6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere in the labeling:

•: Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)]
•: Pneumonitis [see Warnings and Precautions (5.2)]
•: Venous Thromboembolism [see Warnings and Precautions (5.3)]

6.1 Clinical Trial 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.

Unless otherwise specified, the data described in the WARNINGS AND PRECAUTIONS reflect exposure to Lynparza as a single agent in 2901 patients; 2135 patients with exposure to 300 mg twice daily tablet dose including five controlled, randomized, trials (SOLO-1, SOLO-2, OlympiAD, POLO, and PROfound) and to 400 mg twice daily capsule dose in 766 patients in other trials that were pooled to conduct safety analyses. In addition to the 2901 patients, certain subsections in the WARNINGS AND PRECAUTIONS include adverse reactions observed with exposure to Lynparza with abiraterone (n=398) in PROpel. All patients with metastatic castration resistant prostate cancer received concomitant ADT or previous bilateral orchiectomy.

In the pooled safety population, 56% of patients were exposed for 6 months or longer and 28% were exposed for greater than one year in the Lynparza group.

In this pooled safety population, the most common adverse reactions in ≥10% of patients were nausea (60%), fatigue (55%), anemia (36%), vomiting (32%), diarrhea (24%), decreased appetite (22%), headache (16%), dysgeusia (15%), cough (15%), neutropenia (14%), dyspnea (14%), dizziness (12%), dyspepsia (12%), leukopenia (11%), and thrombocytopenia (10%).

First-Line Maintenance Treatment of BRCA-mutated Advanced Ovarian Cancer

SOLO-1

The safety of Lynparza for the maintenance treatment of patients with BRCA-mutated advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was investigated in SOLO-1 [see Clinical Studies (14.1)]. Patients received Lynparza tablets 300 mg orally twice daily (n=260) or placebo (n=130) until disease progression or unacceptable toxicity. The median duration of study treatment was 25 months for patients who received Lynparza and 14 months for patients who received placebo.

Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 52% and dose reductions due to an adverse reaction occurred in 28%. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (23%), nausea (14%), and vomiting (10%). Discontinuation due to adverse reactions occurred in 12% of patients receiving Lynparza. The most frequent adverse reactions that led to discontinuation of Lynparza were fatigue (3.1%), anemia (2.3%), and nausea (2.3%).

Tables 2 and 3 summarize adverse reactions and laboratory abnormalities in SOLO-1.

Table 2 Adverse Reactions* in SOLO-1 (≥10% of Patients Who Received Lynparza)
* Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. † Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal distension, abdominal discomfort, and abdominal tenderness. ‡ Includes colitis, diarrhea, and gastroenteritis. § Includes stomatitis, aphthous ulcer, and mouth ulceration. ¶ Includes asthenia, fatigue, lethargy, and malaise. # Includes neutropenia and febrile neutropenia. Þ Includes leukopenia and white blood cell count decreased. ß Includes platelet count decreased and thrombocytopenia. à Includes urosepsis, urinary tract infection, urinary tract pain, and pyuria. è Includes dyspnea and dyspnea exertional.
Adverse Reaction	Lynparza tablets n=260		Placebo n=130
Adverse Reaction	All Grades (%)	Grades 3 – 4 (%)	All Grades (%)	Grades 3 – 4 (%)
Gastrointestinal Disorders
Nausea	77	1	38	0
Abdominal pain†	45	2	35	1
Vomiting	40	0	15	1
Diarrhea‡	37	3	26	0
Constipation	28	0	19	0
Dyspepsia	17	0	12	0
Stomatitis§	11	0	2	0
General Disorders and Administration Site Conditions
Fatigue¶	67	4	42	2
Blood and Lymphatic System Disorders
Anemia	38	21	9	2
Neutropenia#	17	6	7	3
LeukopeniaÞ	13	3	8	0
Thrombocytopeniaß	11	1	4	2
Infections and Infestations
Upper respiratory tract infection/ influenza/nasopharyngitis/bronchitis	28	0	23	0
UTIà	13	1	7	0
Nervous System Disorders
Dysgeusia	26	0	4	0
Dizziness	20	0	15	1
Metabolism and Nutrition Disorders
Decreased appetite	20	0	10	0
Respiratory, Thoracic and Mediastinal Disorders
Dyspneaè	15	0	6	0

Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza were increased blood creatinine (8%), lymphopenia (6%), VTE (3%), hypersensitivity (2%), MDS/AML (1.9%), dermatitis (1%), and increased mean cell volume (0.4%).

Table 3 Laboratory Abnormalities Reported in ≥25% of Patients in SOLO-1
* Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. † 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.
Laboratory Parameter*	Lynparza tablets n†=260		Placebo n†=130
Laboratory Parameter*	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Decrease in hemoglobin	87	19	63	2
Increase in mean corpuscular volume	87	-	43	-
Decrease in leukocytes	70	7	52	1
Decrease in lymphocytes	67	14	29	5
Decrease in absolute neutrophil count	51	9	38	6
Decrease in platelets	35	1	20	2
Increase in serum creatinine	34	0	18	0

First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab

PAOLA-1

The safety of Lynparza in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer following first-line treatment containing platinum-based chemotherapy and bevacizumab was investigated in PAOLA-1 [see Clinical Studies (14.2)]. This study was a placebo-controlled, double-blind study in which 802 patients received either Lynparza 300 mg BID in combination with bevacizumab (n=535) or placebo in combination with bevacizumab (n=267) until disease progression or unacceptable toxicity. The median duration of treatment with Lynparza was 17.3 months and 11 months for bevacizumab post-randomization on the Lynparza/bevacizumab arm.

Fatal adverse reactions occurred in 1 patient due to concurrent pneumonia and aplastic anemia. Serious adverse reactions occurred in 31% of patients who received Lynparza/bevacizumab. Serious adverse reactions in >5% of patients included hypertension (19%) and anemia (17%).

Dose interruptions due to an adverse reaction of any grade occurred in 54% of patients receiving Lynparza/bevacizumab and dose reductions due to an adverse reaction occurred in 41% of patients who received Lynparza/bevacizumab.

The most frequent adverse reactions leading to dose interruption in the Lynparza/bevacizumab arm were anemia (21%), nausea (7%), vomiting (3%), and fatigue (3%), and the most frequent adverse reactions leading to reduction in the Lynparza/bevacizumab arm were anemia (19%), nausea (7%), and fatigue (4%).

Discontinuation due to adverse reactions occurred in 20% of patients receiving Lynparza/bevacizumab. Specific adverse reactions that most frequently led to discontinuation in patients treated with Lynparza/bevacizumab were anemia (4%) and nausea (3%).

The most common adverse reactions (≥ 10%) for patients receiving Lynparza/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%), diarrhea (18%), neutropenia (18%), leukopenia (18%), urinary tract infection (15%), and headache (14%).

Tables 4 and 5 summarize adverse reactions and laboratory abnormalities in PAOLA-1, respectively.

Table 4 Adverse Reactions* Occurring in ≥10% of Patients Treated with Lynparza/bevacizumab in PAOLA-1 and at ≥5% Frequency Compared to the Placebo/bevacizumab Arm
* Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. † Includes asthenia and fatigue. ‡ Includes anemia, anemia macrocytic, erythropenia, haematocrit decreased, haemoglobin decreased, normochromic anemia, normochromic normocytic anemia, normocytic anemia, and red blood cell count decreased. § Includes B-lymphocyte count decreased, lymphocyte count decreased, lymphopenia, and T-lymphocyte count decreased. ¶ Includes leukopenia and white blood cell count decreased.
Adverse Reactions	Lynparza/bevacizumab n=535		Placebo/bevacizumab n=267
Adverse Reactions	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
General Disorders and Administration Site Conditions
Fatigue (including asthenia)†	53	5	32	1.5
Gastrointestinal Disorders
Nausea	53	2.4	22	0.7
Vomiting	22	1.7	11	1.9
Blood and Lymphatic Disorders
Anemia‡	41	17	10	0.4
Lymphopenia§	24	7	9	1.1
Leukopenia¶	18	1.9	10	1.5

Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza/bevacizumab were dysgeusia (8%), dyspnea (8%), stomatitis (5%), dyspepsia (4.3%), erythema (3%), dizziness (2.6%), hypersensitivity (1.7%), and MDS/AML (0.7%).

Venous thromboembolism occurred more commonly in patients receiving Lynparza/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).

Table 5 Laboratory Abnormalities Reported in ≥25% of Patients in PAOLA-1*
* Reported within 30 days of the last dose. † Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. ‡ 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.
Laboratory Parameter†	Lynparza/bevacizumab n†=535		Placebo/bevacizumab n‡=267
Laboratory Parameter†	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Decrease in hemoglobin	79	13	55	0.4
Decrease in lymphocytes	63	10	42	3.0
Increase in serum creatinine	61	0.4	36	0.4
Decrease in leukocytes	59	3.4	45	2.2
Decrease in absolute neutrophil count	35	7	30	3.7
Decrease in platelets	35	2.4	28	0.4

Maintenance Treatment of BRCA-mutated Recurrent Ovarian Cancer

SOLO-2

The safety of Lynparza for the maintenance treatment of patients with platinum sensitive gBRCAm ovarian cancer was investigated in SOLO-2 [see Clinical Studies (14.3)]. Patients received Lynparza tablets 300 mg orally twice daily (n=195) or placebo (n=99) until disease progression or unacceptable toxicity. The median duration of study treatment was 19.4 months for patients who received Lynparza and 5.6 months for patients who received placebo.

Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 45% and dose reductions due to an adverse reaction occurred in 27%. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (22%), neutropenia (9%), and fatigue/asthenia (8%). Discontinuation due to an adverse reaction occurred in 11% of patients receiving Lynparza.

Tables 6 and 7 summarize adverse reactions and laboratory abnormalities in SOLO-2.

Table 6 Adverse Reactions* in SOLO-2 (≥20% of Patients Who Received Lynparza)
* Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. † Represents grouped term consisting of abscess oral, aphthous ulcer, gingival abscess, gingival disorder, gingival pain, gingivitis, mouth ulceration, mucosal infection, mucosal inflammation, oral candidiasis, oral discomfort, oral herpes, oral infection, oral mucosal erythema, oral pain, oropharyngeal discomfort, and oropharyngeal pain. ‡ Represents grouped term consisting of anemia, hematocrit decreased, hemoglobin decreased, iron deficiency, mean cell volume increased, and red blood cell count decreased.
Adverse Reaction	Lynparza tablets n=195		Placebo n=99
Adverse Reaction	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Gastrointestinal Disorders
Nausea	76	3	33	0
Vomiting	37	3	19	1
Diarrhea	33	2	22	0
Stomatitis†	20	1	16	0
General Disorders and Administration Site Conditions
Fatigue including asthenia	66	4	39	2
Blood and Lymphatic Disorders
Anemia‡	44	20	9	2
Infections and Infestations
Nasopharyngitis/URI/sinusitis/ rhinitis/influenza	36	0	29	0
Musculoskeletal and Connective Tissue Disorders
Arthralgia/myalgia	30	0	28	0
Nervous System Disorders
Dysgeusia	27	0	7	0
Headache	26	1	14	0
Metabolism and Nutrition Disorders
Decreased appetite	22	0	11	0

Clinically relevant adverse reactions that occurred in <20% of patients receiving Lynparza were neutropenia (19%), cough (18%), leukopenia (16%), hypomagnesemia (14%), thrombocytopenia (14%), dizziness (13%), dyspepsia (11%), increased creatinine (11%), MDS/AML (8%), edema (8%), rash (6%), VTE (5%), and lymphopenia (1%).

Table 7 Laboratory Abnormalities Reported in ≥25% of Patients in SOLO-2
* Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. † 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. ‡ Represents the proportion of subjects whose mean corpuscular volume was > upper limit of normal (ULN).
Laboratory Parameter*	Lynparza tablets n†=195		Placebo n†=99
Laboratory Parameter*	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Increase in mean corpuscular volume‡	89	-	52	-
Decrease in hemoglobin	83	17	69	0
Decrease in leukocytes	69	5	48	1
Decrease in lymphocytes	67	11	37	1
Decrease in absolute neutrophil count	51	7	34	3
Increase in serum creatinine	44	0	29	0
Decrease in platelets	42	2	22	1

Adjuvant Treatment of germline BRCA-mutated HER2-negative High Risk Early Breast Cancer

OlympiA

The safety of Lynparza as monotherapy for the adjuvant treatment of patients with gBRCA-mutated HER2-negative high risk early breast cancer was investigated in OlympiA [see Clinical Studies (14.4)]. This study was a randomized, double-blind, multi-center study in which patients received either Lynparza tablets 300 mg orally twice daily (n=911) or placebo (n=904) for a total of 1 year, or until disease recurrence, or unacceptable toxicity. The median duration of treatment was 1 year in both arms.

Dose interruptions due to an adverse reaction of any grade occurred in 31% of patients receiving Lynparza; dose reductions due to an adverse reaction occurred in 23% of patients receiving Lynparza. The most frequent adverse reactions leading to dose interruption of Lynparza were anemia (11%), neutropenia (6%), nausea (5%), leukopenia (3.5%), fatigue (3%), and vomiting (2.9%) and the most frequent adverse reactions leading to dose reduction of Lynparza were anemia (8%), nausea (4.7%), neutropenia (4.2%), fatigue (3.3%), leukopenia (1.8%), and vomiting (1.5%). Discontinuation due to adverse reactions occurred in 10% of patients receiving Lynparza. The adverse reactions that most frequently led to discontinuation of Lynparza were nausea (2%), anemia (1.8%), and fatigue (1.3%).

Tables 8 and 9 summarize the adverse reactions and laboratory abnormalities, respectively, in patients in OlympiA.

Table 8 Adverse Reactions* in OlympiA (≥ 10% of Patients Who Received Lynparza)
* Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 † Includes aphthous ulcer, mouth ulceration, and stomatitis. ‡ Includes anemia, anemia macrocytic, erythropenia, hematocrit decreased, hemoglobin decreased, normochromic anemia, normochromic normocytic anemia, normocytic anemia, and red blood cell count decreased. § Includes leukopenia and white blood cell count decreased. ¶ Includes agranulocytosis, febrile neutropenia, granulocyte count decreased, granulocytopenia, idiopathic neutropenia, neutropenia, neutropenic infection, neutropenic sepsis, and neutrophil count decreased. # Includes dysgeusia and taste disorder.
Adverse Reactions	Lynparza tablets n=911		Placebo n=904
Adverse Reactions	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Gastrointestinal Disorders
Nausea	57	0.8	23	0
Vomiting	23	0.7	8	0
Diarrhea	18	0.3	14	0.3
Stomatitis†	10	0.1	4.5	0
General Disorders and Administration Site Conditions
Fatigue (including asthenia)	42	1.8	28	0.7
Blood and Lymphatic Disorders
Anemia‡	24	9	3.9	0.3
Leukopenia§	17	3	6	0.3
Neutropenia¶	16	5	7	0.8
Nervous System Disorders
Headache	20	0.2	17	0.1
Dysgeusia#	12	0	4.8	0
Dizziness	11	0.1	7	0.1
Metabolism and Nutrition Disorders
Decreased appetite	13	0.2	6	0

Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza were cough (9.2%), lymphopenia (7%), dyspepsia (6%), upper abdominal pain (4.9%), rash (4.9%), dyspnea (4.2%), thrombocytopenia (4.2%), increase in creatinine (2%), hypersensitivity (0.9%), VTE (0.5%), dermatitis (0.5%), increase in mean corpuscular volume (0.2%), and MDS/AML (0.2%).

Table 9 Laboratory Abnormalities Reported in ≥25% of Patients in OlympiA
* Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. † 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. ‡ Represents the proportion of subjects whose mean corpuscular volume was > ULN.
Laboratory Parameter*	Lynparza tablets n†= 911		Placebo n†=904
Laboratory Parameter*	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Decrease in lymphocytes	77	13	59	3.7
Increase in mean corpuscular volume‡	67	0	4.8	0
Decrease in hemoglobin	65	8	31	0.9
Decrease in leukocytes	64	5	42	0.7
Decrease in absolute neutrophil count	39	7	27	1.1

Germline BRCA-mutated HER2-negative Metastatic Breast Cancer

OlympiAD

The safety of Lynparza was evaluated in gBRCAm patients with HER2-negative metastatic breast cancer who had previously received up to two lines of chemotherapy for the treatment of metastatic disease in OlympiAD [see Clinical Studies (14.5)]. Patients received either Lynparza tablets 300 mg orally twice daily (n=205) or a chemotherapy (capecitabine, eribulin, or vinorelbine) of the healthcare provider’s choice (n=91) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.2 months in patients who received Lynparza and 3.4 months in patients who received chemotherapy.

Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 35% and dose reductions due to an adverse reaction occurred in 25%. Discontinuation due to an adverse reaction occurred in 5% of patients receiving Lynparza.

Tables 10 and 11 summarize the adverse reactions and laboratory abnormalities in OlympiAD.

Table 10 Adverse Reactions* in OlympiAD (≥20% of Patients Who Received Lynparza)
* Graded according to NCI CTCAE v4.0. † Represents grouped terms consisting of anemia (anemia erythropenia, hematocrit decreased, hemoglobin decreased, and red blood cell count decreased). ‡ Represents grouped terms consisting of neutropenia (febrile neutropenia, granulocyte count decreased, granulocytopenia, neutropenia, neutropenic infection, neutropenic sepsis, and neutrophil count decreased). § Represents grouped terms consisting of leukopenia (leukopenia and white blood cell count decreased). ¶ Represents grouped terms consisting of bronchitis, influenza, lower respiratory tract infection, nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial.
Adverse Reaction	Lynparza tablets n=205		Chemotherapy n=91
Adverse Reaction	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Gastrointestinal Disorders
Nausea	58	0	35	1
Vomiting	30	0	15	1
Diarrhea	21	1	22	0
Blood and Lymphatic Disorders
Anemia†	40	16	26	4
Neutropenia‡	27	9	50	26
Leukopenia§	25	5	31	13
General Disorders and Administration Site Conditions
Fatigue (including asthenia)	37	4	36	1
Infections and Infestations
Respiratory tract infection¶	27	1	22	0
Nervous System Disorders
Headache	20	1	15	2

Clinically relevant adverse reactions that occurred in <20% of patients receiving Lynparza were cough (18%), decreased appetite (16%), thrombocytopenia (11%), dysgeusia (9%), lymphopenia (8%), dyspepsia (8%), dizziness (7%), stomatitis (7%), upper abdominal pain (7%), rash (5%), increase in serum creatinine (3%), dermatitis (1%), and VTE (1%).

Table 11 Laboratory Abnormalities Reported in ≥25% of Patients in OlympiAD
* Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. † 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. ‡ Represents the proportion of subjects whose mean corpuscular volume was > ULN.
Laboratory Parameter*	Lynparza tablets n†= 205		Chemotherapy n†= 91
Laboratory Parameter*	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Decrease in hemoglobin	82	17	66	3
Decrease in lymphocytes	73	21	63	3
Decrease in leukocytes	71	8	70	23
Increase in mean corpuscular volume‡	71	-	33	-
Decrease in absolute neutrophil count	46	11	65	38
Decrease in platelets	33	3	28	0

First-line Maintenance Treatment of Germline BRCA-mutated Metastatic Pancreatic Adenocarcinoma

POLO

The safety of Lynparza as maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma following first-line treatment with platinum-based chemotherapy was evaluated in POLO [see Clinical Studies (14.6)]. Patients received Lynparza tablets 300 mg orally twice daily (n=90) or placebo (n=61) until disease progression or unacceptable toxicity. Among patients receiving Lynparza, 34% were exposed for 6 months or longer and 25% were exposed for greater than one year.

Among patients who received Lynparza, dosage interruptions due to an adverse reaction of any grade occurred in 35% and dosage reductions due to an adverse reaction occurred in 17%. The most frequent adverse reactions leading to dosage interruption or reduction in patients who received Lynparza were anemia (11%), vomiting (5%), abdominal pain (4%), asthenia (3%), and fatigue (2%). Discontinuation due to adverse reactions occurred in 6% of patients receiving Lynparza. The most frequent adverse reaction that led to discontinuation of Lynparza was fatigue (2.2%).

Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities in patients in POLO.

Table 12 Adverse Reactions* in POLO (Occurring in ≥10% of Patients who Received Lynparza)
Adverse Reaction	Lynparza tablets (n=91)†		Placebo (n=60)†
Adverse Reaction	All Grades (%)	Grades 3 – 4 (%)	All Grades (%)	Grades 3 – 4 (%)
* Graded according to NCI CTCAE, version 4.0. † 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. ‡ Includes asthenia and fatigue. § Includes abdominal pain, abdominal pain upper, and abdominal pain lower. ¶ Includes stomatitis and mouth ulceration. # Includes platelets count decreased and thrombocytopenia. Þ Includes neutropenia, febrile neutropenia, and neutrophil count decreased. ß Includes rash erythematous, rash macular, and rash maculo-papular. à Includes dyspnea and dyspnea exertional.
General Disorders and Administration Site Conditions
Fatigue‡	60	5	35	2
Gastrointestinal Disorders
Nausea	45	0	23	2
Abdominal pain§	34	2	37	5
Diarrhea	29	0	15	0
Constipation	23	0	10	0
Vomiting	20	1	15	2
Stomatitis¶	10	0	5	0
Blood and Lymphatic System Disorders
Anemia	27	11	17	3
Thrombocytopenia#	14	3	7	0
NeutropeniaÞ	12	4	8	3
Metabolism and Nutrition Disorders
Decreased appetite	25	3	7	0
Musculoskeletal and Connective Tissue Disorders
Back pain	19	0	17	2
Arthralgia	15	1	10	0
Skin and Subcutaneous Tissue Disorder
Rashß	15	0	5	0
Respiratory, Thoracic and Mediastinal Disorders
Dyspneaà	13	0	5	2
Infections and Infestations
Nasopharyngitis	12	0	3	0
Nervous System Disorders
Dysgeusia	11	0	5	0

Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza were cough (9%), abdominal pain upper (7%), blood creatinine increased (7%), dizziness (7%), headache (7%), dyspepsia (5%), leukopenia (5%), VTE (3%), hypersensitivity (2%), and lymphopenia (2%).

Table 13 Laboratory Abnormalities Reported in ≥25% of Patients in POLO
* Patients were allowed to enter POLO with hemoglobin ≥9 g/dL (CTCAE Grade 2) and other laboratory values of CTCAE Grade 1. † 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. ‡ Represents the proportion of subjects whose mean corpuscular volume was > ULN.
Laboratory Parameter*	Lynparza tablets n†=91		Placebo n†=60
Laboratory Parameter*	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Increase in serum creatinine	99	2	85	0
Decrease in hemoglobin	86	11	65	0
Increase in mean corpuscular volume‡	71	-	30	-
Decrease in lymphocytes	61	9	27	0
Decrease in platelets	56	2	39	0
Decrease in leukocytes	50	3	23	0
Decrease in absolute neutrophil count	25	3	10	0

HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer

PROfound

The safety of Lynparza as monotherapy was evaluated in patients with mCRPC and HRR gene mutations who have progressed following prior treatment with enzalutamide or abiraterone in PROfound [see Clinical Studies (14.7)]. This study was a randomized, open-label, multi-center study in which 386 patients received either Lynparza tablets 300 mg orally twice daily (n=256) or investigator’s choice of enzalutamide or abiraterone acetate (n=130) until disease progression or unacceptable toxicity. Among patients receiving Lynparza, 62% were exposed for 6 months or longer and 20% were exposed for greater than one year.

Fatal adverse reactions occurred in 4% of patients treated with Lynparza. These included pneumonia (1.2%), cardiopulmonary failure (0.4%), aspiration pneumonia (0.4%), intestinal diverticulum (0.4%), septic shock (0.4%), Budd-Chiari Syndrome (0.4%), sudden death (0.4%), and acute cardiac failure (0.4%).

Serious adverse reactions occurred in 36% of patients receiving Lynparza. The most frequent serious adverse reactions (≥2%) were anemia (9%), pneumonia (4%), pulmonary embolism (2%), fatigue/asthenia (2%), and urinary tract infection (2%).

Dose interruptions due to an adverse reaction of any grade occurred in 45% of patients receiving Lynparza; dose reductions due to an adverse reaction occurred in 22% of Lynparza patients. The most frequent adverse reactions leading to dose interruption of Lynparza were anemia (25%) and thrombocytopenia (6%) and the most frequent adverse reaction leading to reduction of Lynparza was anemia (16%). Discontinuation due to adverse reactions occurred in 18% of Lynparza. The adverse reaction that most frequently led to discontinuation of Lynparza was anemia (7%).

Tables 14 and 15 summarize the adverse reactions and laboratory abnormalities, respectively, in patients in PROfound.

Table 14 Adverse Reactions* Reported in ≥10% of Patients in PROfound
* Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. † Includes anemia and hemoglobin decreased. ‡ Includes platelet count decreased and thrombocytopenia.
Adverse Reactions	Lynparza tablets n=256		Enzalutamide or abiraterone n=130
Adverse Reactions	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Blood and lymphatic disorders
Anemia†	46	21	15	5
Thrombocytopenia‡	12	4	3	0
Gastrointestinal disorders
Nausea	41	1	19	0
Diarrhea	21	1	7	0
Vomiting	18	2	12	1
General disorders and administration site conditions
Fatigue (including asthenia)	41	3	32	5
Metabolism and nutrition disorders
Decreased appetite	30	1	18	1
Respiratory, thoracic, and mediastinal disorders
Cough	11	0	2	0
Dyspnea	10	2	3	0

Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza were neutropenia (9%), VTE (7%), dizziness (7%), dysgeusia (7%), dyspepsia (7%), headache (6%), pneumonia (5%), stomatitis (5%), rash (4%), blood creatinine increase (4%), pneumonitis (2%), upper abdominal pain (2%), and hypersensitivity (1%).

Table 15 Laboratory Abnormalities Reported in ≥25% of Patients in PROfound
* Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. † 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.
Laboratory Parameter*	Lynparza tablets n†= 256		Enzalutamide or abiraterone n†=130
Laboratory Parameter*	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Decrease in hemoglobin	98	13	73	4
Decrease in lymphocytes	62	23	34	13
Decrease in leukocytes	53	4	21	0
Decrease in absolute neutrophil count	34	3	9	0

Treatment of BRCA-mutated Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone

PROpel

The safety of Lynparza in combination with abiraterone and prednisone or prednisolone for the treatment of patients in the first-line mCRPC setting was investigated in PROpel [see Clinical Studies (14.8)]. Patients were randomized to receive either Lynparza tablets 300 mg orally twice daily plus abiraterone tablets 1000 mg once daily (Lynparza/abiraterone) (n=398), or placebo plus abiraterone 1000 mg once daily (placebo/abiraterone) (n=396) until disease progression or unacceptable toxicity. Patients in both arms also received either prednisone or prednisolone 5 mg twice daily.

Fatal adverse reactions occurred in 6% of patients, including COVID-19 (3%) and pneumonias (0.5%).

Serious adverse reactions occurred in 39% of patients. Serious adverse reactions reported in > 2% of patients included anemia (6%), COVID-19 (6%), pneumonia (4.5%), pulmonary embolism (3.5%), and urinary tract infection (3%).

Permanent discontinuation of Lynparza due to adverse reactions occurred in 16% of patients treated in the Lynparza with abiraterone arm. The most common adverse reactions which resulted in permanent discontinuation of Lynparza were anemia (4.3%) and pneumonia (1.5%).

Dosage interruption of Lynparza due to adverse reactions occurred in 48% of patients treated in the Lynparza with abiraterone arm. The most common (>2%) adverse reactions requiring dosage interruption of Lynparza were anemia (16%), COVID-19 (6%) fatigue (3.5%), nausea (2.8%), pulmonary embolism (2.3%), and diarrhea (2.3%).

Dose reduction of Lynparza due to adverse reactions occurred in 21% of patients treated in the Lynparza with abiraterone arm. The most common (>2%) adverse reactions requiring dosage reductions of Lynparza were anemia (11%) and fatigue (2.5%).

The most common adverse reactions (≥10%) in patients who received Lynparza/abiraterone were anemia (48%), fatigue (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), abdominal pain (13%), and dizziness (14%).

Tables 16 and 17 summarize adverse reactions and laboratory abnormalities in PROpel, respectively.

Table 16 Adverse Reactions (≥10%) in Patients Who Received Lynparza (with a Difference of ≥5% Compared to Placebo) in PROpel
* Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. † Includes anemia, anemia macrocytic, and red blood cell count decreased ‡ Includes lymphocyte count decreased and lymphopenia § Includes abdominal discomfort, abdominal pain, abdominal pain upper, and abdominal pain lower ¶ Includes dizziness and vertigo.
Adverse Reactions*	Lynparza/abiraterone n=398		Placebo/abiraterone n=396
Adverse Reactions*	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Blood and Lymphatic Disorders
Anemia†	48	16	18	3.3
Lymphopenia‡	14	5	6	1.8
General Disorders and Administration Site Conditions
Fatigue (including asthenia)	38	2.3	30	1.5
Gastrointestinal Disorders
Nausea	30	0.3	14	0.3
Diarrhea	19	1	10	0.3
Abdominal pain§	13	0	7	0.5
Metabolism and nutrition disorders
Decreased appetite	16	1	7	0
Nervous System Disorders
Dizziness¶	14	0.3	7	0

Clinically relevant adverse reactions that occurred in <10% for patients receiving Lynparza plus abiraterone were headache (9%), VTE (8%), rash (7%), dysgeusia (6%), acute kidney injury (3%), and stomatitis (2.5%).

Table 17 Selected Laboratory Abnormalities Reported in ≥20% of Patients in PROpel
* 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.
Laboratory Parameter	Lynparza/abiraterone n=398*		Placebo/abiraterone n=396*
Laboratory Parameter	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Decrease in hemoglobin	97	12	81	1.3
Decrease in lymphocytes	70	23	49	11
Decrease in platelets	23	1.2	20	0.3
Decrease in absolute neutrophil count	23	5	6	0

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Lynparza. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Hypersensitivity including angioedema.

Skin and subcutaneous tissue disorders: Erythema nodosum, rash, dermatitis.