Triple Negative Breast Neoplasms
Conditions
Keywords
Programmed Cell Death Receptor 1 (PD-1, PD1), Programmed Cell Death Receptor Ligand 1 (PD-L1, PDL1), Programmed Cell Death Receptor Ligand 2 (PD-L2, PDL2)
Brief summary
The purpose of this study is to compare the efficacy of olaparib (MK-7339) plus pembrolizumab (MK-3475) with chemotherapy plus pembrolizumab after induction with first-line chemotherapy plus pembrolizumab in triple negative breast cancer (TNBC). The primary hypotheses are: 1. Olaparib plus pembrolizumab is superior to chemotherapy plus pembrolizumab with respect to progression-free survival (PFS). 2. Olaparib plus pembrolizumab is superior to chemotherapy plus pembrolizumab with respect to overall survival (OS). As of Amendment 3, study enrollment was discontinued. Participants who were receiving benefit from the study intervention could continue treatment until criteria for discontinuation are met. Participants who are on study treatment or in follow-up phase will no longer have tumor response assessments by BICR.
Interventions
BIOLOGICALPembrolizumab
intravenous (IV) infusion
DRUGOlaparib
oral tablets
DRUGCarboplatin
IV infusion
DRUGGemcitabine
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Induction Period: * Has locally recurrent inoperable TNBC that has not previously been treated with chemotherapy and that cannot be treated with curative intent OR has metastatic TNBC that has not been previously treated with chemotherapy * Has been treated with anthracycline and/or a taxane in the neoadjuvant/adjuvant setting, if they received systemic treatment in the neoadjuvant/adjuvant setting, unless anthracycline and/or taxane was contraindicated or not considered the best treatment option for the participant in the opinion of the treating physician * Has measurable disease based on RECIST 1.1 * Has provided a recently obtained or archival (no more than 3 years old) core or excisional biopsy of a tumor lesion not previously irradiated * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 as assessed within 7 days prior to the start of induction study treatment * Has a life expectancy ≥27 weeks from the day of first study treatment * Demonstrate adequate organ function within 10 days prior to the start of study treatment * A male participant must agree to be abstinent or use contraception and refrain from donating sperm during the intervention period and for at least the time needed to eliminate each study intervention (95 days for olaparib and chemotherapy; no requirement for pembrolizumab) * A female participant must not be pregnant or breastfeeding and must agree to the following if is a woman of childbearing potential (WOCBP): have a negative pregnancy test within 24 hours before the start of study treatment and agree to be abstinent or use contraception and refrain from donating eggs (ova, oocytes) during the intervention period and for at least the time needed to eliminate each study intervention (180 days for olaparib and chemotherapy; 120 days for pembrolizumab) Post-induction Period: * Has received up to 6 cycles but not less than 4 cycles of induction therapy without permanently discontinuing from pembrolizumab or both carboplatin and gemcitabine * Has achieved complete response (CR), partial response (PR), or stable disease (SD) based on RECIST 1.1 by Blinded Independent Central Review (BICR) at the Week 18 evaluation * Is able to complete during post-induction at least the Cycle 1, Day 1 doses of olaparib and pembrolizumab or the Cycle 1, Day 1 doses of at least one of the chemotherapy agents being administered at the end of induction (carboplatin and/or gemcitabine) in addition to pembrolizumab * Has ECOG performance status of 0 or 1, as assessed within 7 days prior to the start of post-induction study treatment * Has no higher than Grade 1 toxicities related to induction therapy (excluding alopecia) prior to randomization
Exclusion criteria
Induction Period: * Has a known additional malignancy that is progressing or has required active treatment within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, cervical cancer in situ) that have undergone potentially curative therapy * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment * Has an active autoimmune disease that has required systemic treatment in the past 2 years * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis * Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features suggestive of MDS/AML * Has a history of (non-infectious) pneumonitis\\interstitial lung disease that required steroids or current pneumonitis\\interstitial lung disease * Has active, or a history of, interstitial lung disease * Has a known history of active tuberculosis * Has an active infection requiring systemic therapy * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection * Has a history of class II-IV congestive heart failure or myocardial infarction within 6 months of first study treatment * Has neuropathy ≥Grade 2 * Has not recovered (eg, to ≤Grade 1 or to baseline) from AEs due to a previously administered therapy * Has a known history of hypersensitivity or allergy to pembrolizumab, olaparib and any of its components, and/or to any of the study chemotherapies (eg, carboplatin or gemcitabine) and any of their components * Has severe hypersensitivity (≥Grade 3) to the study treatments and/or any of their excipients * Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 180 days after the last dose of study treatment * Is a WOCBP who has a positive urine pregnancy test within 24 hours prior to randomization or treatment allocation * Has received prior therapy with either olaparib or any other poly adenosine diphosphate ribose polymerase (PARP) inhibitor * Has received prior radiotherapy within 2 weeks of start of study treatment * Has received colony-stimulating factors (eg, granulocyte colony stimulating factor \[G-CSF\], granulocyte macrophage colony stimulating factor \[GM-CSF\] or recombinant erythropoietin) within 2 weeks prior to the first dose of study treatment * Has had an allogenic tissue/solid organ transplant. * Has received previous allogenic bone marrow transplant or double umbilical cord transplantation (dUCBT) * Has had major surgery within 2 weeks of starting study treatment or has not recovered from any effects of any major surgery * Has received a live or live-attenuated vaccine within 30 days prior to first study treatment * Is receiving any medication prohibited in combination with study chemotherapies unless medication was stopped within 7 days prior to first study treatment * Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T cell receptor (such as cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], OX-40, CD137) or has previously participated in a study evaluating pembrolizumab regardless of treatment received * Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment * Has presence of uncontrolled, potentially reversible cardiac conditions, as judged by the investigator * Has a history or current evidence of any condition (eg, cytopenia, transfusion-dependent anemia, or thrombocytopenia), therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating investigator * Is either unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption) * Is unlikely to comply with the study procedures, restrictions, and requirements of the study; as judged by the investigator Post-induction Period: * Has severe hypersensitivity (≥Grade 3) to the study treatments and/or any of their excipients * Has permanently discontinued from both carboplatin and gemcitabine during induction due to toxicity * Has permanently discontinued from pembrolizumab during induction due to toxicity * Has received less than 4 cycles of chemotherapy plus pembrolizumab during induction * Is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study * Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to approximately 29 months | PFS was defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR), or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters (SOD) of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS is reported based on the product-limit (Kaplan-Meier) method for censored data. |
| Overall Survival (OS) | Up to approximately 29 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. OS is reported based on the product-limit (Kaplan-Meier) method for censored data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) in Participants With Programmed Cell Death-Ligand 1 (PD-L1) Positive Tumors With a Combined Positive Score (CPS) ≥10 | Up to approximately 29 months | PFS was defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR), or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters (SOD) of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Only participants with a CPS ≥10 were included in this analysis. PFS is reported based on the product-limit (Kaplan-Meier) method for censored data. |
| Overall Survival (OS) in Participants With PD-L1 Positive Tumors With a CPS ≥10 | Up to approximately 29 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Only participants with a CPS ≥10 were included in this analysis. |
| PFS in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors | Up to approximately 29 months | PFS was defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR), or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters (SOD) of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Only participants with BRCAm-positive tumors were included in this analysis. PFS is reported based on the product-limit (Kaplan-Meier) method for censored data. |
| OS in Participants With BRCAm Tumors | Up to approximately 29 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Only participants with BRCAm-positive tumors were included in this analysis. |
| Change From Baseline in Health-Related Quality-of-Life (QoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Combined Score | Baseline and week 18 | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the QoL question "How would you rate your overall quality of life during the past week?" (Item 30) were each scored on a 7-point scale (1=Very Poor to 7=Excellent), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Change from baseline in EORTC QLQ-C30 Items 29 and 30 combined scores was calculated based on a constrained longitudinal data analysis (cLDA) model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1) and BRCA status at randomization (BRCAm vs. BRCAwt)) as covariates. |
| Change From Baseline in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score | Baseline and week 18 | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. The change from baseline in physical functioning (EORTC QLQ-C30 Items 1-5) score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1) and BRCA status at randomization (BRCAm vs. BRCAwt)) as covariates. |
| Change From Baseline in Emotional Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 21-24 Score | Baseline and week 18 | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 4 questions about their emotional functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Change from baseline in emotional functioning (EORTC QLQ-C30 Items 21-24) score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1) and BRCA status at randomization (BRCAm vs. BRCAwt)) as covariates. |
| Change From Baseline in Systemic Therapy Side Effects Using the European Organization for Research and Treatment of Cancer Breast Cancer-Specific QoL Questionnaire (EORTC QLQ-BR23) Items 1-4, 6, 7, and 8 Score | Baseline and week 18 | EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30, consisting of functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All, 4=Very Much). Using linear transformation, raw scores are standardized, so scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in systemic therapy side effects (EORTC QLQ-BR23 Items 1-4, 6, 7, and 8) score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1) and BRCA status at randomization (BRCAm vs. BRCAwt)) as covariates. |
| Change From Baseline in Visual Analogue Scale (VAS) Score on the European Quality of Life 5-dimension, 5-level Questionnaire (EQ-5D-5L) | Baseline and week 18 | The EQ-5D-5L is a questionnaire developed to assess health-related outcomes. The VAS is a component of the EQ-5D-5L that asks participants to rate their overall health on a vertical visual analogue scale, with the scale's ends labelled 'The best health you can imagine' (equivalent to a score of 0) and 'The worst health you can imagine' (equivalent to a score of 100). The change from baseline in VAS score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1) and BRCA status at randomization (BRCAm vs. BRCAwt)) as covariates. |
| Change From Baseline in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Combined Score in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors | Baseline and up to 18 weeks | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the QoL question "How would you rate your overall quality of life during the past week?" (Item 30) were each scored on a 7-point scale (1=Very Poor to 7=Excellent), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. The change from baseline in EORTC QLQ-C30 Items 29 and 30 scores was calculated based on a constrained longitudinal data analysis (cLDA) model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), and baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1)) as covariates. |
| Change From Baseline in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score in Participants With BRCAm Tumors | Baseline and week 18 | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. The change from baseline in physical functioning (EORTC QLQ-C30 Items 1-5) score was calculated based on a constrained longitudinal data analysis (cLDA) model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), and baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1)) as covariates. |
| Change From Baseline in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score in Participants With BRCAm Tumors | Baseline and week 18 | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 4 questions about their emotional functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. The change from baseline in emotional functioning (EORTC QLQ-C30 Items 21-24) score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), and baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1)) as covariates. |
| Change From Baseline in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score in Participants With BRCAm Tumors | Baseline and week 18 | EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30, consisting of functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All, 4=Very Much). Using linear transformation, raw scores are standardized, so scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in systemic therapy side effects (EORTC QLQ-BR23 Items 1-4, 6, 7, and 8) score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), and baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1)) as covariates. |
| Change From Baseline in Visual Analogue Scale (VAS) Score on the EQ-5D-5L in Participants With BRCAm Tumors | Baseline and week 18 | The EQ-5D-5L is a questionnaire developed to assess health-related outcomes. The VAS is a component of the EQ-5D-5L that asks participants to rate their overall health on a vertical visual analogue scale, with the scale's ends labelled 'The best health you can imagine' (equivalent to a score of 0) and 'The worst health you can imagine' (equivalent to a score of 100). The change from baseline in VAS score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), and baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1)) as covariates. |
| Time to Deterioration (TTD) in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Score | Baseline and up to approximately 29 months | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the QoL question "How would you rate your overall quality of life during the past week?" (Item 30) were each scored on a 7-point scale (1=Very Poor to 7=Excellent), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in Items 29 and 30 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data. |
| TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score | Up to approximately 29 months | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in physical functioning Items 1 to 5 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data. |
| TTD in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score | Up to approximately 29 months | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 4 questions about their emotional functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in emotional functioning Items 21-24 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data. |
| TTD in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score | Up to approximately 29 months | EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and four symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in systemic therapy side effects Items 1-4, 6, 7 and 8 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data. |
| TTD in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Score in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors | Baseline and up to approximately 29 months | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the QoL question "How would you rate your overall quality of life during the past week?" (Item 30) were each scored on a 7-point scale (1=Very Poor to 7=Excellent), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in Items 29 and 30 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data. |
| TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score in Participants With BRCAm Tumors | Up to approximately 29 months | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in physical functioning Items 1 to 5 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data. |
| TTD in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score in Participants With BRCAm Tumors | Up to approximately 29 months | EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 4 questions about their emotional functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in emotional functioning Items 21-24 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data. |
| TTD in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score in Participants With BRCAm Tumors | Up to approximately 29 months | EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and four symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in systemic therapy side effects Items 1-4, 6, 7 and 8 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data. |
| Number of Participants Who Experienced At Least One Adverse Event (AE) | Up to approximately 29 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experience at least 1 AE is presented. |
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | Up to approximately 29 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued study treatment due to an AE is presented. |
Countries
Canada, Chile, Colombia, France, Germany, Hungary, Ireland, Japan, Poland, South Korea, Spain, Taiwan, Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Carboplatin + Gemcitabine Induction Treatment Participants receive both carboplatin Area Under The Curve (AUC) 2 with gemcitabine 1000 mg/m\^2 intravenously on Days 1 and 8 of each 21-day cycle plus pembrolizumab 200 mg intravenously on Day 1 of each 21-day cycle during the induction period for 4-6 cycles. These participants did not randomize to a post-induction arm. | 189 |
| Pembrolizumab + Olaparib This arm includes participants who randomized following completion of the induction period. After the induction period, participants received pembrolizumab 200 mg intravenously on Day 1 of each 21-day cycle plus olaparib 300 mg orally twice daily during the post-induction period. | 135 |
| Pembrolizumab + Carboplatin + Gemcitabine This arm includes participants who randomized following completion of the induction period. Participants continued to receive both carboplatin AUC 2 with gemcitabine 1000 mg/m\^2 intravenously on Days 1 and 8 of each 21-day cycle in addition to pembrolizumab 200 mg intravenously on Day 1 of each 21-day cycle in the post-induction period. | 136 |
| Total | 460 |
Baseline characteristics
| Characteristic | Pembrolizumab + Carboplatin + Gemcitabine Induction Treatment | Pembrolizumab + Olaparib | Pembrolizumab + Carboplatin + Gemcitabine | Total |
|---|---|---|---|---|
| Age, Continuous | 53.8 Years STANDARD_DEVIATION 12.7 | 53.9 Years STANDARD_DEVIATION 12 | 52.9 Years STANDARD_DEVIATION 12.5 | 53.6 Years STANDARD_DEVIATION 12.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 33 Participants | 19 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 137 Participants | 79 Participants | 102 Participants | 318 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 26 Participants | 23 Participants | 15 Participants | 64 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 39 Participants | 29 Participants | 30 Participants | 98 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 5 Participants | 2 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 7 Participants | 14 Participants | 7 Participants | 28 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 21 Participants | 17 Participants | 11 Participants | 49 Participants |
| Race (NIH/OMB) White | 112 Participants | 70 Participants | 84 Participants | 266 Participants |
| Sex: Female, Male Female | 188 Participants | 135 Participants | 136 Participants | 459 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 124 / 460 | 50 / 135 | 54 / 136 |
| other Total, other adverse events | 456 / 460 | 121 / 135 | 128 / 133 |
| serious Total, serious adverse events | 80 / 460 | 35 / 135 | 32 / 133 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. OS is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Overall Survival (OS) | 25.1 Months |
| Pembrolizumab + Carboplatin + Gemcitabine | Overall Survival (OS) | 23.4 Months |
p-value: 0.390395% CI: [0.64, 1.4]Log Rank
Primary
Progression-Free Survival (PFS)
PFS was defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR), or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters (SOD) of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Progression-Free Survival (PFS) | 5.5 Months |
| Pembrolizumab + Carboplatin + Gemcitabine | Progression-Free Survival (PFS) | 5.6 Months |
p-value: 0.455695% CI: [0.72, 1.33]Log Rank
Secondary
Change From Baseline in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score in Participants With BRCAm Tumors
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 4 questions about their emotional functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. The change from baseline in emotional functioning (EORTC QLQ-C30 Items 21-24) score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), and baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1)) as covariates.
Time frame: Baseline and week 18
Population: The analysis population included all randomized participants with BRCAm tumors, who received ≥1 dose of study treatment and who completed at least one assessment for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Change From Baseline in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score in Participants With BRCAm Tumors | -1.50 Score on a Scale |
| Pembrolizumab + Carboplatin + Gemcitabine | Change From Baseline in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score in Participants With BRCAm Tumors | -4.02 Score on a Scale |
p-value: 0.613895% CI: [-7.45, 12.49]cLDA
Secondary
Change From Baseline in Emotional Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 21-24 Score
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 4 questions about their emotional functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Change from baseline in emotional functioning (EORTC QLQ-C30 Items 21-24) score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1) and BRCA status at randomization (BRCAm vs. BRCAwt)) as covariates.
Time frame: Baseline and week 18
Population: The analysis population included all randomized participants who received ≥1 dose of study treatment and who completed at least one assessment for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Change From Baseline in Emotional Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 21-24 Score | -0.46 Score on a Scale |
| Pembrolizumab + Carboplatin + Gemcitabine | Change From Baseline in Emotional Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 21-24 Score | -2.53 Score on a Scale |
p-value: 0.435195% CI: [-3.16, 7.31]cLDA
Secondary
Change From Baseline in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Combined Score in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the Global Health Status (GHS) question How would you rate your overall health during the past week? (Item 29) and the QoL question How would you rate your overall quality of life during the past week? (Item 30) were each scored on a 7-point scale (1=Very Poor to 7=Excellent), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. The change from baseline in EORTC QLQ-C30 Items 29 and 30 scores was calculated based on a constrained longitudinal data analysis (cLDA) model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), and baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1)) as covariates.
Time frame: Baseline and up to 18 weeks
Population: The analysis population included all randomized participants with BRCAm tumors, who received ≥1 dose of study treatment and who completed at least one assessment for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Change From Baseline in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Combined Score in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors | -4.85 Score on a Scale |
| Pembrolizumab + Carboplatin + Gemcitabine | Change From Baseline in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Combined Score in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors | -3.51 Score on a Scale |
p-value: 0.79595% CI: [-11.63, 8.95]cLDA
Secondary
Change From Baseline in Health-Related Quality-of-Life (QoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Combined Score
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the Global Health Status (GHS) question How would you rate your overall health during the past week? (Item 29) and the QoL question How would you rate your overall quality of life during the past week? (Item 30) were each scored on a 7-point scale (1=Very Poor to 7=Excellent), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Change from baseline in EORTC QLQ-C30 Items 29 and 30 combined scores was calculated based on a constrained longitudinal data analysis (cLDA) model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1) and BRCA status at randomization (BRCAm vs. BRCAwt)) as covariates.
Time frame: Baseline and week 18
Population: The analysis population included all randomized participants who received ≥1 dose of study treatment and who completed at least one assessment for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Change From Baseline in Health-Related Quality-of-Life (QoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Combined Score | -5.82 Score on a Scale |
| Pembrolizumab + Carboplatin + Gemcitabine | Change From Baseline in Health-Related Quality-of-Life (QoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Combined Score | -2.54 Score on a Scale |
p-value: 0.14395% CI: [-7.69, 1.12]cLDA
Secondary
Change From Baseline in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score in Participants With BRCAm Tumors
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. The change from baseline in physical functioning (EORTC QLQ-C30 Items 1-5) score was calculated based on a constrained longitudinal data analysis (cLDA) model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), and baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1)) as covariates.
Time frame: Baseline and week 18
Population: The analysis population included all randomized participants with BRCAm tumors, who received ≥1 dose of study treatment and who completed at least one assessment for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Change From Baseline in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score in Participants With BRCAm Tumors | 4.12 Score on a Scale |
| Pembrolizumab + Carboplatin + Gemcitabine | Change From Baseline in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score in Participants With BRCAm Tumors | -0.70 Score on a Scale |
p-value: 0.159795% CI: [-1.97, 11.62]cLDA
Secondary
Change From Baseline in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. The change from baseline in physical functioning (EORTC QLQ-C30 Items 1-5) score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1) and BRCA status at randomization (BRCAm vs. BRCAwt)) as covariates.
Time frame: Baseline and week 18
Population: The analysis population included all randomized participants who received ≥1 dose of study treatment and who completed at least one assessment for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Change From Baseline in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score | -2.86 Score on a Scale |
| Pembrolizumab + Carboplatin + Gemcitabine | Change From Baseline in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score | -2.69 Score on a Scale |
p-value: 0.945495% CI: [-4.89, 4.56]cLDA
Secondary
Change From Baseline in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score in Participants With BRCAm Tumors
EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30, consisting of functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All, 4=Very Much). Using linear transformation, raw scores are standardized, so scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in systemic therapy side effects (EORTC QLQ-BR23 Items 1-4, 6, 7, and 8) score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), and baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1)) as covariates.
Time frame: Baseline and week 18
Population: The analysis population included all randomized participants with BRCAm tumors, who received ≥1 dose of study treatment and who completed at least one assessment for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Change From Baseline in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score in Participants With BRCAm Tumors | -4.27 Score on a Scale |
| Pembrolizumab + Carboplatin + Gemcitabine | Change From Baseline in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score in Participants With BRCAm Tumors | -2.67 Score on a Scale |
p-value: 0.556795% CI: [-7.02, 3.83]cLDA
Secondary
Change From Baseline in Systemic Therapy Side Effects Using the European Organization for Research and Treatment of Cancer Breast Cancer-Specific QoL Questionnaire (EORTC QLQ-BR23) Items 1-4, 6, 7, and 8 Score
EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30, consisting of functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All, 4=Very Much). Using linear transformation, raw scores are standardized, so scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in systemic therapy side effects (EORTC QLQ-BR23 Items 1-4, 6, 7, and 8) score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1) and BRCA status at randomization (BRCAm vs. BRCAwt)) as covariates.
Time frame: Baseline and week 18
Population: The analysis population included all randomized participants who received ≥1 dose of study treatment and who completed at least one assessment for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Change From Baseline in Systemic Therapy Side Effects Using the European Organization for Research and Treatment of Cancer Breast Cancer-Specific QoL Questionnaire (EORTC QLQ-BR23) Items 1-4, 6, 7, and 8 Score | -0.91 Score on a Scale |
| Pembrolizumab + Carboplatin + Gemcitabine | Change From Baseline in Systemic Therapy Side Effects Using the European Organization for Research and Treatment of Cancer Breast Cancer-Specific QoL Questionnaire (EORTC QLQ-BR23) Items 1-4, 6, 7, and 8 Score | -1.84 Score on a Scale |
p-value: 0.558895% CI: [-2.2, 4.06]cLDA
Secondary
Change From Baseline in Visual Analogue Scale (VAS) Score on the EQ-5D-5L in Participants With BRCAm Tumors
The EQ-5D-5L is a questionnaire developed to assess health-related outcomes. The VAS is a component of the EQ-5D-5L that asks participants to rate their overall health on a vertical visual analogue scale, with the scale's ends labelled 'The best health you can imagine' (equivalent to a score of 0) and 'The worst health you can imagine' (equivalent to a score of 100). The change from baseline in VAS score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), and baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1)) as covariates.
Time frame: Baseline and week 18
Population: The analysis population included all randomized participants with BRCAm tumors, who received ≥1 dose of study treatment and who completed at least one assessment for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Change From Baseline in Visual Analogue Scale (VAS) Score on the EQ-5D-5L in Participants With BRCAm Tumors | 1.73 Score on a Scale |
| Pembrolizumab + Carboplatin + Gemcitabine | Change From Baseline in Visual Analogue Scale (VAS) Score on the EQ-5D-5L in Participants With BRCAm Tumors | -3.83 Score on a Scale |
p-value: 0.10595% CI: [-1.2, 12.32]cLDA
Secondary
Change From Baseline in Visual Analogue Scale (VAS) Score on the European Quality of Life 5-dimension, 5-level Questionnaire (EQ-5D-5L)
The EQ-5D-5L is a questionnaire developed to assess health-related outcomes. The VAS is a component of the EQ-5D-5L that asks participants to rate their overall health on a vertical visual analogue scale, with the scale's ends labelled 'The best health you can imagine' (equivalent to a score of 0) and 'The worst health you can imagine' (equivalent to a score of 100). The change from baseline in VAS score was calculated based on a cLDA model with scores as response variable with covariates for treatment by time interaction, stratification factors (response at randomization (CR/PR vs. SD), baseline CPS for PD-L1 expression (PD-L1 CPS\<1 vs. PD-L1 CPS≥1) and BRCA status at randomization (BRCAm vs. BRCAwt)) as covariates.
Time frame: Baseline and week 18
Population: The analysis population included all randomized participants who received ≥1 dose of study treatment and who completed at least one assessment for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Change From Baseline in Visual Analogue Scale (VAS) Score on the European Quality of Life 5-dimension, 5-level Questionnaire (EQ-5D-5L) | -2.74 Score on a Scale |
| Pembrolizumab + Carboplatin + Gemcitabine | Change From Baseline in Visual Analogue Scale (VAS) Score on the European Quality of Life 5-dimension, 5-level Questionnaire (EQ-5D-5L) | -2.37 Score on a Scale |
p-value: 0.840895% CI: [-4.03, 3.28]cLDA
Secondary
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued study treatment due to an AE is presented.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants who received ≥1 dose of study drug and who had at least 1 laboratory or vital sign measurement.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Olaparib | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 15 Participants |
| Pembrolizumab + Carboplatin + Gemcitabine | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 28 Participants |
Secondary
Number of Participants Who Experienced At Least One Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experience at least 1 AE is presented.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants who received ≥1 dose of study drug and who had at least 1 laboratory or vital sign measurement.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Olaparib | Number of Participants Who Experienced At Least One Adverse Event (AE) | 126 Participants |
| Pembrolizumab + Carboplatin + Gemcitabine | Number of Participants Who Experienced At Least One Adverse Event (AE) | 130 Participants |
Secondary
OS in Participants With BRCAm Tumors
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Only participants with BRCAm-positive tumors were included in this analysis.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants with BRCAm tumors
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | OS in Participants With BRCAm Tumors | NA Months |
| Pembrolizumab + Carboplatin + Gemcitabine | OS in Participants With BRCAm Tumors | 23.4 Months |
95% CI: [0.28, 2.37]
Secondary
Overall Survival (OS) in Participants With PD-L1 Positive Tumors With a CPS ≥10
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Only participants with a CPS ≥10 were included in this analysis.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants with a CPS ≥10
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Overall Survival (OS) in Participants With PD-L1 Positive Tumors With a CPS ≥10 | NA Months |
| Pembrolizumab + Carboplatin + Gemcitabine | Overall Survival (OS) in Participants With PD-L1 Positive Tumors With a CPS ≥10 | NA Months |
95% CI: [0.53, 1.76]
Secondary
PFS in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors
PFS was defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR), or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters (SOD) of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Only participants with BRCAm-positive tumors were included in this analysis. PFS is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants with BRCAm tumors
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | PFS in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors | 12.4 Months |
| Pembrolizumab + Carboplatin + Gemcitabine | PFS in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors | 8.4 Months |
95% CI: [0.33, 1.48]
Secondary
Progression-Free Survival (PFS) in Participants With Programmed Cell Death-Ligand 1 (PD-L1) Positive Tumors With a Combined Positive Score (CPS) ≥10
PFS was defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR), or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters (SOD) of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Only participants with a CPS ≥10 were included in this analysis. PFS is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 29 months
Population: The analysis populations included all randomized participants with a CPS ≥10
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Progression-Free Survival (PFS) in Participants With Programmed Cell Death-Ligand 1 (PD-L1) Positive Tumors With a Combined Positive Score (CPS) ≥10 | 5.7 Months |
| Pembrolizumab + Carboplatin + Gemcitabine | Progression-Free Survival (PFS) in Participants With Programmed Cell Death-Ligand 1 (PD-L1) Positive Tumors With a Combined Positive Score (CPS) ≥10 | 5.7 Months |
95% CI: [0.59, 1.43]
Secondary
Time to Deterioration (TTD) in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Score
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the Global Health Status (GHS) question How would you rate your overall health during the past week? (Item 29) and the QoL question How would you rate your overall quality of life during the past week? (Item 30) were each scored on a 7-point scale (1=Very Poor to 7=Excellent), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in Items 29 and 30 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Baseline and up to approximately 29 months
Population: The analysis population included all randomized participants who received ≥1 dose of study treatment and who completed the baseline assessment for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | Time to Deterioration (TTD) in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Score | 10.3 Months |
| Pembrolizumab + Carboplatin + Gemcitabine | Time to Deterioration (TTD) in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Score | NA Months |
p-value: 0.0067695% CI: [1.16, 2.71]Log Rank
Secondary
TTD in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 4 questions about their emotional functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in emotional functioning Items 21-24 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants who received ≥1 dose of study treatment and who completed the baseline assessment for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | TTD in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score | NA Months |
| Pembrolizumab + Carboplatin + Gemcitabine | TTD in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score | NA Months |
p-value: 0.7496595% CI: [0.69, 1.71]Log Rank
Secondary
TTD in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score in Participants With BRCAm Tumors
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 4 questions about their emotional functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in emotional functioning Items 21-24 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants with BRCAm tumors, who received ≥1 dose of study treatment and who completed the baseline assessment for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | TTD in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score in Participants With BRCAm Tumors | NA Months |
| Pembrolizumab + Carboplatin + Gemcitabine | TTD in Emotional Functioning Using the EORTC QLQ-C30 Items 21-24 Score in Participants With BRCAm Tumors | NA Months |
p-value: 0.8146395% CI: [0.33, 2.38]Log Rank
Secondary
TTD in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Score in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the Global Health Status (GHS) question How would you rate your overall health during the past week? (Item 29) and the QoL question How would you rate your overall quality of life during the past week? (Item 30) were each scored on a 7-point scale (1=Very Poor to 7=Excellent), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in Items 29 and 30 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Baseline and up to approximately 29 months
Population: The analysis population included all randomized participants with BRCAm tumors, who received ≥1 dose of study treatment and who completed the baseline assessment for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | TTD in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Score in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors | 7.9 Months |
| Pembrolizumab + Carboplatin + Gemcitabine | TTD in Health-Related QoL Using the EORTC QLQ-C30 Items 29 and 30 Score in Participants With Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors | NA Months |
p-value: 0.501995% CI: [0.57, 3]Log Rank
Secondary
TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in physical functioning Items 1 to 5 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants who received ≥1 dose of study treatment and who completed the baseline assessment for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score | NA Months |
| Pembrolizumab + Carboplatin + Gemcitabine | TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score | NA Months |
p-value: 0.9642595% CI: [0.61, 1.69]Log Rank
Secondary
TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score in Participants With BRCAm Tumors
EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in physical functioning Items 1 to 5 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants with BRCAm tumors, who received ≥1 dose of study treatment and who completed the baseline assessment for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score in Participants With BRCAm Tumors | NA Months |
| Pembrolizumab + Carboplatin + Gemcitabine | TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score in Participants With BRCAm Tumors | NA Months |
p-value: 0.4738495% CI: [0.24, 1.97]Log Rank
Secondary
TTD in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score
EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and four symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in systemic therapy side effects Items 1-4, 6, 7 and 8 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants who received ≥1 dose of study treatment and who completed the baseline assessment for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | TTD in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score | NA Months |
| Pembrolizumab + Carboplatin + Gemcitabine | TTD in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score | NA Months |
p-value: 0.1050295% CI: [0.88, 3.53]Log Rank
Secondary
TTD in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score in Participants With BRCAm Tumors
EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and four symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in systemic therapy side effects Items 1-4, 6, 7 and 8 scale scores. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 29 months
Population: The analysis population included all randomized participants with BRCAm tumors, who received ≥1 dose of study treatment and who completed the baseline assessment for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Olaparib | TTD in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score in Participants With BRCAm Tumors | NA Months |
| Pembrolizumab + Carboplatin + Gemcitabine | TTD in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 Items 1-4, 6, 7, and 8 Score in Participants With BRCAm Tumors | NA Months |
p-value: 0.6725595% CI: [0.24, 8.82]Log Rank