Karim Fizazi1, Neal Shore1, Teuvo L Tammela1, Albertas Ulys1, Egils Vjaters1, Sergey Polyakov1, Mindaugas Jievaltas1, Murilo Luz1, Boris Alekseev1, Iris Kuss1, Christian Kappeler1, Amir Snapir1, Toni Sarapohja1, Matthew R Smith1. 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.).
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.).
Authors: Myrto Boukovala; Nicholas Spetsieris; Justin A Weldon; Alexandros Tsikkinis; Anh Hoang; Ana Aparicio; Shi-Ming Tu; John C Araujo; Amado J Zurita; Paul G Corn; Lance Pagliaro; Jeri Kim; Jennifer Wang; Sumit K Subudhi; Nizar M Tannir; Christopher J Logothetis; Patricia Troncoso; Sijin Wen; Eleni Efstathiou Journal: Eur J Cancer Date: 2020-01-24 Impact factor: 9.162
Authors: Emmanuel S Antonarakis; Jun Luo; Andrew J Armstrong; Landon C Brown; Changxue Lu Journal: Prostate Cancer Prostatic Dis Date: 2020-02-24 Impact factor: 5.554