Metastatic Prostate Cancer, Prostate Adenocarcinoma
Conditions
Keywords
prostate cancer, castration-resistant prostate cancer
Brief summary
This is a Phase 3, multi-center, randomized, open-label, controlled study designed to evaluate the safety and efficacy of cabozantinib given in combination with atezolizumab versus a second novel hormonal therapy (NHT) in men with metastatic castration-resistant prostate cancer (mCRPC) who have previously been treated with one, and only one, NHT for their prostate cancer disease.
Detailed description
The primary objective of this study is to evaluate the efficacy of cabozantinib (XL184) in combination with atezolizumab versus a second NHT (abiraterone or enzalutamide) in subjects with mCRPC who have previously been treated with one, and only one, NHT (e.g. abiraterone, apalutamide, darolutamide, or enzalutamide) to treat metastatic castration-sensitive prostate cancer (mCSPC), non-metastatic CRPC (M0 CRPC), or mCRPC, and who have measurable extrapelvic disease. The multiple primary efficacy endpoints comparing the experimental arm and control arm are Duration of Progression Free Survival (PFS) per RECIST 1.1 by Blinded Independent Radiology Committee (BIRC) and Duration of Overall Survival (OS). The secondary efficacy endpoint is Objective Response Rate (ORR) per RECIST 1.1 per BIRC.
Interventions
DRUGCabozantinib
Supplied as 20-mg tablets; administered orally daily at 40mg
DRUGAtezolizumab
Supplied as 1200 mg/20 mL vials; administered as an IV infusion once every 3 weeks (q3w)
DRUGAbiraterone Acetate
Supplied as 500 mg tablets; administered orally daily at 1000mg with prednisone 5 mg orally bid
DRUGEnzalutamide
Supplied as 40 mg capsules; administered orally daily at 160mg
DRUGPrednisone
Supplied as 5 mg tablets; administered orally bid at 5 mg with abiraterone 1000mg orally daily
Sponsors
Roche-Genentech
Takeda
Exelixis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Approximately 580 eligible subjects will be randomized in a 1:1 fashion to the experimental arm receiving cabozantinib and atezolizumab in combination (290) or to the control arm receiving a second NHT (290).
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men with histologically or cytologically confirmed adenocarcinoma of the prostate * Prior treatment with one, and only one, NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) for castration-sensitive locally advanced (T3 or T4) or mCSPC, M0 CRPC, or mCRPC * Surgical or medical castration, with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening * Measurable (extrapelvic soft tissue) metastatic disease per Investigator assessment defined by at least one of the following: measurable visceral disease (eg, adrenal, kidney, liver, lung, pancreas, spleen) per RECIST 1.1; OR measurable extrapelvic adenopathy (ie, adenopathy above the aortic bifurcation) * Progressive disease at study entry as defined by specific criteria for prostate specific antigen (PSA) progression OR soft tissue disease progression in the opinion of the Investigator (Note: subjects with bone disease progression alone are not eligible) * Age ≥ 18 years old or meeting country definition of adult, whichever is older, on the day of consent * ECOG performance status of 0 or 1 * Recovery to baseline or ≤ Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy in the opinion of the Investigator * Adequate organ and marrow function based upon specific laboratory assessments obtained within 21 days prior to randomization * Understanding and ability to comply with protocol requirements
Exclusion criteria
* Any prior nonhormonal therapy initiated for the treatment of mCRPC * Receipt of abiraterone within 1 week; cyproterone within 10 days; or flutamide, nilutamide, bicalutamide, enzalutamide, or other androgen-receptor inhibitors within 2 weeks before randomization * Radiation therapy within 4 weeks (2 weeks for bone metastases) prior to randomization (subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible) * Known brain metastases or cranial epidural disease unless adequately treated and clinically stable at least 4 weeks prior to randomization * Symptomatic or impending spinal cord compression or cauda equina syndrome * Concomitant anticoagulation with oral anticoagulants (some specific exceptions apply) * Administration of a live, attenuated vaccine within 30 days prior to randomization * Systematic treatment with, or any condition requiring, either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to randomization * Uncontrolled, significant intercurrent or recent illness * Major surgery within 4 weeks prior to randomization * Corrected QT interval calculated by the Fridericia formula (QTcF) \> 480 ms per ECG within 21 days before randomization * Inability or unwillingness to swallow pills or receive IV administration * Previously identified allergy or hypersensitivity to components of the study treatment formulations or history of severe infusion-related reactions to monoclonal antibodies * Any other active malignancy at time of randomization or diagnosis of another malignancy within 2 years prior to randomization that requires active treatment (some exceptions apply such as locally curable cancers that have apparently been cured).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Progression Free Survival (PFS) Per Response Evaluable Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Radiology Committee (BIRC) | Up to a maximum of approximately 30 months (Median duration of follow-up was 14.31 months) | Duration of PFS was defined as the time from randomization to the earlier of either the date of radiographic progression (defined as progressive disease \[PD\] per RECIST 1.1) per BIRC or the date of death due to any cause. PD was defined as at least a 20% increase in the sum of diameters of target lesions, with an absolute increase of ≥ 5 mm, unequivocal progression of non-target lesions and/or the appearance of new lesions. |
| Duration of Overall Survival (OS) | Up to a maximum of approximately 45 months (Median duration of follow-up was 24.05 months) | Duration of OS was defined as the time from randomization to death due to any cause. For participants, who were not known to have died at the time of data cutoff and were permanently lost to follow-up, duration of OS was censored at the earlier of the following dates: date the participant was last known to be alive or date of full withdrawal of consent (including survival follow-up), or date of data cutoff. OS was calculated as earlier of date of death or censoring - date of randomization + 1)/30.4375 |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Czechia, France, Georgia, Germany, Greece, Hungary, Israel, Italy, Japan, Mexico, Poland, Portugal, Russia, Singapore, South Korea, Spain, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
The study is ongoing, so the results reported are based on a data cutoff date of 19 April 2024.
Participants by arm
| Arm | Count |
|---|---|
| Experimental Arm: Cabozantinib and Atezolizumab Participants with mCRPC received cabozantinib 40 mg as oral tablets QD throughout the treatment period. Participants also received atezolizumab 1200 mg as an IV infusion once every 3 weeks, administered on Day 1 of each 21-day cycle throughout the treatment period.
Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation. | 289 |
| Control Arm: Second NHT Participants with mCRPC received either abiraterone 1000 mg as oral tablets QD and prednisone 5 mg as oral tablets BID or enzalutamide 160 mg as oral tablets QD throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation. | 286 |
| Total | 575 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 79 | 43 |
| Overall Study | Lack of Clinical Benefit | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Miscellaneous | 26 | 36 |
| Overall Study | Missing Data/Data not yet Received | 1 | 0 |
| Overall Study | No Study Treatment Given | 4 | 3 |
| Overall Study | Radiographic Disease Progression | 132 | 158 |
| Overall Study | Withdrawal by Subject | 24 | 22 |
Baseline characteristics
| Characteristic | Experimental Arm: Cabozantinib and Atezolizumab | Control Arm: Second NHT | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 235 Participants | 219 Participants | 454 Participants |
| Age, Categorical Between 18 and 65 years | 54 Participants | 67 Participants | 121 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 77 Participants | 72 Participants | 149 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 196 Participants | 196 Participants | 392 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 18 Participants | 34 Participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 3 Participants | 9 Participants | 12 Participants |
| Race/Ethnicity, Customized Asian | 39 Participants | 39 Participants | 78 Participants |
| Race/Ethnicity, Customized Black/African American | 0 Participants | 9 Participants | 9 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 16 Participants | 13 Participants | 29 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 227 Participants | 213 Participants | 440 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 289 Participants | 286 Participants | 575 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 173 / 284 | 179 / 284 |
| other Total, other adverse events | 281 / 284 | 254 / 284 |
| serious Total, serious adverse events | 135 / 284 | 89 / 284 |
Outcome results
Primary
Duration of Overall Survival (OS)
Duration of OS was defined as the time from randomization to death due to any cause. For participants, who were not known to have died at the time of data cutoff and were permanently lost to follow-up, duration of OS was censored at the earlier of the following dates: date the participant was last known to be alive or date of full withdrawal of consent (including survival follow-up), or date of data cutoff. OS was calculated as earlier of date of death or censoring - date of randomization + 1)/30.4375
Time frame: Up to a maximum of approximately 45 months (Median duration of follow-up was 24.05 months)
Population: ITT population: Included all participants who were randomized regardless of whether any study treatment or the correct study treatment was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm: Cabozantinib and Atezolizumab | Duration of Overall Survival (OS) | 14.78 months |
| Control Arm: Second NHT | Duration of Overall Survival (OS) | 14.98 months |
p-value: 0.295695% CI: [0.72, 1.1]Log Rank
Primary
Duration of Progression Free Survival (PFS) Per Response Evaluable Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Radiology Committee (BIRC)
Duration of PFS was defined as the time from randomization to the earlier of either the date of radiographic progression (defined as progressive disease \[PD\] per RECIST 1.1) per BIRC or the date of death due to any cause. PD was defined as at least a 20% increase in the sum of diameters of target lesions, with an absolute increase of ≥ 5 mm, unequivocal progression of non-target lesions and/or the appearance of new lesions.
Time frame: Up to a maximum of approximately 30 months (Median duration of follow-up was 14.31 months)
Population: PFS ITT (PITT) analysis population: Included the first 400 participants who were randomized to the Experimental Arm or Control Arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm: Cabozantinib and Atezolizumab | Duration of Progression Free Survival (PFS) Per Response Evaluable Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Radiology Committee (BIRC) | 6.34 months |
| Control Arm: Second NHT | Duration of Progression Free Survival (PFS) Per Response Evaluable Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Radiology Committee (BIRC) | 4.17 months |
p-value: 0.000795% CI: [0.5, 0.84]Log Rank