TALZENNA 8 Adverse Reactions

talazoparib

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8.1 Adverse Reaction Overview

The overall safety profile of TALZENNA is based on pooled data from 494 patients with a median duration of exposure of 5.4 months (range 0.03-61.1) who received TALZENNA at 1 mg daily in clinical studies for solid tumors, including 286 patients from a randomized Phase 3 study (EMBRACA) with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer and 83 patients from a nonrandomized Phase 2 study (ABRAZO) in patients with germline BRCA-mutated locally advanced or metastatic breast cancer.

Very common (≥10%) adverse reactions in patients receiving TALZENNA in these clinical studies were fatigue (57%), anemia (50%), nausea (44%), neutropenia (30%), thrombocytopenia (30%), headache (27%), diarrhea (23%), vomiting (22%), alopecia (22%), abdominal pain (21%), decreased appetite (20%), leukopenia (16%) and dizziness (14%).

The overall frequency of grade 3 and 4 AEs is 66%. The most common (≥ 10%) adverse reactions of CTCAE grade ≥ 3 are anemia (35%), neutropenia (17%), and thrombocytopenia (17%).

The overall frequency of serious adverse events (SAEs) is 32%. The most common SAEs are anemia (5%), dyspnea (2%), and pleural effusion (2%).

Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 62.3% of patients receiving TALZENNA. Very common adverse reactions (≥ 10%) leading to dose modifications were anemia (33%), neutropenia (16%), and thrombocytopenia (13%).

Permanent discontinuation due to an adverse reaction occurred in 4% of patients receiving TALZENNA. The most common adverse event that led to treatment discontinuation is anemia (0.6%). Adverse events associated with death occurred in 4% of patients receiving TALZENNA. The events leading to death reported in more than 1 patient were breast cancer, dyspnea, general physical health deterioration, neoplasm progression, and ovarian cancer.

8.2 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The EMBRACA study, a randomized Phase 3 study with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer includes 286 patients treated with TALZENNA and 126 patients treated with chemotherapy. Chemotherapy included capecitabine (55 patients), eribulin (50), gemcitabine (12), and vinorelbine (9). The median duration of study treatment was 6.1 months in patients who received TALZENNA and 3.9 months in patients who received chemotherapy.

The overall frequency of grade ≥ 3 adverse events is 68%. The most common (≥ 10%) adverse reactions of CTCAE grade ≥ 3 are anemia (39%), neutropenia (21%), and thrombocytopenia (15%).

The overall frequency of serious adverse events (SAEs) is 32%. The most common SAEs are anemia (6%), and pyrexia (2%).

Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 66% of patients receiving TALZENNA. Common adverse reactions (≥ 5%) leading to dose modifications were anemia (38%), neutropenia (19%), thrombocytopenia (11%), and decreased platelet count (7%).

In the EMBRACA study, 13 (5%) patients in the TALZENNA arm and 7 (6%) patients in the chemotherapy arm had an adverse reaction that was the primary reason for permanent study drug discontinuation. Anemia was the only AE reported in more than 1 patient that led to discontinuation on the TALZENNA arm. AEs leading to death occurred in 2% of receiving TALZENNA. AEs leading to death included general physical health deterioration (2 patients), cerebral hemorrhage, liver disorder, neurological symptom, and veno-occlusive liver disease (1 patient each).

Table 4 summarizes the adverse reactions from the EMBRACA study.

Table 4. Adverse Reactions (≥ 1%) in Patients Treated with TALZENNA or Chemotherapy in a Randomized Phase 3 Study with Germline BRCA-Mutated, HER2-Negative Locally Advanced or Metastatic Breast Cancer (EMBRACA Study)

 

System Organ Class

 

ADR Term

TALZENNA

N=286* (%)

Chemotherapy

N=126 (%)

All

Grades**

Grade

3

Grade

4

All

Grades

Grade

3

Grade

4

Blood and  
lymphatic system disorders
Anemiaa533911841
Thrombocytopeniab27114720
Neutropeniac35183432015
Leukopeniad176<11462
Lymphopeniae730301
Metabolism and nutrition disordersDecreased appetite21<1N/A221N/A
Nervous system disordersHeadache332N/A221N/A
Dizziness17<1N/A102N/A
Dysgeusia10N/AN/A9N/AN/A
Gastrointestinal  
disorders
Nausea49<1N/A472N/A
Diarrhea22102660
Vomiting25202320
Abdominal painf191N/A213N/A
Dyspepsia100N/A70N/A
Stomatitis800600

Skin and subcutaneous

tissue disorders

Alopeciag25N/AN/A28N/AN/A
General  
disorders and  
administration 
site conditions
Fatigueh623N/A505N/A
 

Adverse event grades are evaluated based on NCI-CTCAE (version 4.03). Patients with multiple events for a given preferred term are counted once only for each preferred term.

 

Abbreviations: ADR=adverse drug reaction; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; N=number of patients; N/A= not applicable.

*

All patients who received any dose of study drug

**

There were no Grade 5 adverse drug reactions

a.

Includes preferred terms of anemia, hematocrit decreased, and hemoglobin decreased.

b.

Includes preferred terms of thrombocytopenia and platelet count decreased.

c.

Includes preferred terms of neutropenia and neutrophil count decreased.

d.

Includes preferred terms of leukopenia and white blood-cell count decreased.

e

Includes preferred terms lymphocyte count decreased, lymphopenia

f.

Includes preferred terms of abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower.

g.

For talazoparib Grade 1 is 23% and Grade 2 is 2%.

h.

Includes the preferred terms of fatigue or asthenia.

8.3 Less Common Clinical Trial Adverse Reactions

All ADVERSE REACTIONS occurred at > 1% and are presented in Table 4, ADVERSE REACTIONS, Clinical Trial Adverse Reactions

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Tables 5 and 6 summarize the hematologic and chemistry laboratory parameters by grade in patients treated with TALZENNA or chemotherapy from the EMBRACA study.

Table 5 Summary of Postbaseline Hematology Laboratory Parameters by Toxicity Grade reported in > 10% of patients (EMBRACA Study)
 EMBRACA Study
Talazoparib 
N=286* (%)
Chemotherapy 
N=126 (%)
ParameterGrades 1-4Grade 3 or 4Grades 1-4Grade 3 or 4

Decrease in

hemoglobin

9039776
Decrease in platelets5515292
Decrease in neutrophils68217038

Decrease in

lymphocytes

7618539
Decrease in leukocytes84147325
 

Abbreviation: N=number of patients.

*

All patients who received any dose of study drug

 

Table 6 Summary of Postbaseline Chemistry Laboratory Parameters by Toxicity Grade reported in > 10% of patients (EMBRACA Study)
 EMBRACA Study
Talazoparib N=286* (%)Chemotherapy N=126 (%)
ParameterGrades 1-4Grade 3 or 4Grades 1-4Grade 3 or 4
Increase in glucose542512

Increase in aspartate

aminotransferase

372483

Increase in alkaline

phosphatase

362342

Increase in alanine

aminotransferase

331372
Decrease in calcium281160
Decrease in glucose13<150
Increase in bilirubin101111
 

Abbreviation: N=number of patients.

*

All patients who received any dose of study drug

This number represents non-fasting glucose.

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8 Adverse Reactions

8.1 Adverse Reaction Overview

The overall safety profile of TALZENNA is based on pooled data from 494 patients with a median duration of exposure of 5.4 months (range 0.03-61.1) who received TALZENNA at 1 mg daily in clinical studies for solid tumors, including 286 patients from a randomized Phase 3 study (EMBRACA) with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer and 83 patients from a nonrandomized Phase 2 study (ABRAZO) in patients with germline BRCA-mutated locally advanced or metastatic breast cancer.

Very common (≥10%) adverse reactions in patients receiving TALZENNA in these clinical studies were fatigue (57%), anemia (50%), nausea (44%), neutropenia (30%), thrombocytopenia (30%), headache (27%), diarrhea (23%), vomiting (22%), alopecia (22%), abdominal pain (21%), decreased appetite (20%), leukopenia (16%) and dizziness (14%).

The overall frequency of grade 3 and 4 AEs is 66%. The most common (≥ 10%) adverse reactions of CTCAE grade ≥ 3 are anemia (35%), neutropenia (17%), and thrombocytopenia (17%).

The overall frequency of serious adverse events (SAEs) is 32%. The most common SAEs are anemia (5%), dyspnea (2%), and pleural effusion (2%).

Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 62.3% of patients receiving TALZENNA. Very common adverse reactions (≥ 10%) leading to dose modifications were anemia (33%), neutropenia (16%), and thrombocytopenia (13%).

Permanent discontinuation due to an adverse reaction occurred in 4% of patients receiving TALZENNA. The most common adverse event that led to treatment discontinuation is anemia (0.6%). Adverse events associated with death occurred in 4% of patients receiving TALZENNA. The events leading to death reported in more than 1 patient were breast cancer, dyspnea, general physical health deterioration, neoplasm progression, and ovarian cancer.

8.2 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The EMBRACA study, a randomized Phase 3 study with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer includes 286 patients treated with TALZENNA and 126 patients treated with chemotherapy. Chemotherapy included capecitabine (55 patients), eribulin (50), gemcitabine (12), and vinorelbine (9). The median duration of study treatment was 6.1 months in patients who received TALZENNA and 3.9 months in patients who received chemotherapy.

The overall frequency of grade ≥ 3 adverse events is 68%. The most common (≥ 10%) adverse reactions of CTCAE grade ≥ 3 are anemia (39%), neutropenia (21%), and thrombocytopenia (15%).

The overall frequency of serious adverse events (SAEs) is 32%. The most common SAEs are anemia (6%), and pyrexia (2%).

Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 66% of patients receiving TALZENNA. Common adverse reactions (≥ 5%) leading to dose modifications were anemia (38%), neutropenia (19%), thrombocytopenia (11%), and decreased platelet count (7%).

In the EMBRACA study, 13 (5%) patients in the TALZENNA arm and 7 (6%) patients in the chemotherapy arm had an adverse reaction that was the primary reason for permanent study drug discontinuation. Anemia was the only AE reported in more than 1 patient that led to discontinuation on the TALZENNA arm. AEs leading to death occurred in 2% of receiving TALZENNA. AEs leading to death included general physical health deterioration (2 patients), cerebral hemorrhage, liver disorder, neurological symptom, and veno-occlusive liver disease (1 patient each).

Table 4 summarizes the adverse reactions from the EMBRACA study.

Table 4. Adverse Reactions (≥ 1%) in Patients Treated with TALZENNA or Chemotherapy in a Randomized Phase 3 Study with Germline BRCA-Mutated, HER2-Negative Locally Advanced or Metastatic Breast Cancer (EMBRACA Study)

 

System Organ Class

 

ADR Term

TALZENNA

N=286* (%)

Chemotherapy

N=126 (%)

All

Grades**

Grade

3

Grade

4

All

Grades

Grade

3

Grade

4

Blood and  
lymphatic system disorders
Anemiaa533911841
Thrombocytopeniab27114720
Neutropeniac35183432015
Leukopeniad176<11462
Lymphopeniae730301
Metabolism and nutrition disordersDecreased appetite21<1N/A221N/A
Nervous system disordersHeadache332N/A221N/A
Dizziness17<1N/A102N/A
Dysgeusia10N/AN/A9N/AN/A
Gastrointestinal  
disorders
Nausea49<1N/A472N/A
Diarrhea22102660
Vomiting25202320
Abdominal painf191N/A213N/A
Dyspepsia100N/A70N/A
Stomatitis800600

Skin and subcutaneous

tissue disorders

Alopeciag25N/AN/A28N/AN/A
General  
disorders and  
administration 
site conditions
Fatigueh623N/A505N/A
 

Adverse event grades are evaluated based on NCI-CTCAE (version 4.03). Patients with multiple events for a given preferred term are counted once only for each preferred term.

 

Abbreviations: ADR=adverse drug reaction; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; N=number of patients; N/A= not applicable.

*

All patients who received any dose of study drug

**

There were no Grade 5 adverse drug reactions

a.

Includes preferred terms of anemia, hematocrit decreased, and hemoglobin decreased.

b.

Includes preferred terms of thrombocytopenia and platelet count decreased.

c.

Includes preferred terms of neutropenia and neutrophil count decreased.

d.

Includes preferred terms of leukopenia and white blood-cell count decreased.

e

Includes preferred terms lymphocyte count decreased, lymphopenia

f.

Includes preferred terms of abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower.

g.

For talazoparib Grade 1 is 23% and Grade 2 is 2%.

h.

Includes the preferred terms of fatigue or asthenia.

8.3 Less Common Clinical Trial Adverse Reactions

All ADVERSE REACTIONS occurred at > 1% and are presented in Table 4, ADVERSE REACTIONS, Clinical Trial Adverse Reactions

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Tables 5 and 6 summarize the hematologic and chemistry laboratory parameters by grade in patients treated with TALZENNA or chemotherapy from the EMBRACA study.

Table 5 Summary of Postbaseline Hematology Laboratory Parameters by Toxicity Grade reported in > 10% of patients (EMBRACA Study)
 EMBRACA Study
Talazoparib 
N=286* (%)
Chemotherapy 
N=126 (%)
ParameterGrades 1-4Grade 3 or 4Grades 1-4Grade 3 or 4

Decrease in

hemoglobin

9039776
Decrease in platelets5515292
Decrease in neutrophils68217038

Decrease in

lymphocytes

7618539
Decrease in leukocytes84147325
 

Abbreviation: N=number of patients.

*

All patients who received any dose of study drug

 

Table 6 Summary of Postbaseline Chemistry Laboratory Parameters by Toxicity Grade reported in > 10% of patients (EMBRACA Study)
 EMBRACA Study
Talazoparib N=286* (%)Chemotherapy N=126 (%)
ParameterGrades 1-4Grade 3 or 4Grades 1-4Grade 3 or 4
Increase in glucose542512

Increase in aspartate

aminotransferase

372483

Increase in alkaline

phosphatase

362342

Increase in alanine

aminotransferase

331372
Decrease in calcium281160
Decrease in glucose13<150
Increase in bilirubin101111
 

Abbreviation: N=number of patients.

*

All patients who received any dose of study drug

This number represents non-fasting glucose.

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