovey E, Joshi A, Krieger L, Oliveira N, Parnis F, Meran J, Shariat S, Gedrevich Z, Polyakov S, Forget F, Waltregny D, Werbrouck P, Wynendaele W, Alves da Silva BS, Andrade L, Bastos DA, Beato CA, Borges GS, Cruz FJ, De Arruda LM, do Reis R, Eyll BM, Lago S, Lazaretti N, Luz M, Mavignier Carcano F, Murad AM, Paula AP, Pires LA, Rios L, Silveira GC, Zereu M, Mladenov D, Stamboliyski V, Chin J, Emmenegger U, Fleshner N, Gotto G, Jacobson A, Jansz KG, Ouellette P Jr, Rendon R, Siemens R, Correa JJ, Lobaton Ramirez JF, Rey MS, Capoun O, Heracek J, Jandeisek J, Krolupper M, Matouskova M, Vseticka J, Pokker H, Hirvonen O, Marttila T, Rannikko A, Tammela T, Azria D, Azzouzi AR, Cathelineau X, Coloby P, Culine S, de la Taille A, Dourthe LM, Eymard JC, Fizazi K, Mouillet G, Haillot O, Helissey C, Lagneau E, Lebret T, Mahammedi H, Pfister C, Rigaud J, Rotarski M, Roubaud G, Ruffion A, Spaeth D, Tourani JM, Vincendeau S, Banek S, Binder M, Bogemann M, Carl S, Feyerabend S, Gleissner J, Heinemann V, Maier S, Niegisch G, Rudolph R, Schmitz-Drager B, Schneider T, Schostak M, Stenzl A, Stroelin P, Thomas C, Warnack W, Wiegl A, Wirth M, Ali T, Arkosy P, Beli L, Csoszi T, Nyirady P, Pajor L, Szabo A, Torzsok F, Toth Z, Grikshats E, Aglietta M, Damiano R, Facchini G, Gasparro D, Mucciardi G, Natoli C, Sabbatini R, Scagliotti GV, Schepisi G, Serretta V, Anai S, Asano K, Ebara S, Fukasawa S, Fukaya Y, Hirata A, Iinuma M, Kasuya Y, Kato M, Kawakita M, Kitamura H, Kobayashi K, Kondo Y, Masumori N, Matsubara N, Matsumoto H, Matsushima H, Miki K, Mizusawa H, Momma T, Motoyama D, Miyagi T, Nagata M, Namima T, Nishimatsu H, Nishimura K, Noguchi M, Okegawa T, Oya M, Sakai H, Shin T, Suzuki K, Tabata K, Takamoto A, Tamada S, Tobe T, Tsurusaki T, Uemura H, Uemura H, Ukimura O, Yamaguchi S, Buldinskis G, Hublarovs O, Laukmanis A, Lietuvietis V, Litavniece D, Vjaters E, Auskalnis S, Jievaltas M, Ramonas H, Ulys A, Venckus R, Abrill Mendoza GV, Alarcon-Rozas AE, Aleman Polanco DS, Philco Salas MJ, Badzio A, Kmieciak R, Majek A, Marcheluk A, Mruk A, Niezabitowski J, Senkus-Konefka E, Nyk L, Skoneczna IA, Wiechno P, Campos Pinheiro L, Faustino I, Fonseca J, Lima E, Marialva C, Mauricio J, Pina F, Prisco R, Rodrigues T, Silva E, Bumbu G, Cauni V, Cebotaru CL, Chibelean BC, Dinu M, Ghizdavescu GD, Harza M, Jinga V, Lungulescu DS, Schenker M, Al-Shukri SH, Alekseev B, Alyasova A, Apolikhin O, Buiniakova A, Dykhno Y, Fomkin R, Ivanov S, Khvorostenko D, Kogan M, Kopyltsov E, Lykov A, Pimenov I, Rodicheva N, Safina SZ, Semenov A, Shirinkin VB, Vladimirov V, Zavyalov M, Filipovic Z, Stojanovic V, Breza J, Goncalves F, Sokol R, Ackermann H, Coetzee L, Harris JK, Kraus P, Lazarus J, Chung BH, Hong SJ, Kang TW, Kim CS, Kim CI, Kim S, Kim WJ, Kwak C, Kwon TG, Seo SI, Yoon SJ, Alvarez-Ossorio J, Benejam JM, Carles J, Casas Nebra FJ, Garcio-Rojo D, Garde Noguera J, Gomez Veiga F, Gomez-Ferrer A, Gonzalez Del Alba A, Gonzalez Enguita C, Hernandez Fernandez C, Guijarro Gil J, Juarez A, Jurado JM, Llorente Abarca C, Loizaga A, Medina Lopez RA, Mendez Vidal MJ, Pinto Marin A, Puente Vazquez J, Ribal Caparros MJ, Rodriguez Antolin A, Saez Medina M, Suarez JF, Virizuela JA, Andren O, Damber JE, Haggman M, Hellstrom M, Chen CH, Huang SP, Pang ST, Wu TL, Yang CK, Esen A, Muezzinoglu T, Ozyurt C, Sozen TS, Yildirim A, Adamchuk H, Antonyan I, Bondarenko I, Grygorenko V, Ivashchenko P, Rusyn A, Sagan O, Zaitsev V, Beesley S, Beresford M, Birtle A, Bryan N, Dixit S, Jones R, Kanaga Sundaram S, Koh P, Kynaston H, Madaan S, Ng Y, Rogers P, Syndikus I, Vengalil S, Agamah E, Albany C, Aragon-Ching J, Aronson WJ, Bailen J, Belkoff L, Bernstein G, Bidair M, Bowles DW, Brown G, Cinman A, Clark RL, Clark W, Cohen T, Cookson M, Deguenther M, El Ayass W, Brede CM, Franks M, Gabrail NY, Gartrell B, Given RW, Karsh L, Koletsky A, Korman H, Martin B, Matrana M, Merrick G, Millard FE, Morris D, Moss RA, Nordquist L, Ornstein M, Patel K, Pieczonka C, Pliskin MJ, Rivera I, Rosenberg SJ, Schwab WC, Sharifi R, Shevrin D, Shore N, Smith M, Taksey J, Tebyani N, Thara E, Tolia BM, Trainer AF, Tutrone RF, Wertheim MS.

Author information

1
From Institut Gustave Roussy, Université Paris-Sud, Villejuif, France (K.F.); Carolina Urologic Research Center, Myrtle Beach, SC (N.S.); Tampere University Hospital and University of Tampere, Tampere (T.L.T.), and Orion Pharma, Orion Corporation, Espoo (A.S., T.S.) - all in Finland; National Cancer Institute, Vilnius (A.U.), and Medical Academy, Lithuanian University of Health Sciences, Kaunas (M.J.) - both in Lithuania; Stradins Clinical University Hospital, Riga, Latvia (E.V.); N.N. Alexandrov National Cancer Center of Belarus, Minsk, Belarus (S.P.); Hospital Erasto Gaertner, Curitiba, Brazil (M.L.); National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow (B.A.); Bayer, Berlin (I.K., C.K.); and Massachusetts General Hospital Cancer Center, Boston (M.R.S.).

Abstract

BACKGROUND:

Darolutamide is a structurally unique androgen-receptor antagonist that is under development for the treatment of prostate cancer. We evaluated the efficacy of darolutamide for delaying metastasis and death in men with nonmetastatic, castration-resistant prostate cancer.

METHODS:

We conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg [two 300-mg tablets] twice daily) or placebo while continuing androgen-deprivation therapy. The primary end point was metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks.

RESULTS:

In total, 1509 patients underwent randomization (955 to the darolutamide group and 554 to the placebo group). In the planned primary analysis, which was performed after 437 primary end-point events had occurred, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41; 95% confidence interval, 0.34 to 0.50; P<0.001). Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. The incidence of adverse events that occurred or worsened during the treatment period and had a frequency of 5% or more or were of grade 3 or higher was similar in the two groups; all such events except fatigue occurred in less than 10% of patients in either group. The percentage of patients who discontinued the assigned regimen because of adverse events was 8.9% in the darolutamide group and 8.7% in the placebo group. Darolutamide was not associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension than placebo.

CONCLUSIONS:

Among men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo. The incidence of adverse events was similar for darolutamide and placebo. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).

PMID:
30763142
DOI:
10.1056/NEJMoa1815671
[Indexed for MEDLINE]

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