olaparib 150 MG Oral Tablet [Lynparza]

INDICATIONS AND USAGE 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. ( 1.1 , 2.1 ) • in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: • a deleterious or suspected deleterious BRCA mutation, and/or • genomic instability. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.2 , 2.1 ) • 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. ( 1.3 , 2.1 ) 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. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.4 , 2.1 ) • 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. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.5 , 2.1 ) 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. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.6 , 2.1 ) 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. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.7 , 2.1 ) • 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. ( 1.8 , 2.1 ) 1.1 First-Line Maintenance Treatment of BRCA -mutated Advanced Ovarian Cancer Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA -mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ] . 1.2 First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab Lynparza is indicated in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: • a deleterious or suspected deleterious BRCA mutation, and/or • genomic instability. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ]. 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 [see Dosage and Administration (2.1) ]. 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 [ see Dosage and Administration (2.1) ]. 1.5 Germline BRCA -mutated HER2-negative Metastatic Breast Cancer Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious 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. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ] . 1.6 First-Line Maintenance Treatment of Germline BRCA -mutated Metastatic Pancreatic Adenocarcinoma Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious 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 [see Dosage and Administration (2.1) ] . 1.7 HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ]. 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). Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ] .

DOSAGE AND ADMINISTRATION • Recommended dosage is 300 mg taken orally twice daily with or without food. See Full Prescribing Information for the recommended duration. (2.2) • Patients receiving Lynparza for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. (2.2) • For moderate renal impairment (CLcr 31-50 mL/min), reduce Lynparza dosage to 200 mg orally twice daily. (2.5) 2.1 Patient Selection Information on FDA-approved tests for the detection of genetic mutations is available at http://www.fda.gov/companiondiagnostics . Select patients for treatment with Lynparza based on the presence of deleterious or suspected deleterious HRR gene mutations, including BRCA mutations, or genomic instability based on the indication, biomarker, and sample type (Table 1). Table 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 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 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. Refer to the Prescribing 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. Germline or Somatic BRCA -mutated Recurrent Ovarian Cancer, Germline BRCA -mutated HER2-negative Metastatic Breast Cancer, Germline BRCA -mutated Metastatic Pancreatic Adenocarcinoma, and HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer Continue treatment until disease progression or unacceptable toxicity for: • 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. When used with 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. Refer to the Prescribing 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. If concomitant use cannot be avoided, reduce Lynparza dosage to: • 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 3 to 5 elimination half-lives, resume the Lynparza dose taken prior to initiating the CYP3A inhibitor [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ]. 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

WARNINGS AND PRECAUTIONS • Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.2% of patients with various BRCA m, g BRCA m, HRR gene-mutated or HRD-positive cancers exposed to Lynparza and the majority of events had a fatal outcome. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed. (5.1) • Pneumonitis: Occurred in 1.0% of patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed. (5.2) • Venous thromboembolism (VTE), including severe or fatal pulmonary embolism (PE), occurred in patients treated with Lynparza. VTE occurred in 8% of patients with mCRPC. Monitor patients for signs and symptoms of VTE and PE and treat as medically appropriate. ( 5.3 ) • Hepatotoxicity, Including Drug-induced liver injury (DILI): Occurred in patients treated with Lynparza. If DILI is suspected, interrupt Lynparza. If DILI is confirmed, discontinue treatment. ( 5.4 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 ) 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML) has occurred in patients treated with Lynparza and some cases were fatal. In clinical studies, among 2219 patients with various BRCA m, g BRCA m, HRR gene-mutated or HRD-positive cancers who received Lynparza as a single agent or as part of combination regimen, consistent with approved indications, the cumulative incidence of MDS/AML was approximately 1.2% (26/2219) [see Adverse Reactions (6.1) ]. Of these, 54% (14/26) had a fatal outcome. The median duration of therapy with Lynparza in patients who developed MDS/AML was approximately 2 years (range: < 6 months to > 4 years). All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. In SOLO1, patients with newly diagnosed advanced BRCA m ovarian cancer, the incidence of MDS/AML was 1.9% (5/260) in patients who received Lynparza and 0.8% (1/130) in patients who received placebo based on an updated analysis. In PAOLA-1, of patients with newly diagnosed advanced ovarian cancer with HRD-positive status, the incidence of MDS/AML was 1.6% (4/255) in patients who received Lynparza and 2.3% (3/131) in the control arm. In SOLO2, patients with BRCA m platinum-sensitive relapsed ovarian cancer, the incidence of MDS/AML was 8% (15/195) in patients who received Lynparza and 4% (4/99) in patients who received placebo. The duration of Lynparza treatment prior to the diagnosis of MDS/AML ranged from 0.6 years to 4.5 years. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza. 5.2 Pneumonitis Pneumonitis, including severe and fatal cases, has occurred in patients treated with Lynparza. In clinical studies, among patients who received Lynparza as a single agent or as part of a combination regimen [see Error! Hyperlink reference not valid. ] , the incidence of pneumonitis, including fatal cases, was 1.0% (29/2851). If patients present with new or worsening respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, interrupt Lynparza treatment and promptly assess the source of the symptoms. If pneumonitis is confirmed, discontinue Lynparza treatment and treat the patient appropriately . 5.3 Venous Thromboembolism Venous thromboembolism (VTE), including severe or fatal pulmonary embolism (PE), occurred in patients treated with Lynparza [see Adverse Reactions (6.1) ] . In the combined data of two randomized, placebo-controlled clinical studies (PROfound and PROpel) in patients with metastatic castration-resistant prostate cancer (N=1180), VTE occurred in 8% of patients who received Lynparza, including pulmonary embolism in 6%. In the control arms, VTE occurred in 2.5% including pulmonary embolism in 1.5%. Monitor patients for clinical signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated. 5.4 Hepatotoxicity, Including Drug-Induced Liver Injury Hepatotoxicity, including severe and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Lynparza [see Adverse Reactions (6.2) ] . Evaluate bilirubin and transaminases at baseline and throughout treatment with Lynparza. For patients who develop abnormal liver tests after Lynparza, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold Lynparza. Upon confirmation of DILI, discontinue Lynparza. 5.5 Embryo-Fetal Toxicity Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. In an animal reproduction study, administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 300 mg twice daily. Apprise pregnant women of the potential hazard to a fetus and the potential risk for loss of the pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Lynparza. Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Lynparza [see Use in Specific Populations ( 8.1 , 8.3 )] .

CONTRAINDICATIONS None. None. (4)

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