Prostatic Neoplasms
Conditions
Keywords
Metastatic hormone-sensitive prostate cancer
Brief summary
The purpose of the study is to assess the efficacy and safety of darolutamide in combination with standard androgen deprivation therapy (ADT) in patients with metastatic hormone sensitive prostate cancer.
Interventions
Coated tablet, oral administration
DRUGPlacebo
Coated tablet matching Darolutamide in appearance, oral administration
OTHERAndrogen deprivation therapy (ADT)
Luteinizing hormone-releasing hormone (LHRH) agonist/antagonists or orchiectomy
Sponsors
Bayer
Orion Corporation, Orion Pharma
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 * Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation anti-androgen, but not earlier than 12 weeks before randomization * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2 * Adequate bone marrow, liver and renal function
Exclusion criteria
* Prior treatment with: LHRH agonist/antagonists except neoadjuvant and /or adjuvant therapy; Second-generation androgen receptor (AR) inhibitors such as enzalutamide, darolutamide, apalutamide or other investigational AR inhibitors; Cytochrome P17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as anti-cancer treatment for prostate cancer; Chemotherapy including docetaxel or immunotherapy for prostate cancer; Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days prior to randomization; Radiopharmaceuticals; Any other anti-cancer treatment for prostate cancer, excluding local therapies and ADT. * Treatment with radiotherapy within 2 weeks before randomization * Contraindication to iodinated CT and gadolinium chelate MRI intravenous contrast agent(s) * 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) * Uncontrolled hypertension as indicated by a resting systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite medical management * A gastrointestinal (GI) disorder or procedure which is expected to interfere significantly with absorption of study drug * Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 5 years prior to randomization * Inability to swallow oral medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiological Progression-free Survival (rPFS) Assessed by Central Review | From randomization to the date when 222 rPFS events were observed, approximately 36 months | rPFS used conventional imaging method (99mTc-phosphonate bone scan, CT/MRI scan). rPFS was defined as the time from the date of randomization to the date of progressive disease in malignant soft tissue lesions, progressive disease in malignant bone lesions, or death due to any cause, whichever occurs first. Malignant soft tissue lesions were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and malignant bone lesions were assessed by Prostate Cancer Clinical Trials Working Group (PCWG3) criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization to the date when 222 rPFS events were observed, approximately 36 months | Time from the date of randomization to the date of death from any cause. |
| Time to Castration-Resistant Prostate Cancer (CRPC) | From randomization to the date when 222 rPFS events were observed, approximately 36 months | Time from the date of randomization to the date of first castration resistant event (radiological progression, Prostate-specific antigen (PSA) progression or symptomatic skeletal events, whichever occurs first). |
| Time to Initiation of Subsequent Anti-cancer Therapy | From randomization to the date when 222 rPFS events were observed, approximately 36 months | Time from the date of randomization to initiation of first subsequent anti-cancer therapy for prostate cancer. |
| Time to PSA Progression | From randomization to the date when 222 rPFS events were observed, approximately 36 months | Time from the date of randomization to the date of first prostate-specific antigen (PSA) progression. PSA progression with serum testosterone being at castrate level \<0.50 ng/mL, is defined as a ≥25% increase above the nadir (lowest at or after baseline) value and an increase in absolute value of ≥2 ng/mL above nadir, and is at least 12 weeks from randomization date, which is confirmed by a second value 3 or more weeks later. All PSA values between the initial assessment meeting the PSA progression criteria and confirmation assessment must be ≥2 ng/mL and ≥25% increase above nadir, serum testosterone at castrate levels \<0.50 ng/mL is requested at initial assessment. |
| PSA Undetectable Rates (<0.2 ng/mL) | From randomization to the date when 222 rPFS events were observed, approximately 36 months | Percentage of subjects with detectable PSA values of ≥0.2 ng/mL at baseline which became undetectable with any PSA values \<0.2 ng/mL during the period between randomization and 30 days after last dose of study drug or start of new anti-cancer therapy whichever occurred earliest, based on the subjects had detectable PSA value at baseline. |
| Time to Pain Progression | From randomization to the date when 222 rPFS events were observed, approximately 36 months | Pain progression was assessed by Question 3 (Q3) of the BPI-SF questionnaire related to the worst pain in the last 24 hours (worst pain subscale \[WPS\]) taken as an average for post baseline score, or initiation of short or long-acting opioids for malignant disease for ≥7 consecutive days after randomization. Pain progression was defined as: (1) for asymptomatic subjects with WPS=0 at baseline, an increase of 2 or more points in the WPS score from nadir observed at 2 consecutive evaluations ≥4 weeks apart, or initiation of short- or long-acting opioid use for malignant disease for ≥7 consecutive days after randomization; (2) for symptomatic subjects with WPS \>0 at baseline, an increase of 2 or more points in the WPS score from nadir observed at 2 consecutive evaluations ≥4 weeks apart and a WPS ≥5, or initiation of short- or long-acting opioid use for malignant disease for ≥7 consecutive days after randomization. |
| Number of Participants With Adverse Events as a Measure of Safety | From start of study drug administration until 30 days after the last administration | An AE is any untoward medical occurrence in a patient or clinical study participant, after providing written IC for participation in the study, may or may not be temporally associated with the use of study drug, whether or not considered related to the study drug. Treatment-emergent AE (TEAE) is defined as any event arising or worsening after the first dose of study drug until 30 days after the last dose of study drug. |
Countries
Australia, Brazil, Canada, Chile, China, India, Latvia, Lithuania, New Zealand, Peru, Russia, South Africa, Spain, Taiwan, Ukraine
Participant flow
Recruitment details
Study was conducted at 133 centers in Europe/Rest of the world (ROW), Asia, and Latin America between 23-Feb-2021 (first participant first visit) and 07-Jun-2024 (primary completion date). Study is still ongoing.
Pre-assignment details
In total 889 participants were screened in the study and 202 participants were screen failures. An additional 18 participants prematurely discontinued screening. A total of 669 participants were randomized (446 to the darolutamide arm and 223 to the placebo arm).
Participants by arm
| Arm | Count |
|---|---|
| Darolutamide+ADT Participants received darolutamide (BAY1841788) 600 mg (2 tablets of 300 mg) twice daily with food and androgen deprivation therapy (ADT) of investigator's choice as standard therapy. | 446 |
| Placebo+ADT Participants received matching placebo twice daily with food and androgen deprivation therapy (ADT) of investigator's choice as standard therapy. | 223 |
| Total | 669 |
Baseline characteristics
| Characteristic | Darolutamide+ADT | Placebo+ADT | Total |
|---|---|---|---|
| Age, Continuous | 69.6 Years STANDARD_DEVIATION 8.8 | 69.2 Years STANDARD_DEVIATION 8.9 | 69.5 Years STANDARD_DEVIATION 8.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 104 Participants | 58 Participants | 162 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 334 Participants | 157 Participants | 491 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 8 Participants | 16 Participants |
| Race/Ethnicity, Customized Asian | 144 Participants | 65 Participants | 209 Participants |
| Race/Ethnicity, Customized Black or African American | 41 Participants | 24 Participants | 65 Participants |
| Race/Ethnicity, Customized Other | 10 Participants | 9 Participants | 19 Participants |
| Race/Ethnicity, Customized White | 251 Participants | 125 Participants | 376 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 446 Participants | 223 Participants | 669 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 105 / 445 | 61 / 221 |
| other Total, other adverse events | 321 / 445 | 149 / 221 |
| serious Total, serious adverse events | 105 / 445 | 52 / 221 |
Outcome results
Primary
Radiological Progression-free Survival (rPFS) Assessed by Central Review
rPFS used conventional imaging method (99mTc-phosphonate bone scan, CT/MRI scan). rPFS was defined as the time from the date of randomization to the date of progressive disease in malignant soft tissue lesions, progressive disease in malignant bone lesions, or death due to any cause, whichever occurs first. Malignant soft tissue lesions were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and malignant bone lesions were assessed by Prostate Cancer Clinical Trials Working Group (PCWG3) criteria.
Time frame: From randomization to the date when 222 rPFS events were observed, approximately 36 months
Population: Full analysis set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide+ADT | Radiological Progression-free Survival (rPFS) Assessed by Central Review | NA Months |
| Placebo+ADT | Radiological Progression-free Survival (rPFS) Assessed by Central Review | 25.0 Months |
Comparison: Analyzed with log-rank test and Cox regression proportional hazard model, stratified by the same factor as used for randomization visceral disease (present versus absent), prior local therapy (Yes versus No).p-value: <0.000195% CI: [0.413, 0.707]Log Rank
Secondary
Number of Participants With Adverse Events as a Measure of Safety
An AE is any untoward medical occurrence in a patient or clinical study participant, after providing written IC for participation in the study, may or may not be temporally associated with the use of study drug, whether or not considered related to the study drug. Treatment-emergent AE (TEAE) is defined as any event arising or worsening after the first dose of study drug until 30 days after the last dose of study drug.
Time frame: From start of study drug administration until 30 days after the last administration
Population: Safety analysis set (SAF)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darolutamide+ADT | Number of Participants With Adverse Events as a Measure of Safety | Any TEAE | 405 Participants |
| Darolutamide+ADT | Number of Participants With Adverse Events as a Measure of Safety | Any TESAE | 105 Participants |
| Darolutamide+ADT | Number of Participants With Adverse Events as a Measure of Safety | Any study drug-related TEAE | 144 Participants |
| Placebo+ADT | Number of Participants With Adverse Events as a Measure of Safety | Any TEAE | 199 Participants |
| Placebo+ADT | Number of Participants With Adverse Events as a Measure of Safety | Any TESAE | 52 Participants |
| Placebo+ADT | Number of Participants With Adverse Events as a Measure of Safety | Any study drug-related TEAE | 64 Participants |
Secondary
Overall Survival (OS)
Time from the date of randomization to the date of death from any cause.
Time frame: From randomization to the date when 222 rPFS events were observed, approximately 36 months
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide+ADT | Overall Survival (OS) | NA Months |
| Placebo+ADT | Overall Survival (OS) | NA Months |
Comparison: Analyzed with log-rank test and Cox regression proportional hazard model, stratified by the same factor as used for randomization visceral disease (present versus absent), prior local therapy (Yes versus No).p-value: 0.100795% CI: [0.591, 1.118]Log Rank
Secondary
PSA Undetectable Rates (<0.2 ng/mL)
Percentage of subjects with detectable PSA values of ≥0.2 ng/mL at baseline which became undetectable with any PSA values \<0.2 ng/mL during the period between randomization and 30 days after last dose of study drug or start of new anti-cancer therapy whichever occurred earliest, based on the subjects had detectable PSA value at baseline.
Time frame: From randomization to the date when 222 rPFS events were observed, approximately 36 months
Population: Participants with detectable PSA values ≥0.2 ng/mL at baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Darolutamide+ADT | PSA Undetectable Rates (<0.2 ng/mL) | 62.6 Percentage of participants |
| Placebo+ADT | PSA Undetectable Rates (<0.2 ng/mL) | 18.5 Percentage of participants |
Comparison: Analyzed with log-rank test and Cox regression proportional hazard model, stratified by the same factor as used for randomization visceral disease (present versus absent), prior local therapy (Yes versus No).95% CI: [37.4, 51.2]
Secondary
Time to Castration-Resistant Prostate Cancer (CRPC)
Time from the date of randomization to the date of first castration resistant event (radiological progression, Prostate-specific antigen (PSA) progression or symptomatic skeletal events, whichever occurs first).
Time frame: From randomization to the date when 222 rPFS events were observed, approximately 36 months
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide+ADT | Time to Castration-Resistant Prostate Cancer (CRPC) | NA Months |
| Placebo+ADT | Time to Castration-Resistant Prostate Cancer (CRPC) | 13.8 Months |
Comparison: Analyzed with log-rank test and Cox regression proportional hazard model, stratified by the same factor as used for randomization visceral disease (present versus absent), prior local therapy (Yes versus No).95% CI: [0.321, 0.508]
Secondary
Time to Initiation of Subsequent Anti-cancer Therapy
Time from the date of randomization to initiation of first subsequent anti-cancer therapy for prostate cancer.
Time frame: From randomization to the date when 222 rPFS events were observed, approximately 36 months
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide+ADT | Time to Initiation of Subsequent Anti-cancer Therapy | NA Months |
| Placebo+ADT | Time to Initiation of Subsequent Anti-cancer Therapy | NA Months |
Comparison: Analyzed with log-rank test and Cox regression proportional hazard model, stratified by the same factor as used for randomization visceral disease (present versus absent), prior local therapy (Yes versus No).95% CI: [0.288, 0.558]
Secondary
Time to Pain Progression
Pain progression was assessed by Question 3 (Q3) of the BPI-SF questionnaire related to the worst pain in the last 24 hours (worst pain subscale \[WPS\]) taken as an average for post baseline score, or initiation of short or long-acting opioids for malignant disease for ≥7 consecutive days after randomization. Pain progression was defined as: (1) for asymptomatic subjects with WPS=0 at baseline, an increase of 2 or more points in the WPS score from nadir observed at 2 consecutive evaluations ≥4 weeks apart, or initiation of short- or long-acting opioid use for malignant disease for ≥7 consecutive days after randomization; (2) for symptomatic subjects with WPS \>0 at baseline, an increase of 2 or more points in the WPS score from nadir observed at 2 consecutive evaluations ≥4 weeks apart and a WPS ≥5, or initiation of short- or long-acting opioid use for malignant disease for ≥7 consecutive days after randomization.
Time frame: From randomization to the date when 222 rPFS events were observed, approximately 36 months
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide+ADT | Time to Pain Progression | NA Months |
| Placebo+ADT | Time to Pain Progression | 29.9 Months |
Comparison: Analyzed with log-rank test and Cox regression proportional hazard model, stratified by the same factor as used for randomization visceral disease (present versus absent), prior local therapy (Yes versus No).95% CI: [0.544, 0.957]
Secondary
Time to PSA Progression
Time from the date of randomization to the date of first prostate-specific antigen (PSA) progression. PSA progression with serum testosterone being at castrate level \<0.50 ng/mL, is defined as a ≥25% increase above the nadir (lowest at or after baseline) value and an increase in absolute value of ≥2 ng/mL above nadir, and is at least 12 weeks from randomization date, which is confirmed by a second value 3 or more weeks later. All PSA values between the initial assessment meeting the PSA progression criteria and confirmation assessment must be ≥2 ng/mL and ≥25% increase above nadir, serum testosterone at castrate levels \<0.50 ng/mL is requested at initial assessment.
Time frame: From randomization to the date when 222 rPFS events were observed, approximately 36 months
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darolutamide+ADT | Time to PSA Progression | NA Months |
| Placebo+ADT | Time to PSA Progression | 16.8 Months |
Comparison: Analyzed with log-rank test and Cox regression proportional hazard model, stratified by the same factor as used for randomization visceral disease (present versus absent), prior local therapy (Yes versus No).95% CI: [0.231, 0.405]