1 INDICATIONS AND USAGE
1.1 Ovarian Cancer
• Rubraca is indicated for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca [see Dosage and Administration (2.1)].
1.2 Metastatic Castration-Resistant Prostate Cancer with BRCA Mutations
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 and a taxane-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca [see Dosage and Administration (2.1)].
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Treatment of BRCA-mutated Ovarian Cancer after 2 or More Chemotherapies
Select patients for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer with Rubraca based on the presence of a deleterious BRCA mutation (germline and/or somatic) [see Clinical Studies (14.1)].
Treatment of BRCA-mutated mCRPC after Androgen Receptor-directed Therapy and Chemotherapy
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.
7 DRUG INTERACTIONS
7.1 Effect of Rucaparib on Cytochrome p450 (CYP) Substrates
Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of toxicities of these drugs.
Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing the frequency of international normalized ratio (INR) monitoring.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Rucaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play a role in DNA repair. In vitro studies have shown that rucaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cancer cell death. Increased rucaparib-induced cytotoxicity and anti-tumor activity was observed in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib has been shown to decrease tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA.
12.3 Pharmacokinetics
Elimination
Metabolism: In vitro, rucaparib had a low metabolic turnover rate and was metabolized primarily by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4.
Specific Populations
CYP Enzyme Polymorphism: Based on population pharmacokinetic analyses, steady-state concentrations following rucaparib 600 mg twice daily did not differ significantly across CYP2D6 or CYP1A2 genotype subgroups.
Drug Interaction Studies
Effect of Rucaparib on Other Drugs
In Vitro Studies: Rucaparib inhibited CYP2C8, CYP2D6, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Rucaparib induced CYP1A2, and down regulated CYP3A4 and CYP2B6.
Rucaparib inhibited the P-glycoprotein (P-gp) efflux transporter, breast cancer resistance protein (BCRP), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), organic anion transporters 1 and 3 (OAT1 and OAT3), multidrug and toxin extrusion 1 and 2-k (MATE1 and MATE2-K), organic cation transporters 1 and 2 (OCT1 and OCT2), and multidrug resistance-associated protein 4 (MRP4). No apparent inhibition was observed for MRP2, MRP3, or BSEP.
Effects of Other Drugs on Rucaparib
In Vitro Studies: Rucaparib was a substrate of P-gp and BCRP; however, rucaparib was not a substrate of OATP1B1, OATP1B3, OAT1, OAT3, and OCT2.
14 CLINICAL STUDIES
14.1 Ovarian Cancer
Maintenance Treatment of Recurrent Ovarian Cancer
A deleterious BRCA mutation or high genomic loss of heterozygosity
Table 8. Efficacy Results -ARIEL3 (Investigator Assessment)
|
|
Rubraca |
Placebo |
|
All Patientsa |
||
|
Patients, N |
375 |
189 |
|
PFS events, n (%) |
234 (62%) |
167 (88%) |
|
PFS, median in months |
10.8 |
5.4 |
|
HR (95% CI) |
0.36 (0.30, 0.45) |
|
|
p-value |
< 0.0001 |
|
|
HRD Groupb |
||
|
Patients, N |
236 |
118 |
|
PFS events, n (%) |
134 (57%) |
101 (86%) |
|
PFS, median in months |
13.6 |
5.4 |
|
HR (95% CI) |
0.32 (0.24, 0.42) |
|
|
p-value |
< 0.0001 |
|
|
tBRCA Groupc |
||
|
Patients, N |
130 |
66 |
|
PFS events, n (%) |
67 (52%) |
56 (85%) |
|
PFS, median in months |
16.6 |
5.4 |
|
HR (95% CI) |
0.23 (0.16, 0.34) |
|
|
p-value |
< 0.0001 |
|
a. All randomized patients.
b. HRD includes all patients with a deleterious germline or somatic BRCA mutation or high genomic loss of heterozygosity, as determined by the CTA.
c. tBRCA includes all patients with a deleterious germline or somatic BRCA mutation, as determined by the CTA.
(2022.12.16 업데이트)