Clinical Trial Results:
A randomized, double-blind, placebo-controlled Phase III study of darolutamide (ODM-201) versus placebo in addition to standard androgen deprivation therapy and docetaxel in patients with metastatic hormone-sensitive prostate cancer
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Summary
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EudraCT number |
2015-002590-38 |
Trial protocol |
GB SE BE ES FI DE CZ NL PL FR BG IT |
Global end of trial date |
11 Apr 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Apr 2024
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First version publication date |
10 Apr 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BAY1841788/17777
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02799602 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bayer AG
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Sponsor organisation address |
Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
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Public contact |
Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com
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Scientific contact |
Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
11 Apr 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Apr 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate the superiority in overall survival (OS) of darolutamide in addition to standard androgen deprivation therapy (ADT) and docetaxel over placebo in addition to standard ADT and docetaxel.
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Protection of trial subjects |
The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
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Background therapy |
ADT of the investigator’s choice (luteinizing hormone-releasing hormone [LHRH] agonist/antagonist or orchiectomy) as standard therapy, started ≤12 weeks before randomization. Docetaxel at a dose of 75 mg/m2 as an intravenous infusion every 21 days for 6 cycles, starting within 6 weeks after the start of the study drug, and in combination with prednisone/prednisolone at the discretion of the investigator. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Nov 2016
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy | ||
Long term follow-up duration |
59 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 21
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Country: Number of subjects enrolled |
Belgium: 24
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Country: Number of subjects enrolled |
Brazil: 53
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Country: Number of subjects enrolled |
Bulgaria: 17
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Country: Number of subjects enrolled |
Canada: 26
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Country: Number of subjects enrolled |
China: 203
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Country: Number of subjects enrolled |
Czechia: 13
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Country: Number of subjects enrolled |
Finland: 24
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Country: Number of subjects enrolled |
France: 43
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Country: Number of subjects enrolled |
Germany: 54
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Country: Number of subjects enrolled |
Israel: 28
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Country: Number of subjects enrolled |
Italy: 17
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Country: Number of subjects enrolled |
Japan: 148
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Country: Number of subjects enrolled |
Mexico: 14
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Country: Number of subjects enrolled |
Netherlands: 33
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Country: Number of subjects enrolled |
Poland: 17
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Country: Number of subjects enrolled |
Russian Federation: 91
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Country: Number of subjects enrolled |
Korea, Republic of: 85
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Country: Number of subjects enrolled |
Spain: 75
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Country: Number of subjects enrolled |
Sweden: 35
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Country: Number of subjects enrolled |
Taiwan: 37
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Country: Number of subjects enrolled |
United Kingdom: 29
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Country: Number of subjects enrolled |
United States: 218
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Worldwide total number of subjects |
1305
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EEA total number of subjects |
352
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
477
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From 65 to 84 years |
821
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85 years and over |
7
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Recruitment
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Recruitment details |
This multinational study was conducted between 30-Nov-2016 First Subject First Visit and 11-Apr-2023 Last Subject Last Visit in 23 countries/regions: Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, Finland, France, Germany, Israel, Italy, Japan, Mexico, Netherlands, Poland, Russia, South Korea, Spain, Sweden, Taiwan, UK and US | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
1306 subjects were randomly assigned in a 1:1 ratio to study treatment and 1305 subjects were considered valid for efficacy analyses. A total of 1302 subjects started treatment and were included to safety analyses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Investigator, Monitor, Data analyst, Carer, Subject, Assessor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Double-blind
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Darolutamide (BAY1841788) + Docetaxel | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Darolutamide (Nubeqa, BAY1841788)
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Investigational medicinal product code |
BAY1841788
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg.
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Arm title
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Placebo + Docetaxel | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Matching placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The dosing of placebo is the same as for darolutamide
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Baseline characteristics reporting groups
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Reporting group title |
Darolutamide (BAY1841788) + Docetaxel
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Reporting group description |
Subjects received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo + Docetaxel
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Reporting group description |
Subjects received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Darolutamide (BAY1841788) + Docetaxel
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Reporting group description |
Subjects received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization. | ||
Reporting group title |
Placebo + Docetaxel
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Reporting group description |
Subjects received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization. | ||
Subject analysis set title |
Full analysis set (FAS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects who were randomized were included in the FAS
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Subject analysis set title |
Safety analysis set (SAF)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All randomized subjects who received at least 1 dose of darolutamide or placebo were included in the SAF.
Subjects were included in the darolutamide+docetaxel arm if they received any dose of darolutamide and were included in the placebo+docetaxel arm if they only received the placebo.
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End point title |
OS from date of randomization until death from any cause - Number of events | |||||||||||||||
End point description |
Overall survival (OS) was defined as the time from the date of randomization until death from any cause.
Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
Long-term (Survival) follow-up period: After Active follow-up, patients continued to be contacted approximately every 12 weeks by phone. The end of the Survival follow-up period was defined as when the patient died, was lost to follow-up, withdrew consent, or at the end-of-study.
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End point type |
Primary
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End point timeframe |
From randomization of the first subject until death from any cause up to 25 OCT 2021 cut-off date 533 OS events were reached (approximate 59 months)
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| Notes [1] - FAS [2] - FAS |
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Statistical analysis title |
OS - Inferential statistics | |||||||||||||||
Statistical analysis description |
One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
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Comparison groups |
Darolutamide (BAY1841788) + Docetaxel v Placebo + Docetaxel
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Number of subjects included in analysis |
1305
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | |||||||||||||||
P-value |
< 0.0001 [4] | |||||||||||||||
Method |
Logrank | |||||||||||||||
Parameter type |
Hazard ratio (HR) | |||||||||||||||
Point estimate |
0.675
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.568 | |||||||||||||||
upper limit |
0.801 | |||||||||||||||
| Notes [3] - Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN). [4] - One-sided p-value. |
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End point title |
OS from date of randomization until death from any cause - Month [5] | ||||||||||||
End point description |
Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
Long-term (Survival) follow-up period: After Active follow-up, patients continued to be contacted approximately every 12 weeks by phone. The end of the Survival follow-up period was defined as when the patient died, was lost to follow-up, withdrew consent, or at the end-of-study.
Median, percentile and other 95% CIs were computed using Kaplan-Meier estimates.
99999 = Value cannot be estimated due to censored
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End point type |
Primary
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End point timeframe |
From randomization of the first subject until death from any cause up to 25 OCT 2021 cut-off date 533 OS events were reached (approximate 59 months)
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Refer to inferential statistics table above under endpoint "Primary: OS from date of randomization until death from any cause - Number of events". |
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| Notes [6] - FAS [7] - FAS |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of subjects with TEAEs | ||||||||||||||||||||||||||||||||||||||||||
End point description |
TEAEs = Treatment-emergent adverse events, were defined as any event(s) arising or worsening after the first dose of darolutamide or placebo, until 30 days after the last dose of darolutamide or placebo administration.
Number of Subjects Analyzed for arm "Darolutamide (BAY1841788) + Docetaxel" should be 652. One subject was randomized to the placebo+docetaxel arm but received at least one dose of darolutamide. This subject was included in the darolutamide+docetaxel arm in the analysis of all safety variables
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End point type |
Secondary
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End point timeframe |
From the first dose of darolutamide or placebo until 30 days after the last dose of darolutamide or placebo administration up to cut-off date for the final completion analysis 11 APR 2023 (approximately 77 months)
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| Notes [8] - SAF: Number of Subjects Analyzed should be 652. Details refer to "End point description" above. [9] - SAF |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Time to castration–resistant prostate cancer (CRPC) - Month | ||||||||||||
End point description |
Time to castration-resistant prostate cancer was defined as the time from randomization to the first occurrence of one of the following events: PSA progression, Radiological progression by bone lesions, or Radiological progression by soft tissue and visceral lesions.
Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
99999 = Value cannot be estimated due to censored data
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End point type |
Secondary
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End point timeframe |
From randomization of the first subject to the first occurrence of an CRPC event up to 25 OCT 2021 cut-off date approximately 59 months
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| Notes [10] - FAS [11] - FAS |
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Statistical analysis title |
CRPC - Inferential statistics | ||||||||||||
Statistical analysis description |
One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
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Comparison groups |
Darolutamide (BAY1841788) + Docetaxel v Placebo + Docetaxel
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Number of subjects included in analysis |
1305
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Analysis specification |
Pre-specified
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Analysis type |
superiority [12] | ||||||||||||
P-value |
< 0.0001 [13] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.357
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.302 | ||||||||||||
upper limit |
0.421 | ||||||||||||
| Notes [12] - Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN). [13] - One-sided p-value. |
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End point title |
Time to castration–resistant prostate cancer (CRPC) - Number of events | |||||||||||||||
End point description |
Time to castration-resistant prostate cancer was defined as the time from randomization to the first occurrence of one of the following events: PSA progression, Radiological progression by bone lesions, or Radiological progression by soft tissue and visceral lesions.
Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
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End point type |
Secondary
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End point timeframe |
From randomization of the first subject to the first occurrence of an CRPC event up to 25 OCT 2021 cut-off date approximately 59 months
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| Notes [14] - FAS [15] - FAS |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Time to pain progression - Month | ||||||||||||
End point description |
Time to pain progression was defined as the time from randomization to the first date a patient experienced pain progression.
Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
99999 = Value cannot be estimated due to censored data
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End point type |
Secondary
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End point timeframe |
From randomization of the first subject to the first occurrence of a pain progression event up to 25 OCT 2021 cut-off date approximately 59 months
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| Notes [16] - FAS [17] - FAS |
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Statistical analysis title |
Time to pain progression-Inferential statistics | ||||||||||||
Statistical analysis description |
One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
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Comparison groups |
Darolutamide (BAY1841788) + Docetaxel v Placebo + Docetaxel
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Number of subjects included in analysis |
1305
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Analysis specification |
Pre-specified
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Analysis type |
superiority [18] | ||||||||||||
P-value |
= 0.0058 [19] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.792
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.66 | ||||||||||||
upper limit |
0.95 | ||||||||||||
| Notes [18] - Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN). [19] - One-sided p-value. |
|||||||||||||
|
||||||||||||||||
End point title |
Time to pain progression - Number of events | |||||||||||||||
End point description |
Time to pain progression was defined as the time from randomization to the first date a patient experienced pain progression.
Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From randomization of the first subject to the first occurrence of a pain progression event up to 25 OCT 2021 cut-off date approximately 59 months
|
|||||||||||||||
|
||||||||||||||||
| Notes [20] - FAS [21] - FAS |
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||
End point title |
Symptomatic skeletal event free survival (SSE–FS) - Number of events | |||||||||||||||
End point description |
Symptomatic skeletal event-free survival (SSE-FS) was defined as the time from randomization to the first occurrence of an SSE or death from any cause, whichever occurred first.
Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From randomization of the first subject to the first occurrence of an SSE event or death from any cause, whichever occurred first up to 25 OCT 2021 cut-off date approximately 59 months
|
|||||||||||||||
|
||||||||||||||||
| Notes [22] - FAS [23] - FAS |
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||
End point title |
Time to first symptomatic skeletal event (SSE) - Number of events | |||||||||||||||
End point description |
Time to the first SSE was defined as the time from randomization to the first occurrence of an SSE. Identical to the definition used for SSE-FS. Death was not considered as an event in this endpoint.
Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From randomization of the first subject to the first occurrence of an SSE event up to 25 OCT 2021 cut-off date approximately 59 months
|
|||||||||||||||
|
||||||||||||||||
| Notes [24] - FAS [25] - FAS |
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||
End point title |
Symptomatic skeletal event free survival (SSE–FS) - Month | ||||||||||||
End point description |
Symptomatic skeletal event-free survival (SSE-FS) was defined as the time from randomization to the first occurrence of an SSE or death from any cause, whichever occurred first.
Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
99999 = Value cannot be estimated due to censored data
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomization of the first subject to the first occurrence of an SSE event or death from any cause, whichever occurred first up to 25 OCT 2021 cut-off date approximately 59 months
|
||||||||||||
|
|||||||||||||
| Notes [26] - FAS [27] - FAS |
|||||||||||||
Statistical analysis title |
SSE–FS - Inferential statistics | ||||||||||||
Statistical analysis description |
One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
|
||||||||||||
Comparison groups |
Darolutamide (BAY1841788) + Docetaxel v Placebo + Docetaxel
|
||||||||||||
Number of subjects included in analysis |
1305
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [28] | ||||||||||||
P-value |
< 0.0001 [29] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.609
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.516 | ||||||||||||
upper limit |
0.718 | ||||||||||||
| Notes [28] - Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN). [29] - One-sided p-value. |
|||||||||||||
|
||||||||||||||||
End point title |
Time to initiation of subsequent antineoplastic therapy - Number of events | |||||||||||||||
End point description |
Time to initiation of subsequent systemic antineoplastic therapy was defined as the time from randomization to the initiation of first subsequent systemic antineoplastic therapy.
Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From randomization of the first subject to the initiation of first subsequent systemic antineoplastic therapy up to 25 OCT 2021 cut-off date approximately 59 months
|
|||||||||||||||
|
||||||||||||||||
| Notes [30] - FAS [31] - FAS |
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||
End point title |
Time to first symptomatic skeletal event (SSE) - Month | ||||||||||||
End point description |
Time to the first SSE was defined as the time from randomization to the first occurrence of an SSE. Identical to the definition used for SSE-FS. Death was not considered as an event in this endpoint.
Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
99999 = Value cannot be estimated due to censored data
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomization of the first subject to the first occurrence of an SSE event up to 25 OCT 2021 cut-off date approximately 59 months
|
||||||||||||
|
|||||||||||||
| Notes [32] - FAS [33] - FAS |
|||||||||||||
Statistical analysis title |
SSE - Inferential statistics | ||||||||||||
Statistical analysis description |
One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
|
||||||||||||
Comparison groups |
Darolutamide (BAY1841788) + Docetaxel v Placebo + Docetaxel
|
||||||||||||
Number of subjects included in analysis |
1305
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [34] | ||||||||||||
P-value |
= 0.0081 [35] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.712
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.539 | ||||||||||||
upper limit |
0.94 | ||||||||||||
| Notes [34] - Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN). [35] - One-sided p-value. |
|||||||||||||
|
|||||||||||||
End point title |
Time to initiation of subsequent antineoplastic therapy - Month | ||||||||||||
End point description |
Time to initiation of subsequent systemic antineoplastic therapy was defined as the time from randomization to the initiation of first subsequent systemic antineoplastic therapy.
Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
99999 = Value cannot be estimated due to censored data
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomization of the first subject to the initiation of first subsequent systemic antineoplastic therapy up to 25 OCT 2021 cut-off date approximately 59 months
|
||||||||||||
|
|||||||||||||
| Notes [36] - FAS [37] - FAS |
|||||||||||||
Statistical analysis title |
Inferential statistics | ||||||||||||
Statistical analysis description |
One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
|
||||||||||||
Comparison groups |
Darolutamide (BAY1841788) + Docetaxel v Placebo + Docetaxel
|
||||||||||||
Number of subjects included in analysis |
1305
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [38] | ||||||||||||
P-value |
< 0.0001 [39] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Log hazard ratio | ||||||||||||
Point estimate |
0.388
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.328 | ||||||||||||
upper limit |
0.458 | ||||||||||||
| Notes [38] - Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN). [39] - One-sided p-value. |
|||||||||||||
|
|||||||||||||
End point title |
Time to worsening of disease–related physical symptoms - Month | ||||||||||||
End point description |
Time to worsening of disease-related physical symptoms was defined as the time from randomization to the first date a patient experienced an increase in disease-related physical
symptoms based on the NCCN-FACT-FPSI-17 questionnaire.
Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomization of the first subject to the first increase in disease-related physical symptoms based on the NCCN-FACT-FPSI-17 questionnaire up to 25 OCT 2021 cut-off date approximately 59 months
|
||||||||||||
|
|||||||||||||
| Notes [40] - FAS [41] - FAS |
|||||||||||||
Statistical analysis title |
Worsening of disease - Inferential statistics | ||||||||||||
Statistical analysis description |
One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
|
||||||||||||
Comparison groups |
Darolutamide (BAY1841788) + Docetaxel v Placebo + Docetaxel
|
||||||||||||
Number of subjects included in analysis |
1305
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [42] | ||||||||||||
P-value |
= 0.7073 [43] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.043
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.894 | ||||||||||||
upper limit |
1.217 | ||||||||||||
| Notes [42] - Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN). [43] - One-sided p-value. |
|||||||||||||
|
||||||||||||||||
End point title |
Time to worsening of disease–related physical symptoms - Number of events | |||||||||||||||
End point description |
Time to worsening of disease-related physical symptoms was defined as the time from randomization to the first date a patient experienced an increase in disease-related physical
symptoms based on the NCCN-FACT-FPSI-17 questionnaire.
Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From randomization of the first subject to the first increase in disease-related physical symptoms based on the NCCN-FACT-FPSI-17 questionnaire up to 25 OCT 2021 cut-off date approximately 59 months
|
|||||||||||||||
|
||||||||||||||||
| Notes [44] - FAS [45] - FAS |
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||
End point title |
Time to initiation of opioid use for ≥7 consecutive days - Number of events | |||||||||||||||
End point description |
Time to the initiation of opioid use for ≥7 consecutive days was defined as the time fromrandomization to the date of the first opioid use for ≥7 consecutive days. Data of opioid use related to cancer pain was included in the analysis, and opioid use for non-malignant causes was excluded.
Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From randomization of the first subject to the first opioid use for ≥7 consecutive days up to 25 OCT 2021 cut-off date approximately 59 months
|
|||||||||||||||
|
||||||||||||||||
| Notes [46] - FAS [47] - FAS |
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||
End point title |
Time to initiation of opioid use for ≥7 consecutive days - Month | ||||||||||||
End point description |
Time to the initiation of opioid use for ≥7 consecutive days was defined as the time fromrandomization to the date of the first opioid use for ≥7 consecutive days. Data of opioid use related to cancer pain was included in the analysis, and opioid use for non-malignant causes was excluded.
Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance.
Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
99999 = Value cannot be estimated due to censored data
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomization of the first subject to the first opioid use for ≥7 consecutive days up to 25 OCT 2021 cut-off date approximately 59 months
|
||||||||||||
|
|||||||||||||
| Notes [48] - FAS [49] - FAS |
|||||||||||||
Statistical analysis title |
Initiation of opioid - Inferential statistics | ||||||||||||
Statistical analysis description |
One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
|
||||||||||||
Comparison groups |
Darolutamide (BAY1841788) + Docetaxel v Placebo + Docetaxel
|
||||||||||||
Number of subjects included in analysis |
1305
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [50] | ||||||||||||
P-value |
= 0.0037 [51] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.688
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.523 | ||||||||||||
upper limit |
0.906 | ||||||||||||
| Notes [50] - Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN). [51] - One-sided p-value. |
|||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From start of study drug administration until 30 days after the last administration, including adverse event of deaths (all causes) at any time during the study, up to cut-off date for the final completion analysis 11 APR 2023 (approximately 77 months).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
TEAEs were defined as any event arising or worsening after the first dose of darolutamide or placebo, until 30 days after the last dose of darolutamide or placebo administration.
Events causally related to treatment were considered as events causally related to either darolutamide/Docetaxel or Placebo/Docetaxel.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
Placebo + Docetaxel
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Reporting group description |
Subjects received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started <=12 weeks before randomization. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Darolutamide (BAY1841788) + Docetaxel
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Reporting group description |
Subjects received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started <=12 weeks before randomization. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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20 Sep 2016 |
Protocol Amendment 1, dated 20 SEP 2016, was valid only for centers located in China. The main modification was:
• Addition of new China specific pharmacokinetic (PK) sub-study |
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04 Oct 2016 |
Protocol Amendment 2, dated 04 OCT 2016, was globally implemented. The main modifications were:
• New drug-drug interaction data added
• Clarification of PK analysis
o Patients participating to the detailed PK analysis (dense PK sampling) had received at least one cycle of docetaxel
o Clarified the timing of the sparse PK sampling
o Additional analysis of docetaxel in all the randomized patients
• Addition of non-protein-bound (free) testosterone analysis |
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04 Nov 2016 |
Protocol Amendment 3, dated 04 NOV 2016, was valid only for centers located in UK. The main modification was:
• List of acceptable effective contraception methods to be used was added by request of the Medicines and Healthcare Products Regulatory Agency (MHRA)
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31 Jan 2017 |
Protocol Amendment 4, dated 31 JAN 2017, was valid only for centers located in Japan. The main modification was:
• Added reporting requirements for medical device failures for imported and non-approved third-party devices used in Bayer-sponsored clinical trials in Japan to the PMDA, IECs/IRBs and investigators
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12 Feb 2018 |
Protocol Amendment 5, dated 12 FEB 2018, was globally implemented. The main modifications were:
• New drug-drug interaction data added
• Modification of the dosing language to align darolutamide dosing wording across the development program
• Clarification of docetaxel dosage and administration in accordance with the label and clarified that the first cycle of docetaxel should be administered within 6 weeks after start of study drug instead of 6 weeks after randomization
• Guidance on laboratory tests before each docetaxel cycle to be in line with docetaxel label requirements
• Clarification added for the evaluation of soft tissue and visceral lesions; these were to be performed using the same radiological methods and assessed by RECIST criteria
• ADT switch to LHRH agonist was added to the list of prohibited concomitant medications and treatments and a clarification was added to allow an ADT switch to an antagonist during study treatment
• Collection of whole blood sample for pharmacogenetics test allowed at other visits if missed at Visit 1
• Clarification added for:
o Unblinding in non–emergency situations was not permitted
o For PK sampling
o For laboratory safety assessments
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10 Dec 2019 |
Protocol Amendment 6, dated 10 DEC 2019, was globally implemented. The main modifications were:
• Option to continue darolutamide treatment in a separate program was added for those patients who are ongoing on darolutamide treatment; patients assigned to placebo would discontinue treatment and complete the study
• Additional survival sweeps were added
• Detailed information on darolutamide drug-drug interactions was removed and information on the effect of darolutamide on the PK of docetaxel was updated
• Guidance and cautions for specific drug-drug interactions were removed based on new data on these interactions becoming available
• AE reporting was modified to clarify that disease progression should not be reported as an AE; only the associated signs and symptoms should be reported as AEs
• In a subset of patients, additional determination of total and free testosterone was added to be performed also at the EOT Visit
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26 May 2020 |
Protocol Amendment 7, dated 26 MAY 2020, was globally implemented. The main modifications were:
• Planned second interim analysis was removed due to the implications of the COVID–19 pandemic on the conduct of study procedures and data collection at the study sites. The risk for not achieving the needed quality of data for a formal analysis at that point in time was considered to be too high
• Clarification added for biomarker analysis and reporting
• Added text regarding ranking of secondary endpoints
• Due to removal of interim analysis 2, the sentence regarding alpha–spending was removed and a statement about beta–spending was added for clarification
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30 Aug 2021 |
Protocol Amendment 8, dated 30 AUG 2021 was valid only for centers located in Japan. The main modifications were:
• To minimize the burden for subjects still enrolled after the study reached primary completion, the number of procedures will be reduced to a minimum, to guarantee patient treatment continuation and safety
• Japanese subjects will be provided the opportunity to continue treatment at the discretion of the investigator
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02 Aug 2022 |
Protocol Amendment 9, dated 02 AUG 2022 was valid only for centers located in Japan. However, it was prepared as a consolidated protocol and therefore also includes the latest global protocol version 5.0 (amendment 7). It provided guidance on the criteria for study drug discontinuation in the event of a suspected drug-induced liver injury (DILI) because of newly identified safety data across darolutamide clinical trials, including cases of idiosyncratic hepatic reactions that were reversible upon treatment discontinuation. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
