6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•: Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)]
•: Myelosuppression [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to single agent TALZENNA in solid tumor clinical studies, including 286 patients enrolled in EMBRACA trial and to TALZENNA 0.5 mg daily in combination with enzalutamide in 511 patients enrolled in the TALAPRO-2 trial that included 197 patients with HRR gene-mutated mCRPC.

gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer

EMBRACA

The safety of TALZENNA as a single agent was evaluated in gBRCAm patients with HER2-negative locally advanced or metastatic breast cancer who had previously received no more than 3 lines of chemotherapy for the treatment of locally advanced/metastatic disease [see Clinical Studies (14.1)]. EMBRACA was a randomized, open-label, multi-center study in which 412 patients received either TALZENNA 1 mg once daily (N=286) or a chemotherapy agent (capecitabine, eribulin, gemcitabine, or vinorelbine) of the healthcare provider's choice (N=126) until disease progression or unacceptable toxicity. The median duration of study treatment was 6.1 months in patients who received TALZENNA and 3.9 months in patients who received chemotherapy.

Serious adverse reactions of TALZENNA occurred in 32% of patients. Serious adverse reactions reported in >2% of patients included anemia (6%) and pyrexia (2%). Fatal adverse reactions occurred in 1% of patients, including cerebral hemorrhage, liver disorder, veno-occlusive liver disease, and worsening neurological symptoms (1 patient each).

Permanent discontinuation due to adverse reactions occurred in 5% of TALZENNA patients. Dosing interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving TALZENNA; dose reductions due to any cause occurred in 53% of TALZENNA patients.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, neutrophils decreased, lymphocytes decreased, platelets decreased, fatigue, glucose increased, aspartate aminotransferase increased, alkaline phosphatase increased, alanine aminotransferase increased, calcium decreased, nausea, headache, vomiting, alopecia, diarrhea, and decreased appetite.

Table 5 and Table 6 summarize the most common adverse reactions and laboratory abnormalities, respectively, in patients treated with TALZENNA or chemotherapy in the EMBRACA study.

Table 5. Adverse Reactions* (≥20%) in Patients Receiving TALZENNA in EMBRACA
Adverse Reactions	TALZENNA N=286 (%)			Chemotherapy N=126 (%)
Adverse Reactions	Grades 1–4	Grade 3	Grade 4	Grades 1–4	Grade 3	Grade 4
Abbreviation: N=number of patients.
* Graded according to NCI CTCAE 4.03. † Includes fatigue and asthenia.
General disorders and administration site conditions
Fatigue†	62	3	0	50	5	0
Gastrointestinal disorders
Nausea	49	0.3	0	47	2	0
Vomiting	25	2	0	23	2	0
Diarrhea	22	1	0	26	6	0
Nervous system disorders
Headache	33	2	0	22	1	0
Skin and subcutaneous tissue disorders
Alopecia	25	0	0	28	0	0
Metabolism and nutrition disorders
Decreased appetite	21	0.3	0	22	1	0

Clinically relevant adverse reactions in <20% of patients who received TALZENNA included abdominal pain (19%), dizziness (17%), dysgeusia (10%), dyspepsia (10%), stomatitis (8%), and febrile neutropenia (0.3%).

Table 6. Select Laboratory Abnormalities (≥25%) of Patients in EMBRACA
	TALZENNA N*=286 (%)			Chemotherapy N*=126 (%)
Parameter	Grades 1–4	Grade 3	Grade 4	Grades 1–4	Grade 3	Grade 4
Abbreviation: N=number of patients.
* This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter. † This number represents non-fasting glucose.
Hemoglobin decreased	90	39	0	77	6	0
Neutrophils decreased	68	17	3	70	21	17
Lymphocytes decreased	76	17	0.7	53	8	0.8
Platelets decreased	55	11	4	29	2	0
Glucose increased†	54	2	0	51	2	0
Aspartate aminotransferase Increased	37	2	0	48	3	0
Alkaline phosphatase increased	36	2	0	34	2	0
Alanine aminotransferase increased	33	1	0	37	2	0
Calcium decreased	28	1	0	16	0	0

HRR Gene-mutated mCRPC

The safety of TALZENNA in combination with enzalutamide was evaluated in patients with HRR gene-mutated mCRPC enrolled in TALAPRO-2 [see Clinical Studies (14.2)]. Patients were randomized to receive either TALZENNA 0.5 mg in combination with enzalutamide 160 mg once daily (n=197), or placebo in enzalutamide 160 mg once daily (n=199) until disease progression or unacceptable toxicity. Among patients receiving TALZENNA, 86% were exposed for 6 months or longer, 60% were exposed for greater than one year, and 18% were exposed for greater than two years.

Serious adverse reactions of TALZENNA in combination with enzalutamide occurred in 30% of patients. Serious adverse reactions reported in >2% of patients included anemia (9%) and fracture (3%). Fatal adverse reactions occurred in 1.5% of patients, including pneumonia, COVID infection, and sepsis (1 patient each).

Permanent discontinuation of TALZENNA due to adverse reactions occurred in 10% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in permanent discontinuation of TALZENNA were anemia (4%), fatigue, bone fracture, ischemic heart disease, and spinal cord compression (1% each).

Dosage interruption of TALZENNA due to adverse reactions occurred in 58% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in dose interruption of TALZENNA were anemia (42%), neutropenia (15%), and platelet count decreased (9%) and fatigue (5%).

Dose reduction of TALZENNA due to adverse reactions occurred in 52% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in dose reduction of TALZENNA were anemia (43%), neutrophil count decreased (15%), platelet count decreased (6%), and fatigue (4%).

The most common adverse reactions (≥10%), including laboratory abnormalities, in patients who received TALZENNA with enzalutamide were hemoglobin decreased, neutrophils decreased, lymphocytes decreased, fatigue, platelets decreased, calcium decreased, nausea, decreased appetite, sodium decreased, phosphate decreased, fractures, magnesium decreased, dizziness, bilirubin increased, potassium decreased, and dysgeusia.

Table 7 and Table 8 summarize the most common adverse reactions and laboratory abnormalities, respectively, in the TALAPRO-2 study.

Table 7. Adverse Reactions* (≥10%) in Patients Receiving TALZENNA [with a Difference Between Arms of ≥2%] in TALAPRO-2
Abbreviation: N=number of patients.
* Graded according to NCI CTCAE 4.03. † Includes fatigue and asthenia. ‡ Fractures include multiple similar terms. § Includes dizziness, dizziness postural, vertigo. ¶ Includes ageusia, anosmia, dysgeusia.
	TALZENNA with Enzalutamide N=197			Placebo with Enzalutamide N=199
	Grades 1-4 %	Grade 3 %	Grade 4 %	Grades 1-4 %	Grade 3 %	Grade 4 %
Fatigue†	49	4	0	40	1	0
Nausea	21	2	0	17	1	0.5
Decreased appetite	20	1	0	14	1	1
Fractures‡	14	3	0	10	1.5	0
Dizziness§	13	1.5	0	9	1.5	0
Dysgeusia¶	10	0	0	4.5	0	0

Clinically relevant adverse reactions in <10% of patients who received TALZENNA with enzalutamide included abdominal pain (9%), vomiting (9%), alopecia (7%), dyspepsia (4%), venous thromboembolism (3%) and stomatitis (2%).

Table 8. Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients Who Received TALZENNA in TALAPRO-2
Abbreviation: N=number of patients.
* The denominator used to calculate the rate varied from 198 to 199 in the placebo with enzalutamide arm based on the number of patients with a baseline value and at least one post-treatment value.
Laboratory Abnormality	TALZENNA with Enzalutamide N=197*			Placebo with Enzalutamide N=199*
Laboratory Abnormality	Grades 1‑4 %	Grade 3 %	Grade 4 %	Grades 1‑4 %	Grade 3 %	Grade 4 %
Hemoglobin decreased	79	41	0	34	6	0
Neutrophils decreased	60	18	1	18	0	1
Lymphocytes decreased	58	13	0	36	7	0
Platelets decreased	45	6	3	8	0.5	0
Calcium decreased	25	0	1	11	0	1
Sodium decreased	22	3	0	20	1.5	0
Phosphate decreased	17	3	1	13	2	0
Magnesium decreased	14	0	1	12	0	0.5
Bilirubin increased	11	0.5	0	7	0	0
Potassium decreased	11	0	1	7	1	0.5