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These highlights do not include all the information needed to use LYNPARZA safely and effectively. See full prescribing information for LYNPARZA. LYNPARZA (olaparib) tablets, for oral useInitial U.S. Approval: 2014 | Lynparza [AstraZeneca Pharmaceuticals LP] | BioPortfolio

12:40 EST 27th January 2019 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

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

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.

Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious gBRCAmadvanced 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) ].

Lynparza is indicated in 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 a 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) ].

Information on FDA-approved tests for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics.

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

Select patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy for maintenance treatment with Lynparza based on the presence of deleterious or suspected deleterious gBRCAm or sBRCAm [see Indications and Usage (1.1) and Clinical Studies (14.2) ] . An FDA-approved test for the detection of tumor BRCA gene mutation for the first-line maintenance treatment of advanced ovarian cancer is not currently available.

Advanced gBRCAm Ovarian Cancer

Select patients with advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious gBRCA-mutation [see Indications and Usage (1.3) and Clinical Studies (14.2)].

gBRCAm HER2-negative Metastatic Breast Cancer

Select patients for the treatment of HER2-negative metastatic breast cancer with Lynparza based on the presence of deleterious or suspected deleterious gBRCA-mutation [see Indications and Usage (1.4) and Clinical Studies (14.3) ] .

The recommended dose of Lynparza is 300 mg (two 150 mg tablets) taken orally twice daily, with or without food, for a total daily dose of 600 mg. The 100 mg tablet is available for dose reduction.

If a patient misses a 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 [see How Supplied/Storage and Handling (16.2) ].

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

Continue treatment until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment. Patients with evidence of disease at 2 years, who in the opinion of the treating healthcare provider can derive further benefit from continuous treatment, can be treated beyond 2 years.

Maintenance Treatment of Recurrent Ovarian Cancer

Continue treatment until disease progression or unacceptable toxicity.

Advanced gBRCA-mutated Ovarian Cancer

Continue treatment until disease progression or unacceptable toxicity.

Germline BRCA-mutated HER2-negative Metastatic Breast Cancer

Continue treatment until disease progression or unacceptable toxicity.

To manage adverse reactions, consider interruption of treatment or dose reduction. The recommended dose reduction is 250 mg (one 150 mg tablet and one 100 mg tablet) taken twice daily, for a total daily dose of 500 mg.

If a further dose reduction is required, then reduce to 200 mg (two 100 mg tablets) taken twice daily, for a total daily dose of 400 mg.

Avoid concomitant use of strong or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If a strong CYP3A inhibitor must be co-administered, reduce the Lynparza dose to 100 mg (one 100 mg tablet) taken twice daily (equivalent to a total daily dose of 200 mg). If a moderate CYP3A inhibitor must be co-administered, reduce the Lynparza dose to 150 mg (one 150 mg tablet) taken twice daily (equivalent to a total daily dose of 300 mg) [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Patients with mild renal impairment (CLcr 51-80 mL/min as estimated by Cockcroft-Gault equation) do not require an adjustment in Lynparza dosing. In patients with moderate renal impairment (CLcr 31-50 mL/min) the recommended dose reduction is to 200 mg (two 100 mg tablets) twice daily, for a total daily dose of 400 mg. The pharmacokinetics of Lynparza have not been evaluated in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Tablets:

None.

Overall, the incidence of Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) in patients treated with Lynparza monotherapy in clinical trials, including long-term follow up, was <1.5% (26/2258) and the majority of events had a fatal outcome. Of these, 22/26 patients had a documented BRCA mutation, 2 patients had gBRCA wildtype and in 2 patients the BRCA mutation status was unknown. Additional cases of MDS/AML have been documented in patients treated with Lynparza in combination studies and in postmarketing reports. The duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Some of these patients also had a history of more than one primary malignancy or of bone marrow dysplasia.

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

Pneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, interrupt Lynparza treatment and promptly assess the source of the symptoms. If pneumonitis is confirmed, discontinue Lynparza treatment and treat the patient appropriately.

Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. In an animal reproduction study, administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 300 mg twice daily. Apprise pregnant women of the potential hazard to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Lynparza [see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1) ] .

Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Lynparza [see Use in Specific Populations (8.1 , 8.3) ] .

The following adverse reactions are discussed elsewhere in the labeling:

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

Adverse reactions presented below were reported from clinical trials in 1467 patients with ovarian or breast cancer (1019 received Lynparza, 448 received placebo or active comparator). The safety profile of olaparib was consistent across these clinical trials.

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

SOLO-1

The safety of Lynparza for the maintenance treatment of patients with BRCA-mutated advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was investigated in SOLO-1, a placebo-controlled, double-blind study in which 390 patients received either Lynparza 300 mg BID (n=260) or placebo tablets (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.

Dose interruptions due to an adverse reaction of any grade occurred in 52% of patients receiving Lynparza and 17% of those receiving placebo; dose reductions due to an adverse reaction occurred in 28% of Lynparza patients and 3% of placebo patients. 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 Lynparza patients and 2% in placebo patients. Specific adverse reactions that most frequently led to discontinuation in patients treated with Lynparza were fatigue (3.1%), anemia (2.3%), and nausea (2.3%).

In addition, the adverse reactions observed in SOLO-1 that occurred in <10% of patients receiving Lynparza were blood creatinine increased (8%), lymphopenia (6%), hypersensitivity (2%), dermatitis (1%), and mean cell volume increased (0.4%).

Maintenance Treatment of Recurrent Ovarian Cancer

SOLO-2

The safety of Lynparza for the maintenance treatment of patients with platinum sensitive gBRCAm ovarian cancer was investigated in SOLO-2. This study was a placebo-controlled, double-blind study in which 294 patients received either Lynparza 300 mg (2 x 150 mg tablets) twice daily (n=195) or placebo tablets twice daily (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. Dose interruptions due to an adverse reaction of any grade occurred in 45% of patients receiving Lynparza and 18% of those receiving placebo; dose reductions due to an adverse reaction occurred in 27% of Lynparza patients and 3% of placebo patients. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (22%), neutropenia (9%), and fatigue/asthenia (8%). Discontinuation occurred in 11% of Lynparza patients and 2% in placebo patients.

Table 3 summarizes the adverse reactions that occurred in at least 20% of patients who received Lynparza in SOLO-2. Table 4 presents the laboratory abnormalities that occurred in at least 25% of patients who received Lynparza in SOLO-2.

In 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%), increase in creatinine (11%), edema (8%), rash (6%), and lymphopenia (1%).

Study 19

The safety of Lynparza capsules as maintenance monotherapy was also evaluated in patients with platinum sensitive ovarian cancer who had received 2 or more previous platinum containing regimens in Study 19, a randomized, placebo-controlled, double-blind, multi-center study in which 264 patients received Lynparza 400 mg 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 those receiving Lynparza and 10% of those receiving placebo; dose reductions in 26% of Lynparza and 4% of placebo; and discontinuation in 6% of Lynparza and 2% in placebo.

Table 5 summarizes the adverse reactions that occurred in at least 20% of patients who received Lynparza in Study 19. Table 6 presents the laboratory abnormalities that occurred in at least 25% of patients from Study 19.

In 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%), and lymphopenia (1%).

Treatment of Advanced gBRCAm Ovarian Cancer After 3 or More Lines of Chemotherapy

Pooled data

Treatment with Lynparza (capsule formulation) as monotherapy was studied in 223 patients (pooled from 6 studies) with gBRCAm advanced ovarian cancer who had received 3 or more prior lines of chemotherapy. Adverse reactions led to dose interruption in 40% of patients, dose reduction in 4% of patients, and discontinuation in 7% of patients. There were 8 (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. The median exposure to Lynparza capsules in these patients was 5.2 months.

Table 7 presents adverse reactions reported in ≥20% of patients and Table 8 presents laboratory abnormalities that occurred in at least 25% of patients from the pooled studies.

The 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%) and venous thrombosis (including pulmonary embolism) (1%).

Treatment of gBRCAm HER2-negative Metastatic Breast Cancer

OlympiAD

The safety of Lynparza tablets as monotherapy was also 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. This study was a randomized, open-label, multi-center study in which 296 patients received either Lynparza 300 mg twice daily (n=205) or a chemotherapy (capecitabine, eribulin, or vinorelbine) of the healthcare provider’s choice (n=91) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.2 months in patients who received Lynparza and 3.4 months in patients who received chemotherapy. Dose interruptions due to an adverse reaction of any grade occurred in 35% of patients receiving Lynparza and 28% of those receiving chemotherapy; dose reductions due to an adverse reaction occurred in 25% of Lynparza patients and 31% of chemotherapy patients. Discontinuation occurred in 5% of Lynparza patients and 8% in chemotherapy patients.

Table 9 summarizes the adverse reactions that occurred in at least 20% of patients who received Lynparza in OlympiAD. Table 10 presents the laboratory abnormalities that occurred in at least 25% of patients who received Lynparza in OlympiAD.

In 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%).

General Disorders and Administration Site Conditions FatigueIncludes asthenia, fatigue, lethargy, malaise AnemiaNeutropeniaIncludes neutropenia, febrile neutropeniaLeukopeniaIncludes leukopenia, white blood cell count decreasedThrombocytopeniaIncludes: platelet count decreased, thrombocytopenia Gastrointestinal Disorders NauseaVomitingAbdominal painIncludes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal distension, abdominal discomfort, abdominal tendernessDiarrheaIncludes colitis, diarrhea, gastroenteritisDyspepsiaConstipationStomatitisIncludes stomatitis, aphthous ulcer; mouth ulceration Infections and Infestations Upper respiratory tract infection/influenza/nasopharyngitis/bronchitisUTIIncludes: urosepsis, urinary tract infection, urinary tract pain, pyuriaDecreased appetite Respiratory, Thoracic and Mediastinal Disorders DyspneaIncludes dyspnea and dyspnea exertional Nervous System Disorders DysgeusiaDizziness
Table 1 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 versus Placebo in SOLO-1
Lynparza
(n=260)
Placebo
(n=130)
Adverse Reaction All Grades (%) Grades
3 - 4 (%)
All Grades (%) Grades
3 - 4 (%)
 
 
67 4 42 2
Blood and Lymphatic System Disorders
 
38 21 9 2
 
17 6 7 3
 
13 3 8 0
 
11 1 4 2
 
 
77 1 38 0
 
40 0 15 1
 
45 2 35 1
 
37 3 26 0
 
17 0 12 0
 
28 0 19 0
 
11 0 2 0
 
 
28 0 23 0
 
13 1 7 0
Metabolism and Nutrition Disorders
 
20 0 10 0
 
 
15 0 6 0
 
 
26 0 4 0
 
20 0 15 1
Table 2 Laboratory Abnormalities Reported in ≥25% of Patients in SOLO-1
Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. Lynparza tablets n 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. =260 Placebo n =130
Grades 1-4 % Grades 3-4 % Grades 1-4 % Grades 3-4 %
Decrease in hemoglobin 87 19 63 2
Increase in Mean corpuscular volume 87 0 43 0
Decrease in leukocytes 70 7 52 1
Decrease in lymphocytes 67 14 29 5
Decrease in absolute neutrophil count 51 9 38 6
Increase in serum creatinine 34 0 18 0
Decrease in platelets 35 1 20 2
Table 3 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 Reactions Lynparza tablets n=195 Placebo n=99
Grades 1-4 % Grades 3-4 % Grades 1-4 % Grades 3-4 %
Blood 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. 44 20 9 2
Gastrointestinal disorders
     Nausea 76 3 33 0
     Vomiting 37 3 19 1
     Diarrhea 33 2 22 0
     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. 20 1 16 0
Infections and Infestations
     Nasopharyngitis/URI/sinusitis/rhinitis/influenza 36 0 29 0
General disorders and administration site conditions
     Fatigue including asthenia 66 4 39 2
Metabolism and nutrition disorders
     Decreased appetite 22 0 11 0
Musculoskeletal and connective tissue disorder
     Arthralgia/myalgia 30 0 28 0
Nervous system disorders
     Dysgeusia 27 0 7 0
     Headache 26 1 14 0
Table 4 Laboratory Abnormalities Reported in ≥25% of Patients in SOLO-2
Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. Lynparza tablets n 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. =195 Placebo n =99
Grades 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 hemoglobin 83 17 69 0
Decrease in leukocytes 69 5 48 1
Decrease in lymphocytes 67 11 37 1
Decrease in absolute neutrophil count 51 7 34 3
Increase in serum creatinine 44 0 29 0
Decrease in platelets 42 2 22 1
Table 5 Adverse ReactionsGraded according to NCI CTCAE v4.0. in Study 19 (≥20% of Patients Who Received Lynparza)
Adverse Reactions Lynparza capsules n=136 Placebo n=128
Grades 1-4 % Grades 3-4 % Grades 1-4 % Grades 3-4 %
Blood and lymphatic disorders
     AnemiaRepresents grouped terms of related terms that reflect the medical concept of the adverse reaction. 23 7 7 1
Gastrointestinal disorders
     Nausea 71 2 36 0
     Vomiting 35 2 14 1
     Diarrhea 28 2 25 2
     Constipation 22 1 12 0
     Dyspepsia 20 0 9 0
General disorders and administration site conditions
     Fatigue (including asthenia) 63 9 46 3
Infections and infestations
     Respiratory tract infection 22 2 11 0
Metabolism and nutrition disorders
     Decreased appetite 21 0 13 0
Nervous system disorders
     Headache 21 0 13 1
Table 6 Laboratory Abnormalities Reported in ≥25% of Patients in Study 19
Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. Lynparza capsules n 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. =136 Placebo n =129
Grades 1-4 % Grades 3-4 % Grades 1-4 % Grades 3-4 %
Decrease in hemoglobin 82 8 58 1
Increase in mean corpuscular volumeRepresents the proportion of subjects whose mean corpuscular volume was > ULN. 82 - 51 -
Decrease in leukocytes 58 4 37 2
Decrease in lymphocytes 52 10 32 3
Decrease in absolute neutrophil count 47 7 40 2
Increase in serum creatinine 45 0 14 0
Decrease in platelets 36 4 18 0
     Nasopharyngitis/URI
Table 7 Adverse Reactions Reported in Pooled Data (≥20% of Patients Who Received Lynparza)
Adverse Reactions 3 or more lines of prior Chemotherapy
Grades 1-4 n=223 (%) Grades 3-4 n=223 (%)
Blood and Lymphatic disorders
     Anemia 34 18
Gastrointestinal disorders
     Decreased appetite 22 1
     Nausea 64 3
     Vomiting 43 4
     Diarrhea 31 1
     Dyspepsia 25 0
General disorders
     Fatigue/asthenia 66 8
Infections and infestations
 
26 0
Musculoskeletal and Connective Tissue disorders
     Arthralgia/musculoskeletal pain 21 0
     Myalgia 22 0
Table 8 Laboratory Abnormalities Reported ≥25% of Patients in Pooled Data
Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. 3 or more lines of prior Chemotherapy
Grades 1-4 n 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. =223 (%) Grades 3-4 n =223 (%)
Decrease in hemoglobin 90 15
Decrease in absolute neutrophil count 25 7
Decrease in platelets 30 3
Decrease in lymphocytes 56 17
Mean corpuscular volume elevation 57 -
Increase in creatinine 30 2
Table 9 Adverse ReactionsGraded according to NCI CTCAE v4.0.in OlympiAD (≥20% of Patients Who received Lynparza)
Adverse Reactions Lynparza tablets n=205 Chemotherapy n=91
Grades 1-4 % Grades 3-4 % Grades 1-4 % Grades 3-4 %
Blood and lymphatic disorders
     AnemiaRepresents grouped terms consisting of anemia (anemia erythropenia, hematocrit decreased, hemoglobin decreased and red blood cell count decreased). 40 16 26 4
     LeukopeniaRepresents grouped terms consisting of leukopenia (leukopenia and white blood cell count decreased). 25 5 31 13
     NeutropeniaRepresents grouped terms consisting of neutropenia (febrile neutropenia, granulocyte count decreased, granulocytopenia, neutropenia, neutropenic infection, neutropenic sepsis, neutrophil count decreased). 27 9 50 26
Gastrointestinal disorders
     Nausea 58 0 35 1
     Vomiting 30 0 15 1
     Diarrhea 21 1 22 0
Infections 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. 27 1 22 0
General disorders and administration site conditions
     Fatigue (including asthenia) 37 4 36 1
Nervous system disorders
     Headache 20 1 15 2
Table 10 Laboratory Abnormalities Reported ≥25% of Patients in OlympiAD
Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. Lynparza tablets n 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. = 205 Chemotherapy n = 91
Grades 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 > ULN. 71 - 33 -
Decrease in hemoglobin 82 17 66 3
Decrease in leukocytes 71 8 70 23
Decrease in lymphocytes 73 21 63 3
Decrease in absolute neutrophil count 46 11 65 38
Decrease in platelets 33 3 28 0

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

Immune System Disorders: Hypersensitivity (rash/dermatitis).

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

Olaparib is primarily metabolized by CYP3A. In patients (n=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 170%. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 121%.

Avoid concomitant use of strong CYP3A inhibitors such as itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir or moderate CYP3A inhibitors such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil. If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [see Dosage and Administration (2.5)].

Avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during Lynparza treatment since they are CYP3A inhibitors [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

In patients (n=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by approximately 60%.

Avoid concomitant use of strong CYP3A inducers such as phenytoin, rifampicin, carbamazepine, and St. John’s Wort or moderate CYP3A4 inducers such as bosentan, efavirenz, etravirine, modafinil, and nafcillin. If a moderate CYP3A inducer cannot be avoided, there is a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3)].

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 a 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 Data

In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to Day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 7% of the human exposure (AUC) 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. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.18% of human exposure (AUC) 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 a dose of 0.05 mg/kg/day olaparib at lower incidence.

Risk Summary

No 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 a lactating woman not to breastfeed during treatment with Lynparza and for one month after receiving the last dose.

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with Lynparza.

Contraception

Females

Lynparza can cause fetal harm when administered to a 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 6 months following the last dose.

Males

Based 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 3 months following the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].

The safety and efficacy of Lynparza have not been established in pediatric patients.

In clinical studies of Lynparza enrolling 687 patients with advanced solid tumors who received Lynparza tablets 300 mg twice daily as monotherapy, 146 (21%) patients were aged ≥65 years, and this included 29 (4%) patients who were aged ≥75 years. No patients were aged ≥85 years. No overall differences in the safety or effectiveness of Lynparza were observed between younger and older patients.

No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment. A 15% increase and an 8% increase in mean exposure (AUC), respectively, were observed in patients with mild and moderate hepatic impairment (Child-Pugh classification A and B) compared to patients with normal hepatic function. There are no data in patients with severe hepatic impairment (Child-Pugh classification C) [see Clinical Pharmacology (12.3)].

No adjustment to the starting dose is required in patients with mild renal impairment, but patients should be monitored closely for toxicity. A 24% increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr=51-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). A 44% increase in AUC was observed in patients with moderate renal impairment (CLcr=31-50 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). For patients with moderate renal impairment, reduce the dose of Lynparza to 200 mg twice daily [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)].

There is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat the patient symptomatically.

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

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

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

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

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

Lynparza 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 BRCA and non-BRCA proteins 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.

Cardiac Electrophysiology

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

The oral bioavailability of the tablet formulation is higher than the capsule formulation. Population pharmacokinetic analyses have shown that the steady state exposure (AUC) following 300 mg tablet twice daily was 77% higher compared to that following 400 mg capsule twice daily. The olaparib geometric mean AUC and C following a single 300 mg tablet dose were 42.0 μg*h/mL (n=204) and 5.8 μg/mL (n=204), respectively, and the steady state geometric mean AUC and C following 300 mg tablet twice daily were 49.0 μg*h/mL (n=227) and 7.7 μg/mL (n=227), respectively. Olaparib showed time-dependent PK that the steady state clearance decreased by 15% after multiple dosing.

Absorption

Following oral administration of olaparib, absorption is rapid with median peak plasma concentrations typically achieved 1.5 hours after dosing. An AUC mean accumulation ratio of 1.8 is observed at steady state following multiple dosing of 300 mg tablets twice daily.

Systemic exposure (single dose AUC) to olaparib increases approximately proportionally with doses over the dose range of 25 mg to 450 mg, C increased slightly less than proportionally for the same dose range.

Co-administration of a high fat meal with olaparib slowed the rate (t delayed by 2.5 hours) of absorption, but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 8%).

Distribution

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

Metabolism

In vitro, CYP3A4/5 were shown to be the enzymes primarily responsible for the metabolism of olaparib.

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

Excretion

A mean (± standard deviation) terminal plasma half-life of 14.9 ± 8.2 hours and apparent plasma clearance of 7.4 ± 3.9 L/h were observed after a single 300 mg dose of olaparib.

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

Drug Interactions

Based on the data from a drug-interaction trial (n=57), the AUC and C of olaparib increased by 170% and 42%, respectively, when olaparib was administered in combination with itraconazole, a strong CYP3A inhibitor. Simulations suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and C of olaparib by 121% and 14%, respectively.

Based on the data from a drug-interaction trial (n=22), the AUC and C of olaparib decreased by 87% and 71%, respectively, when olaparib was administered in combination with rifampicin, a strong CYP3A inducer. Simulations suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC and C of olaparib by approximately 60% and 31%, respectively.

In vitro studies have shown that olaparib is both an inhibitor and inducer of CYP3A and an inducer of CYP2B6. Olaparib is predicted to be a weak CYP3A inhibitor in humans. In vitro studies also indicated that olaparib is an inhibitor of UGT1A1, BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown. In vitro, olaparib is a substrate of, and inhibits, the efflux transporter P-gp. The potential for olaparib to induce P-gp has not been evaluated.

Pharmacokinetics in Specific Populations

Hepatic Impairment

In a hepatic impairment trial, the mean AUC increased by 15% and the mean C 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 C 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 had 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).

Renal Impairment

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

Carcinogenicity studies have not been conducted with olaparib.

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

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

In a male fertility study, olaparib had no effect on mating and fertility in rats at oral doses up to 40 mg/kg/day following at least 70 days of olaparib treatment (with systemic exposures of approximately 5% of the human exposure (AUC) at the recommended dose).

SOLO-1

SOLO-1 (NCT01844986) was a randomized, double-blind, placebo-controlled, multi-center trial that compared the efficacy of Lynparza with placebo in patients with BRCA-mutated (BRCAm) advanced ovarian, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy in which 391 patients were randomized (2:1) to receive Lynparza tablets 300 mg orally twice daily (n=260) or placebo (n=131). Treatment was continued for up to 2 years or until disease progression or unacceptable toxicity; however, patients with evidence of disease at 2 years, who in the opinion of the treating healthcare provider could derive further benefit from continuous treatment, could be treated beyond 2 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.

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 score was 0 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 2 patients had somatic BRCAm (sBRCAm).

Of the 391 patients randomized in SOLO-1, 386 were retrospectively or prospectively tested with 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 only based on an investigational tissue assay.

SOLO-1 demonstrated a statistically significant improvement in investigator-assessed PFS for Lynparza compared to placebo. Results from a 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).

NR not reached; CI Confidence Interval.

 

Figure 1 Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival-SOLO-1

Table 11 Efficacy Results - SOLO-1 (Investigator Assessment)
Lynparza tablets (n=260) Placebo (n=131)
Progression-Free Survival Median follow up of 41 months in both treatment arms.
     Number of events (%) 102 (39%) 96 (73%)
     Median, months NR 13.8
     Hazard ratioA value <1 favors olaparib. Hazard ratio from a Cox proportional hazards model including response to previous platinum chemotherapy (complete response versus partial response) as a covariate.(95% CI) 0.30 (0.23-0.41)
     p-valueThe p-value is derived from a stratified log-rank test. <0.0001

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-2

SOLO-2 (NCT01874353) was a double-blind, placebo-controlled trial in which patients (n=295) with gBRCAm ovarian, fallopian tube, or primary peritoneal cancer were randomized (2:1) to receive 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. All patients had a deleterious or suspected deleterious germline BRCA-mutation as detected either by a local test (n=236) or central Myriad CLIA test (n=59), subsequently confirmed by BRACAnalysis CDx(n=286).

The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST, version 1.1. An additional endpoint included OS.

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 performance score was 0 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 a 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.

SOLO-2 demonstrated a statistically significant improvement in investigator-assessed PFS in patients randomized to Lynparza as compared with placebo (Table 12 and Figure 2). Results from a blinded independent review were consistent. At the time of the analysis of PFS, OS data were not mature with 24% of events.

Figure 2 Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival – SOLO-2

Study 19

Study 19 (NCT00753545) was a double-blind, placebo-controlled trial in which patients (n=265) with platinum-sensitive ovarian cancer who had received 2 or more previous platinum-containing regimens were randomized (1:1) to receive Lynparza capsules 400 mg orally twice daily or placebo until unacceptable toxicity or progressive disease. Randomization was stratified by response to last platinum chemotherapy (CR versus PR), 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 of the study was investigator-assessed PFS evaluated according to RECIST, version 1.0.

The median age of patients treated with Lynparza (n=136) was 58 years (range: 21 to 89) and 59 years (range 33 to 84) among patients treated with placebo (n=129). ECOG performance status was 0 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 a 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. A 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.

Study 19 demonstrated a statistically significant improvement in investigator-assessed PFS in patients treated with Lynparza versus placebo (Table 13 and Figure 3).

Figure 3: Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival – Study 19

Table 12 Efficacy Results - SOLO-2 (Investigator Assessment)
Lynparza tablets (n=196) Placebo (n=99)
Progression-Free Survival
     Number of events (%) 107 (54.6%) 80 (80.8%)
     Median, months 19.1 5.5
     Hazard ratioHazard ratio from a 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 a stratified log-rank test. <0.0001
Table 13 Efficacy Results - Study 19 (Investigator Assessment)
Lynparza capsules (n=136) Placebo (n=129)
Progression-Free Survival
     Number of events (%) 60 (44%) 94 (73%)
     Median, months 8.4 4.8
     Hazard ratioHazard ratio from a 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 a Cox proportional hazards model. <0.0001
Overall Survival Without adjusting for multiple analyses.
     Number of events (%) 98 (72%) 112 (87%)
     Median, months 29.8 27.8
    Hazard ratio (95% CI)                                                      0.73 (0.55, 0.95)

The efficacy of Lynparza was also investigated in a single-arm study of patients with deleterious or suspected deleterious gBRCAm advanced cancers. A 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 at a dose of 400 mg twice daily as monotherapy until disease progression or intolerable toxicity. Objective response rate (ORR) and duration of response (DOR) were 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 0 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 CDx™. Efficacy results are summarized in Table 14.

Table 14 Overall Response and Duration of Response in Patients with gBRCA-mutated Advanced Ovarian Cancer Who Received 3 or More Lines of Chemotherapy
n=137
Objective Response Rate (95% CI) 34% (26, 42)
Complete Response 2%
Partial Response 32%
Median DOR in months (95% CI) 7.9 (5.6, 9.6)

OlympiAD

OlympiAD (NCT02000622) was an open-label study in which patients (n=302) with gBRCAm HER2-negative metastatic breast cancer were randomized 2:1 to receive Lynparza 300 mg tablets or healthcare provider’s 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). Patients were required to have received treatment with an anthracycline (unless contraindicated) and a taxane, in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor-positive disease must have progressed on at least 1 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 a PARP inhibitor was permitted. Of the 302 patients randomized onto OlympiAD, 299 were tested with the BRACAnalysis CDxand 297 were confirmed to have deleterious or suspected deleterious gBRCAm status; 202 were randomized to the Lynparza arm and 95 to the healthcare provider’s choice of chemotherapy arm.

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 0 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 a median of 1 prior chemotherapy regimen for metastatic disease; approximately 30% had not received a 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.

The major efficacy outcome measure was PFS assessed by blinded independent central review (BICR) using RECIST version 1.1. 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 15 and Figure 4. 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.

Figure 4: Kaplan-Meier Curves of Progression-Free Survival – OlympiAD

Table 15 Efficacy Results - OlympiAD (BICR-assessed)
Lynparza tablets (n=205) Chemotherapy (n=97)
Progression-Free Survival
     Number of events (%) 163 (80%) 71 (73%)
     Median, months 7.0 4.2
     Hazard ratio (95% CI)Hazard ratio is derived from a 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. 0.0009
Patients with Measurable Disease n=167 n=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, months 19.3 17.1
    Hazard ratio (95% CI) 0.90 (0.66, 1.23)

Lynparza is available as 150 mg and 100 mg tablets.

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.

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

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2018

weakness weight loss fever frequent infectionsblood in urine or stool shortness of breath feeling very tired bruising or bleeding more easilybefore treatment with Lynparza every month during treatment with Lynparza weekly if you have low blood cell counts that last a 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 a 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.advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with a certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene. Lynparza is used as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you. ovarian 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. advanced ovarian cancer with a certain type of abnormal inherited BRCA gene, and have received treatment with 3 or more prior types of chemotherapy medicines. Your healthcare provider will perform a test to make sure that Lynparza is right for you. a certain type of abnormal inherited BRCA gene, human epidermal growth factor receptor 2 (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 a test to make sure that Lynparza is right for you.It is not known if Lynparza is safe and effective in children.have lung or breathing problems have kidney problems are 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 a 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 6 months after the last dose of Lynparza. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant Males with female partners who are pregnant or able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 3 months after the last dose of Lynparza Do not donate sperm during treatment with Lynparza and for 3 months after your final dose are breastfeeding or plan to breastfeed. It is not known if Lynparza passes into your breast milk. Do not breastfeed during treatment with Lynparza and for 1 month after receiving the last dose of Lynparza. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking Lynparza and certain other medicines may affect how Lynparza works and may cause side effects. Take Lynparza tablets exactly as your healthcare provider tells you. Do 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. Your healthcare provider will decide how long you stay on treatment. Do not take more than 4 Lynparza tablets in 1 day. If you have any questions about Lynparza, please talk to your healthcare provider or pharmacist. Take Lynparza by mouth 2 times a day. Each dose should be taken about 12 hours apart. Swallow Lynparza tablets whole. Do not chew, crush, dissolve, or divide the tablets. Take Lynparza with or without food. If you miss a dose of Lynparza, take your next dose at your usual scheduled time. Do not take an extra dose to make up for a missed dose. If you take too much Lynparza, call your healthcare provider or go to the nearest hospital emergency room right away.Avoid grapefruit, grapefruit juice, Seville oranges and Seville orange juice during treatment with Lynparza since they may increase the level of Lynparza in your blood.nausea or vomiting. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms. low number of red or white blood cells stomach-area (abdominal) pain dizziness tiredness or weakness sore throat or runny nose diarrhea joint, muscle, and back pain headache constipationmouth sores respiratory tract infections changes in kidney function blood test changes in the way food tastes loss of appetite low number of platelets indigestion or heartburnStore Lynparza at room temperature, between 68°F to 77°F (20°C to 25°C). Store Lynparza in the original bottle to protect it from moisture. Keep Lynparza and all medicines out of the reach of children.
Medication Guide Lynparza® (Lin-par-zah) (olaparib) tablets
What is the most important information I should know about Lynparza? Lynparza may cause serious side effects, including: Bone marrow problems called Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Some people who have 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 a sign of serious bone marrow problems, including MDS or AML. Symptoms may include:
Your healthcare provider will do blood tests to check your blood cell counts:
What is Lynparza? Lynparza is a prescription medicine used to treat adults who have:
Before taking Lynparza, tell your healthcare provider about all of your medical conditions, including if you:
How should I take Lynparza?
What should I avoid while taking Lynparza?
What are the possible side effects of Lynparza? Lynparza may cause serious side effects. See “What is the most important information I should know about Lynparza?” The most common side effects of Lynparza are:
 
o o o o o o o o o
o o o o o o o
These are not all of the possible side effects of Lynparza. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Lynparza?
General information about the safe and effective use of Lynparza Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Lynparza for a condition for which it was not prescribed. Do not give Lynparza to other people, even if they have the same symptoms 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 Lynparza? Active ingredient: olaparib Inactive ingredients: Tablet contains: copovidone, mannitol, colloidal silicon dioxide and sodium stearyl fumarate Tablet coating contains: hypromellose, polyethylene glycol 400, titanium dioxide, ferric oxide yellow and ferrosoferric oxide (150 mg tablet only)
Lynparza is a registered trademark of the AstraZeneca group of companies. © AstraZeneca 2018   Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 For more information, call 1-800-236-9933 or go to www.Lynparza.com.

NDC 0310-0668-60

Lynparza

(olaparib) tablets

100 mg

Attention: Lynparza Tablets and Capsules

are NOT substitutable. Do NOT take more than 4 Tablets a day.

60 Tablets

Rx only

AstraZeneca

NDC 0310-0679-12

Lynparza

(olaparib) tablets

150 mg

Attention: Lynparza Tablets and Capsules

are NOT substitutable. Do NOT take more than 4 Tablets a day.

120 Tablets

Rx only

AstraZeneca

Manufacturer

AstraZeneca Pharmaceuticals LP

Active Ingredients

Source

Drugs and Medications [1 Associated Drugs and Medications listed on BioPortfolio]

Lynparza [astrazeneca pharmaceuticals lp]

These highlights do not include all the information needed to use LYNPARZA safely and effectively. See full prescribing information for LYNPARZA. LYNPARZA (olaparib) capsules, for oral useInitial U.S....

Clinical Trials [7 Associated Clinical Trials listed on BioPortfolio]

Lynparza Breast Cancer Clinical Experience Investigation

To characterise the development of ADRs of bone marrow depression in patients under actual post-marketing use.

A Phase Ib/II Study of Olaparib With Sapacitabine in BRCA Mutant Breast Cancer

This research study is studying a combination of drugs as a possible treatment for breast cancer with a BRCA mutation. The interventions involved in this study are: - Sapacitabi...

Olaparib in Recurrent IDH-mutant Glioma

Recent data demonstrate that in IDH-mutant gliomas, 2 hydroxy-glutarate production induces a homologous recombination defect that renders tumor cells exquisitely sensitive to poly(adenosin...

Circulating Tumor DNA Guiding (Olaparib) Lynparza® Treatment in Ovarian Cancer

This is a randomized, open-label, two-arm study in patients with relapsed epithelial ovarian tumors. Patients will be randomized in a 1:1 ratio to receive olaparib or standard chemotherapy...

Lynparza Ovarian Cancer Clinical Experience Investigation (All Case Investigation)

The objective of the Clinical Experience Investigation (CEI) is to collect following data to characterise safety and efficacy of LYMPARZA Tablets 100mg and 150mg (LYMPARZA) in usual post-m...

PubMed Articles [0 Results]

None

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