Homologous Recombination Deficiency (HRD), Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Conditions
Brief summary
This study is designed to evaluate the efficacy of pamiparib in participants with metastatic castration-resistant prostate cancer (mCRPC) positive for circulating tumor cells (CTC) with homologous recombination deficiency (CTC-HRD). All participants will receive pamiparib. The purpose of this study is to demonstrate that pamiparib will improve Objective Response Rate (ORR) and Prostate-Specific Antigen (PSA) response rate
Detailed description
This is a global, Phase 2, open-label study of pamiparib in approximately 100 participants with metastatic castration-resistant prostate cancer (mCRPC) positive for circulating tumor cells (CTC) with homologous recombination deficiency (CTC-HRD). Participants in Cohort 1 will include 50 mCRPC participants with CTC-HRD-positive, measurable metastatic disease (soft tissue with/without bone lesions), and positive BRCA1/2 mutation or negative/unknown BRCA1/2 mutation. Cohort 2 will include 30 mCRPC CTC-HRD positive participants with bone metastasis only and positive or negative/unknown BRCA1/2. Cohort 3 and 4 will include 20 mCRPC CTC-HRD negative/unknown participants with BRCA1/2 positive mutations, metastatic disease (measurable soft tissue with/without bone), and bone only. Participants will undergo PSA level assessments approximately every 4 weeks as well as tumor assessments every 8 weeks for 24 weeks and the every 12 weeks, or as clinically indicated. Administration of pamiparib will continue until disease progression, unacceptable toxicity, death or another discontinuation criterion is met.
Interventions
DRUGPamiparib
60 mg orally twice daily (BID)
Sponsors
BeiGene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Men (≥ 18 years of age) with histologically or cytologically confirmed adenocarcinoma or poorly differentiated adenocarcinoma of the prostate without neuroendocrine differentiation with HRD deficiency by CTC-HRD assay and/or deleterious germline or somatic mutation in BRCA1 or BRCA2; mCRPC measurable disease and/or bone disease. • PSA progression with ≥ 3 rising PSA levels with ≥ 1 week between determinations and a screening PSA ≥ 2 μg/L (2 ng/mL). * Must be surgically or medically castrated with serum testosterone levels of ≤1.73 nmol/L (50 ng/dL), must have received ≥ 1 prior androgen receptor-targeted therapy, and must have received ≥ 1 taxane-based therapy. * mCRPC with 1 or 2 of the following: * Measurable disease per RECIST v1.1 * Bone disease * CTC-HRD+ or BRCA1/2 mutation * PSA progression (PCWG3 criteria) * ≥1 androgen receptor-targeted therapy (eg, abiraterone acetate/prednisone or enzalutamide) for mCRPC with progressive disease * ≥1 taxane for metastatic prostate cancer Key
Exclusion criteria
* Chemotherapy, hormonal therapy, biologic therapy, radionuclide therapy, immunotherapy, investigational agent, anticancer Chinese medicine, or herbal remedies ≤ 5 half-lives if the half-life is known, ≤ 14 days if not known, before start of study treatment * Continued treatment with a bisphosphonate or denosumab is allowed, if administered at a stable dose \> 28 days before start of study treatment * Radiotherapy ≤ 21 days (≤ 14 days, if single fraction of radiotherapy) before start of study treatment Prior treatment for prostate cancer with any of the following: * poly ADP ribose polymerase (PARP) inhibitor * Platinum * Cyclophosphamide * Mitoxantrone NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Determined by Independent Review Committee | Up to 1 year and 6 months | ORR is the percentage of participants with a best objective response of complete response (CR) or partial response (PR) confirmed at a subsequent timepoint ≥ 4 weeks later by an Independent Review Committee (IRC). |
| Prostate-Specific Antigen (PSA) Response Rate | Up to 1 year and 6 months | PSA response rate is defined as the percentage of participants with PSA decline ≥ 50% from baseline \[confirmed by a second PSA value ≥ 3 weeks later\] for CTC-HRD-positive participants with or without measurable disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Objective Response by Investigator | Up to 1 year and 6 months | Time to objective response is defined as the time from the date of the first dose of study drug to the first documented confirmed response of CR or PR assessed by the investigator and summarized for participants who have achieved a confirmed objective response. |
| Clinical Benefit Rate By Investigator | Up to 1 year and 6 months | Clinical Benefit Rate is the percentage of participants who achieved confirmed CR, PR, or SD or NON-CR/NON-PD. The minimum interval for confirmed CR and PR is 4 weeks and the measurement of SD or NON-CR/NON-PD is 7 weeks after first dose date. |
| Time to PSA Response | Up to 1 year and 6 months | Time to PSA response is defined as the time from the date of the first dose of study drug to the first PSA decline ≥ 50% that is subsequently confirmed. Assessments are summarized for participants who have achieved a confirmed PSA response. |
| Duration of PSA Response | Up to 1 year and 7 months | Duration of PSA response is defined as the time from the date of the earliest documented PSA response (that is subsequently confirmed) to PSA progression or death due to any cause, whichever occurs first. PSA progression is defined as a ≥ 25% increase in PSA with an absolute increase of ≥ 2 μg/L above the nadir (or above the baseline for participants with no PSA decline) after12 weeks, confirmed by a second value ≥ 3 weeks later. The nadir is defined as the lowest value at or after baseline. |
| Duration of Response (DOR) by IRC | Up to 1 year and 7 months | DOR is defined as the time from the date of the earliest documented CR or PR (that is subsequently confirmed) to radiographic disease progression or death due to any cause, whichever occurs first. |
| Time to Symptomatic Skeletal Event | Up to 1 year and 7 months | Time to symptomatic skeletal event (SSE) is defined as time from the date of the first dose of study drug to the first symptomatic fracture, radiation or surgery to bone, or spinal cord compression. |
| Radiographic Progression-Free Survival by IRC | Up to 1 year and 7 months | Radiographic progression-free survival is defined as the time from the date of the first dose of study drug to radiographic disease progression by IRC or death due to any cause, whichever occurs first. |
| Overall Survival (OS) | Up to 1 year and 7 months | Overall survival is defined as the time from the date of the first dose of study drug to death due to any cause. |
| Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | From the date of first Pamiparib dose until 30 days after the last dose or initiation of new anti-cancer therapy, whichever occurs first. (Up to 1 year and 7 months) | — |
| Time to PSA Progression | Up to 1 year and 7 months | Time to PSA progression is defined as the time from the date of the first dose of study drug to a ≥ 25% increase in PSA with an absolute increase of ≥ 2 ng/mL above the nadir (or above the baseline for participants with no PSA decline) after 12 weeks, confirmed by a second value ≥ 3 weeks later. Death for the participants with no PSA progression is also considered as an event. |
| Objective Response Rate by Investigator | Up to 1 year and 6 months | ORR is the percentage of participants with a best objective response of complete response (CR) or partial response (PR) confirmed at a subsequent timepoint ≥ 4 weeks later by the investigator. |
Countries
Australia, Puerto Rico, Spain, United States
Participant flow
Recruitment details
Eighteen subjects were screened; 5 subjects failed screening and 13 subjects were dosed.
Pre-assignment details
All subjects enrolled had unknown BRCA1/2 status at study entry and were assigned to cohorts 1B or 2B; there were no subjects known to be BRCA1/2 positive at enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Pamiparib Participants received 60 mg pamiparib orally twice daily | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 7 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Progressive Disease | 2 |
| Overall Study | Study Terminated by Sponsor | 3 |
Baseline characteristics
| Characteristic | Pamiparib |
|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 9.49 |
| Race/Ethnicity, Customized Ethnicity: Not Hispanic or Latino | 7 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 Participants |
| Race/Ethnicity, Customized Not Reported/Unknown | 3 Participants |
| Race/Ethnicity, Customized Race: American Indian or Alaska Native, White | 1 Participants |
| Race/Ethnicity, Customized Race: Not Reported | 1 Participants |
| Race/Ethnicity, Customized Race: Other | 1 Participants |
| Race/Ethnicity, Customized Race: Unknown | 3 Participants |
| Race/Ethnicity, Customized Race: White | 7 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 9 / 13 |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 6 / 13 |
Outcome results
Primary
Objective Response Rate (ORR) Determined by Independent Review Committee
ORR is the percentage of participants with a best objective response of complete response (CR) or partial response (PR) confirmed at a subsequent timepoint ≥ 4 weeks later by an Independent Review Committee (IRC).
Time frame: Up to 1 year and 6 months
Population: Efficacy-Evaluable Analysis Set: includes all participants in the Safety Analysis Set who had measurable disease at baseline and at least 1 post-baseline tumor assessment, unless they permanently discontinue pamiparib or the study early due to clinical progression or death before tumor assessment. Participants with available data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pamiparib | Objective Response Rate (ORR) Determined by Independent Review Committee | 0 Percentage of participants |
Primary
Prostate-Specific Antigen (PSA) Response Rate
PSA response rate is defined as the percentage of participants with PSA decline ≥ 50% from baseline \[confirmed by a second PSA value ≥ 3 weeks later\] for CTC-HRD-positive participants with or without measurable disease.
Time frame: Up to 1 year and 6 months
Population: PSA-Evaluable Analysis Set: includes all participants in the Safety Analysis Set with ≥3 rising PSA levels with ≥ 1 week between determinations and screening PSA ≥ 2 μg/L) and who had at least 1 post-baseline PSA measurement unless they permanently discontinue pamiparib or the study early due to clinical progression or death before completed PSA assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pamiparib | Prostate-Specific Antigen (PSA) Response Rate | 0 Percentage of participants |
Secondary
Clinical Benefit Rate By Investigator
Clinical Benefit Rate is the percentage of participants who achieved confirmed CR, PR, or SD or NON-CR/NON-PD. The minimum interval for confirmed CR and PR is 4 weeks and the measurement of SD or NON-CR/NON-PD is 7 weeks after first dose date.
Time frame: Up to 1 year and 6 months
Population: Efficacy-Evaluable Analysis Set: includes all participants in the Safety Analysis Set who had measurable disease at baseline and at least 1 post-baseline tumor assessment, unless they permanently discontinue pamiparib or the study early due to clinical progression or death before tumor assessment. Participants with available data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pamiparib | Clinical Benefit Rate By Investigator | 25 Percentage of participants |
Secondary
Duration of PSA Response
Duration of PSA response is defined as the time from the date of the earliest documented PSA response (that is subsequently confirmed) to PSA progression or death due to any cause, whichever occurs first. PSA progression is defined as a ≥ 25% increase in PSA with an absolute increase of ≥ 2 μg/L above the nadir (or above the baseline for participants with no PSA decline) after12 weeks, confirmed by a second value ≥ 3 weeks later. The nadir is defined as the lowest value at or after baseline.
Time frame: Up to 1 year and 7 months
Population: PSA-Evaluable Analysis Set: includes all participants in the Safety Analysis Set with ≥3 rising PSA levels with ≥ 1 week between determinations and screening PSA ≥ 2 μg/L) and who had at least 1 post-baseline PSA measurement, unless they permanently discontinue pamiparib or the study early due to clinical progression or death before completed PSA assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pamiparib | Duration of PSA Response | NA Months |
Secondary
Duration of Response (DOR) by IRC
DOR is defined as the time from the date of the earliest documented CR or PR (that is subsequently confirmed) to radiographic disease progression or death due to any cause, whichever occurs first.
Time frame: Up to 1 year and 7 months
Population: Efficacy-Evaluable Analysis Set: includes all participants in the Safety Analysis Set who had measurable disease at baseline and at least 1 post-baseline tumor assessment, unless they permanently discontinue pamiparib or the study early due to clinical progression or death before tumor assessment. Participants with available data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pamiparib | Duration of Response (DOR) by IRC | NA Months |
Secondary
Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03
Time frame: From the date of first Pamiparib dose until 30 days after the last dose or initiation of new anti-cancer therapy, whichever occurs first. (Up to 1 year and 7 months)
Population: Safety Analysis Set: includes all participants enrolled in the study who received any dose of pamiparib
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Participants with at Least One TEAE | 13 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Grade 3 or Higher | 11 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Serious | 6 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Leading to Death | 1 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Leading to Treatment Discontinuation | 3 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Leading to Dose Modification | 11 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Leading to Dose Interruption | 9 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Leading to Dose Reduction | 5 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Treatment Related TEAEs | 11 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Treatment Related Grade 3 or Higher | 7 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Treatment Related Serious | 1 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Treatment Related Leading to Death | 0 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Treatment Related Leading to Treatment Discontinuation | 3 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Treatment Related Leading to Dose Modification | 7 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Treatment Related Leading to Dose Interruption | 6 number of participants |
| Pamiparib | Number of Participants With Treatment-Emergent Adverse Events Graded According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Treatment Related Leading to Dose Reduction | 3 number of participants |
Secondary
Objective Response Rate by Investigator
ORR is the percentage of participants with a best objective response of complete response (CR) or partial response (PR) confirmed at a subsequent timepoint ≥ 4 weeks later by the investigator.
Time frame: Up to 1 year and 6 months
Population: Efficacy-Evaluable Analysis Set: includes all participants in the Safety Analysis Set who had measurable disease at baseline and at least 1 post-baseline tumor assessment, unless they permanently discontinue pamiparib or the study early due to clinical progression or death before tumor assessment. Participants with available data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pamiparib | Objective Response Rate by Investigator | 0 Percentage of participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from the date of the first dose of study drug to death due to any cause.
Time frame: Up to 1 year and 7 months
Population: Safety Analysis Set: includes all participants enrolled in the study who received any dose of pamiparib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pamiparib | Overall Survival (OS) | 5.8 Months |
Secondary
Radiographic Progression-Free Survival by IRC
Radiographic progression-free survival is defined as the time from the date of the first dose of study drug to radiographic disease progression by IRC or death due to any cause, whichever occurs first.
Time frame: Up to 1 year and 7 months
Population: Safety Analysis Set : includes all participants enrolled in the study who received any dose of pamiparib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pamiparib | Radiographic Progression-Free Survival by IRC | 2.6 Months |
Secondary
Time to Objective Response by Investigator
Time to objective response is defined as the time from the date of the first dose of study drug to the first documented confirmed response of CR or PR assessed by the investigator and summarized for participants who have achieved a confirmed objective response.
Time frame: Up to 1 year and 6 months
Population: Efficacy-Evaluable Analysis Set: includes all participants in the Safety Analysis Set who had measurable disease at baseline and at least 1 post-baseline tumor assessment, unless they permanently discontinue pamiparib or the study early due to clinical progression or death before tumor assessment. Participants with available data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pamiparib | Time to Objective Response by Investigator | NA Months |
Secondary
Time to PSA Progression
Time to PSA progression is defined as the time from the date of the first dose of study drug to a ≥ 25% increase in PSA with an absolute increase of ≥ 2 ng/mL above the nadir (or above the baseline for participants with no PSA decline) after 12 weeks, confirmed by a second value ≥ 3 weeks later. Death for the participants with no PSA progression is also considered as an event.
Time frame: Up to 1 year and 7 months
Population: Safety Analysis Set : includes all participants enrolled into the study who received any dose of pamiparib.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pamiparib | Time to PSA Progression | 3.13 Months | Standard Deviation 1.533 |
Secondary
Time to PSA Response
Time to PSA response is defined as the time from the date of the first dose of study drug to the first PSA decline ≥ 50% that is subsequently confirmed. Assessments are summarized for participants who have achieved a confirmed PSA response.
Time frame: Up to 1 year and 6 months
Population: PSA-Evaluable Analysis Set: includes all participants in the Safety Analysis Set with ≥3 rising PSA levels with ≥ 1 week between determinations and screening PSA ≥ 2 μg/L and who had at least 1 post-baseline PSA measurement, unless they permanently discontinue pamiparib or the study early due to clinical progression or death before completed PSA assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pamiparib | Time to PSA Response | NA Months |
Secondary
Time to Symptomatic Skeletal Event
Time to symptomatic skeletal event (SSE) is defined as time from the date of the first dose of study drug to the first symptomatic fracture, radiation or surgery to bone, or spinal cord compression.
Time frame: Up to 1 year and 7 months
Population: Safety Analysis Set: includes all participants enrolled in the study who received any dose of pamiparib
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pamiparib | Time to Symptomatic Skeletal Event | NA Months |