Metastatic Castration-resistant Prostate Cancer
Conditions
Keywords
metastatic castration-resistant prostate cancer (mCRPC), homologous recombination repair (HRR)
Brief summary
The purpose of this study is to evaluate the efficacy and safety of olaparib versus enzalutamide or abiraterone acetate in subjects with metastatic castration-resistant prostate cancer who have failed prior treatment with a new hormonal agent and have homologous recombination repair gene mutations.
Detailed description
This is a prospective, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of olaparib versus enzalutamide or abiraterone in subjects with metastatic castration-resistant prostate cancer (mCRPC) who have failed prior treatment with a new hormonal agent (NHA) and have a qualifying tumor mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway. Subjects will be divided into two cohorts based on HRR gene mutation status. Approximately 340 subjects will be randomized 2:1 (olaparib : investigator choice of enzalutamide or abiraterone acetate) into the trial.
Interventions
DRUGolaparib
300 mg (2x 150 mg tablets) twice daily
DRUGenzalutamide
160 mg (4 x 40 mg capsules) once daily
DRUGabiraterone acetate
1,000 mg (4 x 250 mg tablets) once daily
Sponsors
Merck Sharp & Dohme LLC
Foundation Medicine
Myriad Genetics, Inc.
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed diagnosis of prostate cancer. 2. Documented evidence of metastatic castration resistant prostate cancer (mCRPC). 3. Subjects must have progressed on prior new hormonal agent (e.g. abiraterone acetate and/or enzalutamide) for the treatment of metastatic prostate cancer and/or CRPC . 4. Ongoing therapy with LHRH analog or bilateral orchiectomy. 5. Radiographic progression at study entry while on androgen deprivation therapy (or after bilateral orchiectomy). 6. Qualifying HRR mutation in tumor tissue.
Exclusion criteria
1. Any previous treatment with PARP inhibitor, including olaparib. 2. Subjects who have any previous treatment with DNA-damaging cytotoxic chemotherapy, except if for non-prostate cancer indication and last dose \> 5 years prior to randomization. 3. Other malignancy (including MDS and MGUS) within the last 5 years except: adequately treated non-melanoma skin cancer or other solid tumors curatively treated with no evidence of disease for ≥5 years. 4. Subjects with known brain metastases.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A Only | Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively). | The time from randomisation until the date of objective radiological disease progression (determined by RECIST 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG-3) (bone)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Progression is defined using (i) Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for soft tissue, as a \>=20% increase in the sum of diameters of target lesions and an absolute increase of \>=5mm taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters; (ii) Prostate Cancer Working Group 3 (PGWG-3) for bone as \>= 2 new bone lesions on the 1st week 8 scan compared to baseline. The confirmatory scan, \>=6 weeks later, must show \>=2 more new bone lesions (for a total of \>=4 new bone lesions since baseline). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) - Cohort A Only | Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively). | ORR is the percentage of patients with at least one visit response of Complete response (CR) or Partial response (PR), in their soft tissue disease assessed by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), in the absence of progression on bone scan assessed by Prostate Cancer Working Group 3 (PCWG3)). Per RECIST v1.1, CR=Disappearance of all target lesions; PR = \>=30% decrease in the sum of diameters of target lesions; For each treatment group, ORR is the number of patients with a CR and PR. |
| Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A+B | Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively). | The time from randomisation until the date of objective radiological disease progression (by RECIST 1.1 and Prostate Cancer Working Group 3 (PGWG-3)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. |
| Time to Pain Progression - Cohort A Only | Every 4 weeks from randomisation (for 7 consecutive days) throughout the study (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively). | Time from randomisation to time point at which worsening in pain is observed (ie date of pain progression - date of randomisation + 1). Based on average Brief Pain Inventory - short form (BPI-SF) worst pain \[Item 3\] and Analgesic Quantification Algorithm \[AQA\] score. |
| Overall Survival (OS) - Cohort A Only | Approximately 35 months after the first patient was randomised. | Number of Participants with Overall Survival (OS) - Cohort A only. |
Countries
Argentina, Australia, Austria, Brazil, Canada, Denmark, France, Germany, Israel, Italy, Japan, Netherlands, Norway, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Subjects were divided into two cohorts based on HRR gene mutation status. Subjects with mutations in either BRCA1, BRCA2, or ATM are in Cohort A whereas subjects with mutations among 12 other genes involved in the HRR pathway (BARD1, BRIP1, CDK12, CHEK1,CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L) are in Cohort B.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Olaparib 300mg bd 2x150mg film-coated tablets | 162 |
| Cohort A Investigators Choice of NHA either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone) | 83 |
| Cohort B Olaparib 300mg bd 2x150mg film-coated tablets | 94 |
| Cohort B Investigators Choice of NHA either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone) | 48 |
| Total | 387 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 88 | 54 | 67 | 28 |
| Overall Study | Disease progression | 0 | 0 | 0 | 1 |
| Overall Study | Investigator decision | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 0 | 1 | 0 |
| Overall Study | Ongoing study at data cut off | 49 | 21 | 19 | 12 |
| Overall Study | Screen failure | 0 | 0 | 0 | 1 |
| Overall Study | Study terminated by sponsor | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 21 | 7 | 7 | 6 |
Baseline characteristics
| Characteristic | Cohort A Olaparib 300mg bd | Cohort A Investigators Choice of NHA | Cohort B Olaparib 300mg bd | Cohort B Investigators Choice of NHA | Total |
|---|---|---|---|---|---|
| Age, Continuous | 68.0 Years STANDARD_DEVIATION 8.23 | 68.1 Years STANDARD_DEVIATION 7.36 | 69.2 Years STANDARD_DEVIATION 8.79 | 70.3 Years STANDARD_DEVIATION 7.83 | 68.6 Years STANDARD_DEVIATION 8.15 |
| Race/Ethnicity, Customized Asian | 43 Participants | 19 Participants | 26 Participants | 17 Participants | 105 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 1 Participants | 5 Participants | 0 Participants | 8 Participants |
| Race/Ethnicity, Customized Missing | 7 Participants | 7 Participants | 8 Participants | 1 Participants | 23 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 109 Participants | 55 Participants | 54 Participants | 30 Participants | 248 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 162 Participants | 83 Participants | 94 Participants | 48 Participants | 387 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 160 / 256 | 88 / 131 |
| other Total, other adverse events | 241 / 256 | 112 / 130 |
| serious Total, serious adverse events | 94 / 256 | 39 / 130 |
Outcome results
Primary
Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A Only
The time from randomisation until the date of objective radiological disease progression (determined by RECIST 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG-3) (bone)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Progression is defined using (i) Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for soft tissue, as a \>=20% increase in the sum of diameters of target lesions and an absolute increase of \>=5mm taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters; (ii) Prostate Cancer Working Group 3 (PGWG-3) for bone as \>= 2 new bone lesions on the 1st week 8 scan compared to baseline. The confirmatory scan, \>=6 weeks later, must show \>=2 more new bone lesions (for a total of \>=4 new bone lesions since baseline).
Time frame: Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A Olaparib 300mg bd | Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A Only | 7.39 Months |
| Cohort A Investigators Choice of NHA | Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A Only | 3.55 Months |
p-value: <0.000195% CI: [0.25, 0.47]Regression, Cox
Secondary
Confirmed Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) - Cohort A Only
ORR is the percentage of patients with at least one visit response of Complete response (CR) or Partial response (PR), in their soft tissue disease assessed by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), in the absence of progression on bone scan assessed by Prostate Cancer Working Group 3 (PCWG3)). Per RECIST v1.1, CR=Disappearance of all target lesions; PR = \>=30% decrease in the sum of diameters of target lesions; For each treatment group, ORR is the number of patients with a CR and PR.
Time frame: Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).
Population: Evaluable for response
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A Olaparib 300mg bd | Confirmed Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) - Cohort A Only | Response | 28 Participants |
| Cohort A Olaparib 300mg bd | Confirmed Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) - Cohort A Only | No response | 56 Participants |
| Cohort A Investigators Choice of NHA | Confirmed Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) - Cohort A Only | Response | 1 Participants |
| Cohort A Investigators Choice of NHA | Confirmed Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) - Cohort A Only | No response | 42 Participants |
p-value: <0.000195% CI: [4.18, 379.18]Regression, Logistic
Secondary
Overall Survival (OS) - Cohort A Only
Number of Participants with Overall Survival (OS) - Cohort A only.
Time frame: Approximately 35 months after the first patient was randomised.
Population: Full analysis set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A Olaparib 300mg bd | Overall Survival (OS) - Cohort A Only | Died | 91 Participants |
| Cohort A Olaparib 300mg bd | Overall Survival (OS) - Cohort A Only | Alive at data cut-off | 49 Participants |
| Cohort A Olaparib 300mg bd | Overall Survival (OS) - Cohort A Only | Terminated prior to death (withdrawn consent) | 22 Participants |
| Cohort A Investigators Choice of NHA | Overall Survival (OS) - Cohort A Only | Died | 57 Participants |
| Cohort A Investigators Choice of NHA | Overall Survival (OS) - Cohort A Only | Alive at data cut-off | 21 Participants |
| Cohort A Investigators Choice of NHA | Overall Survival (OS) - Cohort A Only | Terminated prior to death (withdrawn consent) | 5 Participants |
p-value: 0.017595% CI: [0.5, 0.97]Regression, Cox
Secondary
Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A+B
The time from randomisation until the date of objective radiological disease progression (by RECIST 1.1 and Prostate Cancer Working Group 3 (PGWG-3)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression.
Time frame: Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A Olaparib 300mg bd | Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A+B | 5.82 Months |
| Cohort A Investigators Choice of NHA | Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A+B | 3.52 Months |
p-value: <0.000195% CI: [0.38, 0.63]Regression, Cox
Secondary
Time to Pain Progression - Cohort A Only
Time from randomisation to time point at which worsening in pain is observed (ie date of pain progression - date of randomisation + 1). Based on average Brief Pain Inventory - short form (BPI-SF) worst pain \[Item 3\] and Analgesic Quantification Algorithm \[AQA\] score.
Time frame: Every 4 weeks from randomisation (for 7 consecutive days) throughout the study (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A Olaparib 300mg bd | Time to Pain Progression - Cohort A Only | NA Months |
| Cohort A Investigators Choice of NHA | Time to Pain Progression - Cohort A Only | 9.92 Months |
p-value: 0.019295% CI: [0.22, 0.91]Regression, Cox