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Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer

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Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer The new england journal of medicine Original Article Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer Karim Fizazi, M.D., Neal Shore, M.D., Teuvo L. Tammela, M.D., Ph.D., Albertas Ulys, M.D., Egils Vjaters, M.D., Sergey Polyakov, M.D., Mindaugas Jievaltas, M.D., Murilo Luz, M.D., Boris Alekseev, M.D., Iris Kuss, M.D., Christian Kappeler, Ph.D., Amir Snapir, M.D., Ph.D., Toni Sarapohja, M.Sc., and Matthew R. Smith, M.D., Ph.D., for the ARAMIS Investigators*​​ ABSTRACT BACKGROUND Darolutamide is a structurally unique androgen-receptor antagonist that is under de- From Institut Gustave Roussy, Université velopment for the treatment of prostate cancer. We evaluated the efficacy of darolu- Paris-Sud, Villejuif, France (K.F.); Carolina Urologic Research Center, Myrtle Beach, tamide for delaying metastasis and death in men with nonmetastatic, castration- SC (N.S.); Tampere University Hospital resistant prostate cancer. and University of Tampere, Tampere (T.L.T.), and Orion Pharma, Orion Corporation, METHODS Espoo (A.S., T.S.) — all in Finland; Na- tional Cancer Institute, Vilnius (A.U.), We conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving and Medical Academy, Lithuanian Uni- men with nonmetastatic, castration-resistant prostate cancer and a prostate-specific versity of Health Sciences, Kaunas (M.J.) antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 — both in Lithuania; Stradins Clinical University Hospital, Riga, Latvia (E.V.); ratio to receive darolutamide (600 mg [two 300-mg tablets] twice daily) or placebo N.N. Alexandrov National Cancer Center while continuing androgen-deprivation therapy. The primary end point was metas- of Belarus, Minsk, Belarus (S.P.); Hospital tasis-free survival, with the presence of metastasis determined by independent cen- Erasto Gaertner, Curitiba, Brazil (M.L.); National Medical Research Radiological tral review of radiographic imaging every 16 weeks. Center, Ministry of Health of the Russian Federation, Moscow (B.A.); Bayer, Berlin RESULTS (I.K., C.K.); and Massachusetts General In total, 1509 patients underwent randomization (955 to the darolutamide group and Hospital Cancer Center, Boston (M.R.S.). 554 to the placebo group). In the planned primary analysis, which was performed Address reprint requests to Dr. Fizazi at the Department of Cancer Medicine, In- after 437 primary end-point events had occurred, the median metastasis-free survival stitut Gustave Roussy, 114 Rue Edouard was 40.4 months with darolutamide, as compared with 18.4 months with placebo Vaillant, 94800 Villejuif, France, or at (hazard ratio for metastasis or death in the darolutamide group, 0.41; 95% confidence karim . fizazi@gustaveroussy . fr. interval, 0.34 to 0.50; P<0.001). Darolutamide was also associated with benefits with *The complete list of ARAMIS investiga- regard to all secondary end points, including overall survival, time to pain progres- tors is provided in the Supplementary Appendix, available with the full text of sion, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. The this article at NEJM.org. incidence of adverse events that occurred or worsened during the treatment period This article was published on February 14, and had a frequency of 5% or more or were of grade 3 or higher was similar in the 2019, at NEJM.org. two groups; all such events except fatigue occurred in less than 10% of patients in N Engl J Med 2019;380:1235-46. either group. The percentage of patients who discontinued the assigned regimen DOI: 10.1056/NEJMoa1815671 because of adverse events was 8.9% in the darolutamide group and 8.7% in the Copyright © 2019 Massachusetts Medical Society. 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.) n engl j med 380;13 nejm.org March 28, 2019 1235 The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on March 31, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. The new england journal of medicine ndrogen-deprivation therapy is Methods part of the standard of care for patients whose prostate cancer recurs after pri- Trial Design and Conduct A 1-4 mary treatment. However, despite receiving an- The trial was sponsored by Orion Pharma and drogen-deprivation therapy, most of these pa- Bayer HealthCare; both sponsors developed the tients will have disease progression, initially trial design with the first and last authors. The manifesting as rising levels of prostate-specific trial was conducted in 36 countries worldwide in antigen (PSA).5 Some of these patients have an 409 centers. The institutional review board at absence of metastases on conventional imaging each participating institution approved the trial, and are classified as having nonmetastatic, which was conducted in compliance with the castration-resistant prostate cancer.6 Delaying principles of the Declaration of Helsinki and in the development of metastases in these patients accordance with the International Conference on is a key therapeutic goal, since metastasis in Harmonisation guidelines for Good Clinical Prac- bone, soft tissue, or viscera is associated with tice. All patients provided written informed con- both morbidity and prostate cancer–specific mor- sent. An independent data and safety monitoring tality.7-9 board reviewed unblinded safety data through- The androgen-receptor inhibitors apalu- out the trial. The data were collected by the in- tamide and enzalutamide have recently been vestigators, analyzed by statisticians who were approved for the treatment of nonmetastatic, employed by the sponsors, and interpreted by the castration-resistant prostate cancer on the basis authors, including employees of the sponsors. of phase 3 trials showing significantly longer Bayer HealthCare provided funding for medical metastasis-free survival with these agents than writing and editing assistance. The authors re- with placebo.10,11 Data on overall survival or pain viewed and approved the manuscript that was associated with these agents are still immature. submitted for publication. The authors assume However, patients with nonmetastatic, castra- responsibility for the completeness and accuracy tion-resistant prostate cancer, who may have of the data and for the fidelity of the trial and adverse effects from their ongoing androgen- this report to the protocol and statistical analysis deprivation therapy, may have additional associ- plan, available with the full text of this article at ated adverse events and toxic effects from these NEJM.org. agents. Thus, there is a need for therapies with improved safety and toxicity profiles. Patients Darolutamide is an androgen-receptor antag- Patients were eligible for participation if they onist with a distinct structure that offers a po- were 18 years of age or older and had histologi- tential for fewer and less severe toxic effects cally or cytologically confirmed adenocarcinoma than apalutamide and enzalutamide because of of the prostate. Patients were required to have its low penetration of the blood–brain barrier12-14 castration-resistant prostate cancer, a baseline PSA and low binding affinity for γ-aminobutyric acid level of at least 2 ng per milliliter, a PSA doubling type A receptors, as shown in preclinical stud- time of 10 months or less, and an Eastern Coop- ies.15 After observing the significant antitumor erative Oncology Group (ECOG) performance sta- activity and good side-effect profile shown in tus of 0 or 1 (scores range from 0 to 5, with phase 1 and 2 studies involving men with meta- higher numbers reflecting greater disability). At static, castration-resistant prostate cancer,16-19 we screening, all patients underwent a radionuclide conducted the multinational, randomized, dou- bone scan of the whole body and computed to- ble-blind, placebo-controlled, phase 3 Androgen mography (CT) or magnetic resonance imaging Receptor Antagonizing Agent for Metastasis-free (MRI) of the pelvis, abdomen, and chest; patients Survival (ARAMIS) trial to evaluate the efficacy with detectable metastases or a history of meta- and safety of darolutamide in men with non- static disease were excluded, although the pres- metastatic, castration-resistant prostate cancer. ence of pelvic lymph nodes less than 2 cm in The primary end point was metastasis-free sur- diameter in the short axis below the aortic bifur- vival, an established end point in trials involving cation was allowed. Previous seizure or condi- castration-resistant prostate cancer. tions predisposing to seizure were not exclusion- 1236 n engl j med 380;13 nejm.org March 28, 2019 The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on March 31, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. Darolutamide in Prostate Cancer ary. Full details of the criteria for patient selection the generic EuroQol Group 5-dimension 3-level are provided in the Supplementary Appendix, (EQ-5D-3L; five dimensions, each with three lev- available at NEJM.org. els of response, are summarized as an index score ranging from −0.59 to 1, with higher scores in- Trial Design and Regimens dicating better health states; minimum clinically At trial initiation, patients were randomly assigned important difference, 0.06 points); the FACT-P in a 2:1 ratio in a double-blind manner to receive PCS was also given every 16 weeks until the end either darolutamide (600 mg given as two 300-mg of the trial or death. The European Organisation tablets) twice daily with food (a daily dose of for Research and Treatment of Cancer quality of 1200 mg) or matched placebo.
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