Niraparib

1 INDICATIONS AND USAGE AKEEGA with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA2 -mutated ( BRCA2 m) metastatic castration-sensitive prostate cancer (mCSPC). AKEEGA with prednisone is indicated 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 test for AKEEGA [see Dosage and Administration (2.1) ] . AKEEGA is a combination of niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and abiraterone acetate, a CYP17 inhibitor indicated with prednisone for the treatment of adult patients with: deleterious or suspected deleterious BRCA2 -mutated ( BRCA2 m) metastatic castration-sensitive prostate cancer (mCSPC). deleterious or suspected deleterious BRCA -mutated ( BRCA m) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved test for AKEEGA. ( 1 , 2.1 )

12.1 Mechanism of Action Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased niraparib‑induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2 . Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient‑derived xenograft tumor models with homologous recombination deficiency (HRD) that had either mutated or wild-type BRCA1/2 . Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis. CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals [see Warnings and Precautions (5.9) ] . Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Abiraterone decreased serum testosterone and other androgens in patients in the placebo-controlled clinical trial. It is not necessary to monitor the effect of abiraterone on serum testosterone levels. Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients. In mouse xenograft models of prostate cancer, the combination of niraparib and abiraterone acetate increased anti-tumor activity when compared to either drug alone.

2 DOSAGE AND ADMINISTRATION BRCA2 m mCSPC: The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 5 mg prednisone daily until disease progression or unacceptable toxicity. ( 2.2 ) BRCA m mCRPC : The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 10 mg prednisone daily until disease progression or unacceptable toxicity. ( 2.2 ) Patients receiving AKEEGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.2 ) Take AKEEGA on an empty stomach at least one hour before or two hours after food. ( 2.2 ) For adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. ( 2.3 ) 2.1 Patient Selection Select patients for the treatment of mCSPC with AKEEGA based on the presence of a BRCA2 gene alteration [see Clinical Studies (14.1) ] . Select patients for the treatment of mCRPC with AKEEGA based on the presence of a BRCA gene alteration [see Clinical Studies (14.2) ] . Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage BRCA2- mutated ( BRCA2 m) Metastatic Castration-Sensitive Prostate Cancer (mCSPC) The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 5 mg prednisone once daily until disease progression or unacceptable toxicity. BRCA -mutated ( BRCA m) Metastatic Castration-Resistant Prostate Cancer (mCRPC) The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 10 mg prednisone once daily until disease progression or unacceptable toxicity. Patients receiving AKEEGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Take AKEEGA on an empty stomach at least one hour before or two hours after food. Swallow tablets whole with water. Do not break, crush, or chew tablets. If a patient misses a dose, instruct patients to take the dose as soon as possible on the same day and resume their next dose at the normal schedule the following day. 2.3 Dosage Modification for Adverse Reactions The recommended dosage modifications for AKEEGA are provided in Table 1. Treatment with AKEEGA should not be reinitiated until the toxicity has resolved to Grade 1 or baseline. If the toxicity is attributed to one component of AKEEGA, the other component of AKEEGA may be continued as a single agent at the current dose until the adverse reaction resolves and AKEEGA can be resumed (see Table 1 ). Table 1: Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Myelosuppression [see Warnings and Precautions (5.2) ] Hemoglobin <8 g/dL Withhold AKEEGA and monitor blood counts weekly. When hemoglobin returns to ≥9 g/dL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated. Permanently discontinue AKEEGA if hemoglobin has not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to 100 mg/1,000 mg once daily. If myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) is confirmed, discontinue AKEEGA [see Warnings and Precautions (5.1)]. Platelet count <100,000/mcL First occurrence: Withhold AKEEGA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥100,000/mcL. Resume AKEEGA at same or the reduced dose of 100 mg/1,000 mg once daily. If platelet count is <75,000/mcL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Second occurrence: Withhold AKEEGA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥100,000/mcL. Resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Permanently d

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Myelodysplastic syndrome/acute myeloid leukemia [see Warnings and Precautions (5.1) ] Myelosuppression [see Warnings and Precautions (5.2) ] Hypokalemia, fluid retention, and cardiovascular adverse reactions [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Adrenocortical insufficiency [see Warnings and Precautions (5.5) ] Hypoglycemia [see Warnings and Precautions (5.6) ] Increased fractures and mortality in combination with Radium 223 Dichloride [see Warnings and Precautions (5.7) ] Posterior reversible encephalopathy syndrome [see Warnings and Precautions (5.8) ] The most common adverse reactions (≥20%), including laboratory abnormalities, are decreased hemoglobin, decreased lymphocytes, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, increased AST, fluid retention/edema, increased bilirubin, respiratory tract infection and arrhythmia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 safety population described in the WARNINGS and PRECAUTIONS reflect exposure to AKEEGA (niraparib 200 mg and abiraterone acetate 1,000 mg) in BRCA2 m patients (N=162) in the AMPLITUDE study and in BRCA m patients in Cohort 1 (N=113) in the MAGNITUDE study unless otherwise specified. BRCA2 -mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC) The safety of AKEEGA in patients with BRCA2 m mCSPC was evaluated in AMPLITUDE [see Clinical Studies (14.1) ]. Patients were randomized to receive either AKEEGA (niraparib 200 mg and abiraterone acetate 1,000 mg once daily) (n=162), or placebo and abiraterone acetate (n=161) until unacceptable toxicity or progression. Patients in both arms also received prednisone 5 mg daily. The median duration of exposure for AKEEGA was 26 months (range: 0 to 48 months). Serious adverse reactions occurred in 36% of patients who received AKEEGA. Serious adverse reactions reported in >2% of patients included anemia (4.9%), and pneumonia (3.7%). Fatal adverse reactions occurred in 4.9% of patients who received AKEEGA, including sudden death (1.9%), COVID-19 pneumonia (1.2%), pneumocystis jirovecii pneumonia (0.6%), pneumonia (0.6%), and cardio-respiratory arrest (0.6%). Permanent discontinuation of any component of AKEEGA due to an adverse reaction occurred in 13% of patients. Dosage interruptions of any component of AKEEGA due to an adverse reaction occurred in 67% of patients. Adverse reactions which required dosage interruption in >2% of patients included anemia (30%), COVID-19 (10%), hypertension (9%), neutropenia (8%), thrombocytopenia (8%), hypokalemia (7%), vomiting (4.9%), fatigue (4.3%), diarrhea (2.5%), and pneumonia (2.5%). Dose reductions of any component of AKEEGA due to an adverse reaction occurred in 25% of patients. Adverse reactions which required dose reductions in >2% of patients included anemia (17%). The most common adverse reactions (>20%), including laboratory abnormalities, in patients who received AKEEGA were decreased hemoglobin, decreased lymphocyte count, hypertension, decreased neutrophil count, musculoskeletal pain, decreased platelet count, constipation, fatigue, decreased potassium, increase creatinine, nausea, increased alkaline phosphate, increased aspartate aminotransferase, respiratory tract infection, arrhythmia, increased blood bilirubin, and fluid retention/edema. Table 2: Adverse Reactio

5 WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) : MDS/AML, including a case with fatal outcome, has been observed in patients treated with AKEEGA. Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed. ( 5.1 ) Myelosuppression: Test complete blood counts weekly for the first month, every two weeks for the next two months, monthly for the remainder of the first year, then every other month, and as clinically indicated. ( 2.3 , 5.2 ) Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions: Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention. Control hypertension and correct hypokalemia before and during treatment with AKEEGA. ( 5.3 ) Hepatotoxicity: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue treatment as recommended. ( 2.3 , 5.4 ) Adrenocortical insufficiency : Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations. ( 5.5 ) Hypoglycemia: Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes during and assess if antidiabetic agent dose modifications are required. ( 5.6 ) Increased fractures and mortality in combination with radium Ra 223 dichloride : Use of AKEEGA plus prednisone in combination with radium Ra 223 dichloride is not recommended. ( 5.7 ) Posterior Reversible Encephalopathy Syndrome (PRES): PRES has been observed in patients treated with niraparib, a component of AKEEGA. Discontinue AKEEGA if PRES is confirmed. ( 5.8 ) Embryo-Fetal Toxicity: AKEEGA can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception. ( 5.9 , 8.1 , 8.3 ) 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia AKEEGA may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). In the individual AMPLITUDE and MAGNITUDE studies, MDS or AML, including cases with fatal outcomes, were reported in 0.6% (2/347) and 0.5% (1/212) of patients treated with AKEEGA plus prednisone, respectively. All patients in other tumor types treated with niraparib, a component of AKEEGA, who developed secondary MDS/cancer-therapy-related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue AKEEGA if MDS/AML is confirmed. 5.2 Myelosuppression AKEEGA may cause myelosuppression (anemia, thrombocytopenia, or neutropenia). In AMPLITUDE, Grade 3–4 anemia, neutropenia, and thrombocytopenia were reported, respectively in 29%, 10%, and 4.9% of patients receiving AKEEGA. Overall, 25% of patients with anemia required a red blood cell transfusion, including 15% who required more than one transfusion. Discontinuation due to anemia occurred in 1.2% of patients. In MAGNITUDE Cohort 1, Grade 3–4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving AKEEGA. Overall, 27% of patients with anemia required a red blood cell transfusion, including 19.5% who required more than one transfusion. Discontinuation due to anemia occurred in 3% of patients. Monitor complete blood counts weekly during the first month of AKEEGA treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start AKEEGA until patients have adequately recovered from hematologic

4 CONTRAINDICATIONS None. None. ( 4 )

10 OVERDOSAGE In the event of an overdose, administration of AKEEGA should be stopped and general supportive measures undertaken, including monitoring for arrhythmias and cardiac failure and assessing liver function. There is no specific treatment in the event of AKEEGA overdose.