ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere in the labeling:oMyelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)]oPneumonitis [see Warnings and Precautions (5.2)]oVenous Thromboembolic Events [see Warnings and Precautions (5.4)]. oMyelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)]. oPneumonitis [see Warnings and Precautions (5.2)]. oVenous Thromboembolic Events [see Warnings and Precautions (5.4)]. Most common adverse reactions (>=10%) in clinical trials:oas single agent were nausea, fatigue (including asthenia), anemia, vomiting, diarrhea, decreased appetite, headache, dysgeusia, cough, neutropenia, dyspnea, dizziness, dyspepsia, leukopenia, and thrombocytopenia. (6.1)oin combination with bevacizumab were nausea, fatigue (including asthenia), anemia, lymphopenia, vomiting, diarrhea, neutropenia, leukopenia, urinary tract infection, and headache. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oas single agent were nausea, fatigue (including asthenia), anemia, vomiting, diarrhea, decreased appetite, headache, dysgeusia, cough, neutropenia, dyspnea, dizziness, dyspepsia, leukopenia, and thrombocytopenia. (6.1). oin combination with bevacizumab were nausea, fatigue (including asthenia), anemia, lymphopenia, vomiting, diarrhea, neutropenia, leukopenia, urinary tract infection, and headache. (6.1). 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described in the WARNINGS AND PRECAUTIONS reflect exposure to Lynparza as 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 these trials, 56% of patients were exposed for 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 CancerSOLO-1The 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 and summarize adverse reactions and laboratory abnormalities in SOLO-1.Table Adverse ReactionsGraded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. in SOLO-1 (>=10% of Patients Who Received Lynparza)Adverse ReactionLynparza tabletsn=260Placebon=130All Grades(%)Grades3 4 (%)AllGrades(%)Grades3 4 (%)Gastrointestinal Disorders Nausea771380 Abdominal painIncludes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal distension, abdominal discomfort, and abdominal tenderness. 452351 Vomiting400151 DiarrheaIncludes colitis, diarrhea, and gastroenteritis. 373260 Constipation280190 Dyspepsia170120 StomatitisIncludes stomatitis, aphthous ulcer; and mouth ulceration. 11020General Disorders and Administration Site Conditions FatigueIncludes asthenia, fatigue, lethargy, and malaise. 674422Blood and Lymphatic System Disorders Anemia382192 NeutropeniaIncludes neutropenia, and febrile neutropenia. 17673 LeukopeniaIncludes leukopenia, and white blood cell count decreased. 13380 ThrombocytopeniaIncludes platelet count decreased, and thrombocytopenia. 11142Infections and Infestations Upper respiratory tract infection/ influenza/ nasopharyngitis/bronchitis 280230 UTIIncludes urosepsis, urinary tract infection, urinary tract pain, and pyuria. 13170Nervous System Disorders Dysgeusia26040 Dizziness200151Metabolism and Nutrition Disorders Decreased appetite200100Respiratory, Thoracic and Mediastinal Disorders DyspneaIncludes dyspnea, and dyspnea exertional. 15060In addition, the adverse reactions observed in SOLO-1 that occurred in <10% of patients receiving Lynparza were increased blood creatinine (8%), lymphopenia (6%), hypersensitivity (2%), MDS/AML (1%), dermatitis (1%), and increased mean cell volume (0.4%).Table Laboratory Abnormalities Reported in >=25% of Patients in SOLO-1Laboratory ParameterPatients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. Lynparza tabletsnThis number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.=260Placebon=130Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Decrease in hemoglobin8719632Increase in mean corpuscular volume87-43-Decrease in leukocytes707521Decrease in lymphocytes6714295Decrease in absolute neutrophil count519386Decrease in platelets351202Increase in serum creatinine340180First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with BevacizumabPAOLA-1The 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 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 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%). Tables and summarize adverse reactions and laboratory abnormalities in PAOLA-1, respectively.Table Adverse ReactionsGraded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. Occurring in >=10% of Patients Treated with Lynparza/bevacizumab in PAOLA-1 and at >=5% Frequency Compared to the Placebo/bevacizumab ArmAdverse ReactionsLynparza/bevacizumabn=535Placebo/bevacizumab n=267Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)General Disorders and Administration Site Conditions Fatigue (including asthenia)Includes asthenia, and fatigue. 535321.5Gastrointestinal Disorders Nausea532.4220.7 Vomiting221.7111.9Blood and Lymphatic Disorders AnemiaIncludes anemia, anemia macrocytic, erythropenia, haematocrit decreased, haemoglobin decreased, normochromic anemia, normochromic normocytic anemia, normocytic anemia, and red blood cell count decreased. 4117100.4 LymphopeniaIncludes B-lymphocyte count decreased, lymphocyte count decreased, lymphopenia, and T-lymphocyte count decreased. 24791.1 LeukopeniaIncludes leukopenia, and white blood cell count decreased. 181.9101.5The 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%).The 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%).In addition, venous thromboembolic events occurred more commonly in patients receiving Lynparza/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).Table Laboratory Abnormalities Reported in >=25% of Patients in PAOLA-1Reported within 30 days of the last dose. Laboratory ParameterPatients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.Lynparza/bevacizumab n=535Placebo/bevacizumab nThis number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.=267Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Decrease in hemoglobin7913550.4Decrease in lymphocytes6310423.0Increase in serum creatinine610.4360.4Decrease in leukocytes593.4452.2Decrease in absolute neutrophil count357303.7Decrease in platelets352.4280.4Maintenance Treatment of Recurrent Ovarian CancerSOLO-2The 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 and summarize adverse reactions and laboratory abnormalities in SOLO-2.Table Adverse ReactionsGraded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. in SOLO-2 (>=20% of Patients Who Received Lynparza)Adverse ReactionLynparza tabletsn=195Placebon=99Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Gastrointestinal Disorders Nausea763330 Vomiting373191 Diarrhea332220 StomatitisRepresents 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. 201160General Disorders and Administration Site Conditions Fatigue including asthenia664392Blood and Lymphatic Disorders AnemiaRepresents grouped term consisting of anemia, hematocrit decreased, hemoglobin decreased, iron deficiency, mean cell volume increased and red blood cell count decreased. 442092Infections and Infestations Nasopharyngitis/URI/sinusitis/ rhinitis/influenza360290Musculoskeletal and Connective Tissue Disorders Arthralgia/myalgia300280Nervous System Disorders Dysgeusia27070 Headache261140Metabolism and Nutrition Disorders Decreased appetite220110In addition, the adverse reactions observed in SOLO-2 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%), and lymphopenia (1%).Table Laboratory Abnormalities Reported in >=25% of Patients in SOLO-2Laboratory ParameterPatients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.Lynparza tabletsnThis number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.=195Placebon=99Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Increase in mean corpuscular volumeRepresents the proportion of subjects whose mean corpuscular volume was upper limit of normal (ULN). 89-52-Decrease in hemoglobin8317690Decrease in leukocytes695481Decrease in lymphocytes6711371Decrease in absolute neutrophil count517343Increase in serum creatinine440290Decrease in platelets422221Study 19The safety of Lynparza as maintenance monotherapy was evaluated in patients with platinum sensitive ovarian cancer who had received or more previous platinum containing regimens in Study 19 [see Clinical Studies (14.3)]. Patients received Lynparza capsules 400 mg orally twice daily (n=136) or placebo (n=128). At the time of final analysis, the median duration of exposure was 8.7 months in patients who received Lynparza and 4.6 months in patients who received placebo.Adverse reactions led to dose interruptions in 35% of patients receiving Lynparza; dose reductions in 26% and discontinuation in 6% of patients receiving Lynparza.Tables and summarize adverse reactions and laboratory abnormalities in Study 19.Table Adverse ReactionsGraded according to NCI CTCAE v4.0. in Study 19 (>=20% of Patients Who Received Lynparza)Adverse ReactionLynparza capsulesn=136Placebon=128Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Gastrointestinal Disorders Nausea712360 Vomiting352141 Diarrhea282252 Constipation221120 Dyspepsia20090General Disorders and Administration Site Conditions Fatigue (including asthenia)639463Blood and Lymphatic Disorders AnemiaRepresents grouped terms of related terms that reflect the medical concept of the adverse reaction. 23771Infections and Infestations Respiratory tract infection222110Metabolism and Nutrition Disorders Decreased appetite210130Nervous System Disorders Headache210131In addition, the adverse reactions in Study 19 that occurred in <20% of patients receiving Lynparza were dysgeusia (16%), dizziness (15%), dyspnea (13%), pyrexia (10%), stomatitis (9%), edema (9%), increase in creatinine (7%), neutropenia (5%), thrombocytopenia (4%), leukopenia (2%), MDS/AML (1%) and lymphopenia (1%).Table Laboratory Abnormalities Reported in >=25% of Patients in Study 19Laboratory ParameterPatients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.Lynparza capsulesnThis number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.=136Placebon=129Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Decrease in hemoglobin828581Increase in mean corpuscular volumeRepresents the proportion of subjects whose mean corpuscular volume was ULN. 82-51-Decrease in leukocytes584372Decrease in lymphocytes5210323Decrease in absolute neutrophil count477402Increase in serum creatinine450140Decrease in platelets364180Advanced Germline BRCA-mutated Ovarian Cancer After or More Lines of ChemotherapyPooled DataThe safety of Lynparza was investigated in 223 patients (pooled from studies) with gBRCAm advanced ovarian cancer who had received or more prior lines of chemotherapy [see Clinical Studies (14.4)]. Patients received Lynparza capsules 400 mg orally twice daily until disease progression or unacceptable tolerability. The median exposure to Lynparza in these patients was 5.2 months.There were (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. Tables 10 and 11 summarize the adverse reactions and laboratory abnormalities from the pooled studies.Table 10 Adverse Reactions Reported in Pooled Data (>=20% of Patients Who Received Lynparza)Adverse ReactionLynparza capsulesn=223Grades 1-4(%)Grades 3-4(%)General Disorders Fatigue/asthenia668Gastrointestinal Disorders Nausea643 Vomiting434 Diarrhea311 Dyspepsia250 Decreased appetite221Blood and Lymphatic Disorders Anemia3418Infections and Infestations Nasopharyngitis/URI260Musculoskeletal and Connective Tissue Disorders Arthralgia/musculoskeletal pain210 Myalgia220Table 11 Laboratory Abnormalities Reported in >=25% of Patients in Pooled DataLaboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.Lynparza capsulesnThis number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.=223Grades 1-4(%)Grades 3-4(%)Decrease in hemoglobin 9015Mean corpuscular volume elevation57-Decrease in lymphocytes 5617Decrease in platelets 303Increase in creatinine302Decrease in absolute neutrophil count 257The following adverse reactions and laboratory abnormalities have been identified in >=10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough (16%), constipation (16%), dysgeusia (16%), headache (15%), peripheral edema (14%), back pain (14%), urinary tract infection (14%), dyspnea (13%), and dizziness (11%).The following adverse reactions and laboratory abnormalities have been identified in <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia (9%), pyrexia (8%), peripheral neuropathy (5%), hypomagnesemia (5%), rash (5%), stomatitis (4%), MDS/AML (1.8%), and venous thrombosis (including pulmonary embolism) (1%).Germline BRCA-mutated HER2-negative Metastatic Breast Cancer OlympiADThe 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 chemotherapy (capecitabine, eribulin, or vinorelbine) of the healthcare providers 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 12 and 13 summarize the adverse reactions and laboratory abnormalities in OlympiAD.Table 12 Adverse ReactionsGraded according to NCI CTCAE v4.0. in OlympiAD (>=20% of Patients Who Received Lynparza)Adverse ReactionLynparza tabletsn=205Chemotherapyn=91Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Gastrointestinal Disorders Nausea580351 Vomiting300151 Diarrhea211220Blood and Lymphatic Disorders AnemiaRepresents grouped terms consisting of anemia (anemia erythropenia, hematocrit decreased, hemoglobin decreased and red blood cell count decreased). 4016264 NeutropeniaRepresents grouped terms consisting of neutropenia (febrile neutropenia, granulocyte count decreased, granulocytopenia, neutropenia, neutropenic infection, neutropenic sepsis, and neutrophil count decreased). 2795026 LeukopeniaRepresents grouped terms consisting of leukopenia (leukopenia and white blood cell count decreased). 2553113General Disorders and Administration Site Conditions Fatigue (including asthenia)374361Infections and Infestations Respiratory tract infectionRepresents 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. 271220Nervous System Disorders Headache201152In addition, adverse reactions in OlympiAD 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%), and dermatitis (1%). Table 13 Laboratory Abnormalities Reported in >=25% of Patients in OlympiADLaboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.Lynparza tabletsnThis number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.= 205Chemotherapyn= 91Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Decrease in hemoglobin8217663Decrease in lymphocytes7321633Decrease in leukocytes7187023Increase in mean corpuscular volumeRepresents the proportion of subjects whose mean corpuscular volume was ULN. 71-33-Decrease in absolute neutrophil count46116538Decrease in platelets333280First-line Maintenance Treatment of Germline BRCA-mutated Metastatic Pancreatic AdenocarcinomaPOLOThe 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 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 14 and 15 summarize the adverse reactions and laboratory abnormalities in patients in POLO.Table 14 Adverse ReactionsGraded according to NCI CTCAE, version 4.0 in POLO (Occurring in >=10% of Patients who Received Lynparza)Adverse ReactionLynparza tablets(n=91)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. Placebo(n=60) All Grades(%)Grades3 4 (%)All Grades(%)Grades3 4 (%)General Disorders and Administration Site Conditions FatigueIncludes asthenia and fatigue 605352Gastrointestinal Disorders Nausea450232 Abdominal painIncludes abdominal pain, abdominal pain upper, abdominal pain lower 342375 Diarrhea290150 Constipation230100 Vomiting201152 StomatitisIncludes stomatitis and mouth ulceration 10050Blood and Lymphatic System Disorders Anemia2711173 ThrombocytopeniaIncludes platelets count decreased and thrombocytopenia 14370 NeutropeniaIncludes neutropenia, febrile neutropenia and neutrophil count decreased 12483Metabolism and Nutrition Disorders Decreased appetite25370Musculoskeletal and Connective Tissue Disorders Back pain190172 Arthralgia151100Skin and Subcutaneous Tissue Disorder RashIncludes rash erythematous, rash macular and rash maculo-papular 15050Respiratory, Thoracic and Mediastinal Disorders DyspneaIncludes dyspnea and dyspnea exertional 13052Infections and Infestations Nasopharyngitis12030Nervous System Disorders Dysgeusia11050In addition, the adverse reactions observed in POLO 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%), hypersensitivity (2%), and lymphopenia (2%).Table 15 Laboratory Abnormalities Reported in >=25% of Patients in POLOLaboratory ParameterPatients were allowed to enter POLO with hemoglobin >=9 g/dL (CTCAE Grade 2) and other laboratory values of CTCAE Grade 1. Lynparza tabletsnThis number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.=91Placebon=60Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Increase in serum creatinine992850Decrease in hemoglobin8611650Increase in mean corpuscular volumeRepresents the proportion of subjects whose mean corpuscular volume was ULN. 71-30-Decrease in lymphocytes619270Decrease in platelets562390Decrease in leukocytes503230Decrease in absolute neutrophil count253100HRR Gene-mutated Metastatic Castration-Resistant Prostate CancerPROfoundThe 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 randomized, open-label, multi-center study in which 386 patients received either Lynparza tablets 300 mg orally twice daily (n=256) or investigators choice of enzalutamide or abiraterone acetate (n=130) until disease progression or unacceptable toxicity. Among patients receiving Lynparza, 62% were exposed for 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 16 and 17 summarize the adverse reactions and laboratory abnormalities, respectively, in patients in PROfound.Table 16 Adverse ReactionsGraded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 Reported in >=10% of Patients in PROfoundAdverse ReactionsLynparza tabletsn=256Enzalutamide or abiraterone n=130Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Blood and lymphatic disorders AnemiaIncludes anemia and hemoglobin decreased 4621155 ThrombocytopeniaIncludes platelet count decreased and thrombocytopenia 12430Gastrointestinal disorders Nausea411190 Diarrhea21170 Vomiting182121General disorders and administration site conditions Fatigue (including asthenia)413325Metabolism and nutrition disorders Decreased appetite 301181Respiratory, thoracic, and mediastinal disorders Cough11020 Dyspnea10230In addition, adverse reactions of clinical relevance in PROfound that occurred in <10% of patients receiving Lynparza were neutropenia (9%), venous thromboembolic events (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 17 Laboratory Abnormalities Reported in >=25% of Patients in PROfoundLaboratoryParameterPatients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. Lynparza tabletsnThis number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.= 256Enzalutamide or abiraterone n=130Grades 1-4n=247 (%)Grades 3-4n=247 (%)Grades 1-4n=124 (%)Grades 3-4n=124 (%)Decrease in hemoglobin 242 (98)33 (13)91 (73)5 (4)Decrease in lymphocytes 154 (62)57 (23)42 (34)16 (13)Decrease in leukocytes130 (53)9 (4)26 (21)0Decrease in absolute neutrophil count83 (34)8 (3)11 (9)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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune System Disorders: Hypersensitivity including angioedema.Skin and subcutaneous tissue disorders: Erythema nodosum, rash, dermatitis.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 First-Line Maintenance Treatment of BRCA-mutated Advanced Ovarian Cancer The efficacy of Lynparza was evaluated in SOLO-1 (NCT01844986), randomized (2:1), double-blind, placebo-controlled, multi-center trial in patients with BRCA-mutated advanced ovarian, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy. Patients were randomized to receive Lynparza tablets 300 mg orally twice daily or placebo. Treatment was continued for up to years or until disease progression or unacceptable toxicity; however, patients with evidence of disease at years, who in the opinion of the treating healthcare provider could derive further benefit from continuous treatment, could be treated beyond years. Randomization was stratified by response to first-line platinum-based chemotherapy (complete or partial response). The major efficacy outcome was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.A total of 391 patients were randomized, 260 to Lynparza and 131 to placebo. The median age of patients treated with Lynparza was 53 years (range: 29 to 82) and 53 years (range: 31 to 84) among patients on placebo. The ECOG performance status (PS) was in 77% of patients receiving Lynparza and 80% of patients receiving placebo. Of all patients, 82% were White, 36% were enrolled in the U.S. or Canada, and 82% were in complete response to their most recent platinum-based regimen. The majority of patients (n=389) had germline BRCA mutation (gBRCAm), and patients had somatic BRCAm (sBRCAm). Of the 391 patients randomized in SOLO-1, 386 were retrospectively or prospectively tested with Myriad BRACAnalysis test and 383 patients were confirmed to have deleterious or suspected deleterious gBRCAm status; 253 were randomized to the Lynparza arm and 130 to the placebo arm. Two out of 391 patients randomized in SOLO-1 were confirmed to have sBRCAm based on an investigational Foundation Medicine tissue test.SOLO-1 demonstrated statistically significant improvement in investigator-assessed PFS for Lynparza compared to placebo. Results from blinded independent review were consistent. At the time of the analysis of PFS, overall survival (OS) data were not mature (21% of patients had died). Efficacy results are presented in Table 18 and Figure 1.Table 18 Efficacy Results SOLO-1 (Investigator Assessment)Lynparza tablets(n=260)Placebo(n=131)Progression-Free SurvivalMedian follow up of 41 months in both treatment arms. Number of events (%)102 (39%)96 (73%) Median, monthsNR13.8 Hazard ratioA value <1 favors olaparib. Hazard ratio from Cox proportional hazards model including response to previous platinum chemotherapy (complete response versus partial response) as covariate. (95% CI)0.30 (0.23, 0.41) p-valueThe p-value is derived from stratified log-rank test. <0.0001NR not reached; CI Confidence Interval.Figure Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival SOLO-1 Figure 1. 14.2 First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab PAOLA-1 (NCT02477644) was randomized, double-blind, placebo-controlled, multi-center trial that compared the efficacy of Lynparza in combination with bevacizumab versus placebo/bevacizumab for the maintenance treatment of advanced high-grade epithelial ovarian cancer, fallopian tube or primary peritoneal cancer following first-line platinum-based chemotherapy and bevacizumab. Randomization was stratified by first-line treatment outcome (timing and outcome of cytoreductive surgery and response to platinum-based chemotherapy) and tBRCAm status, determined by prospective local testing. All available clinical samples were retrospectively tested with Myriad myChoice(R) CDx. Patients were required to have no evidence of disease (NED) due to complete surgical resection, or who were in complete response (CR), or partial response (PR) following completion of first-line platinum-containing chemotherapy and bevacizumab. Patients were randomized (2:1) to receive Lynparza tablets 300 mg orally twice daily in combination with bevacizumab (n=537) 15 mg/kg every three weeks or placebo/bevacizumab (n=269) Patients continued bevacizumab in the maintenance setting and started treatment with Lynparza after minimum of weeks and up to maximum of weeks following completion of their last dose of chemotherapy. Lynparza treatment was continued for up to years or until progression of the underlying disease or unacceptable toxicity. Patients who in the opinion of the treating physician could derive further benefit from continuous treatment could be treated beyond years. Treatment with bevacizumab was for total of up to 15 months, including the period given with chemotherapy and given as maintenance. The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST, version 1.1. An additional efficacy endpoint was overall survival (OS).The median age of patients in both arms was 61 years overall (range 26 to 87). Ovarian cancer was the primary tumor type in 86% of patients in both arms. Ninety six percent (96%) were serous histological type. The ECOG performance score was in 70% of patients and in 28% of patients, overall. All patients had received first-line platinum-based therapy and bevacizumab. First-line treatment outcomes at screening indicated that patients had no evidence of disease with complete macroscopic resection at initial debulking surgery (32%, both arms), no evidence of disease/ CR with complete macroscopic resection at interval debulking surgery (31%, both arms), no evidence of disease/ CR in patients who had either incomplete resection (at initial or interval debulking surgery) or no debulking surgery (15%, both arms) and patients with partial response (22%, both arms). Thirty percent (30%) of patients in both arms had deleterious mutation. Patients were not restricted by the surgical outcome with 65% having complete cytoreduction at initial or interval debulking surgery and 35% having residual macroscopic disease. Demographics and baseline disease characteristics were balanced and comparable between the study and placebo arms in the Intention to Treat (ITT) population and also in the HRD-positive subgroup.Efficacy results from biomarker subgroup analysis of 387 patients with HRD-positive tumors, identified post-randomization using the Myriad myChoice(R) HRD Plus tumor test, who received Lynparza/bevacizumab (n=255) or placebo/bevacizumab (n=132), are summarized in Table 19 and Figure 2. Results from blinded independent review of PFS were consistent. Overall survival data in this subpopulation were immature with 16% deaths.Table 19 Efficacy Results PAOLA-1 (HRD-positive statusMedian follow-up of 27.4 months in Lynparza/bevacizumab arm and 27.5 months in placebo/bevacizumab arm., Investigator Assessment)Lynparza/bevacizumab(n=255)Placebo/bevacizumab(n=132)Progression-Free Survival Number of events (%)87 (34%)92 (70%) Median, months37.217.7 Hazard ratioThe analysis was performed using an unstratified Cox proportional hazards model. (95% CI)0.33 (0.25, 0.45)CI Confidence intervalFigure Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival PAOLA-1 (HRD-positive status). Figure 2. 14.3 Maintenance Treatment of Recurrent Ovarian Cancer The efficacy of Lynparza was investigated in two randomized, placebo-controlled, double-blind, multi-center studies in patients with recurrent ovarian cancers who were in response to platinum-based therapy.SOLO-2The efficacy of Lynparza was evaluated in SOLO-2 (NCT01874353), randomized (2:1) double-blind, placebo-controlled trial in patients with gBRCAm ovarian, fallopian tube, or primary peritoneal cancer. Patients were randomized to Lynparza tablets 300 mg orally twice daily or placebo until unacceptable toxicity or progressive disease. Randomization was stratified by response to last platinum chemotherapy (complete versus partial) and time to disease progression in the penultimate platinum-based chemotherapy prior to enrollment (6-12 months versus >12 months). All patients had received at least two prior platinum-containing regimens and were in response (complete or partial) to their most recent platinum-based regimen. The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST, version 1.1. An additional efficacy outcome measure was OS.A total of 295 patients were randomized, 196 to Lynparza and 99 to placebo. The median age of patients treated with Lynparza was 56 years (range: 28 to 83) and 56 years (range: 39 to 78) among patients treated with placebo. The ECOG PS was in 83% of patients receiving Lynparza and 78% of patients receiving placebo. Of all patients, 89% were White, 17% were enrolled in the U.S. or Canada, 47% were in complete response to their most recent platinum-based regimen, and 40% had progression-free interval of 6-12 months since their penultimate platinum regimen. Prior bevacizumab therapy was reported for 17% of those treated with Lynparza and 20% of those receiving placebo. Approximately 44% of patients on the Lynparza arm and 37% on placebo had received three or more lines of platinum-based treatment.All patients had deleterious or suspected deleterious germline BRCA mutation as detected either by local test (n=236) or central Myriad CLIA test (n=59), subsequently confirmed by BRACAnalysis CDx(R) (n=286).SOLO-2 demonstrated statistically significant improvement in investigator-assessed PFS in patients randomized to Lynparza as compared with placebo. Results from blinded independent review were consistent. The final analysis of OS did not reach statistical significance. Efficacy results are presented in Table 20 and Figures and 4.Table 20 Efficacy Results SOLO-2 (Investigator Assessment)Lynparza tablets(n=196)Placebo(n=99)Progression-Free Survival Number of events (%)107 (55%)80 (81%) Median, months19.15.5 Hazard ratioHazard ratio from Cox proportional hazards model including response to last platinum chemotherapy (complete response versus partial response) and time to disease progression in the penultimate platinum-based chemotherapy prior to enrollment (6-12 month versus >12 months) as covariates. (95% CI)0.30 (0.22, 0.41) p-valueThe p-value is derived from stratified log-rank test. <0.0001Overall Survival Number of events (%)116 (59)65 (66) Median, months51.738.8 Hazard ratio (95% CI)0.74 (0.54, 1.00) p-value 0.0537Figure Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival SOLO-2Figure Kaplan-Meier Curves of Overall Survival SOLO-2Study 19The efficacy of Lynparza was evaluated in Study 19 (NCT00753545), randomized (1:1) double-blind, placebo-controlled trial in patients with platinum-sensitive ovarian cancer who had received or more previous platinum-containing regimens. Patients were randomized to Lynparza capsules 400 mg orally twice daily or placebo until unacceptable toxicity or progressive disease. Randomization was stratified by response to last platinum chemotherapy (complete response versus partial response), time to disease progression in the penultimate platinum-based chemotherapy (6-12 months versus >12 months), and descent (Jewish versus non-Jewish). The major efficacy outcome measure was investigator-assessed PFS according to RECIST, version 1.0. total of 265 patients were randomized, 136 to Lynparza and 129 to placebo. The median age of patients treated with Lynparza was 58 years (range: 21 to 89) and 59 years (range 33 to 84) among patients treated with placebo. ECOG PS was in 81% of patients receiving Lynparza and 74% of patients receiving placebo. Of all patients, 97% were White, 19% were enrolled in the US or Canada, 45% were in complete response following their most recent platinum chemotherapy regimen, and 40% had progression-free interval of 6-12 months since their penultimate platinum. Prior bevacizumab therapy was reported for 13% of patients receiving Lynparza and 16% of patients receiving placebo. retrospective analysis for germline BRCA mutation status, some performed using the Myriad test, indicated that 36% (n=96) of patients from the ITT population had deleterious gBRCA mutation, including 39% (n=53) of patients on Lynparza and 33% (n=43) of patients on placebo.Efficacy results are presented in Table 21 and Figure 5. Study 19 demonstrated statistically significant improvement in investigator-assessed PFS in patients treated with Lynparza versus placebo.Table 21 Efficacy Results Study 19 (Investigator Assessment)Lynparza capsules(n=136)Placebo(n=129)Progression-Free Survival Number of events (%)60 (44%)94 (73%) Median, months8.44.8 Hazard ratioHazard ratio from Cox proportional hazards model including response to last platinum chemotherapy (complete response versus partial response), time to disease progression in the penultimate platinum-based chemotherapy (6-12 months versus >12 months) and Jewish descent (yes versus no) as covariates. (95% CI)0.35 (0.25, 0.49) p-valueThe p-value is derived from Cox proportional hazards model. <0.0001Overall SurvivalWithout adjusting for multiple analyses. Number of events (%)98 (72%)112 (87%) Median, months29.827.8 Hazard ratio (95% CI)0.73 (0.55, 0.95)Figure Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival Study 19. Figure 3. Figure 4. Figure 5. 14.4 Advanced Germline BRCA-mutated Ovarian Cancer Treated with or More Prior Lines of Chemotherapy The efficacy of Lynparza was investigated in single-arm study of patients with deleterious or suspected deleterious gBRCAm advanced cancers. total of 137 patients with measurable, advanced gBRCAm ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. All patients received Lynparza capsules 400 mg orally twice daily until disease progression or intolerable toxicity. The efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as assessed by the investigator according to RECIST, version 1.0.The median age of the patients was 58 years, the majority were White (94%) and 93% had an ECOG PS of or 1. Deleterious or suspected deleterious gBRCAm status was verified retrospectively in 97% (59/61) of the patients for whom blood samples were available by the BRACAnalysis CDxTM. Efficacy results are summarized in Table 22.Table 22 Overall Response and Duration of Response in Patients with gBRCA-mutated Advanced Ovarian Cancer Who Received or More Lines of ChemotherapyLynparza Capsulesn=137Objective Response Rate (95% CI)34% (26, 42) Complete response2% Partial response32%Median DOR in months (95% CI)7.9 (5.6, 9.6). 14.5 Treatment of Germline BRCA-mutated HER2-negative Metastatic Breast Cancer The efficacy of Lynparza was evaluated in OlympiAD (NCT02000622), an open-label randomized (2:1) study in patients with gBRCAm HER2-negative metastatic breast cancer. Patients were required to have received treatment with an anthracycline (unless contraindicated) and taxane, in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor-positive disease must have progressed on at least endocrine therapy (adjuvant or metastatic), or have disease that the treating healthcare provider believed to be inappropriate for endocrine therapy. Patients with prior platinum therapy were required to have no evidence of disease progress during platinum treatment. No prior treatment with PARP inhibitor was permitted. Patients were randomized to Lynparza tablets 300 mg orally twice daily or healthcare providers choice of chemotherapy (capecitabine, eribulin, or vinorelbine, at standard doses) until progression or unacceptable toxicity. Randomization was stratified by prior use of chemotherapy for metastatic disease (yes vs no), hormone receptor status (hormone receptor positive vs triple negative), and previous use of platinum-based chemotherapy (yes vs no). The major efficacy outcome measure was PFS assessed by blinded independent central review (BICR) using RECIST version 1.1.A total of 302 patients were randomized, 205 to Lynparza and 97 to chemotherapy. Among the 205 patients treated with Lynparza, the median age was 44 years (range: 22 to 76), 65% were White, 4% were males and all the patients had an ECOG PS of or 1. Approximately 50% of patients had triple-negative tumors and 50% had estrogen receptor and/or progesterone receptor positive tumors and the proportions were balanced across treatment arms. Patients in each treatment arm had received median of prior chemotherapy regimen for metastatic disease; approximately 30% had not received prior chemotherapy regimen for metastatic breast cancer. Twenty-one percent of patients in the Lynparza arm and 14% in the chemotherapy arm had received platinum therapy for metastatic disease. Seven percent of patients in each treatment arm had received platinum therapy for localized disease. Of the 302 patients randomized onto OlympiAD, 299 were tested with the BRACAnalysis CDx(R) and 297 were confirmed to have deleterious or suspected deleterious gBRCAm status; 202 were randomized to the Lynparza arm and 95 to the healthcare providers choice of chemotherapy arm.A statistically significant improvement in PFS was demonstrated for the Lynparza arm compared to the chemotherapy arm. Efficacy data for OlympiAD are displayed in Table 23 and Figure 6. Consistent results were observed across patient subgroups defined by study stratification factors. An exploratory analysis of investigator-assessed PFS was consistent with the BICR-assessed PFS results.Table 23 Efficacy Results OlympiAD (BICR-assessed)Lynparza tablets(n=205)Chemotherapy(n=97)Progression-Free Survival Number of events (%)163 (80%)71 (73%) Median, months7.04.2 Hazard ratio (95% CI)Hazard ratio is derived from stratified log-rank test, stratified by ER, PgR negative versus ER and or PgR positive and prior chemotherapy (yes versus no). 0.58 (0.43, 0.80) p-valueFor PFS, p-value (2-sided) was compared to 0.05. 0.0009Patients with Measurable Diseasen=167n=66 Objective Response Rate (95% CI)Response based on confirmed responses. The confirmed complete response rate was 7.8% for Lynparza compared to 1.5% for chemotherapy arm. 52% (44, 60)23% (13, 35)Overall Survival Number of events (%)130 (63%)62 (64%) Median, months19.317.1 Hazard ratio (95% CI) 0.90 (0.66, 1.23)Figure Kaplan-Meier Curves of Progression-Free Survival OlympiAD Figure 6. 14.6 First-Line Maintenance Treatment of Germline BRCA-mutated Metastatic Pancreatic Adenocarcinoma The efficacy of Lynparza was evaluated in POLO (NCT02184195), randomized (3:2), double-blind placebo-controlled, multi-center trial. Patients were required to have metastatic pancreatic adenocarcinoma with deleterious or suspected deleterious germline BRCA mutation (gBRCAm) and absence of disease progression after receipt of first-line platinum-based chemotherapy for at least 16 weeks. Patients were randomized to receive Lynparza tablets 300 mg orally twice daily or placebo until disease progression or unacceptable toxicity. The major efficacy outcome measure was PFS by BICR using RECIST, version 1.1 modified to assess patients with clinical complete response at entry who were assessed as having no evidence of disease unless they had progressed based on the appearance of new lesions. Additional efficacy outcome measures were OS and ORR.A total of 154 patients were randomized, 92 to Lynparza and 62 to placebo. The median age was 57 years (range 36 to 84); 54% were male; 92% were White, 4% were Asian, and 3% were Black; baseline ECOG PS was (67%) or (31%). The median time from initiation of first-line platinum-based chemotherapy to randomization was 5.8 months (range 3.4 to 33.4 months). Seventy-five percent (75%) of patients received FOLFIRINOX with median of cycles (range 4-61), 8% received FOLFOX or XELOX, 4% received GEMOX, and 3% received gemcitabine plus cisplatin; 49% achieved complete or partial response to platinum-based chemotherapy.All patients had deleterious or suspected deleterious germline BRCA-mutation as detected by the Myriad BRACAnalysis (R) or BRACAnalysis CDx(R) at central laboratory only (n=106), local BRCA test only (n=4), or both local and central testing (n=44). Among the 150 patients with central test results, 30% had mutation in BRCA1; 69% had mutation in BRCA2; and patient (1%) had mutations in both BRCA1 and BRCA2.POLO demonstrated statistically significant improvement in BICR-assessed PFS in patients randomized to Lynparza as compared with placebo. The final analysis of OS did not reach statistical significance. Efficacy results of POLO are provided in Table 24 and Figure 7.Table 24 Efficacy Results POLO (BICR-assessed)Lynparza tablets(n=92)Placebo(n=62)Progression-Free Survival Number of events (%)Number of events: Progression Lynparza 55, placebo 44; death before BICR-documented progression Lynparza 5, placebo 60 (65)44 (71) Median, months (95% CI)7.4 (4.1, 11.0)3.8 (3.5, 4.9) Hazard ratioHazard ratio, 95% CI, and p-value calculated from log-rank test. hazard ratio <1 favors Lynparza. (95% CI)0.53 (0.35, 0.81) p-value0.0035Overall Survival Number of events (%)61 (66)47 (76) Median, months (95% CI)19.0 (15.3, 26.3)19.2 (14.3, 26.1) Hazard ratio (95% CI)0.83 (0.56, 1.22) p-value 0.3487Patients with Measurable Diseasen=78n=52Objective Response Rate (95% CI) 23% (14, 34)12% (4, 23) Complete response (%)2 (2.6)0 Partial response (%)16 (21)6 (12)Duration of Response (DOR) Median time in months (95% CI)25 (15, NC)4 (2, NC)NC Not calculableFigure Kaplan-Meier Curves of BICR-Assessed Progression-Free Survival POLO. Number of events (%)Number of events: Progression Lynparza 55, placebo 44; death before BICR-documented progression Lynparza 5, placebo . Figure 7. 14.7 HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer The efficacy of Lynparza was evaluated in PROfound (NCT02987543), randomized, open-label, multi-center trial that evaluated the efficacy of Lynparza 300 mg twice daily versus comparator arm of investigators choice of enzalutamide or abiraterone acetate in men with metastatic castration-resistant prostate cancer (mCRPC). All patients received GnRH analog or had prior bilateral orchiectomy. Patients needed to have progressed on prior enzalutamide or abiraterone for the treatment of metastatic prostate cancer and/or CRPC and have tumor mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway. Patients were divided into two cohorts based on HRR gene mutation status. Patients with mutations in either BRCA1, BRCA2, or ATM were randomized in Cohort A; patients with mutations among 12 other genes involved in the HRR pathway (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L) were randomized in Cohort B; patients with co-mutations (BRCA1, BRCA2, or ATM plus Cohort gene) were assigned to Cohort A. Although patients with PPP2R2A gene mutations were enrolled in the trial, Lynparza is not indicated for the treatment of patients with this gene mutation due to unfavorable risk-benefit. Patients were randomized (2:1), 256 to Lynparza arm and 131 to enzalutamide or abiraterone acetate arm; in Cohort there were 245 (162 Lynparza arm and 83 in enzalutamide or abiraterone acetate arm) and in Cohort there were 142 patients (94 in Lynparza arm and 48 in enzalutamide or abiraterone acetate arm). Randomization was stratified by prior receipt of taxane chemotherapy and presence of measurable disease by RECIST 1.1. Treatment was continued until objective radiological disease progression determined by BICR. Upon radiological progression confirmed by BICR, patients randomized to enzalutamide or abiraterone acetate were given the option to switch to olaparib. Patients with HRR gene mutations were identified by tissue-based testing using the Foundation Medicine FoundationOne(R) clinical trial HRR assay performed at central laboratory.Determination of deleterious or suspected deleterious somatic or germline HRR mutation status in line with the FDA approved mutation classification and testing criteria for the Foundation Medicine F1CDx tissue-based assay and assessment of the germline-BRCA status using the Myriad BRACAnalysis CDx blood-based assay was performed retrospectively. Representation of individual gene mutations by cohort is provided in Table 25. No patients were enrolled who had mutations in two of the 15 pre-specified HRR genes: FANCL and RAD51C.Table 25 Frequency of Patients with HRR Mutations Enrolled in PROfoundHRR MutationCohort AN=245n (%)Cohort BThree patients with single BRCA2 or ATM gene mutations and patient with co-occurring BRCA2+CDK12 gene mutations were incorrectly assigned to Cohort B.N=142n (%)Single mutation224 (91)135 (95) BRCA2127 (52)1 (<1) ATM84 (34)2 (1) BRCA113 (5)0 CDK12089 (63) CHEK2012 (8) PPP2R2ALynparza is not indicated for patients with PPP2R2A mutations.010 (7) RAD51B05 (4) RAD54L05 (4) PALB204 (3) BRIP103 (2) CHEK102 (1) BARD101 (<1) RAD51D01 (<1)Co-occurring mutationPatients with co-occurring mutations (BRCA1, BRCA2, or ATM plus Cohort gene) were assigned to Cohort A. 21 (9)7 (5)In Cohort A+B, the median age was 69 years (range: 47 to 91 years) in both arms; 69% were White, 29% were Asian, and 1% were Black. The ECOG performance score was or in most patients (95%) in both arms. In patients treated with Lynparza, the proportion of patients with RECIST 1.1 measurable disease at baseline was 58%, including 17% with lung and 10% with liver metastases, respectively. At randomization, 66% of patients had received prior taxane chemotherapy, 40% had received enzalutamide, 38% had received abiraterone acetate, and 20% had received both enzalutamide and abiraterone acetate. Patient characteristics were well-balanced between arms.The major efficacy outcome of the study was radiological progression free survival (rPFS) (Cohort A) as determined by BICR using RECIST version 1.1 and Prostate Cancer Clinical Trials Working Group (PCWG3) (bone) criteria. Additional efficacy outcomes included confirmed objective response rate (ORR) (Cohort A), rPFS (combined Cohorts A+B) as assessed by BICR, and overall survival (OS) (Cohort A). PROfound demonstrated statistically significant improvement in BICR-assessed rPFS for Lynparza compared to investigators choice of enzalutamide or abiraterone acetate in Cohort and Cohort A+B. In an exploratory analysis for patients in Cohort B, the median rPFS was 4.8 months for Lynparza vs 3.3 months for comparator with HR of 0.88 (95% CI 0.58, 1.36). The major efficacy outcome was supported by statistically significant improvement in ORR by BICR for patients with measurable disease at baseline in Cohort A. In Cohort B, ORR by BICR was 3.7% (95% CI 0.5, 12.7) in Lynparza treated patients and 8.3% (95% CI 1.0, 27.0) in patients treated with enzalutamide or abiraterone acetate.The final analysis of overall survival (OS) demonstrated statistically significant improvement in OS in patients randomized to Lynparza compared to patients in the enzalutamide or abiraterone acetate arm in Cohort A.Efficacy results of PROfound are provided in Tables 26 and 27 and Figures and 9.Table 26 Efficacy Results PROfound (BICR-assessed)Cohort ACohort A+BAlthough 10 patients with PPP2R2A mutation were included in all analyses of Cohort A+B, Lynparza is not indicated for this population due to unfavorable risk-benefit.Lynparza tablets(n=162)Enzalutamide or Abiraterone acetate(n=83)Lynparza tablets(n=256)Enzalutamide or Abiraterone acetate(n=131)Radiological Progression-Free Survival (rPFS) Number of events (%)106 (65)68 (82)180 (70)99 (76) Median (95% CI), in months 7.4 (6.2, 9.3)3.6 (1.9, 3.7)5.8 (5.5, 7.4)3.5 (2.2, 3.7) Hazard ratio (95% CI)The HR and CI were calculated using Cox proportional hazards model adjusted for prior taxane use and measurable disease. An HR <1 favors Lynparza 300 mg bd. 0.34 (0.25, 0.47)0.49 (0.38, 0.63) p-valueThe analysis was performed using the log-rank test stratified by prior taxane use and measurable disease. <0.0001<0.0001Confirmed ORR Patients with measurable disease at baselinen=84n=43-- ORR, (%)28 (33)1 (2)-- (95% CI)(23, 45)(0, 12)-- p-value <0.0001-Overall Survival n=162n=83-- Number of events (%)91 (56)57 (69)-- Median (95% CI), in months19.1 (17.4, 23.4)14.7 (11.9, 18.8)-- Hazard ratio (95% CI) 0.69 (0.50, 0.97)- p-value 0.0175-CI Confidence intervalFigure Kaplan-Meier Curves of BICR-Assessed Radiological Progression-Free Survival PROfound Cohort AConsistent results were observed in exploratory analyses of rPFS for patients who received or did not receive prior taxane therapy and for those with germline-BRCA mutations identified using the Myriad BRACAnalysis CDx assay compared with those with BRCA mutations identified using the Foundation Medicine F1CDx assay.Figure Kaplan-Meier Curves of Overall Survival PROfound Cohort AResponse data by HRR mutations for patients in the Lynparza arm are presented in Table 27. In the comparator arm of Cohorts and B, total of three patients achieved partial response, including one patient with an ATM mutation alone and patients with co-occurring mutations (one with PALB2+PPP2R2A and one with CDK12+PALB2).Table 27 Response Rate and Duration of Response by HRR Mutation in Patients with Measurable Disease at Baseline on the Lynparza Arm PROfound (BICR-assessed)HRR mutationNo patients with FANCL or RAD51C enrolled. Three patients with PPP2R2A mutations had measurable disease, however, Lynparza is not indicated for patients with PPP2R2A mutation. Patients (N=138) Confirmed ORRIn patients with single BRCA2 mutation the median duration of response in the Lynparza arm (n=24) was 5.6 months (95% C.I: 5.5, 9.2). In the responders with single ATM mutation in the Lynparza arm, the duration of response ranged from 5.8+ to 9.0 months. In the responders with single CDK12 mutation in the Lynparza arm, the duration of response was 3.7 and 7.2 months. denotes ongoing response. (%) 95% CISingle mutationBRCA2 43 24 (56) (40, 71)ATM 30 (10) (2, 27)CDK12 34 (6) (1, 20)BRCA1 SD, PD (4), NE NACHEK2 SD (2), PD (2) NABRIP1 SD, PD NAPALB2 SD, PD NACHEK1 PD NARAD51B SD NARAD51D PD NARAD54L SD NACo-occurring mutationsBRCA2/CDK12 PR, SD NABRCA2/ATM SD, SD NABRCA2/BARD1 PD NABRCA2/CHEK2 SD NACDK12/CHEK1 SD NACDK12/PALB2 PD NABRCA2/CDK12/CHEK2 PD NABRCA2/CHEK2/RAD51D SD NA PR Partial response; SD Stable disease; PD Progressive disease; NE Not evaluable; NA Not applicable due to small numbers or lack of response.. Patients. (N=138). Confirmed ORRIn patients with single BRCA2 mutation the median duration of response in the Lynparza arm (n=24) was 5.6 months (95% C.I: 5.5, 9.2). In the responders with single ATM mutation in the Lynparza arm, the duration of response ranged from 5.8+ to 9.0 months. In the responders with single CDK12 mutation in the Lynparza arm, the duration of response was 3.7 and 7.2 months. denotes ongoing response.. (%). 95% CI. 43. 24 (56). (40, 71). 30. (10). (2, 27). 34. (6). (1, 20). 6. SD, PD (4), NE. NA. 4. SD (2), PD (2). NA. 2. SD, PD. NA. 2. SD, PD. NA. 1. PD. NA. 1. SD. NA. 1. PD. NA. 1. SD. NA. 2. PR, SD. NA. 2. SD, SD. NA. 1. PD. NA. 1. SD. NA. 1. SD. NA. 1. PD. NA. 1. PD. NA. 1. SD. NA. PR Partial response; SD Stable disease; PD Progressive disease; NE Not evaluable; NA Not applicable due to small numbers or lack of response.. Figure 8. Figure 9.

GERIATRIC USE SECTION.

8.5 Geriatric Use Of the 2901 patients with advanced solid tumors who received Lynparza as single agent, 680 (23%) patients were aged >=65 years, and this included 206 (7%) patients who were aged >=75 years. Thirteen (0.4%) patients were aged >=85 years. Of the 535 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with bevacizumab, 204 (38%) patients were aged >=65 years, and this included 31 (6%) patients who were aged >=75 years. No overall differences in the safety or effectiveness of Lynparza were observed between these patients and younger patients.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Safety and effectiveness of Lynparza have not been established in pediatric patients.

PHARMACOKINETICS SECTION.

12.3 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 dose of 300 mg twice daily.The mean (CV%) olaparib Cmax is 5.4 ug/mL (32%) and AUC is 39.2 ugh/mL (44%) following single 300 mg dose. The mean steady state olaparib Cmax and AUC is 7.6 ug/mL (35%) and 49.2 ugh/mL (44%), following dose of 300 mg twice daily.AbsorptionFollowing oral administration of olaparib, the median time to peak plasma concentration is 1.5 hours. Effect of Food Co-administration of 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%).DistributionThe mean (+- standard deviation) apparent volume of distribution of olaparib is 158 +- 136 following single 300 mg dose of Lynparza. The protein binding of olaparib is approximately 82% in vitro.EliminationThe 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 single 300 mg dose of Lynparza.MetabolismOlaparib 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 number of the components produced undergoing subsequent glucuronide or sulfate conjugation.ExcretionFollowing single dose of radiolabeled olaparib, 86% of the dosed radioactivity was recovered within 7-day collection period, 44% via the urine and 42% via the feces. The majority of the material was excreted as metabolites.Specific PopulationsPatients with Renal ImpairmentIn 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 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 ImpairmentIn 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 StudiesCYP3A 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 StudiesCYP Enzymes: Olaparib is both an inhibitor and inducer of CYP3A and an inducer of CYP2B6. Olaparib is predicted to be 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 substrate and inhibitor of the efflux transporter P-gp. The potential for olaparib to induce P-gp has not been evaluated.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 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 bacterial reverse mutation (Ames) test.In 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 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 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. 12.2 Pharmacodynamics Cardiac ElectrophysiologyThe effect of olaparib on cardiac repolarization was assessed in 119 patients following 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.. 12.3 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 dose of 300 mg twice daily.The mean (CV%) olaparib Cmax is 5.4 ug/mL (32%) and AUC is 39.2 ugh/mL (44%) following single 300 mg dose. The mean steady state olaparib Cmax and AUC is 7.6 ug/mL (35%) and 49.2 ugh/mL (44%), following dose of 300 mg twice daily.AbsorptionFollowing oral administration of olaparib, the median time to peak plasma concentration is 1.5 hours. Effect of Food Co-administration of 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%).DistributionThe mean (+- standard deviation) apparent volume of distribution of olaparib is 158 +- 136 following single 300 mg dose of Lynparza. The protein binding of olaparib is approximately 82% in vitro.EliminationThe 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 single 300 mg dose of Lynparza.MetabolismOlaparib 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 number of the components produced undergoing subsequent glucuronide or sulfate conjugation.ExcretionFollowing single dose of radiolabeled olaparib, 86% of the dosed radioactivity was recovered within 7-day collection period, 44% via the urine and 42% via the feces. The majority of the material was excreted as metabolites.Specific PopulationsPatients with Renal ImpairmentIn 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 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 ImpairmentIn 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 StudiesCYP3A 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 StudiesCYP Enzymes: Olaparib is both an inhibitor and inducer of CYP3A and an inducer of CYP2B6. Olaparib is predicted to be 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 substrate and inhibitor of the efflux transporter P-gp. The potential for olaparib to induce P-gp has not been evaluated.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Olaparib is poly (ADP-ribose) polymerase (PARP) inhibitor. The chemical name is 4-[(3-[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl-4-fluorophenyl)methyl]phthalazin-1(2H)-one. The empirical molecular formula for Lynparza is C24H23FN4O3 and the relative molecular mass is 434.46. It has the following chemical structure:Olaparib is crystalline solid, is non-chiral and shows pH-independent low solubility across the physiological pH range.Lynparza (olaparib) tablets for oral use 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).. ChecmicalStructure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oRecommended dosage is 300 mg taken orally twice daily with or without food. See Full Prescribing Information for the recommended duration. (2.2)oPatients receiving Lynparza for mCRPC should also receive gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. (2.2)oFor moderate renal impairment (CLcr 31-50 mL/min), reduce Lynparza dosage to 200 mg orally twice daily. (2.5). oRecommended dosage is 300 mg taken orally twice daily with or without food. See Full Prescribing Information for the recommended duration. (2.2). oPatients receiving Lynparza for mCRPC should also receive gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. (2.2). oFor moderate renal impairment (CLcr 31-50 mL/min), reduce Lynparza dosage to 200 mg orally twice daily. (2.5). 2.1 Patient Selection. Information on FDA-approved tests for the detection of genetic mutations is available at http://www.fda.gov/companiondiagnostics.Select patients for treatment with Lynparza based on the presence of deleterious or suspected deleterious HRR gene mutations, including BRCA mutations, or genomic instability based on the indication, biomarker, and sample type (Table 1).Table 1Where testing fails or tissue sample is unavailable/insufficient, or when germline testing is negative, consider using an alternative test, if available. IndicationBiomarkerSample typeTumorBloodPlasma(ctDNA)First-line maintenance treatment of germline or somatic BRCAm advanced ovarian cancerBRCA1m, BRCA2mXXFirst-line maintenance treatment of HRD-positive advanced ovarian cancer in combination with bevacizumabBRCA1m, BRCA2m and/or genomic instabilityXMaintenance treatment of recurrent ovarian cancerNo requirement for biomarker testingAdvanced gBRCAm ovarian cancergBRCA1m, gBRCA2mXgBRCAm HER2-negative metastatic breast cancergBRCA1m, gBRCA2mXFirst-line maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinomagBRCA1m, gBRCA2mXGermline or somatic HRR gene-mutated metastatic castration-resistant prostate cancerATMm, BRCA1m, BRCA2m, BARD1m, BRIP1m, CDK12m, CHEK1m, CHEK2m, FANCLm, PALB2m, RAD51Bm, RAD51Cm, RAD51Dm, RAD54LmXgBRCA1m, gBRCA2mXATMm, BRCA1m, BRCA2mX. 2.2 Recommended Dosage The recommended dosage of Lynparza is 300 mg taken orally twice daily, with or without food.If patient misses dose of Lynparza, instruct patient to take their next dose at its scheduled time. Instruct patients to swallow tablets whole. Do not chew, crush, dissolve, or divide tablet.First-Line Maintenance Treatment of BRCA-mutated Advanced Ovarian Cancer Continue treatment until disease progression, unacceptable toxicity, or completion of years of treatment. Patients with complete response (no radiological evidence of disease) at years should stop treatment. Patients with evidence of disease at years, who in the opinion of the treating healthcare provider can derive further benefit from continuous treatment, can be treated beyond years.First-Line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with BevacizumabContinue Lynparza treatment until disease progression, unacceptable toxicity, or completion of years of treatment. Patients with complete response (no radiological evidence of disease) at years should stop treatment. Patients with evidence of disease at years, who in the opinion of the treating healthcare provider can derive further benefit from continuous Lynparza treatment, can be treated beyond years. When used with Lynparza, the recommended dose of bevacizumab is 15 mg/kg every three weeks. Bevacizumab should be given for total of 15 months including the period given with chemotherapy and given as maintenance. Refer to the Prescribing Information for bevacizumab when used in combination with Lynparza for more information.Recurrent Ovarian Cancer, Germline BRCAm Advanced Ovarian Cancer, HER2-negative Metastatic Breast Cancer, Metastatic Pancreatic Adenocarcinoma, and HRR Gene-mutated Metastatic Castration-Resistant Prostate CancerContinue treatment until disease progression or unacceptable toxicity for: oMaintenance treatment of recurrent ovarian canceroAdvanced germline BRCA-mutated ovarian canceroGermline BRCA-mutated HER-2 negative metastatic breast canceroFirst-line maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma.oHRR gene-mutated metastatic castration-resistant prostate cancerPatients receiving Lynparza for mCRPC should also receive gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.. oMaintenance treatment of recurrent ovarian canceroAdvanced germline BRCA-mutated ovarian canceroGermline BRCA-mutated HER-2 negative metastatic breast canceroFirst-line maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma.oHRR gene-mutated metastatic castration-resistant prostate cancer. oMaintenance treatment of recurrent ovarian cancer. oAdvanced germline BRCA-mutated ovarian cancer. oGermline BRCA-mutated HER-2 negative metastatic breast cancer. oFirst-line maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma.. oHRR gene-mutated metastatic castration-resistant prostate cancer. 2.3 Dosage Modifications for Adverse Reactions To manage adverse reactions, consider interruption of treatment or dose reduction. The recommended dose reduction is 250 mg taken twice daily.If further dose reduction is required, then reduce to 200 mg taken twice daily.. 2.4 Dosage Modifications for Concomitant Use with Strong or Moderate CYP3A Inhibitors Avoid concomitant use of strong or moderate CYP3A inhibitors with Lynparza. If concomitant use cannot be avoided, reduce Lynparza dosage to:o100 mg twice daily when used concomitantly with strong CYP3A inhibitor.o150 mg twice daily when used concomitantly with moderate CYP3A inhibitor.After the inhibitor has been discontinued for to elimination half-lives, resume the Lynparza dose taken prior to initiating the CYP3A inhibitor [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. o100 mg twice daily when used concomitantly with strong CYP3A inhibitor.. o150 mg twice daily when used concomitantly with moderate CYP3A inhibitor.. 2.5 Dosage Modifications for Renal Impairment Moderate Renal ImpairmentIn patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the Lynparza dosage to 200 mg orally twice daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets:o150 mg: green to green/grey, oval, bi-convex, film-coated, with debossment OP150 on one side and plain on the reverse side.o100 mg: yellow to dark yellow, oval, bi-convex, film-coated, with debossment OP100 on one side and plain on the reverse side.. o150 mg: green to green/grey, oval, bi-convex, film-coated, with debossment OP150 on one side and plain on the reverse side.. o100 mg: yellow to dark yellow, oval, bi-convex, film-coated, with debossment OP100 on one side and plain on the reverse side.. Tablets: 150 mg, 100 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oStrong or moderate CYP3A inhibitors: Avoid concomitant use. If concomitant use cannot be avoided, reduce Lynparza dosage. (2.4, 7.2, 12.3)oStrong or moderate CYP3A inducers: Avoid concomitant use. (7.2, 12.3). oStrong or moderate CYP3A inhibitors: Avoid concomitant use. If concomitant use cannot be avoided, reduce Lynparza dosage. (2.4, 7.2, 12.3). oStrong or moderate CYP3A inducers: Avoid concomitant use. (7.2, 12.3). 7.1 Use with Anticancer Agents. Clinical studies of Lynparza with other myelosuppressive anticancer agents, including DNA damaging agents, indicate potentiation and prolongation of myelosuppressive toxicity.. 7.2 Effect of Other Drugs on Lynparza. Strong and Moderate CYP3A InhibitorsCoadministration 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 InducersConcomitant use with 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential Pregnancy TestingRecommend pregnancy testing for females of reproductive potential prior to initiating treatment with Lynparza.ContraceptionFemalesLynparza can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least months following the last dose.MalesBased on findings in 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 months following the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for months following the last dose of Lynparza [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Lynparza is available as 150 mg and 100 mg tablets.o150 mg tablets: green to green/grey, oval, bi-convex, film-coated tablet, with debossment OP150 on one side and plain on the reverse, are available in:Bottles of 60 tablets (NDC 0310-0679-60) and Bottles of 120 tablets (NDC 0310-0679-12). o100 mg tablets: yellow to dark yellow, oval, bi-convex, film-coated tablet, with debossment OP100 on one side and plain on the reverse, are available in:Bottles of 60 tablets (NDC 0310-0668-60) and Bottles of 120 tablets (NDC 0310-0668-12). Store at 20oC to 25oC (68oF to 77oF), excursions permitted to 15oC to 30oC (59oF to 86oF) [see USP Controlled Room Temperature]. Store in original bottle to protect from moisture.. o150 mg tablets: green to green/grey, oval, bi-convex, film-coated tablet, with debossment OP150 on one side and plain on the reverse, are available in:Bottles of 60 tablets (NDC 0310-0679-60) and Bottles of 120 tablets (NDC 0310-0679-12). Bottles of 60 tablets (NDC 0310-0679-60) and Bottles of 120 tablets (NDC 0310-0679-12).. o100 mg tablets: yellow to dark yellow, oval, bi-convex, film-coated tablet, with debossment OP100 on one side and plain on the reverse, are available in:Bottles of 60 tablets (NDC 0310-0668-60) and Bottles of 120 tablets (NDC 0310-0668-12). Bottles of 60 tablets (NDC 0310-0668-60) and Bottles of 120 tablets (NDC 0310-0668-12).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Lynparza is poly (ADP-ribose) polymerase (PARP) inhibitor indicated:Ovarian cancerofor the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (1.1, 2.1) oin combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either:oa deleterious or suspected deleterious BRCA mutation, and/or ogenomic instability. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza (1.2, 2.1).ofor the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy. (1.3)ofor the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (1.4, 2.1)Breast cancerofor the treatment of adult patients with deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (1.5, 2.1)Pancreatic cancerofor the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (1.6, 2.1)Prostate cancerofor the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (1.7, 2.1). ofor the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (1.1, 2.1) oin combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either:oa deleterious or suspected deleterious BRCA mutation, and/or ogenomic instability. oa deleterious or suspected deleterious BRCA mutation, and/or ogenomic instability. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza (1.2, 2.1).. ofor the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy. (1.3). ofor the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (1.4, 2.1). ofor the treatment of adult patients with deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (1.5, 2.1). ofor the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (1.6, 2.1). ofor the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (1.7, 2.1). 1.1 First-Line Maintenance Treatment of BRCA-mutated Advanced Ovarian Cancer Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ].. 1.2 First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab Lynparza is indicated in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either:oa deleterious or suspected deleterious BRCA mutation, and/orogenomic instability.Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1)].. oa deleterious or suspected deleterious BRCA mutation, and/or. ogenomic instability.. 1.3 Maintenance Treatment of Recurrent Ovarian Cancer. Lynparza is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.. 1.4 Advanced Germline BRCA-mutated Ovarian Cancer After or More Lines of Chemotherapy Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ]. 1.5 Germline BRCA-mutated HER2-negative Metastatic Breast Cancer Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer, who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1)].. 1.6 First-Line Maintenance Treatment of Germline BRCA-mutated Metastatic Pancreatic Adenocarcinoma Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1)].. 1.7 HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).MDS/AMLAdvise 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 need for blood transfusions. This may be sign of hematological toxicity or 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)].PneumonitisAdvise 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)].Embryo-Fetal ToxicityInform pregnant women of the risk to 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 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 months after receiving the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for months following the last dose of Lynparza [see Warnings and Precautions (5.3) and Use in Specific Populations (8.3) ]. Venous Thromboembolic EventsAdvise patients with metastatic castration-resistant prostate cancer 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 and Precautions (5.4)].LactationAdvise patients not to breastfeed while taking Lynparza and for one month after receiving the last dose [see Use in Specific Populations (8.2)].Drug InteractionsAdvise 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/VomitingAdvise 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)].Distributed by:AstraZeneca Pharmaceuticals LPWilmington, DE 19850(C) AstraZeneca 2022.

LACTATION SECTION.

8.2 Lactation Risk SummaryNo data are available regarding the presence of olaparib in human milk, or on its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infants from Lynparza, advise lactating woman not to breastfeed during treatment with Lynparza and for one month after receiving the last dose.

MECHANISM OF ACTION SECTION.

12.1 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 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 bacterial reverse mutation (Ames) test.In 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 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).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 100 mg. NDC 0310-0668-60Lynparza(R) (olaparib) tablets100 mg Dispense accompanying Medication Guide to each patient.60 TabletsRx onlyAstraZeneca. lynparza100mg60tabletbottlelabel.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], Lynparza can cause fetal harm when administered to pregnant woman. There are no available data on Lynparza use in pregnant women to inform the drug-associated risk. In an animal reproduction study, the 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 (see Data). Apprise pregnant women of the potential hazard to the fetus and the potential risk for loss of the pregnancy.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2-4%; and the risk for spontaneous abortion is approximately 15-20% in clinically recognized pregnancies.. Data Animal DataIn fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to Day of pregnancy, which resulted in increased post-implantation loss at dose level of 15 mg/kg/day (with maternal systemic exposures approximately 7% of the human exposure (AUC0-24h) at the recommended dose).In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.18% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital), and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter, and umbilical artery. Some findings noted above in the eyes, ribs, and ureter were observed at dose of 0.05 mg/kg/day olaparib at lower incidence.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Myelodysplastic Syndrome/Acute Myeloid Leukemia (5.1) 3/2021.

SPL MEDGUIDE SECTION.

Medication GuideLynparza(R) (Lin-par-zah)(olaparib)tablets What is the most important information should know about LynparzaLynparza may cause serious side effects, including:Bone marrow problems called Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Some people who have ovarian cancer or breast cancer and 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. If you develop MDS or AML, your healthcare provider will stop treatment with Lynparza. Symptoms of low blood cell counts are common during treatment with Lynparza, but can be sign of serious bone marrow problems, including MDS or AML. Symptoms may include:oweaknessoweight lossofeverofrequent infectionsoblood in urine or stooloshortness of breathofeeling very tiredobruising or bleeding more easilyYour healthcare provider will do blood tests to check your blood cell counts:obefore treatment with Lynparzaoevery month during treatment with Lynparzaoweekly if you have low blood cell counts that last long time. Your healthcare provider may stop treatment with Lynparza until your blood cell counts improve.Lung problems (pneumonitis). 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 chest x-ray if you have any of these symptoms. Your healthcare provider may temporarily or completely stop treatment if you develop pneumonitis. Pneumonitis may lead to death.Blood clots (Venous Thromboembolic Events). Some people with prostate cancer who take Lynparza along with gonadotropin-releasing hormone (GnRH) analog therapy may develop blood clot in deep vein, usually in the leg (venous thrombosis) or clot in the lung (pulmonary embolism). Tell your healthcare provider 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.What is LynparzaLynparza is prescription medicine used to treat adults who have: oadvanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene. Lynparza is used alone as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy. Your healthcare provider will perform test to make sure that Lynparza is right for you.oadvanced ovarian cancer, fallopian tube cancer or primary peritoneal cancer with certain type of abnormal BRCA gene or positive laboratory tumor test for genomic instability called HRD. Lynparza is used in combination with another anti-cancer medicine, bevacizumab, as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy. Your healthcare provider will perform test to make sure that Lynparza is right for you.oovarian cancer, fallopian tube cancer, or primary peritoneal cancer, as maintenance treatment, when the cancer has come back. Lynparza is used after the cancer has responded to treatment with platinum-based chemotherapy. oadvanced ovarian cancer with certain type of abnormal inherited BRCA gene, and have received treatment with or more prior types of chemotherapy medicines. Your healthcare provider will perform test to make sure that Lynparza is right for you.oa certain type of abnormal inherited BRCA gene, human epidermal growth factor receptor (HER2)-negative breast cancer that has spread to other parts of the body (metastatic). You should have received chemotherapy medicines, either before or after your cancer has spread. If you have hormone receptor (HR)-positive disease, you should have been treated with hormonal therapy. Your healthcare provider will perform test to make sure that Lynparza is right for you.ometastatic pancreatic cancer with certain type of abnormal inherited BRCA gene. Lynparza is used as maintenance treatment after your cancer has not progressed on at least 16 weeks of treatment with platinum-based chemotherapy. Your healthcare provider will perform test to make sure that Lynparza is right for you.oprostate cancer with certain inherited or acquired abnormal genes called homologous recombination repair (HRR genes). Lynparza is used when the cancer has spread to other parts of the body (metastatic), and no longer responds to medical or surgical treatment that lowers testosterone, and has progressed after treatment with enzalutamide or abiraterone. Your healthcare provider will perform test to make sure 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: ohave lung or breathing problemsohave kidney problems oare pregnant, become pregnant, or plan to become pregnant. Lynparza can harm your unborn baby and may cause loss of pregnancy (miscarriage). If you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with Lynparza.Females who are able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 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 should use effective birth control (contraception) during treatment with Lynparza and for months after the last dose of Lynparza.Do not donate sperm during treatment with Lynparza and for months after your final dose.oare 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 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 take LynparzaoTake Lynparza tablets exactly as your healthcare provider tells you.oDo not change your dose or stop taking Lynparza unless your healthcare provider tells you to. Your healthcare provider may temporarily stop treatment with Lynparza or change your dose of Lynparza if you experience side effects.oYour healthcare provider will decide how long you stay on treatment.oDo not take more than Lynparza tablets in day. If you have any questions about Lynparza, please talk to your healthcare provider or pharmacist.oTake Lynparza by mouth times day. oEach dose should be taken about 12 hours apart.oSwallow Lynparza tablets whole. Do not chew, crush, dissolve, or divide the tablets.oTake Lynparza with or without food.oIf 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 surgery to lower the amount of testosterone in your body (surgical castration).oIf you miss dose of Lynparza, take your next dose at your usual scheduled time. Do not take an extra dose to make up for missed dose.oIf you take too much Lynparza, call your healthcare provider or go to the nearest hospital emergency room right away.What should avoid while taking LynparzaAvoid 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 should know about LynparzaThe most common side effects of Lynparza are:onausea or vomiting. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms.otiredness or weaknessolow red blood cell countsodiarrheaoloss of appetiteoheadacheochanges in the way food tastes ocougholow white blood cell countsoshortness of breathodizzinessoindigestion or heartburnolow platelet countsThese 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 store LynparzaoStore Lynparza at room temperature, between 68F to 77F (20C to 25C).oStore Lynparza in the original bottle to protect it from moisture.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 Medication Guide. Do not use Lynparza for condition for which it was not prescribed. Do not give Lynparza to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about Lynparza that is written for health professionals.What are the ingredients in LynparzaActive ingredient: olaparibInactive 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 registered trademark of the AstraZeneca group of companies.(C) AstraZeneca 2021Distributed by:AstraZeneca Pharmaceuticals LPWilmington, DE 19850For 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. Revised: 3/2021. oweakness. oweight loss. ofever. ofrequent infections. oblood in urine or stool. oshortness of breath. ofeeling very tired. obruising or bleeding more easily. obefore treatment with Lynparza. oevery month during treatment with Lynparza. oweekly if you have low blood cell counts that last long time. Your healthcare provider may stop treatment with Lynparza until your blood cell counts improve.. oadvanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene. Lynparza is used alone as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy. Your healthcare provider will perform test to make sure that Lynparza is right for you.. oadvanced ovarian cancer, fallopian tube cancer or primary peritoneal cancer with certain type of abnormal BRCA gene or positive laboratory tumor test for genomic instability called HRD. Lynparza is used in combination with another anti-cancer medicine, bevacizumab, as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy. Your healthcare provider will perform test to make sure that Lynparza is right for you.. oovarian cancer, fallopian tube cancer, or primary peritoneal cancer, as maintenance treatment, when the cancer has come back. Lynparza is used after the cancer has responded to treatment with platinum-based chemotherapy. oadvanced ovarian cancer with certain type of abnormal inherited BRCA gene, and have received treatment with or more prior types of chemotherapy medicines. Your healthcare provider will perform test to make sure that Lynparza is right for you.. oa certain type of abnormal inherited BRCA gene, human epidermal growth factor receptor (HER2)-negative breast cancer that has spread to other parts of the body (metastatic). You should have received chemotherapy medicines, either before or after your cancer has spread. If you have hormone receptor (HR)-positive disease, you should have been treated with hormonal therapy. Your healthcare provider will perform test to make sure that Lynparza is right for you.. ometastatic pancreatic cancer with certain type of abnormal inherited BRCA gene. Lynparza is used as maintenance treatment after your cancer has not progressed on at least 16 weeks of treatment with platinum-based chemotherapy. Your healthcare provider will perform test to make sure that Lynparza is right for you.. oprostate cancer with certain inherited or acquired abnormal genes called homologous recombination repair (HRR genes). Lynparza is used when the cancer has spread to other parts of the body (metastatic), and no longer responds to medical or surgical treatment that lowers testosterone, and has progressed after treatment with enzalutamide or abiraterone. Your healthcare provider will perform test to make sure Lynparza is right for you.. ohave lung or breathing problems. ohave kidney problems oare pregnant, become pregnant, or plan to become pregnant. Lynparza can harm your unborn baby and may cause loss of pregnancy (miscarriage). If you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with Lynparza.Females who are able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 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 should use effective birth control (contraception) during treatment with Lynparza and for months after the last dose of Lynparza.Do not donate sperm during treatment with Lynparza and for months after your final dose.. If you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with Lynparza.. Females who are able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 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 should use effective birth control (contraception) during treatment with Lynparza and for months after the last dose of Lynparza.. Do not donate sperm during treatment with Lynparza and for months after your final dose.. oare 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 month after receiving the last dose of Lynparza. Talk to your healthcare provider about the best way to feed your baby during this time.. oTake Lynparza tablets exactly as your healthcare provider tells you.. oDo not change your dose or stop taking Lynparza unless your healthcare provider tells you to. Your healthcare provider may temporarily stop treatment with Lynparza or change your dose of Lynparza if you experience side effects.. oYour healthcare provider will decide how long you stay on treatment.. oDo not take more than Lynparza tablets in day. If you have any questions about Lynparza, please talk to your healthcare provider or pharmacist.. oTake Lynparza by mouth times day. oEach dose should be taken about 12 hours apart.. oSwallow Lynparza tablets whole. Do not chew, crush, dissolve, or divide the tablets.. oTake Lynparza with or without food.. oIf 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 surgery to lower the amount of testosterone in your body (surgical castration).. oIf you miss dose of Lynparza, take your next dose at your usual scheduled time. Do not take an extra dose to make up for missed dose.. oIf you take too much Lynparza, call your healthcare provider or go to the nearest hospital emergency room right away.. onausea or vomiting. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms.. otiredness or weakness. olow red blood cell counts. odiarrhea. oloss of appetite. oheadache. ochanges in the way food tastes ocough. olow white blood cell counts. oshortness of breath. odizziness. oindigestion or heartburn. olow platelet counts. oStore Lynparza at room temperature, between 68F to 77F (20C to 25C).. oStore Lynparza in the original bottle to protect it from moisture.

SPL UNCLASSIFIED SECTION.

1.1 First-Line Maintenance Treatment of BRCA-mutated Advanced Ovarian Cancer Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], Lynparza can cause fetal harm when administered to pregnant woman. There are no available data on Lynparza use in pregnant women to inform the drug-associated risk. In an animal reproduction study, the 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 (see Data). Apprise pregnant women of the potential hazard to the fetus and the potential risk for loss of the pregnancy.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2-4%; and the risk for spontaneous abortion is approximately 15-20% in clinically recognized pregnancies.. Data Animal DataIn fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to Day of pregnancy, which resulted in increased post-implantation loss at dose level of 15 mg/kg/day (with maternal systemic exposures approximately 7% of the human exposure (AUC0-24h) at the recommended dose).In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.18% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital), and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter, and umbilical artery. Some findings noted above in the eyes, ribs, and ureter were observed at dose of 0.05 mg/kg/day olaparib at lower incidence.. 8.2 Lactation Risk SummaryNo data are available regarding the presence of olaparib in human milk, or on its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infants from Lynparza, advise lactating woman not to breastfeed during treatment with Lynparza and for one month after receiving the last dose.. 8.3 Females and Males of Reproductive Potential Pregnancy TestingRecommend pregnancy testing for females of reproductive potential prior to initiating treatment with Lynparza.ContraceptionFemalesLynparza can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least months following the last dose.MalesBased on findings in 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 months following the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for months following the last dose of Lynparza [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use Safety and effectiveness of Lynparza have not been established in pediatric patients.. 8.5 Geriatric Use Of the 2901 patients with advanced solid tumors who received Lynparza as single agent, 680 (23%) patients were aged >=65 years, and this included 206 (7%) patients who were aged >=75 years. Thirteen (0.4%) patients were aged >=85 years. Of the 535 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with bevacizumab, 204 (38%) patients were aged >=65 years, and this included 31 (6%) patients who were aged >=75 years. No overall differences in the safety or effectiveness of Lynparza were observed between these patients and younger patients.. 8.6 Renal Impairment No dosage modification is recommended in patients with mild renal impairment (CLcr 51 to 80 mL/min estimated by Cockcroft-Gault). Reduce Lynparza dosage to 200 mg twice daily in patients with moderate renal impairment (CLcr 31 to 50 mL/min) [see Dosage and Administration (2.5)]. There are no data in patients with severe renal impairment or end-stage disease (CLcr <=30 mL/min) [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oMyelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.5% of patients exposed to Lynparza monotherapy and the majority of events had fatal outcome. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed. (5.1)oPneumonitis: Occurred in 0.8% of patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed. (5.2)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise of the potential risk to fetus and to use effective contraception. (5.3, 8.1, 8.3)oVenous thromboembolic events including pulmonary embolism occurred in 7% of patients with mCRPC. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. (5.4). oMyelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.5% of patients exposed to Lynparza monotherapy and the majority of events had fatal outcome. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed. (5.1). oPneumonitis: Occurred in 0.8% of patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed. (5.2). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise of the potential risk to fetus and to use effective contraception. (5.3, 8.1, 8.3). oVenous thromboembolic events including pulmonary embolism occurred in 7% of patients with mCRPC. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. (5.4). 5.1 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 enrolling 2901 patients with various cancers who received Lynparza as single agent [see Adverse Reactions (6.1)], the cumulative incidence of MDS/AML was approximately 1.5% (43/2901). Of these, 51% (22/43) had fatal outcome. The median duration of therapy with Lynparza in patients who developed MDS/AML was years (range: 6 months to 10 years). All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy.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 or less after weeks, refer the patient to hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza.. 5.2 Pneumonitis. In clinical studies enrolling 2901 patients with various cancers who received Lynparza as single agent [see Adverse Reactions (6.1)], the incidence of pneumonitis, including fatal cases, was 0.8% (24/2901). If patients present with new or worsening respiratory symptoms such as dyspnea, cough and fever, or 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.. 5.3 Embryo-Fetal Toxicity. Lynparza can cause fetal harm when administered to 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 fetus and the potential risk for loss of the pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 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 months following the last dose of Lynparza [see Use in Specific Populations (8.1, 8.3)].. 5.4 Venous Thromboembolic Events Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients with metastatic castration resistant prostate cancer who received Lynparza plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving Lynparza and ADT had 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.