Rucaparib for Ovarian Cancer

INDICATIONS AND USAGE RUBRACA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: Ovarian cancer for the maintenance treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. ( 1.1 ) Prostate cancer for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy. Select patients for therapy based on an FDA-approved companion diagnostic for RUBRACA. ( 1.2 , 2.1 ) 1.1 Maintenance Treatment of BRCA -mutated Recurrent Ovarian Cancer RUBRACA is indicated for the maintenance treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. 1.2 BRCA -mutated Metastatic Castration-Resistant Prostate Cancer RUBRACA is indicated for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy. Select patients for therapy based on an FDA-approved companion diagnostic for RUBRACA [see Dosage and Administration ( 2.1 )]. 1.1 Maintenance Treatment of BRCA -mutated Recurrent Ovarian Cancer RUBRACA is indicated for the maintenance treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. 1.2 BRCA -mutated Metastatic Castration-Resistant Prostate Cancer RUBRACA is indicated for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy. Select patients for therapy based on an FDA-approved companion diagnostic for RUBRACA [see Dosage and Administration ( 2.1 )].

DOSAGE AND ADMINISTRATION Recommended dose is 600 mg orally twice daily with or without food. ( 2.2 ) Continue treatment until disease progression or unacceptable toxicity. ( 2.2 ) For adverse reactions, consider interruption of treatment or dose reduction. ( 2.3 ) Patients receiving RUBRACA for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.2 ) 2.1 Patient Selection Maintenance Treatment of BRCA -mutated Recurrent Ovarian Cancer Select patients for the maintenance treatment of recurrent ovarian cancer with RUBRACA based on the presence of a deleterious BRCA mutation (germline and/or somatic) [see Clinical Studies ( 14.1 )]. An FDA-approved test for the detection of deleterious germline and/or somatic BRCA mutations is not currently available. Treatment of BRCA -mutated mCRPC after Androgen Receptor-directed Therapy Select patients for the treatment of mCRPC with RUBRACA based on the presence of a deleterious BRCA mutation (germline and/or somatic) in plasma specimens [see Clinical Studies ( 14.2 )]. A negative result from a plasma specimen does not mean that the patient’s tumor is negative for BRCA mutations. Should the plasma specimen have a negative result, consider performing further genomic testing using tumor specimens as clinically indicated. Information on the FDA-approved tests for the detection of a BRCA mutation in patients with ovarian cancer or with prostate cancer is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dose The recommended dose of Rubraca is 600 mg (two 300 mg tablets) taken orally twice daily with or without food, for a total daily dose of 1,200 mg. ( 2.2 ) Continue treatment until disease progression or unacceptable toxicity. ( 2.2 ) For adverse reactions, consider interruption of treatment or dose reduction. ( 2.3 ) Patients receiving RUBRACA for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.2 ) 2.3 Dose Modifications for Adverse Reactions To manage adverse reactions, consider interruption of treatment or dose reduction. Recommended Rubraca dose modifications for adverse reactions are indicated in Table 1 . Table 1. Recommended Dose Modifications for Adverse Reactions Dose Reduction Dose Starting Dose 600 mg twice daily (two 300 mg tablets) First Dose Reduction 500 mg twice daily (two 250 mg tablets) Second Dose Reduction 400 mg twice daily (two 200 mg tablets) Third Dose Reduction 300 mg twice daily (one 300 mg tablet) 2.1 Patient Selection Maintenance Treatment of BRCA -mutated Recurrent Ovarian Cancer Select patients for the maintenance treatment of recurrent ovarian cancer with RUBRACA based on the presence of a deleterious BRCA mutation (germline and/or somatic) [see Clinical Studies ( 14.1 )]. An FDA-approved test for the detection of deleterious germline and/or somatic BRCA mutations is not currently available. Treatment of BRCA -mutated mCRPC after Androgen Receptor-directed Therapy Select patients for the treatment of mCRPC with RUBRACA based on the presence of a deleterious BRCA mutation (germline and/or somatic) in plasma specimens [see Clinical Studies ( 14.2 )]. A negative result from a plasma specimen does not mean that the patient’s tumor is negative for BRCA mutations. Should the plasma specimen have a negative result, consider performing further genomic testing using tumor specimens as clinically indicated. Information on the FDA-approved tests for the detection of a BRCA mutation in patients with ovarian cancer or with prostate cancer is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dose The recommended dose of Rubraca is 600 mg (two 300 mg tablets) taken orally twice daily with or without food, for a total daily dose of 1,200 mg. ( 2.2 ) Continue treatment until disease progression or unacceptable toxicity. ( 2.2 ) For adverse reactions, consider interruption of treatment or dose reduction. ( 2.3 ) Patients receiving RUBRACA for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.2 ) 2.3 Dose Modifications for Adverse Reactions To manage adverse reactions, consider interruption of treatment or dose reduction. Recommended Rubraca dose modifications for adverse reactions are indicated in Table 1 . Table 1. Recommended Dose Modifications for Adverse Reactions Dose Reduction Dose Starting Dose 600 mg twice daily (two 300 mg tablets) First Dose Reduction 500 mg twice daily (two 250 mg tablets) Second Dose Reduction 400 mg twice daily (two 200 mg tablets) Third Dose Reduction 300 mg twice daily (one 300 mg tablet)

WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML occurred in patients exposed to RUBRACA, and some cases were fatal. Monitor patients for hematological toxicity at baseline and monthly thereafter. Interrupt or reduce the dose based on severity of reaction. Discontinue if MDS/AML is confirmed. ( 2.3 , 5.1 ) Embryo-Fetal Toxicity: RUBRACA can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception. ( 5.2 , 8.1 , 8.3 ) 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur in patients treated with RUBRACA, and are potentially fatal adverse reactions. In 2141 treated patients with ovarian and prostate cancer [see Adverse Reactions ( 6.1 )], MDS/AML occurred in 34 patients (1.6%), including those in long term follow-up. Of these, 14 occurred during treatment or during the 28-day safety follow-up (0.7%). The duration of RUBRACA treatment prior to the diagnosis of MDS/AML ranged from < 2 months to approximately 72 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing chemotherapy regimens and/or other DNA damaging agents. In ARIEL3, of patients with a germline and/or somatic BRCA mutation treated with RUBRACA, MDS/AML occurred in 9 out of 129 (7%) patients treated with RUBRACA and 4 out of 66 (6%) patients treated with placebo. The duration of therapy with RUBRACA in patients who developed secondary MDS/cancer therapy-related AML varied from 1.2 to 4.7 years. In TRITON3, MDS/AML occurred in 2 out of 201 patients (1%) with a BRCA mutation treated with RUBRACA. The duration of therapy with RUBRACA in patients who developed secondary MDS/cancer therapy-related AML varied from 1.4 to 2.3 years. Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose according to Table 1 [see Dosage and Administration ( 2.3 )] and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca. 5.2 Embryo-Fetal Toxicity Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of rucaparib to pregnant rats during the period of organogenesis resulted in embryo-fetal death at exposures that were 0.04 times the AUC 0-24h in patients receiving the recommended human dose of 600 mg twice daily. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca [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 Rubraca [see Use in Specific Populations ( 8.1 , 8.3 )]. 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur in patients treated with RUBRACA, and are potentially fatal adverse reactions. In 2141 treated patients with ovarian and prostate cancer [see Adverse Reactions ( 6.1 )], MDS/AML occurred in 34 patients (1.6%), including those in long term follow-up. Of these, 14 occurred during treatment or during the 28-day safety follow-up (0.7%). The duration of RUBRACA treatment prior to the diagnosis of MDS/AML ranged from < 2 months to approximately 72 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing chemotherapy regimens and/or other DNA damaging agents. In ARIEL3, of patients with a germline and/or somatic BRCA mutation treated with RUBRACA, MDS/AML occurred in 9 out of 129 (7%) patients treated with RUBRACA and 4 out of 66 (6%) patients treated with placebo. The duration of therapy with RUBRACA in patients who developed secondary MDS/cancer therapy-related AML varied from 1.2 to 4.7 years. In TRITON3, MDS/AML occurred in 2 out of 201 patients (1%) with a BRCA mutation treated with RUBRACA. The duration of therapy with RUBRACA in patients who developed secondary MDS/cancer therapy-related AML varied from 1.4 to 2.3 years. Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose according to Table 1 [see Dosage and Administration ( 2.3 )] and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca. 5.2 Embryo-Fetal Toxicity Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of rucaparib to pregnant rats during the period of organogenesis resulted in embryo-fetal death at exposures that were 0.04 times the AUC 0-24h in patients receiving the recommended human dose of 600 mg twice daily. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca [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 Rubraca [see Use in Specific Populations ( 8.1 , 8.3 )].

DRUG INTERACTIONS 7.1 Effect of Rubraca on Other Drugs Certain CYP1A2, CYP3A, CYP2C9, or CYP2C19 Substrates Concomitant administration of Rubraca with CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates can increase the systemic exposure of these substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the frequency or severity of adverse reactions of these substrates. If concomitant administration is unavoidable between Rubraca and substrates of these enzymes where minimal concentration changes may lead to serious adverse reactions, decrease the substrate dosage in accordance with the approved prescribing information. If concomitant administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing the frequency of international normalized ratio (INR) monitoring. 7.1 Effect of Rubraca on Other Drugs Certain CYP1A2, CYP3A, CYP2C9, or CYP2C19 Substrates Concomitant administration of Rubraca with CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates can increase the systemic exposure of these substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the frequency or severity of adverse reactions of these substrates. If concomitant administration is unavoidable between Rubraca and substrates of these enzymes where minimal concentration changes may lead to serious adverse reactions, decrease the substrate dosage in accordance with the approved prescribing information. If concomitant administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing the frequency of international normalized ratio (INR) monitoring. Certain CYP1A2, CYP3A, CYP2C9, or CYP2C19 Substrates Concomitant administration of Rubraca with CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates can increase the systemic exposure of these substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the frequency or severity of adverse reactions of these substrates. If concomitant administration is unavoidable between Rubraca and substrates of these enzymes where minimal concentration changes may lead to serious adverse reactions, decrease the substrate dosage in accordance with the approved prescribing information. If concomitant administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing the frequency of international normalized ratio (INR) monitoring.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions ( 5.1 )]. Most common adverse reactions (≥10%) among patients with ovarian cancer were nausea, fatigue (including asthenia), anemia, ALT/AST increased, vomiting, diarrhea, decreased appetite, thrombocytopenia, dysgeusia, neutropenia, blood creatinine increased, dyspnea, dizziness, dyspepsia, photosensitivity reaction, and leukopenia. ( 6.1 ) Most common adverse reactions (≥10%) among patients with BRCA -mutated mCRPC were fatigue/asthenia, musculoskeletal pain, nausea, anemia, decreased appetite, increased ALT/AST, constipation, diarrhea, vomiting, thrombocytopenia, dyspnea, increased blood creatinine, edema, dizziness, weight decreased, abdominal pain, dysgeusia, rash, neuropathy peripheral, urinary tract infection, cough, headache, hemorrhage, neutropenia, and photosensitivity reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact pharmaand agent at 1-800-506-8501 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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. The pooled safety population for patients with ovarian and prostate cancer in the WARNINGS AND PRECAUTIONS section reflect exposure to RUBRACA at 600 mg orally twice daily in 2141 patients treated on clinical trials including ARIEL3, TRITON2, and TRITON3. In ARIEL3 among the patients who received RUBRACA, 57% of patients were exposed for 6 months or longer and 33% were exposed for greater than one year. In TRITON3 among the patients with BRCA-mutated mCRPC who received RUBRACA, 66% were exposed for 6 months or longer and 34% were exposed for greater than one year. In the pooled safety population for patients with ovarian cancer, the most common adverse reactions in ≥ 10% of patients were nausea (68%), asthenia/fatigue (65%), anemia/hemoglobin decreased (45%), AST/ALT increased (39%), vomiting (36%), diarrhea (29%), decreased appetite (27%), thrombocytopenia/platelet count decreased (25%), dysgeusia (24%), neutropenia/neutrophil count decreased (21%), blood creatinine increased (17%), dyspnea (16%), dizziness (14%), dyspepsia (11%), photosensitivity reaction (10%), and leukopenia/white blood cell count decreased (10%). In the pooled safety population for patients with BRCA -mutated mCRPC (N=373) from TRITON2 and TRITON3, the most common adverse reactions in ≥ 10% of patients were fatigue/asthenia (61%), musculoskeletal pain (52%), nausea (52%), anemia/decreased hemoglobin (49%), decreased appetite (35%), increased ALT/AST (31%), constipation (30%), diarrhea (27%), vomiting (26%), thrombocytopenia/decreased platelet count (21%), dyspnea (20%), increased blood creatinine (19%), edema (19%), dizziness (19%), weight decreased (16%), abdominal pain (15%), dysgeusia (15%), rash (13%), neuropathy peripheral (13%), urinary tract infection (13%), cough (12%), headache (12%), hemorrhage (12%), neutropenia/decreased neutrophil count (12%), and photosensitivity reaction (10%). Maintenance Treatment of BRCA -mutated Recurrent Ovarian Cancer The safety of RUBRACA for the maintenance treatment of patients with BRCA -mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer was investigated in ARIEL3, a randomized (2:1), double-blind, placebo-controlled study in which 195 patients with a deleterious BRC A mutation received either RUBRACA 600 mg orally twice daily (n=129) or placebo (n=66) until disease progression or unacceptable toxicity. The median duration of study treatment was 13.6 months (range: < 1 month to 39 months) for patients who received RUBRACA and 5.5 months for patients who received placebo. Dose interruptions due to an adverse reaction of any grade occurred in 67% of patients receiving RUBRACA and 14% of those receiving placebo; dose reductions due to an adverse reaction occurred in 57% of RUBRACA patients and 6% of placebo patients. The most frequent adverse reactions leading to dose interruption or dose reduction of RUBRACA were thrombocytopenia (25%), anemia (19%), ALT/AST increased (16%), fatigue/asthenia (14%), and nausea (10%). Discontinuation due to adverse reactions occurred in 15% of RUBRACA patients and 5% of placebo patients. Specific adverse reactions that most frequently led to discontinuation in patients treated with RUBRACA were thrombocytopenia (4%), nausea (3%), and anemia (2%). Table 2 describes the adverse reactions occurring in ≥20% of patients; while Table 3 describes the laboratory abnormalities occurring in ≥25% of patients occurring in ARIEL3. Table 2. Adverse Reactions in ≥ 20% of Patients with BRCA-mutated Ovarian Cancer in ARIEL3 a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03) b Consists of grouped related terms that reflect the medical concept of the adverse reaction Adverse reactions RUBRACA N=129 Placebo N=66 Grades 1-4 a % Grades 3-4 % Grades 1-4 a % Grades 3-4 % Gastrointestinal Disorders Nausea 79 2 29 0 Abdominal pain/distention b 48 3 49 2 Constipation 39 4 36 2 Vomiting 37 4 14 0 Diarrhea 34 2 18 0 Stomatitis b 28 0.8 12 0 General Disorders and Administration Site Conditions Fatigue/asthenia 74 9 52 5 Skin and Subcutaneous Tissue Disorders Rash b 45 0 23 0 Nervous System Disorders Dysgeusia 33 0 6 0 Headache 22 0 15 2 Investigations ALT/AST elevation 33 16 3 0 Blood and Lymphatic System Disorders Anemia 41 26 6 0 Thrombocytopenia 35 6 3 0 Neutropenia 22 8 6 0 Respiratory, Thoracic, and Mediastinal Disorders Nasopharyngitis/Upper respiratory tract infection b 29 0 20 2 Metabolism and Nutrition Disorders Decreased appetite 23 2 14 0 Adverse reactions occurring < 20% of patients treated with RUBRACA include insomnia (19%), dyspnea (17%), dizziness (15%), pyrexia (15%), dyspepsia (12%), peripheral edema (12%), and depression (11%). Table 3. Laboratory Abnormalities in ≥ 25% of Patients with BRCA-mutated Ovarian Cancer in ARIEL3 a Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. b NCI CTCAE version 4.03. Laboratory Parameter a RUBRACA N=129 Placebo N=66 Grades 1-4 b % Grades 3-4 % Grades 1-4 b % Grades 3-4 % Chemistry Increase in creatinine 96 0 89 0 Increase in ALT 67 11 6 0 Increase in AST 59 1 6 0 Increase in cholesterol 39 3 20 0 Increase in Alkaline Phosphatase 39 0 3 0 Hematology Decrease in hemoglobin 61 18 14 2 Decrease in platelets 47 2 8 0 Decrease in leukocytes 39 3 23 0 Decrease in neutrophils 38 6 18 2 Decrease in lymphocytes 33 7 14 2 Treatment of BRCA-mutated mCRPC after Androgen Receptor-directed Therapy TRITON3 The safety of RUBRACA monotherapy was evaluated in patients with BRCA-mutated mCRPC who had progressed following prior treatment with androgen receptor-directed therapy and who had not received treatment with taxane-based chemotherapy in the castration-resistant setting. [see Clinical Studies ( 14.2 )]. TRITON3 was a randomized, open-label, multi-center study, in which 298 patients with a deleterious BRCA mutation received either RUBRACA 600 mg twice daily (n=201) or physicians choice (n=97) of abiraterone acetate or enzalutamide, or docetaxel until disease progression, unacceptable toxicity, or up to 10 cycles for docetaxel. Among the patients who received RUBRACA, 66% were exposed for 6 months or longer and 34% were exposed for greater than one year. Serious adverse reactions occurred in 27% of patients receiving RUBRACA. Serious adverse reactions in ≥2% of patients included anemia (4%), pneumonia (4%), urinary tract infection (3%), acute kidney injury (3%), myocardial ischemia/infarction (2%), and pulmonary embolism (2%). Fatal adverse reactions occurred in 1.5% of patients treated with RUBRA