Castration-Resistant, Prostate Cancer Non-Metastatic
Conditions
Brief summary
The purpose of this study is to assess the safety and efficacy of BAY1841788 (ODM-201) in patients with non-metastatic castration-resistant prostate cancer.
Interventions
Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg.
DRUGPlacebo
Matching placebo 2 tablets twice daily with food.
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 without neuroendocrine differentiation or small cell features. * Castration-resistant prostate cancer (CRPC) with castrate level of serum testosterone. * Prostate-specific Antigen (PSA) doubling time of ≤ 10 months and PSA \> 2ng/ml. * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. * Blood counts at screening: haemoglobin ≥ 9.0 g/dl,absolute neutrophil count ≥ 1500/µl, platelet count ≥ 100,000/µl. * Screening values of serum alanine aminotransferase (ALT) and/or aspartate transaminase (AST) ≤ 2.5 x upper limit of normal (ULN), total bilirubin ≤ 1.5 x ULN, creatinine ≤ 2.0 x ULN. * Sexually active patients, unless surgically sterile, must agree to use condoms as an effective barrier method and refrain from sperm donation during the study treatment and for 3 months after the end of the study treatment.
Exclusion criteria
* History of metastatic disease at any time or presence of detectable metastases. * Acute toxicities of prior treatments and procedures not resolved to grade ≤ 1 or baseline before randomisation. * Prior treatment with: second generation androgen receptor (AR) inhibitors, other investigational AR inhibitors, or CYP17 enzyme inhibitor. * Use of estrogens or 5-α reductase inhibitors or AR inhibitors. * Prior chemotherapy or immunotherapy for prostate cancer. * Use of systemic corticosteroid. * Radiation therapy within 12 weeks before randomisation. * Severe or uncontrolled concurrent disease, infection or co-morbidity. * Treatment with bisphosphonate or denosumab within 12 weeks before randomisation. * Known hypersensitivity to the study treatment or any of its ingredients. * Major surgery within 28 days before randomisation. * Any of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV. * Uncontrolled hypertension. * Prior malignancy. * Gastrointestinal disorder or procedure which expects to interfere significantly with absorption of study treatment. * Active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease. * Treatment with any investigational drug within 28 days before randomisation. * Any condition that in the opinion of the investigator would impair the patients' ability to comply with the study procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Metastasis-Free Survival | From randomization to the time approximately 385 MFS events were observed (approximately 48 months) | Metastasis-Free Survival (MFS) is defined as the time from randomisation to evidence of metastasis or death from any cause, whichever occurs first (cut-off date 15 Nov 2019) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Pain Progression - Primary Analysis | From randomization until last study treatment (assessed every 4 months) (approximately 48 months) | Time to pain progression (PP) is defined as time from randomization to pain progression, where progression is defined as an increase of 2 or more points from baseline in question 3 of the Brief Pain Inventory-Short Form questionnaire (BPI-SF) related to the worst pain in the last 24 hours taken as a 7-day average for post-baseline scores, or initiation of short or long-acting opioids for pain, whichever comes first. Initiation or change in the use of other non-opioid analgesics is not used in the analysis of pain progression. |
| Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Primary Analysis | From randomization until last study treatment (assessed every 4 months) (approximately 48 months) | The time to cytotoxic chemotherapy was defined as the time from randomization to the start of the first cytotoxic chemotherapy cycle. |
| Time to First Symptomatic Skeletal Event (SSE) - Primary Analysis | From randomization until last study treatment (assessed every 4 months) (approximately 48 months) | The time to the first SSE was defined as the time from randomization to the occurrence of the first SSE. |
| Overall Survival - Primary Analysis | From randomization of the first subject to the time approximatively 140 death events were observed (approximately 48 months) | Overall Survival (OS) was defined as the time from randomization to death due to any cause. |
| Time to Pain Progression - Final Analysis | From randomization until last study treatment (assessed every 4 months) (approximately 48 months) | For time to pain progression, the analysis performed using the primary completion cut-off data (03 SEP 2018) was considered final and no new analysis was performed for time to pain progression. |
| Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Final Analysis | From randomization until initiation of first cytotoxic chemotherapy treatment (approximately 59 months) | The time to cytotoxic chemotherapy was defined as the time from randomization to the start of the first cytotoxic chemotherapy cycle. The final analysis was done at the time of the data cut-off (15 NOV 2019). |
| Time to First Symptomatic Skeletal Event (SSE) - Final Analysis | From randomization until occurrence of first SSE event (approximately 59 months) | The time to the first SSE was defined as the time from randomization to the occurrence of the first SSE. The final analysis was done at the time of the data cut-off (15 NOV 2019). |
| Overall Survival - Final Analysis | From randomization of the first subject to the time approximatively 254 death events were observed (approximately 56 months) | Overall Survival (OS) was defined as the time from randomization to death due to any cause. The final analysis was done at the time of the data cut-off (15 NOV 2019). |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Brazil, Bulgaria, Canada, Colombia, Czechia, Estonia, Finland, France, Germany, Hungary, Israel, Italy, Japan, Latvia, Lithuania, Peru, Poland, Portugal, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted at multiple centers in 36 countries between 12 September 2014 (first participant first visit) and 14 June 2021 (last participant last visit).
Pre-assignment details
From 2696 participants who signed informed consent, 1187 participants were discontinued from screening. A total of 1509 participants were randomly assigned to either darolutamide arm or placebo arm. The study was unblinded on 30 OCT 2018 and participants in the placebo arm could cross over to open-label darolutamide treatment.
Participants by arm
| Arm | Count |
|---|---|
| Darolutamide (BAY1841788) Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind \[DB\] + open-label \[OL\]). | 955 |
| Placebo Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over \[CO\]). | 554 |
| Total | 1,509 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Treatment | Adverse Event | 86 | 48 |
| Double Blind Treatment | Confirmed metastasis | 120 | 140 |
| Double Blind Treatment | Judgment of the investigator | 59 | 99 |
| Double Blind Treatment | Metastasis by local reading | 1 | 3 |
| Double Blind Treatment | Not treated | 1 | 0 |
| Double Blind Treatment | Other reason | 6 | 2 |
| Double Blind Treatment | Personal reason | 77 | 85 |
| Double Blind Treatment | Protocol deviation | 14 | 7 |
| Open Label | Adverse Event | 41 | 11 |
| Open Label | Confirmed metastasis | 1 | 0 |
| Open Label | Judgment of the investigator | 29 | 2 |
| Open Label | Metastasis by local reading | 138 | 27 |
| Open Label | Missing | 2 | 2 |
| Open Label | Other reason | 22 | 4 |
| Open Label | Personal reason | 60 | 8 |
| Open Label | Protocol deviation | 3 | 2 |
Baseline characteristics
| Characteristic | Darolutamide (BAY1841788) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 73.9 years STANDARD_DEVIATION 7.8 | 73.2 years STANDARD_DEVIATION 8.2 | 73.6 years STANDARD_DEVIATION 8 |
| Race/Ethnicity, Customized Asia | 122 Participants | 71 Participants | 193 Participants |
| Race/Ethnicity, Customized Black or African American | 28 Participants | 24 Participants | 52 Participants |
| Race/Ethnicity, Customized Missing | 36 Participants | 19 Participants | 55 Participants |
| Race/Ethnicity, Customized Other | 9 Participants | 6 Participants | 15 Participants |
| Race/Ethnicity, Customized White | 760 Participants | 434 Participants | 1194 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 955 Participants | 554 Participants | 1509 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 155 / 954 | 224 / 954 | 137 / 554 | 16 / 170 |
| other Total, other adverse events | 673 / 954 | 742 / 954 | 354 / 554 | 110 / 170 |
| serious Total, serious adverse events | 251 / 954 | 367 / 954 | 121 / 554 | 43 / 170 |
Outcome results
Primary
Metastasis-Free Survival
Metastasis-Free Survival (MFS) is defined as the time from randomisation to evidence of metastasis or death from any cause, whichever occurs first (cut-off date 15 Nov 2019)
Time frame: From randomization to the time approximately 385 MFS events were observed (approximately 48 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) | Metastasis-Free Survival | 40.37 months |
| Placebo | Metastasis-Free Survival | 18.43 months |
p-value: <0.00000195% CI: [0.341, 0.5]Log Rank
Secondary
Overall Survival - Final Analysis
Overall Survival (OS) was defined as the time from randomization to death due to any cause. The final analysis was done at the time of the data cut-off (15 NOV 2019).
Time frame: From randomization of the first subject to the time approximatively 254 death events were observed (approximately 56 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) | Overall Survival - Final Analysis | NA months |
| Placebo | Overall Survival - Final Analysis | NA months |
p-value: 0.00304895% CI: [0.533, 0.881]Log Rank
Secondary
Overall Survival - Primary Analysis
Overall Survival (OS) was defined as the time from randomization to death due to any cause.
Time frame: From randomization of the first subject to the time approximatively 140 death events were observed (approximately 48 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) | Overall Survival - Primary Analysis | NA months |
| Placebo | Overall Survival - Primary Analysis | NA months |
p-value: 0.0452195% CI: [0.501, 0.994]Log Rank
Secondary
Time to First Symptomatic Skeletal Event (SSE) - Final Analysis
The time to the first SSE was defined as the time from randomization to the occurrence of the first SSE. The final analysis was done at the time of the data cut-off (15 NOV 2019).
Time frame: From randomization until occurrence of first SSE event (approximately 59 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) | Time to First Symptomatic Skeletal Event (SSE) - Final Analysis | NA months |
| Placebo | Time to First Symptomatic Skeletal Event (SSE) - Final Analysis | NA months |
p-value: 0.00529495% CI: [0.287, 0.815]Log Rank
Secondary
Time to First Symptomatic Skeletal Event (SSE) - Primary Analysis
The time to the first SSE was defined as the time from randomization to the occurrence of the first SSE.
Time frame: From randomization until last study treatment (assessed every 4 months) (approximately 48 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) | Time to First Symptomatic Skeletal Event (SSE) - Primary Analysis | NA months |
| Placebo | Time to First Symptomatic Skeletal Event (SSE) - Primary Analysis | NA months |
p-value: 0.01126295% CI: [0.218, 0.842]Log Rank
Secondary
Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Final Analysis
The time to cytotoxic chemotherapy was defined as the time from randomization to the start of the first cytotoxic chemotherapy cycle. The final analysis was done at the time of the data cut-off (15 NOV 2019).
Time frame: From randomization until initiation of first cytotoxic chemotherapy treatment (approximately 59 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) | Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Final Analysis | NA months |
| Placebo | Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Final Analysis | NA months |
p-value: 0.00004495% CI: [0.444, 0.755]Log Rank
Secondary
Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Primary Analysis
The time to cytotoxic chemotherapy was defined as the time from randomization to the start of the first cytotoxic chemotherapy cycle.
Time frame: From randomization until last study treatment (assessed every 4 months) (approximately 48 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) | Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Primary Analysis | NA months |
| Placebo | Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Primary Analysis | 38.21 months |
p-value: <0.00000195% CI: [0.314, 0.595]Log Rank
Secondary
Time to Pain Progression - Final Analysis
For time to pain progression, the analysis performed using the primary completion cut-off data (03 SEP 2018) was considered final and no new analysis was performed for time to pain progression.
Time frame: From randomization until last study treatment (assessed every 4 months) (approximately 48 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) | Time to Pain Progression - Final Analysis | 40.31 months |
| Placebo | Time to Pain Progression - Final Analysis | 25.36 months |
p-value: 0.00000895% CI: [0.533, 0.785]Log Rank
Secondary
Time to Pain Progression - Primary Analysis
Time to pain progression (PP) is defined as time from randomization to pain progression, where progression is defined as an increase of 2 or more points from baseline in question 3 of the Brief Pain Inventory-Short Form questionnaire (BPI-SF) related to the worst pain in the last 24 hours taken as a 7-day average for post-baseline scores, or initiation of short or long-acting opioids for pain, whichever comes first. Initiation or change in the use of other non-opioid analgesics is not used in the analysis of pain progression.
Time frame: From randomization until last study treatment (assessed every 4 months) (approximately 48 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide (BAY1841788) | Time to Pain Progression - Primary Analysis | 40.31 months |
| Placebo | Time to Pain Progression - Primary Analysis | 25.36 months |
p-value: 0.00000895% CI: [0.533, 0.785]Log Rank