Prostate Neoplasms
Conditions
Keywords
Prostate neoplasms, Prostate cancer, Metastatic prostate cancer, Abiraterone acetate, ZYTIGA, Prednisone, Androgen deprivation therapy
Brief summary
The purpose of this study is to determine if newly diagnosed (within previous 3 months) participants with metastatic (spread of cancer cells from one part of the body to another ) hormone-naive prostate cancer (mHNPC) who have high-risk prognostic factors will benefit from the addition of abiraterone acetate plus low-dose prednisone to androgen deprivation therapy (ADT; lutenizing hormone releasing hormone \[LHRH\] agonists or surgical castration).
Detailed description
This is a randomized (the treatment group is assigned by chance), double-blind (neither physician nor participant knows the treatment that the participant receives), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial)-controlled study designed to determine the efficacy of abiraterone acetate plus low-dose prednisone in participants with mHNPC. The study consists of 4 parts: Screening Phase (that is, 28 days before study commences on Day 1); Double-blind treatment Phase (consists of 4-week dosing cycles wherein abiraterone acetate will be administered as 1,000 milligram \[mg\] plus 5 mg prednisone or only placebo orally); Follow-up Phase (every 4 months up to 60 months or until death, lost to follow up, withdrawal of consent or study termination) Open-label Extension (OLE) Phase. Participants in the Double-blind Treatment Phase will have the opportunity to enroll into the OLE Phase. The OLE Phase will allow participants to receive active drug (abiraterone acetate plus prednisone) until Long-term Extension (LTE) Phase for an additional period of up to 3 years. Participants will discontinue study treatment at disease progression or unacceptable toxicity unless, in the Investigator's opinion, it is deemed that the participants will continue to derive benefit from study treatment. Participants will be randomized in a 1:1 ratio to the active treatment group (abiraterone acetate 1000 mg daily plus prednisone 5 mg daily plus ADT) or the control group (ADT plus placebos).Efficacy will be evaluated primarily by overall survival and radiographic progression-free survival. Participants' safety will be monitored throughout the study.
Interventions
DRUGAbiraterone acetate
Abiraterone acetate tablets will be administered orally at a total dose of 1000 mg per day until disease progression, withdrawal of consent or unacceptable toxicity.
DRUGPrednisone
Prednisone 5 mg capsule will be administered orally once daily until disease progression, withdrawal of consent or unacceptable toxicity.
OTHERAndrogen deprivation therapy (ADT)
All participants will receive stable regimen of ADT, that is, lutenizing hormone releasing hormone (LHRH) agonists or surgical castration according to local guidelines until disease progression, withdrawal of consent or unacceptable toxicity.
DRUGAbiraterone acetate Placebo
Placebo matched to abiraterone acetate will be administered orally once daily until disease progression, withdrawal of consent or unacceptable toxicity.
Placebo matched to prednisone will be administered orally once daily until disease progression, withdrawal of consent or unacceptable toxicity.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Newly diagnosed metastatic prostate cancer within 3 months prior to randomization with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology * Distant metastatic disease documented by positive bone scan or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI) scan * At least 2 of the following high-risk prognostic factors: Gleason score of greater than or equal to (\>=8); presence of 3 or more lesions on bone scan; presence of measurable visceral (excluding lymph node disease) metastasis on CT or MRI Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 scan * Eastern Cooperative Oncology Group (ECOG) performance status grade of 0, 1 or 2 * Adequate hematologic, hepatic, and renal function * Agrees to protocol-defined use of effective contraception
Exclusion criteria
* Active infection or other medical condition that would make prednisone use contraindicated * Any chronic medical condition requiring a higher systemic dose of corticosteroid than 5 mg prednisone per day * Pathological finding consistent with small cell carcinoma of the prostate * Known brain metastasis * Any prior pharmacotherapy, radiation therapy, or surgery for metastatic prostate cancer (the following exception are permitted): up to 3 months of androgen deprivation therapy (ADT) with lutenizing hormone releasing hormone agonists or antagonists or orchiectomy with or without concurrent anti-androgens prior Cycle 1 Day 1; participants may have one course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 28 days prior to Cycle 1 Day 1)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Progression-Free Survival (PFS) | Up to 44 months | Radiographic PFS was defined as the time (in months) interval from randomization to the first date of radiographic progression or death. Radiographic progression included progression by bone scan (according to modified Prostate Cancer Working Group 2 \[PCWG2\] criteria), defined as at least 2 new lesions on bone scan and progression of soft tissue lesions by computed tomography (CT) or magnetic resonance imaging (MRI) (according to Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 criteria). As per the RECIST 1.1 guideline, progression requires a 20 percent (%) increase in the sum of diameters of all target lesions and a minimum absolute increase of 5 millimeter (mm) in the sum as compared to nadir sum of diameter. |
| Overall Survival (OS) | Up to 66 months | Overall survival was defined as the time from randomization to date of death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Pain Progression | Up to 66 months | Time to pain progression was defined as the time (in months) interval from randomization to the first date a participant experienced a greater than or equal to (\>=) 30 percent (%) increase in Brief Pain Inventory-Short Form (BPI-SF) from baseline in the BPI-SF worst pain intensity (Item 3) observed at 2 consecutive evaluations (\>=4) weeks apart. BPI-SF was an 11-item questionnaire, designed to assess severity and impact of pain on daily functions. Total score ranged from 0 to 10 with 0 representing no pain and 10 representing pain as bad as you can imagine. |
| Time to Initiation of Chemotherapy | Up to 66 months | Time to initiation of chemotherapy was defined as the time (in months) interval from the date of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer. |
| Time to Prostate-Specific Antigen (PSA) Progression | Up to 66 months | Time to PSA progression was defined as the time (in months) interval from the date of randomization to the date of PSA progression, according to PCWG2 criteria. PCWG2 defines PSA progression as the date that a 25 percent (%) or greater increase and an absolute increase of 2 nanogram per milliliter (ng/mL) or more from the nadir is documented, which is confirmed by a second value obtained 3 or more weeks later. |
| Time to Skeletal-Related Event | Up to 66 months | Time to skeletal-related event was defined as the earliest of the following: clinical or pathological fracture, spinal cord compression, palliative radiation to bone, or surgery to bone. |
| Time to Subsequent Therapy for Prostate Cancer | Up to 66 months | Time to subsequent therapy was defined as the time (in months) interval from the date of randomization to the date of initiation of subsequent therapy for prostate cancer. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, Denmark, Finland, France, Germany, Hungary, Israel, Japan, Malaysia, Mexico, Netherlands, New Zealand, Poland, Portugal, Romania, Russia, Slovakia, South Africa, South Korea, Spain, Sweden, Turkey (Türkiye), Ukraine, United Kingdom
Participant flow
Pre-assignment details
1209 participants were enrolled and 1199 were randomized to treatment groups.10 participants from Russian site were excluded from the analysis due to noncompliance with International Conference on Harmonization Good Clinical Practice guidelines at site. The remaining 1199 randomized participants comprised the intent-to-treat population.
Participants by arm
| Arm | Count |
|---|---|
| Abiraterone Acetate+Prednisone+ADT Participants received abiraterone acetate tablet at a total dose of 1000 milligram (mg) plus 5 mg capsule of prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of androgen deprivation therapy (ADT) was administered. | 597 |
| Placebo + ADT Participants received placebo matched to abiraterone acetate plus prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of ADT was administered. | 602 |
| Total | 1,199 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double Blind Period (Up to 23 Months) | Adverse Event | 53 | 31 | 0 |
| Double Blind Period (Up to 23 Months) | Death | 43 | 25 | 0 |
| Double Blind Period (Up to 23 Months) | Lost to Follow-up | 3 | 2 | 0 |
| Double Blind Period (Up to 23 Months) | Noncompliance With Study Drug | 4 | 2 | 0 |
| Double Blind Period (Up to 23 Months) | Other | 167 | 12 | 0 |
| Double Blind Period (Up to 23 Months) | Physician Decision | 21 | 23 | 0 |
| Double Blind Period (Up to 23 Months) | Placebo Cross-Over | 0 | 72 | 0 |
| Double Blind Period (Up to 23 Months) | Progressive Disease | 254 | 388 | 0 |
| Double Blind Period (Up to 23 Months) | Withdrawal by Subject | 52 | 47 | 0 |
| OLE Phase (Up to 15.6 Months) | Adverse Event | 0 | 0 | 1 |
| OLE Phase (Up to 15.6 Months) | Death | 0 | 0 | 4 |
| OLE Phase (Up to 15.6 Months) | Other | 0 | 0 | 60 |
| OLE Phase (Up to 15.6 Months) | Progressive Disease | 0 | 0 | 1 |
| OLE Phase (Up to 15.6 Months) | Withdrawal by Subject | 0 | 0 | 6 |
Baseline characteristics
| Characteristic | Abiraterone Acetate+Prednisone+ADT | Placebo + ADT | Total |
|---|---|---|---|
| Age, Categorical <=18 years <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical <=18 years >=65 years | 376 Participants | 369 Participants | 745 Participants |
| Age, Categorical <=18 years Between 18 and 65 years | 221 Participants | 233 Participants | 454 Participants |
| Age, Continuous | 67.3 years STANDARD_DEVIATION 8.48 | 66.8 years STANDARD_DEVIATION 8.72 | 67.1 years STANDARD_DEVIATION 8.6 |
| Region of Enrollment Argentina | 8 Participants | 8 Participants | 16 Participants |
| Region of Enrollment Australia | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment Belgium | 6 Participants | 7 Participants | 13 Participants |
| Region of Enrollment Brazil | 28 Participants | 28 Participants | 56 Participants |
| Region of Enrollment Bulgaria | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Canada | 16 Participants | 17 Participants | 33 Participants |
| Region of Enrollment Chile | 3 Participants | 4 Participants | 7 Participants |
| Region of Enrollment China | 69 Participants | 68 Participants | 137 Participants |
| Region of Enrollment Colombia | 10 Participants | 7 Participants | 17 Participants |
| Region of Enrollment Czech Republic | 9 Participants | 7 Participants | 16 Participants |
| Region of Enrollment Denmark | 13 Participants | 15 Participants | 28 Participants |
| Region of Enrollment Finland | 4 Participants | 5 Participants | 9 Participants |
| Region of Enrollment France | 7 Participants | 7 Participants | 14 Participants |
| Region of Enrollment Germany | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment Hungary | 17 Participants | 17 Participants | 34 Participants |
| Region of Enrollment Israel | 14 Participants | 16 Participants | 30 Participants |
| Region of Enrollment Italy | 19 Participants | 20 Participants | 39 Participants |
| Region of Enrollment Japan | 35 Participants | 35 Participants | 70 Participants |
| Region of Enrollment Malaysia | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment Mexico | 19 Participants | 19 Participants | 38 Participants |
| Region of Enrollment Netherlands | 6 Participants | 4 Participants | 10 Participants |
| Region of Enrollment New Zeland | 6 Participants | 5 Participants | 11 Participants |
| Region of Enrollment Poland | 20 Participants | 22 Participants | 42 Participants |
| Region of Enrollment Portugal | 19 Participants | 20 Participants | 39 Participants |
| Region of Enrollment Romania | 22 Participants | 21 Participants | 43 Participants |
| Region of Enrollment Russian Federation | 89 Participants | 95 Participants | 184 Participants |
| Region of Enrollment Slovakia | 17 Participants | 14 Participants | 31 Participants |
| Region of Enrollment South Africa | 10 Participants | 10 Participants | 20 Participants |
| Region of Enrollment South Korea | 16 Participants | 16 Participants | 32 Participants |
| Region of Enrollment Spain | 16 Participants | 17 Participants | 33 Participants |
| Region of Enrollment Sweden | 11 Participants | 11 Participants | 22 Participants |
| Region of Enrollment Turkey | 18 Participants | 17 Participants | 35 Participants |
| Region of Enrollment Ukraine | 39 Participants | 40 Participants | 79 Participants |
| Region of Enrollment United Kingdom | 18 Participants | 19 Participants | 37 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 597 Participants | 602 Participants | 1199 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 275 / 597 | 339 / 602 | 4 / 72 |
| other Total, other adverse events | 533 / 597 | 515 / 602 | 35 / 72 |
| serious Total, serious adverse events | 192 / 597 | 151 / 602 | 4 / 72 |
Outcome results
Primary
Overall Survival (OS)
Overall survival was defined as the time from randomization to date of death from any cause.
Time frame: Up to 66 months
Population: ITT analysis set included all subjects randomized into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abiraterone Acetate+Prednisone+ADT | Overall Survival (OS) | 53.32 months |
| Placebo + ADT | Overall Survival (OS) | 36.53 months |
p-value: <0.000195% CI: [0.564, 0.775]Log Rank
Primary
Radiographic Progression-Free Survival (PFS)
Radiographic PFS was defined as the time (in months) interval from randomization to the first date of radiographic progression or death. Radiographic progression included progression by bone scan (according to modified Prostate Cancer Working Group 2 \[PCWG2\] criteria), defined as at least 2 new lesions on bone scan and progression of soft tissue lesions by computed tomography (CT) or magnetic resonance imaging (MRI) (according to Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 criteria). As per the RECIST 1.1 guideline, progression requires a 20 percent (%) increase in the sum of diameters of all target lesions and a minimum absolute increase of 5 millimeter (mm) in the sum as compared to nadir sum of diameter.
Time frame: Up to 44 months
Population: Intention to treat (ITT) analysis set included all subjects randomized into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abiraterone Acetate+Prednisone+ADT | Radiographic Progression-Free Survival (PFS) | 33.02 Months |
| Placebo + ADT | Radiographic Progression-Free Survival (PFS) | 14.78 Months |
p-value: <0.000195% CI: [0.394, 0.55]Log Rank
Secondary
Time to Initiation of Chemotherapy
Time to initiation of chemotherapy was defined as the time (in months) interval from the date of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer.
Time frame: Up to 66 months
Population: ITT analysis set included all subjects randomized into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abiraterone Acetate+Prednisone+ADT | Time to Initiation of Chemotherapy | NA months |
| Placebo + ADT | Time to Initiation of Chemotherapy | 57.59 months |
Secondary
Time to Pain Progression
Time to pain progression was defined as the time (in months) interval from randomization to the first date a participant experienced a greater than or equal to (\>=) 30 percent (%) increase in Brief Pain Inventory-Short Form (BPI-SF) from baseline in the BPI-SF worst pain intensity (Item 3) observed at 2 consecutive evaluations (\>=4) weeks apart. BPI-SF was an 11-item questionnaire, designed to assess severity and impact of pain on daily functions. Total score ranged from 0 to 10 with 0 representing no pain and 10 representing pain as bad as you can imagine.
Time frame: Up to 66 months
Population: ITT analysis set included all subjects randomized into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abiraterone Acetate+Prednisone+ADT | Time to Pain Progression | 47.41 Months |
| Placebo + ADT | Time to Pain Progression | 16.62 Months |
Secondary
Time to Prostate-Specific Antigen (PSA) Progression
Time to PSA progression was defined as the time (in months) interval from the date of randomization to the date of PSA progression, according to PCWG2 criteria. PCWG2 defines PSA progression as the date that a 25 percent (%) or greater increase and an absolute increase of 2 nanogram per milliliter (ng/mL) or more from the nadir is documented, which is confirmed by a second value obtained 3 or more weeks later.
Time frame: Up to 66 months
Population: ITT analysis set included all subjects randomized into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abiraterone Acetate+Prednisone+ADT | Time to Prostate-Specific Antigen (PSA) Progression | 33.31 Months |
| Placebo + ADT | Time to Prostate-Specific Antigen (PSA) Progression | 7.43 Months |
Secondary
Time to Skeletal-Related Event
Time to skeletal-related event was defined as the earliest of the following: clinical or pathological fracture, spinal cord compression, palliative radiation to bone, or surgery to bone.
Time frame: Up to 66 months
Population: ITT analysis set included all subjects randomized into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abiraterone Acetate+Prednisone+ADT | Time to Skeletal-Related Event | NA months |
| Placebo + ADT | Time to Skeletal-Related Event | NA months |
Secondary
Time to Subsequent Therapy for Prostate Cancer
Time to subsequent therapy was defined as the time (in months) interval from the date of randomization to the date of initiation of subsequent therapy for prostate cancer.
Time frame: Up to 66 months
Population: ITT analysis set included all subjects randomized into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abiraterone Acetate+Prednisone+ADT | Time to Subsequent Therapy for Prostate Cancer | 54.87 Months |
| Placebo + ADT | Time to Subsequent Therapy for Prostate Cancer | 21.22 Months |