Lynparza

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Description for Lynparza

Olaparib is an inhibitor of the mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme.

The chemical name is 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4- fluorophenyl)methyl]phthalazin-1(2H)-one and it has the following chemical structure:

The empirical molecular formula for Lynparza is C₂₄H₂₃FN₄O₃ and the relative molecular mass is 434.46.

Olaparib is a crystalline solid, is non-chiral and shows pH-independent low solubility across the physiological pH range.

Lynparza tablets for oral administration contain 100 mg or 150 mg of olaparib. Inactive ingredients in the tablet core are copovidone, mannitol, colloidal silicon dioxide and sodium stearyl fumarate. The tablet coating consists of hypromellose, polyethylene glycol 400, titanium dioxide, ferric oxide yellow and ferrosoferric oxide (150 mg tablet only).

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)]
• Hepatotoxicity, Including Drug-Induced Liver Injury [see Warnings and Precautions (5.4)]

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 or as part of a combination regimen (SOLO-1, SOLO-2, PAOLA-1, OlympiA, OlympiAD, POLO, PROfound, and PROpel) in 2851 patients that were pooled to conduct safety analyses.

Additional data 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 this pooled single agent 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 single agent 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)

Adverse Reaction	Lynparza tablets n=260		Placebo n=130
	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
Thrombocytopenia?	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
* 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. ? Includes platelet count decreased and thrombocytopenia. à Includes urosepsis, urinary tract infection, urinary tract pain, and pyuria. è Includes dyspnea and dyspnea exertional.

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%), pneumonitis (1.9%), dermatitis (1%), and increased mean cell volume (0.4%).

Table 3 Laboratory Abnormalities Reported in ≥25% of Patients in SOLO-1

Laboratory Parameter*	Lynparza tablets n†=260		Placebo n†=130
	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
* 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.

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

Adverse Reactions	Lynparza/bevacizumab n=535		Placebo/bevacizumab n=267
	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
* 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.

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%), pneumonitis (0.9%), 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^*

Laboratory Parameter†	Lynparza/bevacizumab n†=535		Placebo/bevacizumab n‡=267
	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
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
* 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.

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)

Adverse Reaction	Lynparza tablets n=195		Placebo n=99
	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
* 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.

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%), pneumonitis (1%), and lymphopenia (1%).

Table 7 Laboratory Abnormalities Reported in ≥25% of Patients in SOLO-2

Laboratory Parameter*	Lynparza tablets n†=195		Placebo n †=99
	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
* 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).

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)

Adverse Reactions	Lynparza tablets n=911		Placebo n=904
	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
* 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.

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%), pneumonitis (0.8%), 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

Laboratory Parameter*	Lynparza tablets n†= 911		Placebo n †= 904
	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
* 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.

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)

Adverse Reaction	Lynparza tablets n=205		Chemotherapy n=91
	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
* 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.

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

Laboratory Parameter*	Lynparza tablets n†= 205		Chemotherapy n†= 91
	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
* 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.

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)†
	All Grades (%)	Grades 3 – 4 (%)	All Grades (%)	Grades 3 – 4 (%)
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
Rash?	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
* 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. ? Includes rash erythematous, rash macular, and rash maculo-papular. à Includes dyspnea and dyspnea exertional.

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%), lymphopenia (2%), and pneumonitis (1.1%).

Table 13 Laboratory Abnormalities Reported in ≥25% of Patients in POLO

Laboratory Parameter*	Lynparza tablets n†=91		Placebo n†=60
	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
* 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.

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

Adverse Reactions	Lynparza tablets n=256		Enzalutamide or abiraterone n=130
	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
* 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.

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

Laboratory Parameter*	Lynparza tablets n†= 256		Enzalutamide or abiraterone n†=130
	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
* 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.

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%), dizziness (14%), and abdominal pain (13%).

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

Adverse Reactions*	Lynparza/abiraterone n=398		Placebo/abiraterone n=396
	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
* 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.

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%), stomatitis (2.5%), and pneumonitis (1%).

Table 17 Selected Laboratory Abnormalities Reported in ≥20% of Patients in PROpel

Laboratory Parameter	Lynparza/abiraterone n=398*		Placebo/abiraterone n=396*
	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
* 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.

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.

Hepatobiliary Disorders: Drug-induced liver injury.

Immune System Disorders: Hypersensitivity including angioedema.

Skin and Subcutaneous Tissue Disorders: Erythema nodosum, rash, dermatitis.

Drug Interactions for Lynparza

Use with Anticancer Agents

Clinical studies of Lynparza with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

Effect of Other Drugs on Lynparza

Strong and Moderate CYP3A Inhibitors

Coadministration of CYP3A inhibitors can increase olaparib concentrations, which may increase the risk for adverse reactions [see Clinical Pharmacology (12.3)]. Avoid coadministration of strong or moderate CYP3A inhibitors. If the strong or moderate inhibitor must be coadministered, reduce the dose of Lynparza [see Dosage and Administration (2.4)].

Strong and Moderate CYP3A Inducers

Concomitant use with a strong or moderate CYP3A inducer decreased olaparib exposure, which may reduce Lynparza efficacy [see Clinical Pharmacology (12.3)]. Avoid coadministration of strong or moderate CYP3A inducers.

Warnings for Lynparza

Included as part of the PRECAUTIONS section.

Precautions for Lynparza

Myelodysplastic Syndrome/Acute Myeloid Leukemia

Myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML) has occurred in patients treated with Lynparza and some cases were fatal.

In clinical studies, among 2219 patients with various BRCAm, gBRCAm, HRR gene-mutated or HRD- positive cancers who received Lynparza as a single agent or as part of combination regimen, consistent with approved indications, the cumulative incidence of MDS/AML was approximately 1.2% (26/2219) [see Adverse Reactions (6.1)]. Of these, 54% (14/26) had a fatal outcome. The median duration of therapy with Lynparza in patients who developed MDS/AML was approximately 2 years (range: < 6 months to > 4 years). All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy.

In SOLO1, patients with newly diagnosed advanced BRCAm ovarian cancer, the incidence of MDS/AML was 1.9% (5/260) in patients who received Lynparza and 0.8% (1/130) in patients who received placebo based on an updated analysis. In PAOLA-1, of patients with newly diagnosed advanced ovarian cancer with HRD-positive status, the incidence of MDS/AML was 1.6% (4/255) in patients who received Lynparza and 2.3% (3/131) in the control arm.

In SOLO2, patients with BRCAm platinum-sensitive relapsed ovarian cancer, the incidence of MDS/AML was 8% (15/195) in patients who received Lynparza and 4% (4/99) in patients who received placebo. The duration of Lynparza treatment prior to the diagnosis of MDS/AML ranged from 0.6 years to 4.5 years.

Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (£ Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza.

Pneumonitis

Pneumonitis, including severe and fatal cases, has occurred in patients treated with Lynparza.

In clinical studies, among patients who received Lynparza as a single agent or as part of a combination regimen [see Adverse Reactions (6.1)], the incidence of pneumonitis, including fatal cases, was 1.0% (29/2851).

If patients present with new or worsening respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, interrupt Lynparza treatment and promptly assess the source of the symptoms. If pneumonitis is confirmed, discontinue Lynparza treatment and treat the patient appropriately.

Venous Thromboembolism

Venous thromboembolism (VTE), including severe or fatal pulmonary embolism (PE), occurred in patients treated with Lynparza [see Adverse Reactions (6.1)].

In the combined data of two randomized, placebo-controlled clinical studies (PROfound and PROpel) in patients with metastatic castration-resistant prostate cancer (N=1180), VTE occurred in 8% of patients who received Lynparza, including pulmonary embolism in 6%. In the control arms, VTE occurred in 2.5% including pulmonary embolism in 1.5%.

Monitor patients for clinical signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.

Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Lynparza [see Adverse Reactions (6.2)].

Evaluate bilirubin and transaminases at baseline and throughout treatment with Lynparza. For patients who develop abnormal liver tests after Lynparza, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity.

If DILI is suspected, withhold Lynparza. Upon confirmation of DILI, discontinue Lynparza.

Embryo-Fetal Toxicity

Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. In an animal reproduction study, administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 300 mg twice daily. Apprise pregnant women of the potential hazard to a fetus and the potential risk for loss of the pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Lynparza. Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Lynparza [see Use in Specific Populations(8.1,8.3)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with olaparib.

Olaparib was clastogenic in an in vitro chromosomal aberration assay in mammalian Chinese hamster ovary (CHO) cells and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of olaparib and indicates potential for genotoxicity in humans. Olaparib was not mutagenic in a bacterial reverse mutation (Ames) test.

In a fertility study, female rats received oral olaparib at doses of 0.05, 0.5, and 15 mg/kg/day for at least 14 days before mating through the first week of pregnancy. There were no adverse effects on mating and fertility rates at doses up to 15 mg/kg/day (maternal systemic exposures approximately 7% of the human exposure (AUC0-24h) at the recommended dose).

In a male fertility study, olaparib had no effect on mating and fertility in rats at oral doses up to

40 mg/kg/day following at least 70 days of olaparib treatment (with systemic exposures of approximately 5% of the human exposure (AUC0-24h) at the recommended dose).

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

MDS/AML

Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza [see Warnings and Precautions (5.1)].

Pneumonitis

Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see Warnings and Precautions(5.2)].

Venous Thromboembolism

Advise patients to immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia [see Warnings andPrecautions (5.3)].

Hepatotoxicity, Including Drug-Induced Liver Injury

Inform patients that liver problems, including drug-induced liver injury and abnormalities in liver tests, may develop during Lynparza treatment. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.4)].

Embryo-Fetal Toxicity

Inform pregnant women of the risk to a fetus and potential loss of the pregnancy. Advise females to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for 6 months after the last dose [see Use in Specific Populations (8.3)].

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months after receiving the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza [see Warnings and Precautions (5.5) and Use in Specific Populations (8.3)].

Lactation

Advise patients not to breastfeed while taking Lynparza and for one month after receiving the last dose [see Use in Specific Populations (8.2)].

Drug Interactions

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice while taking Lynparza [see Drug Interactions (7.2)].

Nausea/Vomiting

Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options [see Adverse Reactions (6.1)].

OVERDOSAGE

No information provided

Contraindications for Lynparza

No information provided

Clinical Pharmacology for Lynparza

Mechanism of Action

Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular functions, such as DNA transcription and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer, both as monotherapy or following platinum- based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA1/2, ATM, or other genes involved in the homologous recombination repair (HRR) of DNA damage and correlated with platinum response. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death. In prostate cancer models, PARP1 has been shown to contribute to androgen receptor (AR) activity regulation; the combination of olaparib and AR inhibition resulted in cytotoxicity in vitro and anti-tumor activity in mouse xenograft models.

Pharmacodynamics

Cardiac Electrophysiology

The effect of olaparib on cardiac repolarization was assessed in 119 patients following a single dose of 300 mg and in 109 patients following multiple dosing of 300 mg twice daily. No clinically relevant effect of olaparib on QT interval was observed.

Pharmacokinetics

The area under the curve (AUC) of olaparib increases approximately proportionally following administration of single doses of 25 mg to 450 mg (0.08 to 1.5 times the recommended dose) and maximal concentrations (Cmax) increased slightly less than proportionally for the same dose range. Olaparib showed time-dependent pharmacokinetics and an AUC mean accumulation ratio of 1.8 is observed at steady state following a dose of 300 mg twice daily.

The mean (CV%) olaparib Cmax is 5.4 μg/mL (32%) and AUC is 39.2 μg*h/mL (44%) following a single 300 mg dose. The mean steady state olaparib Cmax and AUC is 7.6 μg/mL (35%) and 49.2 μg*h/mL (44%), following a dose of 300 mg twice daily.

Absorption

Following oral administration of olaparib, the median time to peak plasma concentration is 1.5 hours.

Effect of Food

Co-administration of a high fat and high calorie meal (800-1000 kcal, 50% of the calorie content made up from fat) with olaparib slowed the rate (tmax delayed by 2.5 hours) of absorption, but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 8%).

Distribution

The mean (± standard deviation) apparent volume of distribution of olaparib is 158 ± 136 L following a single 300 mg dose of Lynparza. The protein binding of olaparib is approximately 82% in vitro.

Elimination

The mean (± standard deviation) terminal plasma half-life of olaparib is 14.9 ± 8.2 hours and the apparent plasma clearance is 7.4 ± 3.9 L/h following a single 300 mg dose of Lynparza.

Metabolism

Olaparib is metabolized by cytochrome P450 (CYP) 3A in vitro.

Following an oral dose of radiolabeled olaparib to female patients, unchanged olaparib accounted for 70% of the circulating radioactivity in plasma. It was extensively metabolized with unchanged drug accounting for 15% and 6% of radioactivity in urine and feces, respectively. The majority of the metabolism is attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation.

Excretion

Following a single dose of radiolabeled olaparib, 86% of the dosed radioactivity was recovered within a 7-day collection period, 44% via the urine and 42% via the feces. The majority of the material was excreted as metabolites.

Specific Populations

Patients with Renal Impairment

In a renal impairment trial, the mean AUC increased by 24% and Cmax by 15%, when olaparib was dosed in patients with mild renal impairment (CLcr=51-80 mL/min defined by the Cockcroft-Gault equation; n=13) and by 44% and 26%, respectively, when olaparib was dosed in patients with moderate renal impairment (CLcr=31-50 mL/min; n=13), compared to those with normal renal function (CLcr ≥81 mL/min; n=12). There was no evidence of a relationship between the extent of plasma protein binding of olaparib and creatinine clearance. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

Patients with Hepatic Impairment

In a hepatic impairment trial, the mean AUC increased by 15% and the mean Cmax increased by 13% when olaparib was dosed in patients with mild hepatic impairment (Child-Pugh classification A; n=10) and the mean AUC increased by 8% and the mean Cmax decreased by 13% when olaparib was dosed in patients with moderate hepatic impairment (Child-Pugh classification B; n=8), compared to patients with normal hepatic function (n=13). Hepatic impairment has no effect on the protein binding of olaparib and, therefore, total plasma exposure was representative of free drug. There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Drug Interaction Studies

Clinical Studies

CYP3A Inhibitors: Concomitant use of itraconazole (strong CYP3A inhibitor) increased olaparib Cmax by 42% and AUC by 170%. Concomitant use of fluconazole (moderate CYP3A inhibitor) is predicted to increase olaparib Cmax by 14% and AUC by 121%.

CYP3A Inducers: Concomitant use of rifampicin (strong CYP3A inducer) decreased olaparib Cmax by 71% and AUC by 87%. Concomitant use of efavirenz (moderate CYP3A inducer) is predicted to decrease olaparib Cmax by 31% and AUC by 60%.

In vitro Studies

CYP Enzymes: Olaparib is both an inhibitor and inducer of CYP3A and an inducer of CYP2B6. Olaparib is predicted to be a weak CYP3A inhibitor in humans.

UGT Enzymes: Olaparib is an inhibitor of UGT1A1.

Transporters: Olaparib is an inhibitor of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1, and MATE2K. Olaparib is a substrate and inhibitor of the efflux transporter P-gp. The potential for olaparib to induce P-gp has not been evaluated.

Medication Guide
Lynparza^® (Lin-par-zah)
(olaparib)
tablets

What is the most important information I should know about Lynparza? Lynparza may cause serious side effects, including:

• Bone marrow problems called Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Some people who have received previous treatment with chemotherapy, radiotherapy or certain other medicines for their cancer have developed MDS or AML during treatment with Lynparza. MDS or AML may lead to death.
  Symptoms of low blood cell counts are common during treatment with Lynparza, but can be a sign of serious bone marrow problems, including MDS or AML. Symptoms may include:

• weakness weight loss fever frequent infections

  blood in urine or stool shortness of breath feeling very tired bruising or bleeding more easily

  Your healthcare provider will do blood tests to check your blood cell counts:

  • before treatment with Lynparza
  • every month during treatment with Lynparza
  • weekly if you have low blood cell counts that last a long time.
• Lung problems (Pneumonitis). Lynparza can cause serious lung problems that can lead to Tell your healthcare provider if you have any new or worsening symptoms of lung problems, including shortness of breath, fever, cough, or wheezing. Your healthcare provider may do a chest x-ray if you have any of these symptoms.
• Blood clots (Venous Thromboembolism, [VTE]). Some people may develop a blood clot in a deep vein, usually in the leg (venous thrombosis), or a clot in the lungs (pulmonary embolism, [PE]) which may be severe or lead to death. Tell your healthcare provider right away if you have any symptoms such as pain or swelling in an extremity, shortness of breath, chest pain, breathing that is more rapid than normal (tachypnea), or heart beats faster than normal (tachycardia). Your healthcare provider will monitor you for these symptoms and may prescribe blood thinner medicine.
• Liver problems, including Drug-Induced Liver Injury (DILI). People taking Lynparza may develop liver problems which may be severe and can lead to death. Your healthcare provider should do blood tests before and during your treatment with Lynparza. Tell your healthcare provider right away if you notice discomfort on the right side of your stomach-area (abdominal), dark or “tea-colored” urine, or yellowing of your skin or the whites of your eyes (jaundice).

Your healthcare provide may change your dose, temporarily stop, or permanently stop treatment with Lynparza if you get certain side effects.

See “What are the possible side effects of LYNPARZA?” for more information about side effects.

What is Lynparza?

Lynparza is a prescription medicine used to treat adults who have:

• ovarian, fallopian tube, or primary peritoneal cancer:
  • that is advanced and has a certain type of inherited (germline) or acquired (somatic) abnormal BRCA Lynparza is used as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy.
  • in combination with another anti-cancer medicine called bevacizumab when your cancer is advanced and homologous recombination deficiency (HRD) positive, which is identified by a certain type of abnormal BRCA gene or a positive laboratory tumor test for genomic instability. 

    Lynparza is used as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy.

  • that has come back and has a certain type of inherited or acquired abnormal BRCA gene. Lynparza is used as maintenance treatment after the cancer has responded to treatment with platinum-based chemotherapy.
• human epidermal growth factor receptor 2 (HER2)-negative breast cancer with a certain type of inherited abnormal BRCA gene:
  • with a high risk of Lynparza is given after surgery (treatment after surgery is called adjuvant therapy). You should have received chemotherapy medicines before or after surgery to remove the tumor.
  • that has spread to other parts of the body (metastatic). You should have received chemotherapy medicines, either before or after your cancer has If you have hormone receptor (HR)-positive breast cancer, you should have either already received hormonal therapy or hormonal therapy is not the right treatment for you.
• pancreatic cancer (adenocarcinoma) that has spread to other parts of the body and has a certain type of abnormal inherited BRCA Lynparza is used as maintenance treatment after your cancer has not progressed on at least 16 weeks of your first treatment with platinum-based chemotherapy.
• metastatic castration-resistant prostate cancer (mCRPC):
  • with a certain type of inherited or acquired abnormal homologous recombination repair (HRR) genes. Lynparza is used when the cancer has spread to other parts of the body and no longer responds to a medical or surgical treatment that lowers testosterone and has progressed after treatment with other anti-cancer medicines called enzalutamide or abiraterone.
  • with a certain type of abnormal BRCA gene, and the cancer has spread to other parts of the body and no longer responds to a medical or surgical treatment that lowers testosterone. Lynparza is used in combination with another anti-cancer medicine, abiraterone, together with the steroid medicine prednisone or prednisolone.

Your healthcare provider will perform a test to make sure that Lynparza is right for you.

It is not known if Lynparza is safe and effective in children.

Before taking Lynparza, tell your healthcare provider about all of your medical conditions,

including if you:

• have lung or breathing problems
• have kidney problems
• are pregnant, become pregnant, or plan to become Lynparza can harm your unborn baby and may cause loss of pregnancy (miscarriage).
  Females who are able to become pregnant:
• • Your healthcare provider may do a pregnancy test before you start treatment with Lynparza.
  • You should use effective birth control (contraception) during treatment with Lynparza and for 6 months after the last dose of Lynparza. Talk to your healthcare provider about birth control methods that may be right for you.
  • Tell your healthcare provider right away if you become pregnant or think you might be pregnant following treatment with Lynparza.

  Males with female partners who are pregnant or able to become pregnant:

  • You should use effective contraception during treatment with Lynparza and for 3 months after the last dose of Lynparza.
  • Do not donate sperm during treatment with Lynparza and for 3 months after your last dose.
• are breastfeeding or plan to breastfeed. It is not known if Lynparza passes into your breast milk. Do not breastfeed during treatment with Lynparza and for 1 month after receiving the last dose of Lynparza. Talk to your healthcare provider about the best way to feed your baby during this time.

Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements. Taking Lynparza and certain other medicines may affect how Lynparza works and may cause side effects.

How should I take Lynparza?

• Take Lynparza tablets exactly as your healthcare provider tells you.
• Your healthcare provider will decide how long you stay on treatment.
• Do not change your dose or stop taking Lynparza unless your healthcare provider tells you to.
• Take Lynparza by mouth 2 times a day, with or without food.
• Each dose should be taken about 12 hours apart.
• Swallow Lynparza tablets Do not chew, crush, dissolve, or divide the tablets.
• If you are taking Lynparza for early breast cancer and you have HR-positive disease, you should continue to take hormonal therapy during your treatment with Lynparza.
• If you are taking Lynparza for prostate cancer and you are receiving gonadotropin-releasing hormone (GnRH) analog therapy, you should continue with this treatment during your treatment with Lynparza unless you have had a surgery to remove both of your testicles (surgical castration) to lower the amount of testosterone in your body.
• If you miss a dose of Lynparza, take your next dose at your usual scheduled Do not take an extra dose to make up for a missed dose.
• If you take too much Lynparza, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking Lynparza?

Avoid grapefruit, grapefruit juice, Seville oranges and Seville orange juice during treatment with Lynparza since they may increase the level of Lynparza in your blood.

What are the possible side effects of Lynparza? Lynparza may cause serious side effects.

• See “What is the most important information I should know about Lynparza?”
  The most common side effects of Lynparza when used alone are

  tiredness or weakness low red blood cell counts diarrhea loss of appetite headache changes in the way food tastes

  cough low white blood cell counts shortness of breath dizziness indigestion or heartburn low platelet counts

  The most common side effects of Lynparza when used in combination with bevacizumab are:

  tiredness or weakness low red blood cell counts diarrhea

  low white blood cell counts urinary tract infection headache

  The most common side effects of Lynparza when used in combination with abiraterone and prednisone or prednisolone are:

  low red blood cell counts tiredness or weakness diarrhea loss of appetite

  low white blood cell counts dizziness stomach-area (abdominal) pain

  Nausea or vomiting is common during treatment with Lynparza. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms. These are not all of the possible side effects of Lynparza.

  Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

  How should I store Lynparza?

  • Store Lynparza at room temperature, between 68°F to 77°F (20°C to 25°C).
  • Store Lynparza in the original bottle to protect it from

  Keep Lynparza and all medicines out of reach of children.

  General information about the safe and effective use of Lynparza.

  Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Lynparza for a condition for which it was not prescribed. Do not give Lynparza to other people, even if they have the same symptoms that you have. It may harm them.

  You can ask your pharmacist or healthcare provider for information about Lynparza that is written for health professionals

  What are the ingredients in Lynparza?

  Active ingredient: olaparib

  Inactive ingredients:

  Tablet contains: copovidone, mannitol, colloidal silicon dioxide and sodium stearyl fumarate

  Tablet coating contains: hypromellose, polyethylene glycol 400, titanium dioxide, ferric oxide yellow and ferrosoferric oxide (150 mg tablet only)

  Lynparza is a registered trademark of the AstraZeneca group of companies.

  © AstraZeneca 2025 Distributed by:

  AstraZeneca Pharmaceuticals LP Wilmington, DE 19850

  For more information, call 1-800-236-9933 or go to www.Lynparza.com.

  This Medication Guide has been approved by the U.S. Food and Drug Administration.