Efficacy and Safety Study of Darolutamide (ODM-201) in Men With High-risk Non-metastatic Castration-resistant Prostate Cancer (ARAMIS)

• ClinicalTrials.gov Identifier: NCT02200614
• Recruitment Status: Completed
• First Posted: July 25, 2014
• Results First Posted: October 29, 2019
• Last Update Posted: June 28, 2022
• Sponsor: Bayer
• Collaborator: Orion Corporation, Orion Pharma
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: July 22, 2014
• First Posted Date: July 25, 2014
• Results First Submitted Date: August 30, 2019
• Results First Posted Date: October 29, 2019
• Last Update Posted Date: June 28, 2022
• Actual Study Start Date: September 12, 2014
• Actual Primary Completion Date: September 3, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 29, 2020)

Metastasis-Free Survival [ Time Frame: From randomization to the time approximately 385 MFS events were observed (approximately 48 months) ]

Metastasis-Free Survival (MFS) is defined as the time from randomisation to evidence of metastasis or death from any cause, whichever occurs first (cut-off date 15 Nov 2019)

Original Primary Outcome Measures (submitted: July 23, 2014)

Metastasis-Free Survival [ Time Frame: Up to 72 months ]

Time from randomisation to evidence of metastasis or death from any cause, whichever occurs first

Current Secondary Outcome Measures (submitted: June 2, 2022)

• Overall Survival - Primary Analysis [ Time Frame: From randomization of the first subject to the time approximatively 140 death events were observed (approximately 48 months) ]
  Overall Survival (OS) was defined as the time from randomization to death due to any cause.
• Time to Pain Progression - Primary Analysis [ Time Frame: From randomization until last study treatment (assessed every 4 months) (approximately 48 months) ]
  Time to pain progression (PP) is defined as time from randomization to pain progression, where progression is defined as an increase of 2 or more points from baseline in question 3 of the Brief Pain Inventory-Short Form questionnaire (BPI-SF) related to the worst pain in the last 24 hours taken as a 7-day average for post-baseline scores, or initiation of short or long-acting opioids for pain, whichever comes first. Initiation or change in the use of other non-opioid analgesics is not used in the analysis of pain progression.
• Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Primary Analysis [ Time Frame: From randomization until last study treatment (assessed every 4 months) (approximately 48 months) ]
  The time to cytotoxic chemotherapy was defined as the time from randomization to the start of the first cytotoxic chemotherapy cycle.
• Time to First Symptomatic Skeletal Event (SSE) - Primary Analysis [ Time Frame: From randomization until last study treatment (assessed every 4 months) (approximately 48 months) ]
  The time to the first SSE was defined as the time from randomization to the occurrence of the first SSE.
• Overall Survival - Final Analysis [ Time Frame: From randomization of the first subject to the time approximatively 254 death events were observed (approximately 56 months) ]
  Overall Survival (OS) was defined as the time from randomization to death due to any cause. The final analysis was done at the time of the data cut-off (15 NOV 2019).
• Time to Pain Progression - Final Analysis [ Time Frame: From randomization until last study treatment (assessed every 4 months) (approximately 48 months) ]
  For time to pain progression, the analysis performed using the primary completion cut-off data (03 SEP 2018) was considered final and no new analysis was performed for time to pain progression.
• Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Final Analysis [ Time Frame: From randomization until initiation of first cytotoxic chemotherapy treatment (approximately 59 months) ]
  The time to cytotoxic chemotherapy was defined as the time from randomization to the start of the first cytotoxic chemotherapy cycle. The final analysis was done at the time of the data cut-off (15 NOV 2019).
• Time to First Symptomatic Skeletal Event (SSE) - Final Analysis [ Time Frame: From randomization until occurrence of first SSE event (approximately 59 months) ]
  The time to the first SSE was defined as the time from randomization to the occurrence of the first SSE. The final analysis was done at the time of the data cut-off (15 NOV 2019).

Original Secondary Outcome Measures (submitted: July 23, 2014)

• Overall Survival [ Time Frame: Up to 72 months ]
  Date of death and primary cause of death will be recorded.
• Time to first symptomatic skeletal event (SSE) [ Time Frame: Up to 72 months ]
  Date of first SSE will be recorded
• Time to initiation of first cytotoxic chemotherapy [ Time Frame: Up to 72 months ]
  Name and start date of cytotoxic chemotherapy treatment will be recorded
• Time to pain progression [ Time Frame: Up to 72 months ]
  Pain will be assessed by Brief Pain Inventory.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety Study of Darolutamide (ODM-201) in Men With High-risk Non-metastatic Castration-resistant Prostate Cancer
• Official Title: A Multinational, Randomised, Double-blind, Placebo-controlled, Phase III Efficacy and Safety Study of Darolutamide (ODM-201) in Men With High-risk Non-metastatic Castration-resistant Prostate Cancer
• Brief Summary: The purpose of this study is to assess the safety and efficacy of BAY1841788 (ODM-201) in patients with non-metastatic castration-resistant prostate cancer.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Prostate Cancer Non-Metastatic
• Castration-Resistant

Intervention

• Drug: Darolutamide (Nubeqa, BAY1841788)
  Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg.
  Other Name: ODM-201
• Drug: Placebo
  Matching placebo 2 tablets twice daily with food.

Study Arms

• Experimental: Darolutamide (BAY1841788)
  Participants received Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg.
  Intervention: Drug: Darolutamide (Nubeqa, BAY1841788)
• Placebo Comparator: Placebo
  Participants received matching placebo 2 tablets twice daily with food.
  Intervention: Drug: Placebo

Publications *

• Chowdhury S, Oudard S, Uemura H, Joniau S, Dearden L, Capone C, Van Sanden S, Diels J, Hadaschik BA. Apalutamide Compared with Darolutamide for the Treatment of Non-metastatic Castration-Resistant Prostate Cancer: Efficacy and Tolerability in a Matching-Adjusted Indirect Comparison. Adv Ther. 2022 Jan;39(1):518-531. doi: 10.1007/s12325-021-01885-6. Epub 2021 Nov 19.
• Fizazi K, Blue I, Nowak JT. Darolutamide and survival in nonmetastatic, castration-resistant prostate cancer: a patient perspective of the ARAMIS trial. Future Oncol. 2021 May;17(14):1699-1707. doi: 10.2217/fon-2020-1291. Epub 2021 Feb 8. Erratum In: Future Oncol. 2022 Jan;18(2):275.
• Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Le Berre MA, Petrenciuc O, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020 Sep 10;383(11):1040-1049. doi: 10.1056/NEJMoa2001342.
• Shore N, Zurth C, Fricke R, Gieschen H, Graudenz K, Koskinen M, Ploeger B, Moss J, Prien O, Borghesi G, Petrenciuc O, Tammela TL, Kuss I, Verholen F, Smith MR, Fizazi K. Evaluation of Clinically Relevant Drug-Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial. Target Oncol. 2019 Oct;14(5):527-539. doi: 10.1007/s11523-019-00674-0.
• Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2019 Mar 28;380(13):1235-1246. doi: 10.1056/NEJMoa1815671. Epub 2019 Feb 14. Erratum In: N Engl J Med. 2022 Sep 1;387(9):860.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 15, 2021): 1509
• Original Estimated Enrollment (submitted: July 23, 2014): 1500
• Actual Study Completion Date: June 14, 2021
• Actual Primary Completion Date: September 3, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of prostate without neuroendocrine differentiation or small cell features.
• Castration-resistant prostate cancer (CRPC) with castrate level of serum testosterone.
• Prostate-specific Antigen (PSA) doubling time of ≤ 10 months and PSA > 2ng/ml.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Blood counts at screening: haemoglobin ≥ 9.0 g/dl,absolute neutrophil count ≥ 1500/µl, platelet count ≥ 100,000/µl.
• Screening values of serum alanine aminotransferase (ALT) and/or aspartate transaminase (AST) ≤ 2.5 x upper limit of normal (ULN), total bilirubin ≤ 1.5 x ULN, creatinine ≤ 2.0 x ULN.
• Sexually active patients, unless surgically sterile, must agree to use condoms as an effective barrier method and refrain from sperm donation during the study treatment and for 3 months after the end of the study treatment.

Exclusion Criteria:

• History of metastatic disease at any time or presence of detectable metastases.
• Acute toxicities of prior treatments and procedures not resolved to grade ≤ 1 or baseline before randomisation.
• Prior treatment with: second generation androgen receptor (AR) inhibitors, other investigational AR inhibitors, or CYP17 enzyme inhibitor.
• Use of estrogens or 5-α reductase inhibitors or AR inhibitors.
• Prior chemotherapy or immunotherapy for prostate cancer.
• Use of systemic corticosteroid.
• Radiation therapy within 12 weeks before randomisation.
• Severe or uncontrolled concurrent disease, infection or co-morbidity.
• Treatment with bisphosphonate or denosumab within 12 weeks before randomisation.
• Known hypersensitivity to the study treatment or any of its ingredients.
• Major surgery within 28 days before randomisation.
• Any of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV.
• Uncontrolled hypertension.
• Prior malignancy.
• Gastrointestinal disorder or procedure which expects to interfere significantly with absorption of study treatment.
• Active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease.
• Treatment with any investigational drug within 28 days before randomisation.
• Any condition that in the opinion of the investigator would impair the patients' ability to comply with the study procedures.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belarus, Belgium, Brazil, Bulgaria, Canada, Colombia, Czechia, Estonia, Finland, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Latvia, Lithuania, Peru, Poland, Portugal, Romania, Russian Federation, Serbia, Slovakia, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic, Greece

Administrative Information

• NCT Number: NCT02200614
• Other Study ID Numbers: 17712; 2013-003820-36 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bayer
• Original Responsible Party: Orion Corporation, Orion Pharma
• Current Study Sponsor: Bayer
• Original Study Sponsor: Orion Corporation, Orion Pharma
• Collaborators: Orion Corporation, Orion Pharma

Investigators

• Study Director: Bayer Study Director; Bayer

• PRS Account: Bayer
• Verification Date: June 2022