rucaparib

1 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 )].

6 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 RUBRACA, including cardiac failure, myocardial ischemia, and sepsis (1 patient each). Permanent discontinuation due to adverse reactions occurred in 14% of patients treated with RUBRACA. Adverse reactions which resulted in permanent discontinuation of RUBRACA in ≥2% of patients included anemia (6%), fatigue/asthenia (3%), thrombocytopenia/platelet count decreased (3%), and nausea (2%). Dosage interruptions of RUBRACA due to adverse reactions occurred in 53% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included anemia (24%), fatigue/asthenia (10%), nausea (8%), and increase in ALT (5%). Dose reductions of RUBRACA due to an adverse reaction occurred in 36% of patients. Adverse reactions which required dose reduction in ≥5% of patients included anemia (16%) and fatigue/asthenia (8%). The most common adverse reactions (≥10%) in patients who received RUBRACA were fatigue/asthenia, musculoskeletal pain, nausea, decreased appetite, diarrhea, constipation, vomiting, dyspnea, dysgeusia, edema, abdominal pain, dizziness, weight decreased, rash, headache, peripheral neuropathy, photosensitivity reaction, and urinary tract infection. The most common select laboratory abnormalities (≥25%) that worsened from baseline in patients who received RUBRACA were increased ALT, decreased neutrophils, decreased phosphate, decreased hemoglobin, increased AST, increased creatinine, increased glucose, decreased lymphocytes, decreased sodium, decreased platelets, increased calcium. Tables 4 and 5 summarize the adverse reactions and laboratory abnormalities, respectively, in patients with BRCA- mutated mCRPC in TRITON3. Table 4. Adverse Reactions in ≥ 10% of Patients with BRCA-mutated mCRPC in TRITON3 a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0) b Includes multiple related terms Adverse Reaction RUBRACA N=201 ARPI or Docetaxel N=97 Grades 1-4 a (%) Grades 3-4 (%) Grades 1-4 a (%) Grades 3-4 (%) General disorders and administration site conditions Fatigue/Asthenia 61 7 65 10 Edema b 18 0 20 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain b 53 7 57 8 Gastrointestinal disorders Nausea 51 2 22 1 Diarrhea 31 2 29 1 Constipation 31 2 17 1 Vomiting 25 1 10 1 Abdominal pain b 17 1 10 1 Metabolism and nutrition disorders Decreased appetite 34 1 20 2 Respiratory, thoracic and mediastinal disorders Dyspnea b 19 1 13 1 Nervous system disorders Dysgeusia b 18 0 12 0 Dizziness b 16 1 9 0 Headache b 12 0 9 0 Peripheral neuropathy b 12 1 26 1 Investigations Weight decreased 16 1 13 0 Skin and subcutaneous tissue disorders Rash b 13 1 6 0 Photosensitivity reaction b 12 1 0 0 Infections and infestations Urinary tract infection b 10 3 4 1 Clinically relevant adverse reactions occurring in <10% of patients treated with RUBRACA include cough, hemorrhage, fall, hypertension, dyspepsia, pruritus, pyrexia, stomatitis, venous thromboembolism, arrhythmia, hypersensitivity, and febrile neutropenia. Table 5. Laboratory Abnormalities in ≥ 25% of Patients with BRCA-mutated mCRPC in TRITON3 a Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available for 192 to 201 patients in the RUBRACA Arm and 94 to 97 patients in the ARPI or Docetaxel Arm. b NCI CTCAE version 5.0; decrease in phosphate is graded using NCI CTACE Version 4.03 Laboratory Parameter Rubraca N=201 a ARPI or Docetaxel N=97 a Grades 1-4 b (%) Grades 3-4 (%) Grades 1-4 b (%) Grades 3-4 (%) Chemistry Increase in ALT 68 4 8 0 Decrease in phosphate 64 8 45 5 Increase in AST 59 2 7 0 Increase in creatinine 56 1 16 0 Increase in glucose 45 6 38 3 Decrease in sodium 35 5 21 4 Increase in calcium 29 3 19 2 Hematology Decrease in neutrophils 67 9 24 10 Decrease in hemoglobin 60 23 31 2 Decrease in lymphocytes 43 14 45 17 Decrease in platelets 34 6 4 0 TRITON2 The safety of RUBRACA 600 mg twice daily was evaluated in a single arm trial (TRITON2) [see Clinical Studies (14.2)]. TRITON2 enrolled 209 patients with HRR-mutated mCRPC, including 115 with BRCA-mutated mCRPC. Among the patients with BRCA -mutated mCRPC, the median duration of RUBRACA treatment was 6.5 months (range 0.5 to 26.7). Fatal adverse reactions occurred in 1.7% of patients who received RUBRACA, including acute respiratory distress syndrome and pneumonia (1 patient each). Permanent discontinuation of RUBRACA due to an adverse reaction occurred in 8% of patients. Dosage interruption of RUBRACA due to an adverse reaction occurred in 57% of patients. Dose reductions of RUBRACA occurred in 41% of patients. Tables 6 and 7 summarize the adverse reactions and laboratory abnormalities, respectively, in patients with BRCA -mutated mCRPC in TRITON2. Table 6. Adverse Reactions in ≥ 20% of Patients with BRCA-mutated mCRPC in TRITON2 a NCI CTCAE version 4.03. b Includes platelet count decreased c Includes blister, blood blister, dermatitis, dermatitis contact, eczema, genital rash, palmar-plantar erythrodysaesthesia syndrome, photosensitivity reaction, psoriasis, rash, rash maculo-papular, rash pruritic, skin exfoliation, skin lesion, urticaria Adverse Reaction Rubraca N = 115 Grades 1-4 a (%) Grades 3-4 (%) General disorders and administration site conditions Asthenia/Fatigue 62 9 Gastrointestinal disorders Nausea 52 3 Constipation 27 1 Vomiting 22 1 Diarrhea 20 0 Blood and lymphatic system disorders Anemia 43 25 Thrombocytopenia b 25 10 Metabolism and nutrition disorders Decreased appetite 28 2 Skin and subcutaneous tissue disorders Rash c 27 2 Other clinically relevant adverse reactions that occurred in less than 20% of patients included dyspnea, dizziness, bleeding, urinary tract infection, dysgeusia, dyspepsia, hypersensitivity (including flushing, asthma, choking sensation, periorbital swelling, swelling face, and wheezing), pneumonia, sepsis, ischemic cardiovascular events, renal failure, venous thromboembolism, and stomatitis. Table 7. Laboratory Abnormalities in ≥ 35% (Grades 1-4) and ≥ 2% (Grades 3-4) Worsening from Baseline in Patients with BRCA-mutated mCRPC in TRITON2 a Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available for 111 to 115 patients. b NCI CTCAE version 5.0; decrease in phosphate is graded using NCI CTACE Version 4.03 c Grade 3-4 ALT or AST elevation led to drug interruption in 4 patients, of which 1 had dose reduction upon rechallenge. Laboratory Parameter Rubraca N = 115 a Grades 1-4 b (%) Grades 3-4 (%) Clinical Chemistry Increase in ALT c 69 5 Decrease in phosphate 68 15 Increase in alkaline phosphatase 44 2 Increase in creatinine 43 2 Increase in triglycerides 42 5 Decrease in sodium 38 3 Hematologic Decrease in leukocytes 69 5 Decrease in absolute neutrophil count 62 5