LYNPARZA

Olaparib is a 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 C 24 H 23 FN 4 O and the relative molecular mass is 434.46.

It has the following chemical structure

Olaparib is a 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). chemical structure.

Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: Ovarian cancer.

• 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.

• a deleterious or suspected deleterious BRCA mutation, and/or.

• genomic instability.

• for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

Breast cancer.

• for the adjuvant treatment of adult patients with deleterious or suspected deleterious g BRCA m human epidermal growth factor receptor 2 (HER2)-negative high risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy.

• for the treatment of adult patients with deleterious or suspected deleterious gBRCA m, 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.

Pancreatic cancer.

• for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCA m metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.

Prostate cancer.

• 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.

• in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA -mutated ( BRCA m) metastatic castration-resistant prostate cancer (mCRPC).

Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. 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. 1.3 Maintenance Treatment of BRCA-mutated Recurrent Ovarian Cancer Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. 1.4 Adjuvant Treatment of Germline BRCA -mutated HER2-negative High Risk Early Breast Cancer Lynparza is indicated for the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCA m human epidermal growth factor receptor 2 (HER2)-negative high risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy.

Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. 1.5 Germline BRCA -mutated HER2-negative Metastatic Breast Cancer Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious gBRCA m, HER2-negative metastatic breast cancer, who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.

Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. 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 gBRCA m metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.

Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. 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. 1.8 Treatment of BRCA -mutated Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone Lynparza is indicated in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).

Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3.

PARP enzymes are involved in normal cellular functions, such as DNA transcription and DNA repair.

Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer, both as monotherapy or following platinum-based chemotherapy.

Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA1/2, ATM, or other genes involved in the homologous recombination repair (HRR) of DNA damage and correlated with platinum response.

In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

In prostate cancer models, PARP1 has been shown to contribute to androgen receptor (AR) activity regulation; the combination of olaparib and AR inhibition resulted in cytotoxicity in vitro and anti-tumor activity in mouse xenograft models. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of olaparib on cardiac repolarization was assessed in 119 patients following a single dose of 300 mg and in 109 patients following multiple dosing of 300 mg twice daily.

No clinically relevant effect of olaparib on QT interval was observed. 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 (C max ) increased slightly less than proportionally for the same dose range.

Olaparib showed time-dependent pharmacokinetics and an

AUC mean accumulation ratio of 1.8 is observed at steady state following a dose of 300 mg twice daily.

The mean (CV%) olaparib C max is 5.4 μg/mL (32%) and AUC is 39.2 μg*h/mL (44%) following a single 300 mg dose.

The mean steady state olaparib C max and AUC is 7.6 μg/mL (35%) and 49.2 μg*h/mL (44%), following a dose of 300 mg twice daily.

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

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

The mean (± standard deviation) apparent volume of distribution of olaparib is 158 ± 136 L following a single 300 mg dose of Lynparza.

The protein binding of olaparib is approximately 82% in vitro.

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

Metabolism Olaparib is metabolized by cytochrome

P450 (CYP) 3A in vitro.

Following an oral dose of radiolabeled olaparib to female patients, unchanged olaparib accounted for 70% of the circulating radioactivity in plasma.

It was extensively metabolized with unchanged drug accounting for 15% and 6% of radioactivity in urine and feces, respectively.

The majority of the metabolism is attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation.

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

The majority of the material was excreted as metabolites.

Specific Populations Patients with Renal Impairment

In a renal impairment trial, the mean AUC increased by 24% and C max 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).

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

CYP3A Inhibitors: Concomitant use of itraconazole (strong CYP3A inhibitor) increased olaparib C max by 42% and AUC by 170%.

Concomitant use of fluconazole (moderate CYP3A inhibitor) is predicted to increase olaparib C max by 14% and AUC by 121%.

CYP3A Inducers: Concomitant use of rifampicin (strong CYP3A inducer) decreased olaparib C max by 71% and AUC by 87%.

Concomitant use of efavirenz (moderate CYP3A inducer) is predicted to decrease olaparib C max by 31% and AUC by 60%.

In vitro Studies CYP Enzymes

Olaparib is both an inhibitor and inducer of CYP3A and an inducer of CYP2B6.

Olaparib is predicted to be a weak CYP3A inhibitor in humans.

Olaparib is an inhibitor of UGT1A1.

Olaparib is an inhibitor of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1, and MATE2K.

Olaparib is a substrate and inhibitor of the efflux transporter P-gp.

The potential for olaparib to induce

P-gp has not been evaluated.

• as a single agent were nausea, fatigue (including asthenia), anemia, vomiting, diarrhea, decreased appetite, headache, dysgeusia, cough, neutropenia, dyspnea, dizziness, dyspepsia, leukopenia, and thrombocytopenia.

• in combination with bevacizumab were nausea, fatigue (including asthenia), anemia, lymphopenia, vomiting, diarrhea, neutropenia, leukopenia, urinary tract infection, and headache.

• in combination with abiraterone and prednisone or prednisolone were anemia, fatigue, nausea, diarrhea, decreased appetite, lymphopenia, dizziness, and abdominal pain.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Unless otherwise specified, the data described in the WARNINGS AND PRECAUTIONS reflect exposure to Lynparza as a single agent or as part of a combination regimen (SOLO-1, SOLO-2, PAOLA-1, OlympiA, OlympiAD, POLO, PROfound, and PROpel) in 2851 patients that were pooled to conduct safety analyses.

Additional data reflect exposure to

Lynparza as a single agent in 2901 patients; 2135 patients with exposure to 300 mg twice daily tablet dose including five controlled, randomized, trials (SOLO-1, SOLO-2, OlympiAD, POLO, and PROfound) and to 400 mg twice daily capsule dose in 766 patients in other trials that were pooled to conduct safety analyses.

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

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

First-Line Maintenance Treatment of BRCA -mutated Advanced Ovarian Cancer SOLO-1 The safety of Lynparza for the maintenance treatment of patients with BRCA-mutated advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was investigated in SOLO.

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

Table 2 Adverse Reactions Graded 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 Reaction Lynparza tablets n=260 Placebo n=130 All Grades (%) Grades 3 – 4 (%) All Grades (%) Grades 3 – 4 (%) Gastrointestinal.

Disorders Nausea 77 1 38 0 Abdominal pain Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal distension, abdominal discomfort, and abdominal tenderness. 45 2 35 1 Vomiting 40 0 15 1 Diarrhea Includes colitis, diarrhea, and gastroenteritis. 37 3 26 0 Constipation 28 0 19 0 Dyspepsia 17 0 12 0 Stomatitis Includes stomatitis, aphthous ulcer, and mouth ulceration. 11 0 2 0 General.

Disorders and Administration Site Conditions Fatigue Includes asthenia, fatigue, lethargy, and malaise. 67 4 42 2 Blood and Lymphatic System.

Disorders Anemia 38 21 9 2 Neutropenia Includes neutropenia and febrile neutropenia. 17 6 7 3 Leukopenia Includes leukopenia and white blood cell count decreased. 13 3 8 0 Thrombocytopenia Includes platelet count decreased and thrombocytopenia. 11 1 4 2.

Infections and Infestations Upper respiratory tract infection/ influenza/nasopharyngitis/bronchitis 28 0 23 0 UTI Includes urosepsis, urinary tract infection, urinary tract pain, and pyuria. 13 1 7 0 Nervous System.

Disorders Dysgeusia 26 0 4 0 Dizziness 20 0 15 1 Metabolism and Nutrition.

Disorders Decreased appetite 20 0 10 0 Respiratory, Thoracic and Mediastinal.

Disorders Dyspnea Includes dyspnea and dyspnea exertional. 15 0 6 0 Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza were increased blood creatinine (8%), lymphopenia (6%), VTE (3%), hypersensitivity (2%), MDS/AML (1.9%), pneumonitis (1.9%), dermatitis (1%), and increased mean cell volume (0.4%).

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

• Decrease in leukocytes 70 7 52 1 Decrease in lymphocytes 67 14 29 5 Decrease in absolute neutrophil count 51 9 38 6 Decrease in platelets 35 1 20 2 Increase in serum creatinine 34 0 18 0 First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab PAOLA-1 The safety of Lynparza in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer following first-line treatment containing platinum-based chemotherapy and bevacizumab was investigated in PAOLA-1.

This study was a placebo-controlled, double-blind study in which 802 patients received either Lynparza 300 mg BID in combination with bevacizumab (n=535) or placebo in combination with bevacizumab (n=267) until disease progression or unacceptable toxicity.

The median duration of treatment with

Lynparza was 17.3 months and 11 months for bevacizumab post-randomization on the Lynparza/bevacizumab arm.

Fatal adverse reactions occurred in 1 patient due to concurrent pneumonia and aplastic anemia.

Serious adverse reactions occurred in 31% of patients who received Lynparza/bevacizumab.

Serious adverse reactions in >5% of patients included hypertension (19%) and anemia (17%).

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

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

Discontinuation due to adverse reactions occurred in 20% of patients receiving Lynparza/bevacizumab.

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

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

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

Table 4 Adverse Reactions Graded 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 Arm Adverse Reactions Lynparza/bevacizumab n=535 Placebo/bevacizumab n=267 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) General.

Disorders and Administration Site Conditions Fatigue (including asthenia) Includes asthenia and fatigue. 53 5 32 1.5 Gastrointestinal.

Disorders Nausea 53 2.4 22 0.7 Vomiting 22 1.7 11 1.9 Blood and Lymphatic.

Disorders Anemia Includes anemia, anemia macrocytic, erythropenia, haematocrit decreased, haemoglobin decreased, normochromic anemia, normochromic normocytic anemia, normocytic anemia, and red blood cell count decreased. 41 17 10 0.4 Lymphopenia Includes B-lymphocyte count decreased, lymphocyte count decreased, lymphopenia, and T-lymphocyte count decreased. 24 7 9 1.1 Leukopenia Includes leukopenia and white blood cell count decreased. 18 1.9 10 1.5 Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza/bevacizumab were dysgeusia (8%), dyspnea (8%), stomatitis (5%), dyspepsia (4.3%), erythema (3%), dizziness (2.6%), hypersensitivity (1.7%), pneumonitis (0.9%), and MDS/AML (0.7%).

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

Table 5 Laboratory Abnormalities Reported in ≥25% of Patients in PAOLA-1 Reported within 30 days of the last dose.

Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

Lynparza/bevacizumab n =535 Placebo/bevacizumab 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. =267 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Decrease in hemoglobin 79 13 55 0.4 Decrease in lymphocytes 63 10 42 3 Increase in serum creatinine 61 0.4 36 0.4 Decrease in leukocytes 59 3.4 45 2.2 Decrease in absolute neutrophil count 35 7 30 3.7 Decrease in platelets 35 2.4 28 0.4 Maintenance Treatment of BRCA -mutated Recurrent Ovarian Cancer SOLO-2 The safety of Lynparza for the maintenance treatment of patients with platinum sensitive g BRCA m ovarian cancer was investigated in SOLO-2.

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.

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

Table 6 Adverse Reactions Graded.

• Recommended dosage is 300 mg taken orally twice daily with or without food.

Information for the recommended duration.

• Patients receiving Lynparza for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

• For moderate renal impairment (CLcr 31-50 mL/min), reduce Lynparza dosage to 200 mg orally twice daily. 2.1 Patient Selection Information on FDA-approved tests for the detection of genetic mutations is available at.

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 1 Biomarker Testing for Patient Selection Where testing fails or tissue sample is unavailable/insufficient, or when germline testing is negative, consider using an alternative test, if available.

Indication Biomarker Sample type Tumor Blood

Plasma (ctDNA) First-line maintenance treatment of germline or somatic BRCAm advanced ovarian cancer BRCA1 m, BRCA2 m X X First-line maintenance treatment of HRD-positive advanced ovarian cancer in combination with bevacizumab BRCA1 m, BRC A2m and/or genomic instability X Maintenance treatment of germline or somatic BRCA m recurrent ovarian cancer BRCA1 m, BRCA2 m X X Adjuvant treatment of gBRCA m HER2-negative high risk early breast cancer gBRCA1 m, gBRCA2 m X g BRCA m HER2-negative metastatic breast cancer gBRCA1 m, gBRCA2 m X First-line maintenance treatment of germline BRCA -mutated metastatic pancreatic adenocarcinoma gBRCA1 m, gBRCA2 m X Germline or somatic HRR gene-mutated metastatic castration-resistant prostate cancer ATM m, BRCA1 m, BRCA2 m, BARD1 m, BRIP1 m, CDK12 m, CHEK1 m, CHEK2 m, FANCL m, PALB2 m, RAD51B m, RAD51C m, RAD51D m, RAD54L m X g BRCA1 m, g BRCA2 m X ATM m, BRCA1 m, BRCA2 m X BRCA -mutated metastatic castration-resistant prostate cancer in combination with abiraterone and prednisone or prednisolone BRCA1 m, BRCA2 m X X X 2.2 Recommended Dosage The recommended dosage of Lynparza is 300 mg taken orally twice daily, with or without food.

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.

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.

First-Line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab Continue Lynparza treatment until disease progression, unacceptable toxicity, or completion of 2 years of treatment.

Patients with evidence of disease at 2 years, who in the opinion of the treating healthcare provider can derive further benefit from continuous Lynparza treatment, can be treated beyond 2 years.

When used with

Lynparza, the recommended dose of bevacizumab is 15 mg/kg every three weeks.

Bevacizumab should be given for a total of 15 months including the period given with chemotherapy and given as maintenance.

Information for bevacizumab when used in combination with Lynparza for more information.

Adjuvant Treatment of Germline BRCA -mutated

HER2-negative High Risk Early Breast Cancer Continue treatment for a total of 1 year, or until disease recurrence, or unacceptable toxicity, whichever occurs first.

Patients receiving Lynparza for hormone receptor positive HER2-negative breast cancer should continue concurrent treatment with endocrine therapy as per current clinical practice guidelines.

• Maintenance treatment of germline or somatic BRCA -mutated recurrent ovarian cancer.

• Germline BRCA -mutated HER-2 negative metastatic breast cancer.

• First-line maintenance treatment of germline BRCA -mutated metastatic pancreatic adenocarcinoma.

• HRR gene-mutated metastatic castration-resistant prostate cancer.

BRCA -mutated Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone Continue treatment until disease progression or unacceptable toxicity.

Lynparza, the recommended dose of abiraterone is 1000 mg taken orally once daily.

Abiraterone should be given in combination with prednisone or prednisolone 5 mg orally twice daily.

Information for abiraterone for dosing information.

Patients with mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. 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 a 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.

• 100 mg twice daily when used concomitantly with a strong CYP3A inhibitor.

• 150 mg twice daily when used concomitantly with a moderate CYP3A inhibitor.

After the inhibitor has been discontinued for to 5 elimination half-lives, resume the Lynparza dose taken prior to initiating the CYP3A inhibitor. 2.5 Dosage Modifications for Renal Impairment Moderate Renal Impairment In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the Lynparza dosage to 200 mg orally twice daily.

Lynparza is available as 150 mg and 100 mg tablets.

• 150 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).

• 100 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) .

Store in original bottle to protect from moisture.

Based on findings in animals and its mechanism of action, 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.

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.

In a 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 a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 7% of the human exposure (AUC 0-24h ) 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.

A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.18% of human exposure (AUC 0-24h ) 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 a dose of 0.05 mg/kg/day olaparib at lower incidence.

Safety and effectiveness of

Lynparza have not been established in pediatric patients.

Of the 2901 patients with advanced solid tumors who received Lynparza as a 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 (PAOLA-1), 204 (38%) patients were aged ≥65 years, and this included 31 (6%) patients who were aged ≥75 years.

Of the 398 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with abiraterone and prednisone or prednisolone (PROpel), 268 (67%) patients were aged ≥65 years, and this included 95 (24%) patients who were aged ≥75 years.

No overall differences in the safety or effectiveness of Lynparza were observed between these patients and younger patients.