Rubraca

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)

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.

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. 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. 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.

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%).

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. 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.

2)]. TRITON2 enrolled 209 patients with HRR-mutated mCRPC, including 115 with BRCA-mutated mCRPC. 7). 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. 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.

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

If MDS/AML is confirmed, discontinue Rubraca. 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. 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. 1 )]. 3 )]. 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.

6%), including those in long term follow-up. 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. 7 years. In TRITON3, MDS/AML occurred in 2 out of 201 patients (1%) with a BRCA mutation treated with RUBRACA.

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.

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. 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. 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. 1 )]. 3 )].