Prostate Cancer
Conditions
Keywords
Prostate Cancer, JNJ-56021927, Androgen Deprivation Therapy, ARN-509, Apalutamide, TITAN, Metastatic Hormone-sensitive Prostate Cancer
Brief summary
The purpose of this study is to determine if the addition of apalutamide to ADT provides superior efficacy in improving radiographic progression-free survival (rPFS) or overall survival (OS) for participants with mHSPC.
Detailed description
This is a randomized (study medication assigned to participants by chance), double-blind (neither the researchers nor the participants know what treatment the participant is receiving), placebo-controlled, multinational, multicenter study of apalutamide in participants with mHSPC. The study consists of 4 Phases: Screening Phase (up to 28 days before randomization), Treatment Phase (28 day treatment cycles until disease progression or the occurrence of unacceptable treatment related toxicity), an End of Treatment Phase (until 30 days after the last dose of study drug), and then a Survival Follow up Phase. In the event of a positive study result and notification of unblinding at either of the interim analyses or at the final analysis, participants in the treatment Phase will have the opportunity to enroll in an Open-label Extension Phase, which will allow participants to receive active drug (apalutamide) for approximately 3 years. Participants who are receiving apalutamide in the Open-label Extension Phase may continue receiving apalutamide in the Long-term Extension (LTE) Phase if they will continue to derive benefit from treatment (based on investigator assessment). Participants' safety will be monitored throughout the study.
Interventions
DRUGApalutamide
Participants will receive apalutamide 240 mg (4 x 60 mg) tablets orally once daily in each 28 day treatment cycles.
DRUGPlacebo
Participants will receive Placebo orally once daily in each 28 day treatment cycles.
DRUGAndrogen Deprivation Therapy (ADT)
All participants will receive and remain on a stable regimen of ADT (gonadotropin releasing hormone analog \[GnRHa\] or surgical castration). The choice of the GnRHa (agonist or antagonist) will be at discretion of the Investigator. Dosing (dose and frequency of administration) will be consistent with the prescribing information.
Sponsors
Aragon Pharmaceuticals, Inc.
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
* Diagnosis of prostate adenocarcinoma as confirmed by the investigator * Metastatic disease documented by greater than or equal to (\>=) 1 bone lesions on 99mTc bone scan. Participants with a single bone lesion must have confirmation of bone metastasis by computed tomography (CT) or magnetic resonance imaging (MRI) * Eastern Cooperative Oncology Group Performance Status (ECOG PS) grade of 0 or 1 * Participants who received docetaxel treatment must meet the following criteria: a) Received a maximum of 6 cycles of docetaxel therapy for mHSPC; b) Received the last dose of docetaxel \<=2 months prior to randomization; c) Maintained a response to docetaxel of stable disease or better, by investigator assessment of imaging and PSA, prior to randomization * Other allowed prior treatment for mHSPC: a) Maximum of 1 course of radiation or surgical intervention; radiation therapy for metastatic lesions must be completed prior to randomization; b) Less than or equal to (\<=) 6 months of ADT prior to randomization * Allowed prior treatments for localized prostate cancer (all treatments must have been completed \>= 1 year prior to randomization) a) \<= 3 years total of ADT; b) All other forms of prior therapies including radiation therapy, prostatectomy,lymph node dissection, and systemic therapies
Exclusion criteria
* Pathological finding consistent with small cell, ductal or neuroendocrine carcinoma of the prostate * Known brain metastases * Lymph nodes as only sites of metastases * Visceral (ie, liver or lung) metastases as only sites of metastases * Other prior malignancy less than or equal to 5 years prior to randomization with the exception of squamous or basal cell skin carcinoma or non-invasive superficial bladder cancer * Prior treatment with other next generation anti-androgens or other CYP17 inhibitors, immunotherapy or radiopharmaceutical agents for prostate cancer * History of seizures or medications known to lower seizure threshold
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Progression-free Survival (rPFS) | Up to 35 months | rPFS as assessed by the investigator was defined as the duration from the date of randomization to the date of first documentation of radiographic progressive disease or death due to any cause, whichever occurred first. Radiographic progressive disease was defined as progression of soft tissue lesions measured by computed tomography (CT) or magnetic resonance imaging (MRI) as defined by modified Response evaluation criteria in solid tumors (RECIST) 1.1. |
| Overall Survival (OS) | Up to 57 months | OS was defined as the time from date of randomization to date of death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Initiation of Cytotoxic Chemotherapy | Up to 57 months | Time to initiation of cytotoxic chemotherapy was defined as the time from date of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer. |
| Time to Pain Progression | Up to 57 months | Time to pain progression was defined as the time from the date of randomization to the date of the first observation of pain progression. Pain progression was defined as an average increase by 2 points from baseline to greater than (\>) 4 on the Brief Pain Inventory - Short Form (BPI-SF) worst pain intensity (item 3) with no decrease in opioids confirmed greater than equal to (\>=) 3 weeks apart or initiation of chronic opioids, whichever occurred first. BPI-SF is a self-administered questionnaire developed to assess severity of pain and impact of pain on daily functions. Item 3 (worst pain intensity) asks participants to rate worst pain in prior 7-days on a 0-10 numeric rating scale, where "0" indicates "No pain" and "10" indicates "Pain as bad as you can imagine." A lower score is better. |
| Time to Chronic Opioid Use | Up to 57 months | Time to chronic opioid use was defined as the time from date of randomization to the first date of confirmed chronic opioid use. For participants entering the study without receiving opioids, chronic opioid use was defined as administration of opioid analgesics lasting for greater than or equal to (\>=) 3 weeks for oral or \>=7 days for non-oral formulations. For participants entering the study already receiving opioids, chronic opioid use was defined as a \>=30 percent (%) increase in total daily dose of the opioid analgesics lasting for \>= 3 weeks for oral or \>= 7 days for non-oral formulation. |
| Time to Skeletal-related Event (SRE) | Up to 57 months | Time to SRE was defined as the time from the date of randomization to the date of the first observation of an SRE. A SRE was defined as the occurrence of either a pathological fracture, or spinal cord compression, or radiation to bone, or surgery to bone. |
Countries
Argentina, Australia, Brazil, Canada, China, Czechia, France, Germany, Hungary, Israel, Japan, Mexico, Poland, Romania, Russia, South Korea, Spain, Sweden, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORJanssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Participant flow
Pre-assignment details
Per protocol, 208 participants randomized to receive placebo+ADT were switched over to receive apalutamide+ADT after interim analysis and unblinding. Randomized treatment disposition has been reported in participant flow. Response/progression that occurred during a non-randomized switch-over to apalutamide+ADT were not counted towards efficacy outcome measures.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Androgen Deprivation Therapy (ADT) Participants received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog \[GnRHa\] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis participants in treatment phase had opportunity to receive Apalutamide +ADT. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death. | 527 |
| Apalutamide + ADT Participants received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4\*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog \[GnRHa\] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death. | 525 |
| Total | 1,052 |
Baseline characteristics
| Characteristic | Placebo + Androgen Deprivation Therapy (ADT) | Total | Apalutamide + ADT |
|---|---|---|---|
| Age, Continuous | 67.9 years STANDARD_DEVIATION 8.42 | 68.4 years STANDARD_DEVIATION 8.28 | 68.9 years STANDARD_DEVIATION 8.11 |
| Race (NIH/OMB) American Indian or Alaska Native | 11 participants | 17 participants | 6 participants |
| Race (NIH/OMB) Asian | 112 participants | 231 participants | 119 participants |
| Race (NIH/OMB) Black or African American | 9 participants | 19 participants | 10 participants |
| Race (NIH/OMB) More than one race | 0 participants | 1 participants | 1 participants |
| Race (NIH/OMB) Not Reported | 8 participants | 19 participants | 11 participants |
| Race (NIH/OMB) Other | 22 participants | 46 participants | 24 participants |
| Race (NIH/OMB) White | 365 participants | 719 participants | 354 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 11 Participants | 17 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 112 Participants | 231 Participants | 119 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 19 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 30 Participants | 65 Participants | 35 Participants |
| Race (NIH/OMB) White | 365 Participants | 719 Participants | 354 Participants |
| Region of Enrollment ARGENTINA | 20 participants | 37 participants | 17 participants |
| Region of Enrollment AUSTRALIA | 5 participants | 11 participants | 6 participants |
| Region of Enrollment BRAZIL | 38 participants | 92 participants | 54 participants |
| Region of Enrollment CANADA | 16 participants | 30 participants | 14 participants |
| Region of Enrollment CHINA | 46 participants | 94 participants | 48 participants |
| Region of Enrollment CZECH REPUBLIC | 12 participants | 31 participants | 19 participants |
| Region of Enrollment FRANCE | 8 participants | 16 participants | 8 participants |
| Region of Enrollment GERMANY | 10 participants | 17 participants | 7 participants |
| Region of Enrollment HUNGARY | 11 participants | 24 participants | 13 participants |
| Region of Enrollment ISRAEL | 8 participants | 14 participants | 6 participants |
| Region of Enrollment ITALY | 18 participants | 34 participants | 16 participants |
| Region of Enrollment JAPAN | 23 participants | 51 participants | 28 participants |
| Region of Enrollment MEXICO | 25 participants | 48 participants | 23 participants |
| Region of Enrollment POLAND | 12 participants | 19 participants | 7 participants |
| Region of Enrollment ROMANIA | 7 participants | 11 participants | 4 participants |
| Region of Enrollment RUSSIAN FEDERATION | 66 participants | 131 participants | 65 participants |
| Region of Enrollment SOUTH KOREA | 41 participants | 76 participants | 35 participants |
| Region of Enrollment SPAIN | 12 participants | 20 participants | 8 participants |
| Region of Enrollment SWEDEN | 8 participants | 16 participants | 8 participants |
| Region of Enrollment TURKEY | 22 participants | 50 participants | 28 participants |
| Region of Enrollment UKRAINE | 60 participants | 102 participants | 42 participants |
| Region of Enrollment UNITED KINGDOM | 16 participants | 36 participants | 20 participants |
| Region of Enrollment UNITED STATES | 43 participants | 92 participants | 49 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 527 Participants | 1052 Participants | 525 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 35 / 527 | 10 / 208 | 31 / 524 |
| other Total, other adverse events | 485 / 527 | 153 / 208 | 494 / 524 |
| serious Total, serious adverse events | 115 / 527 | 29 / 208 | 153 / 524 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from date of randomization to date of death from any cause.
Time frame: Up to 57 months
Population: ITT population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Androgen Deprivation Therapy (ADT) | Overall Survival (OS) | 52.17 months |
| Apalutamide + ADT | Overall Survival (OS) | NA months |
p-value: <0.000195% CI: [0.534, 0.793]Log Rank
Primary
Radiographic Progression-free Survival (rPFS)
rPFS as assessed by the investigator was defined as the duration from the date of randomization to the date of first documentation of radiographic progressive disease or death due to any cause, whichever occurred first. Radiographic progressive disease was defined as progression of soft tissue lesions measured by computed tomography (CT) or magnetic resonance imaging (MRI) as defined by modified Response evaluation criteria in solid tumors (RECIST) 1.1.
Time frame: Up to 35 months
Population: Intent to treat (ITT) population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Androgen Deprivation Therapy (ADT) | Radiographic Progression-free Survival (rPFS) | 22.08 months |
| Apalutamide + ADT | Radiographic Progression-free Survival (rPFS) | NA months |
p-value: <0.000195% CI: [0.391, 0.6]Log Rank
Secondary
Time to Chronic Opioid Use
Time to chronic opioid use was defined as the time from date of randomization to the first date of confirmed chronic opioid use. For participants entering the study without receiving opioids, chronic opioid use was defined as administration of opioid analgesics lasting for greater than or equal to (\>=) 3 weeks for oral or \>=7 days for non-oral formulations. For participants entering the study already receiving opioids, chronic opioid use was defined as a \>=30 percent (%) increase in total daily dose of the opioid analgesics lasting for \>= 3 weeks for oral or \>= 7 days for non-oral formulation.
Time frame: Up to 57 months
Population: ITT population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Androgen Deprivation Therapy (ADT) | Time to Chronic Opioid Use | NA months |
| Apalutamide + ADT | Time to Chronic Opioid Use | NA months |
p-value: 0.156395% CI: [0.576, 1.094]Log Rank
Secondary
Time to Initiation of Cytotoxic Chemotherapy
Time to initiation of cytotoxic chemotherapy was defined as the time from date of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer.
Time frame: Up to 57 months
Population: ITT population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Androgen Deprivation Therapy (ADT) | Time to Initiation of Cytotoxic Chemotherapy | NA months |
| Apalutamide + ADT | Time to Initiation of Cytotoxic Chemotherapy | NA months |
p-value: <0.000195% CI: [0.35, 0.63]Log Rank
Secondary
Time to Pain Progression
Time to pain progression was defined as the time from the date of randomization to the date of the first observation of pain progression. Pain progression was defined as an average increase by 2 points from baseline to greater than (\>) 4 on the Brief Pain Inventory - Short Form (BPI-SF) worst pain intensity (item 3) with no decrease in opioids confirmed greater than equal to (\>=) 3 weeks apart or initiation of chronic opioids, whichever occurred first. BPI-SF is a self-administered questionnaire developed to assess severity of pain and impact of pain on daily functions. Item 3 (worst pain intensity) asks participants to rate worst pain in prior 7-days on a 0-10 numeric rating scale, where 0 indicates No pain and 10 indicates Pain as bad as you can imagine. A lower score is better.
Time frame: Up to 57 months
Population: ITT population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Androgen Deprivation Therapy (ADT) | Time to Pain Progression | NA months |
| Apalutamide + ADT | Time to Pain Progression | NA months |
p-value: 0.196695% CI: [0.7, 1.076]Log Rank
Secondary
Time to Skeletal-related Event (SRE)
Time to SRE was defined as the time from the date of randomization to the date of the first observation of an SRE. A SRE was defined as the occurrence of either a pathological fracture, or spinal cord compression, or radiation to bone, or surgery to bone.
Time frame: Up to 57 months
Population: ITT population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Androgen Deprivation Therapy (ADT) | Time to Skeletal-related Event (SRE) | NA months |
| Apalutamide + ADT | Time to Skeletal-related Event (SRE) | NA months |
p-value: 0.360895% CI: [0.615, 1.194]Log Rank