Neoplasms

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Neoplasm Metastasis

Breast Neoplasms

Breast Diseases

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SC10914

zhang qingsheng, MD,PhD

wu han, MD

hu xichun, MD

This open label, multi-centre phase II study will assess the efficacy and safety of single agent SC10914 in metastatic breast cancer patients with gBRCA 1/2 mutations.

A Phase II Study to Assess the Efficacy and Safety of SC10914 in the Metastatic Breast Cancer Patients

A Phase 2, Open-Label, Multi-Center Study of SC10914 in Germline BRCA Mutation Subjects With Locally Advanced and/or Metastatic Breast Cancer, Who Have Received More Than 2 Prior Chemotherapy Regimens for Metastatic Disease

Using Independent Central Review Data Assessed by Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)

Using Independent Central Review According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)

from eligible until death due to any cause

Jiangxi Qingfeng Pharmaceutical Co. Ltd.

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Capecitabine

Vinorelbine

Talazoparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Patient will be randomized 2:1 to receive talazoparib oral capsules (1.0 mg) once daily for 21 continuous days

Capecitabine, Eribulin, Gemcitabine or Vinorelbine

Until progression or unacceptable toxicity develops

talazoparib

Physician's-Choice

Pfizer Pfizer CT.gov Call Center

The purpose of this open-label, 2:1 randomized phase III trial is to compare the safety and efficacy of talazoparib (also known as BMN 673) versus protocol-specific physician's choice in patients who have locally advanced and/or metastatic breast cancer with germline BRCA mutations.

A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study)

A PHASE 3, OPEN-LABEL, RANDOMIZED PARALLEL,2-ARM,MULTI-CENTER STUDY OF TALAZOPARIB(BMN 673) VERSUS PHYSICIAN'S CHOICE IN GERMLINE BRCA MUTATION SUBJECTS WITH LOCALLY ADVANCED AND/OR METASTATIC BREAST CANCER, WHO HAVE RECEIVED PRIOR CHEMOTHERAPY REGIMENS FOR METASTATIC DISEASE

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

DOR = time from first radiographic documentation of OR (PR or CR) till radiographic disease progression (PD) as per RECIST v1.1 by investigator assessment or to death due to any cause, whichever was first. RECIST 1.1, a) target lesion (TL): CR= disappearance of all non-nodal TL, target lymph nodes reduce to \<10 mm in short axis, PR= at least 30% decrease in sum of diameters of TL, compared to the sum at baseline, PD= at least 20% increase in sum of TL measurements, compared to smallest sum on study including baseline, absolute increase in sum has to be at least 5 mm; b) for non-TL: CR= disappearance of all non-TL, PD= unequivocal progression of non-TL, such that treatment has failed, disease is progressing, regardless of status of TL; c) PD =and/or appearance of \>=1 new lesions. DOR = (earliest date of progression, death, or censoring-date of first documented OR + 1)/30.4375. Analysis was performed by Kaplan-Meier method.

EORTC QLQ-C30: cancer-specific instrument with 30 questions to assess the participant QoL. First 28 questions used to evaluate 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, nausea and vomiting, pain) and other single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Each question assessed on 4-point scale (1= not at all, 2= a little, 3= quite a bit, 4= very much); functional scales: higher score = better level of functioning; symptom scale: higher score = more severe symptoms; for single items: higher score= more severe problem. Last 2 questions used to evaluate global health status (GHS)/QoL. Each question was assessed on 7-point scale (1= very poor to 7= excellent). Scores averaged, transformed to 0-100 scale; higher score=better quality of life/better level of functioning. Change from baseline was calculated by subtracting the baseline value from the average value of Week 4 to 160.

TTD in global health status (GHS)/QoL=time (in months) from randomization to the first observation with \>=10 point decrease and no subsequent observations with\<10 point decrease from baseline in GHS/QoL score based on EORTC-QLQ-C30. EORTC QLQ-C30 is a cancer-specific instrument with 30 questions to assess participant quality of life. Question 29 and 30 were used to evaluate GHS/QoL. Each question was assessed on a 7-point scale (1=very poor to 7=excellent). Scores averaged, transformed to 0-100 scale; higher score=better quality of life/better level of functioning.

TTD was defined as the time (in months) from randomization to the first observation with a\>=10 point increase and no subsequent observations with a \<10 point increase from baseline in breast symptom score based on the EORTC-QLQ-BR23. EORTC-QLQ-BR23 is a disease-specific module for breast cancer developed as a supplement for the EORTC-QLQ-C30 to assess the quality of life of participants with breast cancer. EORTC-QLQ-BR23 symptoms subscale includes 4 items: systemic therapy side effects, breast symptoms, arm symptoms, upset by hair loss. Each item is rated by choosing 1 of 4 possible responses that record the level of intensity (1= not at all, 2= a little, 3= quite a bit, and 4= very much), higher scores=high level of symptom/problems.

IRF assessed PFS was defined as time (in months) from randomization until the date of first documented radiologic progressive disease per response evaluation criteria in solid tumors (RECIST) version 1.1 or death from any cause, whichever occurs first. As per RECIST v1.1, progression defined as 1) for target lesions: at least a 20% increase in the sum of target lesion measurements, compared to the smallest sum on study (including baseline), the absolute increase in the sum has to be at least 5 millimeter (mm); 2) for non-target lesions: unequivocal progression of non-target lesions, evaluated as a whole, such that it is clear that treatment has failed and disease is progressing, regardless of the status of the target lesions; 3) and/or appearance of one or more new lesions. The analysis was performed by Kaplan-Meier method.

Investigator assessed objective response was defined as the percentage of participants with a partial response (PR) or complete response (CR) as defined by RECIST v1.1. For target lesions: 1) CR: disappearance of all non-nodal target lesions. Target lymph nodes must reduce to less than 10 mm in short axis. 2) PR: At least a 30% decrease in the sum of diameters of target lesions, compared to the sum at baseline. For non-target lesions, CR: disappearance of all non-target lesions. Percentage of participants with objective response reported are based upon unconfirmed CR/PR.

OS was defined as the time (in months) from randomization to death due to any cause. If death was not observed at the time of study cut-off date or permanently lost to follow-up, OS was censored at the date the participant was last known to be alive on or before the study cut-off date, whichever was earlier. The analysis was performed by Kaplan-Meier method.

A predose PK sample was considered dose-compliant based on the following criteria: A participant must have received 21 consecutive days of 1 mg talazoparib without dosing interruption prior to sample collection; and the predose PK sample must have been collected 24 hours +/- 10 percent (2 hours and 24 minutes) after the previous day's dose and no more than 5 minutes (0.083 hours) after the administration of the dose on the day of PK sample collection.

An adverse events (AE) was any untoward medical occurrence (e.g., sign, symptom, illness, disease or injury) in a participant administered study drug or other protocol-imposed intervention, regardless of attribution. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug or the day before initiation of a new antineoplastic therapy or 30 days after the date of the last dose date of study drug, whichever occurred first, that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and all non-SAEs.

Toxicity grades were evaluated based on as National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). NCI CTCAE v4.03 defined the severity grade as: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (potentially life threatening) and grade 5 (death related to AE) for each parameter. Key hematology parameters included hemoglobin (gram per liter \[g/L\]), leukocytes (10\^6 cells per liter), lymphocytes (10\^6 cells per liter), neutrophils (10\^6 cells per liter), and platelets (10\^9 cells per liter). Low value indicated lower values than the baseline values and high value indicated higher values than the baseline values. Only those categories in which at least 1 participant had data were reported.

Toxicity grades were evaluated based on as NCI CTCAE v4.03. NCI CTCAE v4.03 defined the severity grade as: grade 1 (mild), grade 2 (moderate), grade 3 (severe) and grade 4 (potentially life threatening) and grade 5 (death related to AE) for each parameter. Key chemistry parameters included alanine aminotransferase (units per liter), alkaline phosphatase (units per liter), aspartate aminotransferase (units per liter) and bilirubin (micromole per liter). High value indicated higher values than the baseline values and low value indicated lower values than the baseline values. Only those categories in which at least 1 participant had data were reported.

Criteria for potentially clinically significant changes in vital signs included a) Systolic blood pressure: 1) absolute results (AB) greater than (\>) 180 millimeter of mercury (mmHg) and increase from baseline (IFB) greater than or equal to (\>=) 40 mmHg, 2) absolute results less than (\<) 90 mmHg and decrease from baseline (DFB) \>30 mmHg; b) Diastolic blood pressure: 1) absolute results \>110 mmHg and \>=30 mmHg increase from baseline, 2) absolute results \<50 mmHg and \>20 mmHg decrease from baseline 3) \>=20 mmHg increase from baseline; c) Heart rate: 1) absolute results\>120 beats per minute \[bpm\] and \>30 bpm increase from baseline, 2) absolute results \<50 bpm and \>20 bpm decrease from baseline and d) Weight: \>10 percent \[%\] decrease from baseline.

Any medication (other than study drug) which was administered to participants during study after first dose of study drug were considered as concomitant medications.

Medivation, Inc.

Pfizer

Same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study. AEs and SAEs were collected for safety population.

Participants received talazoparib 1 mg, orally, once daily until radiographic disease progression as determined by the central IRF, unacceptable toxicity, consent withdrawal, physician's decision to terminate treatment, or sponsor's decision to terminate the trial (up to a maximum of 70.2 months). One cycle was of 21 days.

Participants received 1 of the following drugs in specified regimens, as per the physician's choice: 1) capecitabine 1250 mg/m\^2 orally twice daily on Day 1 to 14 in each cycle; 2) eribulin mesylate 1.4 mg/m\^2 (equivalent to eribulin 1.23 mg/ m\^2), as 2 to 5 minute IV infusion on Day 1 and 8 in each cycle; 3) gemcitabine 1250 mg/m\^2 as 30-minute IV infusion on Day 1 and 8 in each cycle; 4) vinorelbine 30 mg/m\^2 as 6 to 10 minute IV infusion on Day 1, 8, and 15 in each cycle; until radiographic disease progression as determined by the central IRF, unacceptable toxicity, consent withdrawal, physician's decision to terminate treatment, or Sponsor's decision to terminate the trial (up to a maximum of 45.3 months). One cycle was of 21 days.

Physician's Choice Treatment

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Intent-to-treat (ITT) analysis population included all randomized participants.

Pfizer ClinicalTrials.gov Call Center

Hazard ratio was based on stratified Cox regression model with treatment as the only covariate (stratification factors: number of prior cytotoxic chemotherapy regimens, triple negative status, history of central nervous system metastasis status).

Progression-Free Survival (PFS): Independent Radiological Facility (IRF) Assessment

p-value was based on stratified Cochran-Mantel-Haenszel method. Stratification factors: number of prior cytotoxic chemotherapy regimens, triple negative status, history of central nervous system metastasis status.

ITT with measurable disease analysis population included all participants in the ITT population who had at least 1 target lesion identified at baseline.

Percentage of Participants With Objective Response: Investigator Assessment

ITT analysis population included all randomized participants.

Overall Survival (OS)

Cycle 2 Day 1: Predose

Cycle 3 Day 1: Predose

Cycle 4 Day 1: Predose

Analysis population included participants who received at least 1 dose of talazoparib and had dose compliant pharmacokinetic (PK) predose sample. Here, "number analyzed" signifies number of participants who were evaluable for the specified categories. This endpoint was not planned to be analyzed for the reporting arm "Physician's Choice Treatment".

Trough Plasma Talazoparib Concentrations

TEAEs

SAEs

Safety analysis population included all participants who received at least 1 dose of any study drug (talazoparib or protocol-specified PCT).

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Hemoglobin: Low value

Leukocytes: Low value

Lymphocytes: Low value

Neutrophils: Low value

Platelets: Low value

Number of Participants With Grade 3 or 4 Post-baseline Toxicities in Laboratory Parameters: Hematology

Alanine Aminotransferase: High Value

Alkaline Phosphatase: High Value

Aspartate Aminotransferase: High Value

Bilirubin: High Value

Number of Participants With Grade 3 or 4 Post-baseline Toxicities in Laboratory Parameters: Chemistry

SBP: AB>180 mmHg and IFB >=40 mmHg

SBP: AB<90 mmHg and DFB >30 mmHg

DBP: AB>110 mmHg and IFB >=30 mmHg

DBP: AB<50 mmHg and DFB>20 mmHg

DBP: IFB>=20 mmHg

Heart rate: AB >120 bpm and IFB >30 bpm

Heart rate: AB <50 bpm and DFB >20 bpm

Weight: >10% DFB

Number of Participants With Potentially Clinically Significant Changes From Baseline in Vital Signs

Number of Participants Taking At-least One Concomitant Medication

Duration of Response (DOR): Investigator Assessment

Analysis was based on repeated measures mixed-effect model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate. Analysis was based on restricted maximum likelihood using unstructured covariance matrix.

Patient-reported outcomes (PRO) evaluable population included all participants who completed the PRO questionnaire at baseline and at least 1 visit post-baseline.

Change From Baseline in Global Health Status/Quality of Life (QoL) Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at Average Duration Over Week 4 up to Week 160

Hazard ratio is based on stratified Cox regression model with treatment as the only covariate (stratification factors: number of prior cytotoxic chemotherapy regimens, triple negative status, history of central nervous system metastasis status).

PRO-evaluable population included all participants who completed the PRO questionnaire at baseline and at least 1 visit post-baseline.

Time to Deterioration (TTD) in Global Health Status/Quality of Life (QOL)

Hazard ratio is based on stratified Cox regression model with treatment as the only covariate (stratification factors: number of prior cytotoxic chemotherapy regimens, triple negative status, history of central nervous system).

Time to Deterioration (TTD) in Breast Symptoms Scale as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer Module (EORTC-QLQ-BR23)

Participants received talazoparib 1 milligram (mg), orally, once daily until radiographic disease progression as determined by the central independent radiology facility (IRF), unacceptable toxicity, consent withdrawal, physician's decision to terminate treatment, or sponsor's decision to terminate the trial (up to a maximum of 70.2 months). One cycle was of 21 days.

Participants received 1 of the following drugs in specified regimens, as per the physician's choice: 1) capecitabine 1250 milligram per meter square (mg/m\^2) orally twice daily on Day 1 to 14 in each cycle; 2) eribulin mesylate 1.4 mg/m\^2 (equivalent to eribulin 1.23 mg/ m\^2), as 2 to 5 minute intravenous (IV) infusion on Day 1 and 8 in each cycle; 3) gemcitabine 1250 mg/m\^2 as 30-minute IV infusion on Day 1 and 8 in each cycle; 4) vinorelbine 30 mg/m\^2 as 6 to 10 minute IV infusion on Day 1, 8, and 15 in each cycle; until radiographic disease progression as determined by the central IRF, unacceptable toxicity, consent withdrawal, physician's decision to terminate treatment, or Sponsor's decision to terminate the trial (up to a maximum of 45.3 months). One cycle was of 21 days.

Overall Study

Olaparib

Capecitabine 2500 mg/m2 d1-14 q 21, or Vinorelbine 30 mg/m2 d1,8 q 21, or Eribulin 1.4 mg/m2 d1,8 q 21

Patients will be administered olaparib orally twice daily (bid) at 300 mg. Two (2) x 150 mg olaparib tablets should be taken at the same times each morning and evening of each day, approximately 12 hours apart with approximately 240 mL of water.

Investigators will declare one of the following regimens:

* Capecitabine 2500 mg/m2 po daily (divided in 2 doses) x 14 days, repeat every 21 days
* Vinorelbine 30 mg/m2 IV Day 1 and Day 8, repeat every 21 days
* Eribulin 1.4 mg/m2 IV Day 1 and Day 8, repeat every 21 days

Physician's choice chemotherapy

Mark Robson, MD

This open label, randomised, controlled, multi-centre phase III study will assess the efficacy and safety of single agent olaparib vs standard of care based on physician's choice of capecitabine, vinorelbine or eribulin in metastatic breast cancer patients with gBRCA 1/2 mutations.

Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.

A Phase III, Open Label, Randomised, Controlled, Multi-centre Study to Assess the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Time from randomisation to the earliest of first subsequent cancer therapy start date following study treatment discontinuation, or death.

Time from randomisation to the earliest of second subsequent cancer therapy start date following study treatment discontinuation, or death.

Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Time from randomisation to the earliest of the progression event subsequent to the first objective radiological progression, or death. Second progression may involve any of; objective radiological or symptomatic progression or death. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Symptomatic progression is assessed by investigators based on clinical examination.

Time from randomisation until death due to any cause.

Number of responders according to blinded independent central review (BICR) assessment. Per Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1) for target lesions assessed by CT or MRI: Complete Response (CR) is defined as the disappearance of all target lesions; Partial Response (PR) is defined as \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response = CR + PR.

Change from baseline in global health status/quality of life (QoL) score assessed using a mixed model for repeated measures (MMRM) analysis, including all post-baseline global health status/QoL scores up to the latest scheduled visit where at least 20 patients on each treatment arm have a score. Global health status/QoL score is on a scale from 0 to 100. A higher score represents an improved health status/QoL.

Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Assessed in patients with a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (gene sequencing and large rearrangement analysis).

Myriad Genetic Laboratories, Inc.

Merck Sharp & Dohme LLC

AstraZeneca

Adverse events and serious adverse events are reported in the Safety Analysis Set including all patients who received at least one dose of study treatment (n=296). Six patients on the chemotherapy arm did not receive any study treatment and therefore are excluded from the Safety Analysis Set, leaving n=91 patients on the chemotherapy arm. All cause mortality is reported in the Full Analysis Set (n=302).

Olaparib 300 mg bd

Chemotherapy

Age (years)

Age, Customized

Global

Region of Enrollment

ER = oestrogen receptor, PgR = progesterone receptor. All patients were HER2 negative.

Receptor status

Received prior chemotherapy for metastatic breast cancer

Received prior platinum for breast cancer

Full analysis set consisting of all randomized patients.

Medical Science Director

Study is sized to provide 90% power to detect a true treatment effect of PFS hazard ratio 0.653.

Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin

Full Analysis Set (FAS) consisting of all randomised patients

Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)

Time to Second Progression or Death (PFS2)

Evaluable For Response (EFR) Analysis Set consisting of all randomised patients with measurable disease at baseline, i.e. at least one measurable target lesion assessed by blinded independent central review (BICR)

Objective Response Rate (ORR) Using Blinded Independent Central Review (BICR) Data Assessed by Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)

Subset of Full Analysis Set (FAS) consisting of all randomised patients with an evaluable baseline EORTC QLQ-C30 assessment and at least one evaluable post-baseline assessment

Adjusted Mean Change in Global Health Status/Quality of Life (QoL) Score From the European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30)

Subset of Full Analysis Set (FAS) consisting of all randomised patients who were confirmed as Myriad CDx gBRCAm

Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) in Patients Confirmed as Myriad CDx gBRCAm

Time to First Subsequent Cancer Therapy or Death (TFST)

Time to Second Subsequent Cancer Therapy or Death (TSST)

Overall Survival (OS) at Final OS

Overall Survival (OS) at Extended OS

Time to First Subsequent Cancer Therapy or Death (TFST) at Extended OS

Time to Second Subsequent Cancer Therapy or Death (TSST) at Extended OS

Cohort 1) Subjects with a documented PR or CR to a prior platinum-containing regimen for metastatic disease with disease progression \> 8 weeks following the last dose of platinum

Cohort 2) Subjects who have received \> 2 prior chemotherapy regimens for metastatic disease and who have had no prior platinum therapy for metastatic disease

Pfizer CT.gov Call Center

The purpose of this 2-stage, 2-cohort Phase 2 trial is to evaluate the safety and efficacy of talazoparib (also known as BMN 673) in subjects with locally advanced or metastatic breast cancer with a deleterious germline BRCA 1 or BRCA 2 mutation. Subjects will be assigned to either Cohort 1 or 2 based on prior chemotherapy for metastatic disease:

* Cohort 1) Subjects with a documented PR or CR to a prior platinum-containing regimen for metastatic disease with disease progression \> 8 weeks following the last dose of platinum; or
* Cohort 2) Subjects who have received \> 2 prior chemotherapy regimens for metastatic disease and who have had no prior platinum therapy for metastatic disease

A Phase 2, 2-Stage, 2-Cohort Study of Talazoparib (BMN 673), in Locally Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (ABRAZO Study)

A PHASE 2, 2-STAGE, 2-COHORT STUDY OF TALAZOPARIB (BMN 673) ADMINISTERED TO GERMLINE BRCA MUTATION SUBJECTS WITH LOCALLY ADVANCED AND/OR METASTATIC BREAST CANCER

Time to deterioration was defined as the time from baseline to day to death, first occurrence of progression, or a \>=10 point change from baseline in any of the functional status score and global health status/QOL score based on the EORTC-QLQ-C30, whichever occurred first. EORTC-QLQ-C30 questionnaire is a standardized instrument developed to assess the quality of life of people with cancer. EORTC-QLQ-C30 functional subscale includes 5 items: physical, role, emotional, cognitive, and social functioning. All of the single items of functional status subscale measures and global health status/QOL subscale range from 0 to 100, where higher scores represent a better level of functioning/quality of life.

Time to deterioration was defined as the time from baseline to day to death, first occurrence of progression, or a \>=10 point change from baseline in any of the symptom score based on the EORTC-QLQ-BR23, whichever occurred first. EORTC-QLQ-BR23 is a disease-specific module for breast cancer developed as a supplement for the EORTC-QLQ-C30 to assess the quality of life of participants with breast cancer. EORTC-QLQ-BR23 symptoms subscale includes 4 items: systemic therapy side effects, breast symptoms, arm symptoms, upset by hair loss. Each item is rated by choosing 1 of 4 possible responses that record the level of intensity (1= not at all, 2= a little, 3= quite a bit, and 4= very much) within each scale.

ORR: Percentage of participants with a confirmed best overall complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors version 1.1 (RECIST 1.1). CR: Disappearance of all non-nodal target and non-target lesions, including target and non-target lymph nodes reduction to less than (\<) 10 millimeter (mm) in short axis. PR: Greater than or equal to (\>=) 30 percent (%) decrease in sum of diameters of target lesions, compared to the sum at baseline. Response evaluation was done by an independent radiology facility (IRF).

CBR24: Percentage of participants with a best response of CR, PR or stable disease (SD) sustained for at least 24 weeks, as assessed by IRF using RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions, including target and non-target lymph nodes reduction to \<10 mm in short axis. PR: \>=30% decrease in sum of diameters of target lesions, compared to the sum at baseline. SD: Neither PR nor progression of disease (PD) criteria met. SD follow PR only when sum increases by less than 20% from the nadir, but previously seen 30% decrease from baseline no longer hold. PD: \>=20% increase (\>=5 mm absolute increase) in the sum of target lesion measurements, compared to the smallest sum on study (including baseline), or unequivocal progression of non-target lesions, evaluated as a whole, such that it is clear that treatment has failed and disease is progressing, regardless of the status of the target lesions.

DOR: Time from first documentation of CR or PR, to PD by IRF assessment using RECIST 1.1, or to death due to any cause, whichever occurred first. CR: Disappearance of all non-nodal target and non-target lesions, with target and non-target lymph nodes reduction to \<10 mm in short axis. PR: \>=30% decrease in sum of diameters of target lesions, compared to the sum at baseline. PD: \>=20% increase (\>=5 mm absolute increase) in the sum of target lesion measurements, compared to the smallest sum on study (including baseline), or unequivocal progression of non-target lesions, evaluated as a whole, such that it is clear that treatment has failed and disease is progressing, regardless of the status of the target lesions. Participants with no PD or death at the analysis date were censored at last tumor assessment date prior to on or before initiation of a new anticancer therapy or before the data cutoff date.

PFS was defined as the time in months from the first dose of study drug to the first documentation of PD by investigator assessment using RECIST 1.1 or death on study due to any cause on or before the data cutoff date, whichever occurred first. PD: \>=20% increase (\>=5 mm absolute increase) in the sum of target lesion measurements, compared to the smallest sum on study (including baseline), or unequivocal progression of non-target lesions, evaluated as a whole, such that it is clear that treatment has failed and disease is progressing, regardless of the status of the target lesions. Participants with no PFS event at the analysis were censored at last tumor assessment date prior to data cutoff or date of new anticancer treatment initiation, whichever occurred first.

OS was defined as the time from first dose of study drug to death due to any cause. For participants without a death date at the time of data cutoff or permanently lost to follow-up, OS was right-censored at the date the participant was last known to be alive on or before the data cutoff date.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; an important medical event or reaction, including events requiring medical intervention to prevent worsening to any of the previously noted seriousness criteria. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious AEs.

A treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. A treatment-related SAE was a treatment-related AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; an important medical event or reaction, including events requiring medical intervention to prevent worsening to any of the previously noted seriousness criteria. Related TEAEs are TEAEs that were judged by the investigators as possibly, probably, or definitely related to study drug. AEs included both SAES and non SAES.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Outcome of an AE was response to a question answered by the investigator: 'Is the AE leading to study discontinuation or death?' as 'yes'.

Laboratory tests included hematology (hemoglobin \[low\], leucocytes \[low\], lymphocytes \[low\], neutrophils \[low\], platelets \[low\]). Toxicity grades were evaluated based on national cancer institute- common terminology criteria for adverse events (NCI-CTCAE) version 4.03. Number of participants with increase of 2 or more CTCAE toxicity grades above baseline, for hematology laboratory parameter is reported in this outcome measure.

Laboratory tests included serum chemistry (alanine aminotransferase \[high\], albumin \[low\], alkaline phosphatase \[high\], aspartate aminotransferase \[high\], bilirubin \[high\], calcium \[low\], glucose \[high\], magnesium \[low\], phosphate \[low\], potassium \[high\], potassium \[low\], sodium \[high\], sodium \[low\]). Toxicity grades were evaluated based on national cancer institute- common terminology criteria for adverse events (NCI-CTCAE) version 4.03. Number of participants with increase of 2 or more CTCAE toxicity grades above baseline, for chemistry laboratory parameter is reported in this outcome measure.

Criteria for clinically significant vital signs changes: 1) Blood pressure: systolic blood pressure (SBP): greater than or equal to (\>=30) millimeters of mercury (mmHg) increase from baseline, diastolic blood pressure (DBP): \>=20 mmHg decrease from baseline; 2) Heart rate (HR): absolute HR greater than (\>) 120 beats per minute (bpm) and \>30 bpm increase from baseline, absolute HR less than (\<) 50 bpm and \>20 bpm decrease from baseline; 3) Weight: \>10% decrease from baseline. Number of participants with any clinically significant change from baseline for blood pressure, heart rate and weight are reported in this outcome measure.

Physical examination included examination of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.

Number of participants taking any non-study medications, therapies, including herbal supplements during the treatment-emergent period for the management of an adverse event or for the treatment of any other disease.

Concentrations below the limit of quantitation values less than or equal to (\<=) 25 picogram per milliliter (pg/mL) were set as zero. Pharmacokinetic (PK) analysis was not done separately for each reporting arm and cohorts were combined for PK analysis.

Participants who responded to a prior platinum-containing treatment for metastatic breast cancer, with disease progression of at least 8 weeks following the last dose of platinum, received talazoparib 1.0 mg orally, once daily for 21 days in repeated 21-day cycles until disease progression, occurrence of unacceptable toxicity or permanent treatment discontinuation. Participants were followed-up for survival and new anticancer treatment at every 60 days after the last dose of study drug for the first year, every 90 days thereafter.

Cohort 1: Talazoparib 1 mg

Participants with more than 2 prior non-platinum chemotherapy treatment for metastatic breast cancer, received talazoparib 1.0 mg orally, once daily for 21 days in repeated 21-day cycles until disease progression, occurrence of unacceptable toxicity or permanent treatment discontinuation. Prior adjuvant or neo-adjuvant therapy with a platinum was allowed if first disease recurrence was for more than 6 months since last dose of adjuvant/neo-adjuvant platinum treatment. Participants were followed-up for survival and new anticancer treatment at every 60 days after the last dose of study drug for the first year, every 90 days thereafter.

Cohort 2: Talazoparib 1 mg

Intent-to-treat (ITT) population involved all enrolled participants including participants who were not treated.

Tumor-evaluable population (TEP) included all treated participants who had a baseline and at least 1 post-baseline tumor assessment or who discontinued the study before first scheduled post-baseline tumor scan plus (+) 1 week window.

Objective Response Rate (ORR)

TEP included all treated participants who had a baseline and at least 1 post-baseline tumor assessment or who discontinued the study before first scheduled post-baseline tumor scan + 1 week window.

Clinical Benefit Rate-24 (CBR-24)

TEP included all treated participants who had a baseline and at least 1 post-baseline tumor assessment or who discontinued the study before first scheduled post-baseline tumor scan + 1 week window. Here 'Number of participants analyzed' signifies participants evaluable for this outcome measure.

Duration of Response (DOR)

ITT population involved all enrolled participants including participants who were not treated.

Progression Free Survival (PFS)

Safety population included all participants who received at least 1 dose of talazoparib.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase II Study to Assess the Efficacy and Safety of SC10914 in the Metastatic Breast Cancer Patients	NCT04556292	Breast Cancer M... BRCA 1 Gene Mut... BRCA 2 Gene Mut...	SC10914	18 Years -	Jiangxi Qingfeng Pharmaceutical Co. Ltd.
A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study)	NCT01945775	Breast Neoplasm... BRCA 1 Gene Mut... BRCA 2 Gene Mut...	talazoparib Physician's-Cho...	18 Years -	Pfizer
Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.	NCT02000622	Breast Cancer M... BRCA 1 Gene Mut... BRCA 2 Gene Mut...	Olaparib Physician's cho...	18 Years - 99 Years	AstraZeneca
A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study)	NCT01945775	Breast Neoplasm... BRCA 1 Gene Mut... BRCA 2 Gene Mut...	talazoparib Physician's-Cho...	18 Years -	Pfizer
A Phase II Study to Assess the Efficacy and Safety of SC10914 in the Metastatic Breast Cancer Patients	NCT04556292	Breast Cancer M... BRCA 1 Gene Mut... BRCA 2 Gene Mut...	SC10914	18 Years -	Jiangxi Qingfeng Pharmaceutical Co. Ltd.
Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.	NCT02000622	Breast Cancer M... BRCA 1 Gene Mut... BRCA 2 Gene Mut...	Olaparib Physician's cho...	18 Years - 99 Years	AstraZeneca
Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.	NCT02000622	Breast Cancer M... BRCA 1 Gene Mut... BRCA 2 Gene Mut...	Olaparib Physician's cho...	18 Years - 99 Years	AstraZeneca
A Phase 2, 2-Stage, 2-Cohort Study of Talazoparib (BMN 673), in Locally Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (ABRAZO Study)	NCT02034916	Breast Neoplasm... BRCA 1 Gene Mut... BRCA 2 Gene Mut...	talazoparib	18 Years -	Pfizer
A Phase 2, 2-Stage, 2-Cohort Study of Talazoparib (BMN 673), in Locally Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (ABRAZO Study)	NCT02034916	Breast Neoplasm... BRCA 1 Gene Mut... BRCA 2 Gene Mut...	talazoparib	18 Years -	Pfizer

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