Rubraca

RUBRACA is indicated for the maintenance treatment of adult patients with a deleterious BRCAmutation (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.

RUBRACA is indicated for the treatment of adult patients with a deleterious BRCAmutation (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)].

Maintenance Treatment ofBRCA-mutated Recurrent Ovarian Cancer

Select patients for the maintenance treatment of recurrent ovarian cancer with RUBRACA based on the presence of a deleterious BRCA mutation (germline and/or somatic) [see Clinical Studies ( 14.1)].

An FDA-approved test for the detection of deleterious germline and/or somatic BRCA mutations is not currently available.

Treatment of BRCA -mutated mCRPC after Androgen Receptor-directed Therapy

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: www.fda.gov/CompanionDiagnostics.

The recommended dose of Rubraca is 600 mg (two 300 mg tablets) taken orally twice daily with or without food, for a total daily dose of 1,200 mg. ( 2.2)

Continue treatment until disease progression or unacceptable toxicity. ( 2.2)

For adverse reactions, consider interruption of treatment or dose reduction. ( 2.3)

Patients receiving RUBRACA for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.2)

To manage adverse reactions, consider interruption of treatment or dose reduction. Recommended Rubraca dose modifications for adverse reactions are indicated in Table 1.

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur in patients treated with RUBRACA, and are potentially fatal adverse reactions. In 2141 treated patients with ovarian and prostate cancer [see Adverse Reactions( 6.1)], MDS/AML occurred in 34 patients (1.6%), including those in long term follow-up. Of these, 14 occurred during treatment or during the 28-day safety follow-up (0.7%). 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 BRCAmutation 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. The duration of therapy with RUBRACA in patients who developed secondary MDS/cancer therapy-related AML varied from 1.2 to 4.7 years.

In TRITON3, MDS/AML occurred in 2 out of 201 patients (1%) with a BRCAmutation treated with RUBRACA. The duration of therapy with RUBRACA in patients who developed secondary MDS/cancer therapy-related AML varied from 1.4 to 2.3 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. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose according to Table 1 [see Dosage and Administration ( 2.3)] 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.

Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of rucaparib to pregnant rats during the period of organogenesis resulted in embryo-fetal death at exposures that were 0.04 times the AUC _0-24hin patients receiving the recommended human dose of 600 mg twice daily. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca [see Use in Specific Populations ( 8.1, 8.3) and Clinical Pharmacology ( 12.1)].

Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Rubraca [see Use in Specific Populations ( 8.1, 8.3)].

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%).

Rubraca can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] .

The safety and effectiveness of Rubraca in pediatric patients have not been established.

Of the 937 patients with ovarian cancer who received Rubraca in clinical trials including ARIEL3, 41% were age 65 or older and 10% were 75 years or older. No major differences in safety were observed between younger and older patients with ovarian cancer.

Of the 209 patients with mCRPC who received Rubraca in TRITON2, 77% were age 65 or older and 33% were 75 years or older. No major differences in safety were observed between younger and older patients with mCRPC.

No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] between 30 and 89 mL/min, as estimated by the Cockcroft-Gault method) [see Clinical Pharmacology ( 12.3)]. Rubraca has not been studied in patients with CLcr < 30 mL/min or patients on dialysis.

No dosage modification is recommended for patients with mild to moderate hepatic impairment (total bilirubin ≤ 3 x upper limit of normal [ULN] or AST > ULN) [see Clinical Pharmacology ( 12.3)] . Rubraca has not been studied in patients with severe hepatic impairment (total bilirubin > 3 x ULN and any AST).

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 vitrostudies 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 BRCA1/2and 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.

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of rucaparib has not fully been characterized.

The AUC and C _maxof rucaparib demonstrated linear pharmacokinetics over a dose range from 240 mg to 840 mg twice daily (0.4 times to 1.4 times the approved recommended dosage). The mean (coefficient of variation [CV]) steady-state rucaparib C _maxis 1,940 ng/mL (54%) and AUC _0-12his 16,900 h×ng/mL (54%) at the approved recommended dosage. The mean AUC accumulation ratio is 3.5 to 6.2 fold.

Carcinogenicity studies have not been conducted with rucaparib.

Rucaparib was clastogenic in an in vitrochromosomal aberration assay in cultured human lymphocytes. The clastogenic response in mitotically-stimulated cells was anticipated based on the mechanism of action of rucaparib and indicates potential genotoxicity in humans. Rucaparib was not mutagenic in a bacterial reverse mutation (Ames) test.

Fertility studies with rucaparib have not been conducted. In 3-month repeat-dose general toxicology studies, rucaparib had no effects on male and female reproductive organs at doses up to 100 mg/kg/day and 20 mg/kg/day in rats and dogs, respectively. These dose levels resulted in systemic exposures of approximately 0.3 and 0.09 times the human exposure (AUC _0-24h), respectively, at the recommended dose.

The efficacy of Rubraca was investigated in ARIEL3 ( NCT01968213), a double-blind, multicenter clinical trial in which 564 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were in response to platinum-based chemotherapy were randomized (2:1) to receive Rubraca tablets 600 mg orally twice daily (n=375) or placebo (n=189). Treatment was continued until disease progression or unacceptable toxicity. All patients had achieved a response (complete or partial) to their most recent platinum-based chemotherapy. Randomization was stratified by best response to last platinum (complete or partial), time to progression following the penultimate platinum therapy (6 to ≤12 months and >12 months), and tumor biomarker status.

Tumor tissue samples were tested using a clinical trial assay (CTA) (N=564) and an investigational Foundation Medicine tissue test (n=518). Of the samples evaluated with both tests, tumor BRCA (t BRCA) mutant status was confirmed for 99% (177/178) of t BRCA-positive patients determined by the CTA. Blood samples for 94% (186/196) of the t BRCA patients were evaluated using a central blood germline BRCA test. Based on these results, 70% (130/186) of the t BRCA patients had a germline BRCA mutation and 30% (56/186) had a somatic BRCA mutation. The efficacy results are based on the t BRCA (germline or somatic) subgroup.

The major efficacy outcome was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (v1.1). Overall survival (OS) was an additional outcome measure.

Of the 564 enrolled patients, 196 patients (35%) had a t BRCA mutation. Among the patients who had a tBRCA mutation, the median age was 58 years (range: 42 to 81) for patients receiving Rubraca and 59 years (range: 36 to 84) for those on placebo; the majority were White (84%); and 100% had an ECOG performance status of 0 or 1. All patients had received at least two prior platinum-based chemotherapies (range: 2 to 5). A total of 33% of patients were in complete response (CR) to their most recent therapy. The progression-free interval to penultimate platinum was 6-12 months in 41% of patients and >12 months in 59%. Prior bevacizumab therapy was reported for 22% of patients who received Rubraca and 17% of patients who received placebo. Measurable disease was present at baseline in 32% of patients.

ARIEL3 demonstrated a statistically significant improvement in PFS for patients randomized to Rubraca as compared with placebo in patients who had a t BRCA mutation. Results from a blinded independent radiology review were consistent.

Efficacy results for patients with a t BRCA mutation are summarized in Table 8 and Figure 1.

Figure 1 Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as Assessed by Investigator: tBRCAGroup

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A final OS analysis was conducted after 130 events were observed. Exploratory OS results showed a HR of 0.83 (95% CI: 0.58, 1.19) in the t BRCAsubgroup with a median OS of 45.9 months (95% CI: 37.7, 59.6) for patients treated with Rubraca and 47.8 months (95% CI: 43.2, 55.8) for patients on placebo.

TRITON3

The efficacy of RUBRACA was evaluated in TRITON3 ( NCT02975934), a randomized, open-label, multi-center trial that evaluated RUBRACA compared to an androgen receptor pathway inhibitor (ARPI; enzalutamide or abiraterone acetate) or docetaxel in patients with progressive BRCAor ATMmutated metastatic castrate-resistant prostate cancer (mCRPC). The trial enrolled 405 patients with mCRPC, of whom 302 had BRCAmutations. Patients were required to have progressed on treatment with one ARPI and could not have received prior chemotherapy in the castrate-resistant setting. Prior taxane chemotherapy for castration-sensitive disease was permitted. Patients were required to be surgically or medically castrated with a castrate level of serum testosterone at study entry. BRCA gene mutation status was determined prospectively testing tumor tissue or plasma using Foundation Medicine, Inc. assays or through local testing.

Patients were randomized (2:1) to receive RUBRACA 600 mg twice daily (n=270) or ARPI (enzalutamide or abiraterone acetate; n=60) or docetaxel (n=75). Randomization was stratified by ECOG performance status (0 or 1), hepatic metastases (present or not), and type of mutation ( BRCA1, BRCA2, or ATM). If patients were being treated with androgen deprivation therapy (ADT), therapy was continued throughout the study. Bone-targeted agents were allowed.

Of the 302 patients with BRCAm disease, the median age was 69 years (range: 45 to 92 years); 75% were White, 5% Black, 1.3% Asian, 0.3% American Indian or Alaska Native, 1% multiple races, and 18% unknown; 1.7% were Hispanic/Latino; and baseline ECOG performance status (PS) was 0 (49%) or 1 (51%). Forty percent of patients had bone-only disease; 32% had visceral disease. In the mCSPC setting, 23% of patients had received docetaxel. Among those with BRCAm disease, 40 patients had BRCA1 mutations, and 262 patients had BRCA2 mutations.

The major efficacy outcome measure was radiographic progression-free survival (rPFS) as determined by independent radiology review (IRR) using RECIST version 1.1 and Prostate Cancer Clinical Trials Working Group 3 (PCWG3) (bone) criteria. Additional efficacy outcome measures included overall survival (OS) and IRR-assessed objective response rate (ORR).

TRITON3 demonstrated a statistically significant improvement in IRR-assessed rPFS for RUBRACA compared to ARPI or docetaxel in patients with BRCAm and in the overall population. In an exploratory analysis in the subgroup of 103 (25%) patients with ATMmutations, the rPFS hazard ratio was 0.95 (95% CI: 0.59, 1.52) and the OS hazard ratio was 1.21 (95% CI: 0.77, 1.90), indicating that the improvement in the overall population was primarily attributed to the results seen in the subgroup of patients with BRCAm. Of patients with BRCAm who were randomized to receive ARPI or docetaxel (n=101), 52% crossed over to receive RUBRACA after disease progression.

Efficacy results of the BRCAm population in TRITON3 are provided in Table 9, Figure 2 and Figure 3.

Figure 2 Kaplan-Meier Curves of rPFS from the BRCAm Subgroup of the TRITON3 Study (IRR-assessed)

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Figure 3 Kaplan-Meier Curves of Final OS from the BRCAm Subgroup of the TRITON3 Study

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Exploratory subgroup analysis of rPFS and OS for patients with BRCA1m and BRCA2m (including one patient with a BRCA2 mutation mischaracterized as having an ATM mutation at randomization) were performed. The rPFS and OS hazard ratios were 1.01 (95% CI: 0.48, 2.13) and 0.96 (95% CI: 0.46, 2.00) respectively in the subgroup with BRCA1 mutations (n=40) and 0.46 (95% CI: 0.33, 0.65) and 0.92 (95% CI: 0.68, 1.24) respectively in the subgroup with BRCA2 mutations (n=263).

TRITON2

The efficacy of Rubraca was investigated in TRITON2 ( NCT02952534), an ongoing multi-center, single arm clinical trial in patients with BRCA-mutated mCRPC who had been treated with androgen receptor-directed therapy and taxane-based chemotherapy. There were 115 patients with either germline or somatic BRCAmutations enrolled in TRITON2, of whom 62 patients had measurable disease at baseline by independent radiology review (IRR). Patients received Rubraca 600 mg orally twice daily until disease progression or unacceptable toxicity. Patients also received concomitant GnRH analog or had prior bilateral orchiectomy. Objective response rate (ORR) and duration of response (DOR) were assessed in patients with measurable disease by blinded IRR and by the investigator according to modified RECIST v1.1/ Prostate Cancer Working Group 3 (PCWG3) criteria.

For the 62 patients with measurable disease at baseline, the median age was 73 years (range 52 to 88); the majority were White (73%) and 10% were Black; and 98% of patients had an ECOG performance status of 0 or 1. All patients had received at least one prior androgen receptor-directed therapy, 34% had received 2 prior androgen receptor-directed therapies and 2% had received 3 prior androgen receptor-directed therapies, and all patients also received prior taxane chemotherapy. Eighteen percent of patients had lung and 21% had liver metastases at baseline. Twenty-four percent had metastases to lymph nodes alone. Forty percent had 10 or more bone lesions at baseline.

All 62 patients had a deleterious somatic or germline BRCAmutation detected from either central plasma (26%), central tissue (32%), or local (42%) testing. Of the 62 patients, 66% had a somatic BRCAmutation, 34% had a germline BRCA mutation, 85% had a BRCA2 mutation, and 15% had a BRCA1 mutation.

The major efficacy outcomes of the study were confirmed ORR by IRR using modified RECIST v1.1/PCWG3 criteria and DOR. Efficacy results of TRITON2 are provided in Table 10. The ORR by IRR was similar in patients with germline versus somatic BRCA mutation.

How Supplied

Rubraca is available as 200 mg, 250 mg, and 300 mg tablets.

200 mg Tablets:

• Blue, round, and debossed with “C2” on one side
• Supplied in bottles of 60 tablets (NDC:82154-0783-1)

250 mg Tablets:

• White, diamond, and debossed with “C25” on one side
• Supplied in bottles of 60 tablets (NDC:82154-0784-1)

300 mg Tablets:

• Yellow, oval, and debossed with “C3” on one side
• Supplied in bottles of 60 tablets (NDC:82154-0785-1)

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [ see USP Controlled Room Temperature].