RUBRACA SIDE EFFECTS
- Generic Name: rucaparib
- Brand Name: Rubraca Tablets
- Drug Class: How Do PARP Inhibitors Work?
SIDE EFFECTS
The following serious adverse reactions are discussed elsewhere in the labeling:
- Myelodysplastic Syndrome/Acute Myeloid Leukemia
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 in the section reflect exposure to Rubraca at 600 mg BID in 1146 patients in Study10 (CO-338-010), ARIEL2, ARIEL3, and TRITON2.
Maintenance Treatment Of Recurrent Ovarian Cancer
The safety of Rubraca for the maintenance treatment of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer was investigated in ARIEL3, a randomized (2:1), double-blind, placebo-controlled study in which 561 patients received either Rubraca 600 mg BID (n=372) or placebo (n=189) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.3 months (range: < 1 month to 35 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 65% of patients receiving Rubraca and 10% of those receiving placebo; dose reductions due to an adverse reaction occurred in 55% of Rubraca patients and 4% of placebo patients. The most frequent adverse reactions leading to dose interruption or dose reduction of Rubraca were thrombocytopenia (18%), anemia (17%), nausea (15%), and fatigue/asthenia (13%). Discontinuation due to adverse reactions occurred in 15% of Rubraca patients and 2% of placebo patients. Specific adverse reactions that most frequently led to discontinuation in patients treated with Rubraca were anemia (3%), thrombocytopenia (3%) and nausea (3%). 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 ARIEL3 Occurring in ≥ 20% of Patients
| Adverse reactions | Rubraca N=372 |
Placebo N=189 |
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| Gradesa 1-4 % |
Grades 3-4 % |
Gradesa 1-4 % |
Grades 3-4 % |
|
| Gastrointestinal Disorders | ||||
| Nausea | 76 | 4 | 36 | 0.5 |
| Abdominal pain/distentionb | 46 | 3 | 39 | 0.5 |
| Constipation | 37 | 2 | 24 | 1 |
| Vomiting | 37 | 4 | 15 | 1 |
| Diarrhea | 32 | 0.5 | 22 | 1 |
| Stomatitisb | 28 | 1 | 14 | 0.5 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue/asthenia | 73 | 7 | 46 | 3 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rashb | 43 | 1 | 23 | 0 |
| Nervous System Disorders | ||||
| Dysgeusia | 40 | 0 | 7 | 0 |
| Investigations | ||||
| AST/ALT elevation | 38 | 11 | 4 | 0 |
| Blood and Lymphatic System Disorders | ||||
| Anemia | 39 | 21 | 5 | 0.5 |
| Thrombocytopenia | 29 | 5 | 3 | 0 |
| Neutropenia | 20 | 8 | 5 | 1 |
| Respiratory, Thoracic, and Mediastinal Disorders | ||||
| Nasopharyngitis/Upper respiratory tract infectionb | 29 | 0.3 | 18 | 1 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 23 | 1 | 14 | 0 |
| aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03) bConsists of grouped related terms that reflect the medical concept of the adverse reaction |
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Adverse reactions occurring < 20% of patients treated with Rubraca include headache (18%), dizziness (19%), dyspepsia (19%), insomnia (15%), dyspnea (17%), pyrexia (13%), peripheral edema (11%), and depression (11%).
Table 3. Laboratory Abnormalities in ARIEL3 Occurring in ≥ 25% of Patients
| Laboratory Parametera | Rubraca N=372 |
Placebo N=189 |
||
| Grade 1-4 % |
Grade 3-4 % |
Grade 1-4 % |
Grade 3-4 % |
|
| Chemistry | ||||
| Increase in creatinine | 98 | 0.3 | 90 | 0 |
| Increase in cholesterol | 84 | 4 | 78 | 0 |
| Increase in ALT | 73 | 7 | 4 | 0 |
| Increase in AST | 61 | 1 | 4 | 0 |
| Increase in Alkaline Phosphatase | 37 | 0.3 | 10 | 0 |
| Hematology | ||||
| Decrease in hemoglobin | 88 | 13 | 56 | 1 |
| Decrease in platelets | 44 | 2 | 9 | 0 |
| Decrease in leukocytes | 44 | 3 | 29 | 0 |
| Decrease in neutrophils | 38 | 6 | 22 | 3 |
| Decrease in lymphocytes | 29 | 5 | 20 | 3 |
| aPatients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. | ||||
Treatment Of BRCA-Mutated Recurrent Ovarian Cancer After 2 Or More Chemotherapies
Rubraca 600 mg twice daily as monotherapy has also been studied in 377 patients with epithelial ovarian, fallopian tube or primary peritoneal cancer who have progressed after 2 or more prior chemotherapies in two open-label, single arm trials. In these patients, the median age was 62 years (range: 31 to 86), 100% had an ECOG performance status of 0 or 1, 38% had BRCA-mutated ovarian cancer, 45% had received 3 or more prior lines of chemotherapy, and the median time since ovarian cancer diagnosis was 43 months (range: 6 to 197). Table 4 describes the adverse reactions occurring in ≥20% of patients; while Table 5 describes the laboratory abnormalities occurring in ≥35% of patients occurring in ARIEL2.
Table 4. Adverse Reactions Reported in ≥ 20% of Patients with Ovarian Cancer After ≥ 2 Chemotherapies Treated with Rubraca in Study 10 and ARIEL2
| Adverse Reaction | All Ovarian Cancer Patients (N = 377) |
|
| Gradesa 1-4 (%) |
Grades 3-4 (%) |
|
| Gastrointestinal Disorders | ||
| Nausea | 77 | 5 |
| Vomiting | 46 | 4 |
| Constipation | 40 | 2` |
| Diarrhea | 34 | 2 |
| Abdominal Pain | 32 | 3 |
| General Disorders | ||
| Asthenia/Fatigue | 77 | 11 |
| Blood and Lymphatic System Disorders | ||
| Anemia | 44 | 25 |
| Thrombocytopenia | 21 | 5 |
| Nervous System Disorders | ||
| Dysgeusia | 39 | 0.3 |
| Metabolism and Nutrition Disorders | ||
| Decreased appetite | 39 | 3 |
| Respiratory, Thoracic, and Mediastinal Disorders | ||
| Dyspnea | 21 | 0.5 |
| aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03) | ||
The following adverse reactions have been identified in < 20% of the 377 patients treated with Rubraca 600 mg twice daily: dizziness (17%), neutropenia (15%), rash (includes rash, rash erythematous, rash maculopapular and dermatitis) (13%), pyrexia (11%), photosensitivity reaction (10%), pruritus (includes pruritus and pruritus generalized) (9%), hypersensitivity (includes flushing, wheezing, eyelid edema, drug hypersensitivity, face edema, swelling face) (4%), palmar-plantar erythrodysaesthesia syndrome (2%), and febrile neutropenia (1%).
Table 5. Laboratory Abnormalities Reported in ≥ 35% of Patients with Ovarian Cancer After ≥ 2 Chemotherapies Treated with Rubraca in Study 10 and ARIEL2
| Laboratory Parameter | All Ovarian Cancer Patients (N = 377) |
|
| Gradesa 1-4 (%) |
Grades 3-4 (%) |
|
| Clinical Chemistry | ||
| Increase in creatinine | 92 | 1 |
| Increase in ALTb | 74 | 13 |
| Increase in ASTb | 73 | 5 |
| Increase in cholesterol | 40 | 2 |
| Hematologic | ||
| Decrease in hemoglobin | 67 | 23 |
| Decrease in lymphocytes | 45 | 7 |
| Decrease in platelets | 39 | 6 |
| Decrease in absolute neutrophil count | 35 | 10 |
| aAt least one worsening shift in CTCAE grade and by maximum shift from baseline. bIncrease in ALT/AST led to treatment discontinuation in 0.3% of patients (1/377). |
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Treatment Of BRCA-Mutated mCRPC After Androgen Receptor-Directed Therapy And Chemotherapy
The safety of Rubraca 600 mg twice daily was evaluated in a single arm trial (TRITON2). TRITON2 enrolled 209 patients with HRD-positive 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).
There were 2 (1.7%) patients with adverse reactions leading to death, one each attributed to acute respiratory distress syndrome and pneumonia.
Dose interruptions due to an adverse reaction occurred in 57% of patients receiving Rubraca. Adverse reactions requiring dose interruption in >3% of patients included anemia, thrombocytopenia, asthenia/fatigue, nausea, vomiting, neutropenia, ALT/AST increased, creatinine increased, decreased appetite, acute kidney injury, and hypophosphatemia.
Dose reductions due to an adverse reaction occurred in 41% of patients receiving Rubraca. Adverse reactions requiring dose reduction in >3% of patients were anemia (14%), asthenia/fatigue (10%), thrombocytopenia (7%), nausea (6%), decreased appetite (4%), and rash (3%).
Discontinuation due to adverse reactions occurred in 8% of patients receiving Rubraca. None of the adverse reactions leading to discontinuation of Rubraca (ECG QT prolonged, acute respiratory distress syndrome, anemia, balance disorder, cardiac failure, decreased appetite/fatigue/weight decreased, leukopenia/neutropenia, ALT/AST increased, and pneumonia) occurred in more than one patient (<1%).
Tables 6 and 7 summarize the adverse reactions and laboratory abnormalities, respectively, in patients with BRCA-mutated mCRPC in TRITON2.
Table 6. Adverse Reactions Reported in ≥ 20% of Patients with BRCA-mutated mCRPC in TRITON2
| Adverse Reaction | Rubraca N = 115 |
|
| Gradesa 1-4 (%) |
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 |
| Thrombocytopeniab | 25 | 10 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 28 | 2 |
| Skin and subcutaneous tissue disorders | ||
| Rashc | 27 | 2 |
| Investigations | ||
| ALT/AST increased | 33 | 5 |
| aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03) b Includes platelet count decreased cIncludes 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 |
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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, and venous thromboembolism.
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
| Laboratory Parameter | Rubraca N = 115a |
|
| Grade 1-4b (%) |
Grade 3-4 (%) |
|
| Clinical Chemistry | ||
| Increase in ALTc | 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 | 10 |
| Decrease in hemoglobin | 69 | 25 |
| Decrease in lymphocytes | 42 | 17 |
| Decrease in platelets | 40 | 10 |
| aDenominator 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 cGrade 3-4 ALT or AST elevation led to drug interruption in 4 patients, of which 1 had dose reduction upon rechallenge. |
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