Metastatic Hormone-sensitive Prostate Cancer
Conditions
Brief summary
The purpose of the study is to assess the efficacy and safety of BAY1841788 (darolutamide (ODM-201)) in combination with standard androgen deprivation therapy (ADT) and docetaxel in patients with metastatic hormone sensitive prostate cancer.
Detailed description
This is a randomized, double-blind, placebo-controlled, multicenter phase III study. The study population will consist of approximately 1300 subjects with metastatic hormone sensitive prostate cancer (mHSPC), who will be randomized (1:1 ratio) to receive 600 mg (2 x 300 mg tablets) of darolutamide (ODM-201)/placebo twice daily with food, equivalent to a total daily dose of 1200 mg, in addition to standard androgen deprivation therapy (ADT) and docetaxel. Subjects will be stratified at randomization for the extent of disease and for Alkaline Phosphatase levels. All subjects will be treated with ADT as standard therapy. Six cycles of docetaxel will be administered after randomization. The subjects considered for inclusion in the study will have metastatic prostate cancer and will be candidates for ADT and docetaxel. Treatment with darolutamide (ODM-201)/placebo will be administered until symptomatic progressive disease, change of antineoplastic therapy, unacceptable toxicity, until subject withdraws consent, withdrawal from the study at the discretion of the investigator or his/her designated associate(s), death, non-compliance, or if sponsor terminates the study.
Interventions
DRUGBAY1841788 / darolutamide (ODM-201)
600mg (2 tablets of 300 mg) of darolutamide (ODM-201)/placebo twice daily with food, equivalent to a total a daily dose of 1200 mg in addition to standard ADT (luteinizing hormone releasing hormone (LHRH) agonist/antagonist or orchiectomy) and 6 cycles of docetaxel
As prescribed by the treating physician.
DRUGDocetaxel
As prescribed by the treating physician.
DRUGPlacebo
Placebo matching darolutamide (ODM-201) tablets in appearance, bid orally with food, in addition to standard ADT (luteinizing hormone releasing hormone \[LHRH\] agonist/antagonist or orchiectomy) and 6 cycles of docetaxel.
Sponsors
Orion Corporation, Orion Pharma
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed adenocarcinoma of prostate. * Metastatic disease * Candidates for ADT and docetaxel. * Started ADT with or without first generation anti androgen, but no longer than 12 weeks before randomization * An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Adequate bone marrow, liver and renal function
Exclusion criteria
* Prior treatment with: LHRH agonist/antagonists; second generation androgen receptor (AR) inhibitors such as enzalutamide, ARN-509, darolutamide (ODM-201), other investigational AR inhibitors; CYP17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment for prostate cancer; chemotherapy or immunotherapy for prostate cancer prior to randomization. * Treatment with radiotherapy/radiopharmaceuticals within 2 weeks before randomization. * Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV) * Had a prior malignancy. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e., pTis, pTa, and pT1) is allowed, as well as any other cancer for which treatment has been completed 5 years before randomization and from which the subject has been disease-free * Gastrointestinal disorder or procedure which is expected to interfere significantly with absorption of study treatment. * Inability to swallow oral medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| OS From Date of Randomization Until Death From Any Cause - Number of Events | From randomization of the first participant until death from any cause up to 25 OCT 2021 cut-off date 533 OS events were reached (approximate 59 months) | 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. |
| OS From Date of Randomization Until Death From Any Cause - Month | From randomization of the first participant until death from any cause up to 25 OCT 2021 cut-off date 533 OS events were reached (approximate 59 months) | 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. Median, percentile and other 95% CIs were computed using Kaplan-Meier estimates. NA = Value cannot be estimated due to censored data |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Castration-Resistant Prostate Cancer (CRPC) - Month | From randomization of the first participant to the first occurrence of an CRPC event up to 25 OCT 2021 cut-off date approximately 59 months | 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. NA = Value cannot be estimated due to censored data |
| Time to Pain Progression - Number of Events | From randomization of the first participant to the first occurrence of a pain progression event up to 25 OCT 2021 cut-off date approximately 59 months | 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. |
| Time to Pain Progression - Month | From randomization of the first participant to the first occurrence of a pain progression event up to 25 OCT 2021 cut-off date approximately 59 months | 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. NA = Value cannot be estimated due to censored data |
| Symptomatic Skeletal Event Free Survival (SSE-FS) - Number of Events | From randomization of the first participant 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 | 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. |
| Symptomatic Skeletal Event Free Survival (SSE-FS) - Month | From randomization of the first participant 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 | 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. NA = Value cannot be estimated due to censored data |
| Time to First Symptomatic Skeletal Event (SSE) - Number of Events | From randomization of the first participant to the first occurrence of an SSE event up to 25 OCT 2021 cut-off date approximately 59 months | 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. |
| Number of Participants With TEAEs | 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) | 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. |
| Time to Initiation of Subsequent Antineoplastic Therapy - Number of Events | From randomization of the first participant to the initiation of first subsequent systemic antineoplastic therapy up to 25 OCT 2021 cut-off date approximately 59 months | 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. |
| Time to Initiation of Subsequent Antineoplastic Therapy - Month | From randomization of the first participant to the initiation of first subsequent systemic antineoplastic therapy up to 25 OCT 2021 cut-off date approximately 59 months | 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. NA = Value cannot be estimated due to censored data |
| Time to Worsening of Disease-Related Physical Symptoms - Number of Events | From randomization of the first participant 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 | 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. |
| Time to Worsening of Disease-Related Physical Symptoms - Month | From randomization of the first participant 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 | 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. |
| Time to Initiation of Opioid Use for ≥7 Consecutive Days - Number of Events | From randomization of the first participant to the first opioid use for ≥7 consecutive days up to 25 OCT 2021 cut-off date approximately 59 months | 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. |
| Time to Initiation of Opioid Use for ≥7 Consecutive Days - Month | From randomization of the first participant to the first opioid use for ≥7 consecutive days up to 25 OCT 2021 cut-off date approximately 59 months | 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. NA = Value cannot be estimated due to censored data |
| Time to First Symptomatic Skeletal Event (SSE) - Month | From randomization of the first participant to the first occurrence of an SSE event up to 25 OCT 2021 cut-off date approximately 59 months | 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. NA = Value cannot be estimated due to censored data |
| Time to Castration-Resistant Prostate Cancer (CRPC) - Number of Events | From randomization of the first participant to the first occurrence of an CRPC event up to 25 OCT 2021 cut-off date approximately 59 months | 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. |
Countries
Australia, Belgium, Brazil, Bulgaria, Canada, China, Czechia, Finland, France, Germany, Israel, Italy, Japan, Mexico, Netherlands, Poland, Russia, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This multinational study was conducted between 30-Nov-2016 First Participant First Visit and 11-Apr-2023 Last Participant Last Visit, in 23 countries/regions: Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, Finland, France, Germany, Israel, Italy, Japan, Mexico, Netherlands, Poland, Russian Federation, South Korea, Spain, Sweden, Taiwan, UK, US
Pre-assignment details
1306 were randomly assigned in a 1:1 ratio to study treatment and 1305 were considered valid for efficacy analyses. A total of 1302 participants started treatment and were included to safety analyses.
Participants by arm
| Arm | Count |
|---|---|
| Darolutamide (BAY1841788) + Docetaxel Participants 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. | 651 |
| Placebo + Docetaxel Participants 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. | 654 |
| Total | 1,305 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Additional primary malignancy | 11 | 6 |
| Overall Study | Adverse event associated with clinical disease progression | 24 | 26 |
| Overall Study | Adverse event not associated with clinical disease progression | 49 | 27 |
| Overall Study | Death | 9 | 5 |
| Overall Study | Lost to Follow-up | 4 | 2 |
| Overall Study | Non-compliance with study drug | 14 | 12 |
| Overall Study | Other | 287 | 118 |
| Overall Study | Physician Decision | 5 | 6 |
| Overall Study | Progressive disease - clinical progression | 131 | 276 |
| Overall Study | Progressive disease - radiological progression | 90 | 133 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Study drug never administered | 0 | 3 |
| Overall Study | Withdrawal by Subject | 26 | 40 |
Baseline characteristics
| Characteristic | Darolutamide (BAY1841788) + Docetaxel | Placebo + Docetaxel | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 408 Participants | 420 Participants | 828 Participants |
| Age, Categorical Between 18 and 65 years | 243 Participants | 234 Participants | 477 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 40 Participants | 49 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 561 Participants | 557 Participants | 1118 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 50 Participants | 48 Participants | 98 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 231 Participants | 245 Participants | 476 Participants |
| Race (NIH/OMB) Black or African American | 26 Participants | 28 Participants | 54 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 43 Participants | 46 Participants | 89 Participants |
| Race (NIH/OMB) White | 345 Participants | 333 Participants | 678 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 651 Participants | 654 Participants | 1305 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 231 / 652 | 305 / 650 |
| other Total, other adverse events | 636 / 652 | 634 / 650 |
| serious Total, serious adverse events | 306 / 652 | 276 / 650 |
Outcome results
Primary
OS From Date of Randomization Until Death From Any Cause - Month
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. Median, percentile and other 95% CIs were computed using Kaplan-Meier estimates. NA = Value cannot be estimated due to censored data
Time frame: From randomization of the first participant until death from any cause up to 25 OCT 2021 cut-off date 533 OS events were reached (approximate 59 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | OS From Date of Randomization Until Death From Any Cause - Month | NA Month |
| Placebo + Docetaxel | OS From Date of Randomization Until Death From Any Cause - Month | 48.9 Month |
Primary
OS From Date of Randomization Until Death From Any Cause - Number of Events
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.
Time frame: From randomization of the first participant until death from any cause up to 25 OCT 2021 cut-off date 533 OS events were reached (approximate 59 months)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | OS From Date of Randomization Until Death From Any Cause - Number of Events | Number of patients with event | 229 Participants |
| Darolutamide (BAY1841788) + Docetaxel | OS From Date of Randomization Until Death From Any Cause - Number of Events | Number of patients censored | 422 Participants |
| Placebo + Docetaxel | OS From Date of Randomization Until Death From Any Cause - Number of Events | Number of patients censored | 350 Participants |
| Placebo + Docetaxel | OS From Date of Randomization Until Death From Any Cause - Number of Events | Number of patients with event | 304 Participants |
p-value: <0.000195% CI: [0.568, 0.801]Log Rank
Secondary
Number of Participants With TEAEs
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.
Time frame: 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)
Population: The number of patients who started treatment is presented based on the randomized treatment assignment. One patient was randomized to the placebo+docetaxel arm but received at least one dose of darolutamide. This patient was included in the darolutamide+docetaxel arm in the analysis of all safety variables.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Number of Participants With TEAEs | TEAE leading to permanent discontinuation of study drug | 90 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Number of Participants With TEAEs | Related to protocol-required procedure | 69 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Number of Participants With TEAEs | TEAE leading to study drug dose modification | 172 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Number of Participants With TEAEs | Any study drug-related TEAE | 344 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Number of Participants With TEAEs | TEAE leading to docetaxel dose modification | 216 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Number of Participants With TEAEs | Study drug-related TESAE | 30 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Number of Participants With TEAEs | TESAE | 306 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Number of Participants With TEAEs | Study drug-related TEAE leading to study drug dose modification | 75 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Number of Participants With TEAEs | TEAE leading to permanent discontinuation of docetaxel | 52 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Number of Participants With TEAEs | Study drug-related TEAE leading to permanent discontinuation of study drug | 25 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Number of Participants With TEAEs | Any TEAE | 649 Participants |
| Placebo + Docetaxel | Number of Participants With TEAEs | Study drug-related TEAE leading to permanent discontinuation of study drug | 13 Participants |
| Placebo + Docetaxel | Number of Participants With TEAEs | Any TEAE | 643 Participants |
| Placebo + Docetaxel | Number of Participants With TEAEs | TESAE | 276 Participants |
| Placebo + Docetaxel | Number of Participants With TEAEs | TEAE leading to study drug dose modification | 112 Participants |
| Placebo + Docetaxel | Number of Participants With TEAEs | TEAE leading to permanent discontinuation of study drug | 69 Participants |
| Placebo + Docetaxel | Number of Participants With TEAEs | TEAE leading to docetaxel dose modification | 214 Participants |
| Placebo + Docetaxel | Number of Participants With TEAEs | TEAE leading to permanent discontinuation of docetaxel | 67 Participants |
| Placebo + Docetaxel | Number of Participants With TEAEs | Related to protocol-required procedure | 64 Participants |
| Placebo + Docetaxel | Number of Participants With TEAEs | Any study drug-related TEAE | 309 Participants |
| Placebo + Docetaxel | Number of Participants With TEAEs | Study drug-related TESAE | 24 Participants |
| Placebo + Docetaxel | Number of Participants With TEAEs | Study drug-related TEAE leading to study drug dose modification | 41 Participants |
Secondary
Symptomatic Skeletal Event Free Survival (SSE-FS) - Month
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. NA = Value cannot be estimated due to censored data
Time frame: From randomization of the first participant 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Symptomatic Skeletal Event Free Survival (SSE-FS) - Month | 51.2 Months |
| Placebo + Docetaxel | Symptomatic Skeletal Event Free Survival (SSE-FS) - Month | 39.7 Months |
p-value: <0.000195% CI: [0.516, 0.718]Log Rank
Secondary
Symptomatic Skeletal Event Free Survival (SSE-FS) - Number of Events
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.
Time frame: From randomization of the first participant 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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Symptomatic Skeletal Event Free Survival (SSE-FS) - Number of Events | Number of patients with event | 257 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Symptomatic Skeletal Event Free Survival (SSE-FS) - Number of Events | Number of patients censored | 394 Participants |
| Placebo + Docetaxel | Symptomatic Skeletal Event Free Survival (SSE-FS) - Number of Events | Number of patients with event | 329 Participants |
| Placebo + Docetaxel | Symptomatic Skeletal Event Free Survival (SSE-FS) - Number of Events | Number of patients censored | 325 Participants |
Secondary
Time to Castration-Resistant Prostate Cancer (CRPC) - Month
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. NA = Value cannot be estimated due to censored data
Time frame: From randomization of the first participant to the first occurrence of an CRPC event up to 25 OCT 2021 cut-off date approximately 59 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to Castration-Resistant Prostate Cancer (CRPC) - Month | NA Months |
| Placebo + Docetaxel | Time to Castration-Resistant Prostate Cancer (CRPC) - Month | 19.1 Months |
p-value: <0.000195% CI: [0.302, 0.421]Log Rank
Secondary
Time to Castration-Resistant Prostate Cancer (CRPC) - Number of Events
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.
Time frame: From randomization of the first participant to the first occurrence of an CRPC event up to 25 OCT 2021 cut-off date approximately 59 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to Castration-Resistant Prostate Cancer (CRPC) - Number of Events | Number of patients with event | 225 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Time to Castration-Resistant Prostate Cancer (CRPC) - Number of Events | Number of patients censored | 426 Participants |
| Placebo + Docetaxel | Time to Castration-Resistant Prostate Cancer (CRPC) - Number of Events | Number of patients with event | 391 Participants |
| Placebo + Docetaxel | Time to Castration-Resistant Prostate Cancer (CRPC) - Number of Events | Number of patients censored | 263 Participants |
Secondary
Time to First Symptomatic Skeletal Event (SSE) - Month
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. NA = Value cannot be estimated due to censored data
Time frame: From randomization of the first participant to the first occurrence of an SSE event up to 25 OCT 2021 cut-off date approximately 59 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to First Symptomatic Skeletal Event (SSE) - Month | NA Months |
| Placebo + Docetaxel | Time to First Symptomatic Skeletal Event (SSE) - Month | NA Months |
p-value: 0.008195% CI: [0.539, 0.94]Log Rank
Secondary
Time to First Symptomatic Skeletal Event (SSE) - Number of Events
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.
Time frame: From randomization of the first participant to the first occurrence of an SSE event up to 25 OCT 2021 cut-off date approximately 59 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to First Symptomatic Skeletal Event (SSE) - Number of Events | Number (%) of patients with event | 95 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Time to First Symptomatic Skeletal Event (SSE) - Number of Events | Number (%) of patients censored | 556 Participants |
| Placebo + Docetaxel | Time to First Symptomatic Skeletal Event (SSE) - Number of Events | Number (%) of patients with event | 108 Participants |
| Placebo + Docetaxel | Time to First Symptomatic Skeletal Event (SSE) - Number of Events | Number (%) of patients censored | 546 Participants |
Secondary
Time to Initiation of Opioid Use for ≥7 Consecutive Days - Month
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. NA = Value cannot be estimated due to censored data
Time frame: From randomization of the first participant to the first opioid use for ≥7 consecutive days up to 25 OCT 2021 cut-off date approximately 59 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to Initiation of Opioid Use for ≥7 Consecutive Days - Month | NA Months |
| Placebo + Docetaxel | Time to Initiation of Opioid Use for ≥7 Consecutive Days - Month | NA Months |
p-value: 0.003795% CI: [0.523, 0.906]Log Rank
Secondary
Time to Initiation of Opioid Use for ≥7 Consecutive Days - Number of Events
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.
Time frame: From randomization of the first participant to the first opioid use for ≥7 consecutive days up to 25 OCT 2021 cut-off date approximately 59 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to Initiation of Opioid Use for ≥7 Consecutive Days - Number of Events | Number of patients with event | 92 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Time to Initiation of Opioid Use for ≥7 Consecutive Days - Number of Events | Number of patients censored | 559 Participants |
| Placebo + Docetaxel | Time to Initiation of Opioid Use for ≥7 Consecutive Days - Number of Events | Number of patients with event | 117 Participants |
| Placebo + Docetaxel | Time to Initiation of Opioid Use for ≥7 Consecutive Days - Number of Events | Number of patients censored | 537 Participants |
Secondary
Time to Initiation of Subsequent Antineoplastic Therapy - Month
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. NA = Value cannot be estimated due to censored data
Time frame: From randomization of the first participant to the initiation of first subsequent systemic antineoplastic therapy up to 25 OCT 2021 cut-off date approximately 59 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to Initiation of Subsequent Antineoplastic Therapy - Month | NA Months |
| Placebo + Docetaxel | Time to Initiation of Subsequent Antineoplastic Therapy - Month | 25.3 Months |
p-value: <0.000195% CI: [0.328, 0.458]Log Rank
Secondary
Time to Initiation of Subsequent Antineoplastic Therapy - Number of Events
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.
Time frame: From randomization of the first participant to the initiation of first subsequent systemic antineoplastic therapy up to 25 OCT 2021 cut-off date approximately 59 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to Initiation of Subsequent Antineoplastic Therapy - Number of Events | Number (%) of patients censored | 432 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Time to Initiation of Subsequent Antineoplastic Therapy - Number of Events | Number (%) of patients with event | 219 Participants |
| Placebo + Docetaxel | Time to Initiation of Subsequent Antineoplastic Therapy - Number of Events | Number (%) of patients censored | 259 Participants |
| Placebo + Docetaxel | Time to Initiation of Subsequent Antineoplastic Therapy - Number of Events | Number (%) of patients with event | 395 Participants |
Secondary
Time to Pain Progression - Month
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. NA = Value cannot be estimated due to censored data
Time frame: From randomization of the first participant to the first occurrence of a pain progression event up to 25 OCT 2021 cut-off date approximately 59 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to Pain Progression - Month | NA Months |
| Placebo + Docetaxel | Time to Pain Progression - Month | 27.5 Months |
p-value: 0.005895% CI: [0.66, 0.95]Log Rank
Secondary
Time to Pain Progression - Number of Events
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.
Time frame: From randomization of the first participant to the first occurrence of a pain progression event up to 25 OCT 2021 cut-off date approximately 59 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to Pain Progression - Number of Events | Number of patients with event | 222 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Time to Pain Progression - Number of Events | Number of patients censored | 429 Participants |
| Placebo + Docetaxel | Time to Pain Progression - Number of Events | Number of patients with event | 248 Participants |
| Placebo + Docetaxel | Time to Pain Progression - Number of Events | Number of patients censored | 406 Participants |
Secondary
Time to Worsening of Disease-Related Physical Symptoms - Month
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.
Time frame: From randomization of the first participant 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to Worsening of Disease-Related Physical Symptoms - Month | 19.3 Months |
| Placebo + Docetaxel | Time to Worsening of Disease-Related Physical Symptoms - Month | 19.4 Months |
p-value: 0.707395% CI: [0.894, 1.217]Log Rank
Secondary
Time to Worsening of Disease-Related Physical Symptoms - Number of Events
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.
Time frame: From randomization of the first participant 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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darolutamide (BAY1841788) + Docetaxel | Time to Worsening of Disease-Related Physical Symptoms - Number of Events | Number (%) of patients with event | 351 Participants |
| Darolutamide (BAY1841788) + Docetaxel | Time to Worsening of Disease-Related Physical Symptoms - Number of Events | Number (%) of patients censored | 300 Participants |
| Placebo + Docetaxel | Time to Worsening of Disease-Related Physical Symptoms - Number of Events | Number (%) of patients with event | 308 Participants |
| Placebo + Docetaxel | Time to Worsening of Disease-Related Physical Symptoms - Number of Events | Number (%) of patients censored | 346 Participants |