1. Manufacturer: Clovis Oncology, Inc FDA Approval Date: December 2016
Rubraca™ - Rucaparib
Manufacturer:
Clovis Oncology, Inc
FDA Approval Date:
December 2016

2. Rubraca™ - Rucaparib Objectives
At the end of this presentation participants will be able to:
Appropriately recommend Rubraca™ (rucaparib)
Effectively educate patients on the purpose, proper use and potential adverse effects of Rubraca™ (rucaparib)

3. Rubraca™ - Rucaparib Clinical Application
Indications:
For the treatment of patients with deleterious BRCA mutation associated advanced ovarian cancer who have been treated with two or more chemotherapies.
Place in therapy: Third Line Option
*Approved under accelerated approval based on objective response rate and duration of response.
Rubraca [package insert]. 12/2016

4. Rubraca™ - Rucaparib Clinical Application
Contraindications:
None
Warnings and Precautions:
Myelodysplastic Syndrome/Acute Myeloid Leukemia
Embryo-Fetal Toxicity
MDS/AML reported in 2/377 patients (0.5%). One case of fatal AML. Discontinue if MDS/AML confirmed.
Monitor CBC at baseline and then monthly. Do NOT start Rubraca until patient recovered from previous chemotherapy.
Rubraca [package insert]. 12/2016

5. Rubraca™ - Rucaparib Clinical Application
Pregnancy: Category X
Could cause fetal harm
Based on animal data, no human studies
Advise use of effective contraception during treatment and for 6 months following the last dose
Lactation:
Advise women not to breast feed while taking Rubraca and for 2 weeks after the final dose
Women - Advise women to use effective contraception during treatment and for 6 months after the final dose. Pregnancy testing is recommended prior to initiating treatment
Children - Use in pediatrics has not been established
Elderly - 42% of clinical trial participants ≥65 years of age, no difference in safety
Rubraca [package insert]. 12/2016

6. Rubraca™ - Rucaparib Drug Facts
Pharmacology:
PARP Enzyme Inhibitor
Increases formation of PARP-DNA complexes resulting in DNA damage and cytotoxic effects
Increased efficacy observed in cells lines with BRCA1/2 deficiencies and other mutations to DNA repair genes
PARP = Poly (ADP-Ribose) Polymerase
Involved in DNA repair
Rubraca [package insert].

7. Rubraca™ - Rucaparib Drug Facts
Pharmacokinetics: A
Bioavailability 36%, High fat meals increase Cmax, AUC, Tmax D
Protein-binding 70% M
CYP2D6 (primary), CYP1A2, CYP3A4 E
T1/ h
Rubraca [package insert]. 12/2016

8. Rubraca™ - Rucaparib Drug Interactions
Object Drug: none
Precipitant Drug: none
Based on drug interaction studies
Rubraca [package insert]. 12/2016

9. Rubraca™ - Rucaparib Adverse Effects
Adverse Reaction
Grades
1-4 (3-4)
Nausea
77% (5%)
Decreased Appetite
39% (3%)
Asthenia/Fatigue
77% (11%)
Diarrhea
34% (2%)
Vomiting
46% (4%)
Abdominal Pain
32% (3%)
Anemia
44% (25%)
Thrombocytopenia
21% (5%)
Constipation
40% (2%)
Dyspnea
21% (0.5%)
Dysgeusia
39% (0.3%)
ADRs led to dose reduction/interruption in 62% of patients - anemia (27%) and fatigue (22%)
ADRs led to discontinuation in 10% of patients - fatigue (2%)
Other ADRs include: Dizziness (17%), Neutropenia (15%), Rash (13%), Pyrexia (11%), Photosensitivity (10%), Pruritus (9%), and Febrile Neutropenia (1%)
Rubraca [package insert]. 12/2016

10. Rubraca™ - Rucaparib Adverse Effects
Blood Chemistry
Grades
1-4 (3-4)
Hematology
SCr increase
92% (1%)
Hgb decrease
67% (23%)
ALT increase
74% (13%)
WBC decrease
45% (7%)
AST increase
73% (5%)
PLT decrease
39% (6%)
LDL increase
40% (2%)
ANC decrease
35% (10%)
ADRs led to dose reduction/interruption in 62% of patients - anemia (27%) and fatigue (22%)
ADRs led to discontinuation in 10% of patients - fatigue (2%)
Rubraca [package insert]. 12/2016

11. Rubraca™ - Rucaparib Monitoring Parameters
Complete Blood Count (at baseline and then monthly)
Signs of MS/AML
Pregnancy test before initiation
Rubraca [package insert]. 12/2016

12. Rubraca™ - Rucaparib Prescription Information
Dosing:
Initial Dose: 600 mg PO BID
1st Dose Reduction: 500 mg PO BID
2nd Dose Reduction: 400 mg PO BID
3rd Dose Reduction: 300 mg PO BID
Available as 300mg or 200 mg tablets:
1 Bottle (#60) = $8,244
1-Month Supply = #120 = $16,488
AWP, per UTD accessed 4/2017
Rubraca [package insert].

13. Rubraca™ - Rucaparib Literature Review
Purpose: To identify molecular predictors of rucaparib sensitivity in patients with platinum- sensitive recurrent high-grade ovarian carcinoma
Design: International, Multicenter, Phase 2, Open- Label Study
Funding: Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer—
Ovarian Cancer Research Fund Alliance—National Ovarian Cancer Coalition Dream Team Translational Research
Grant, and V Foundation Translational Award.
Swisher EM, et al. Lancet Oncol

14. Rubraca™ - Rucaparib Literature Review
Single Treatment Arm:
PO Rucaparib 600 mg BID
Continuous 28-day cycles
Until disease progression or discontinuation
Dose reductions of 120 mg allowed for Grade 3 or worse adverse events
Supportive Care allowed
Antiemetics
Analgesics
CT scans at baseline, every 8 weeks
Serum CA-125 at baseline, day1 of each cycle, end of treatment
CBC, Chem, Saftey at baseline, day 1, 15 of cycle 1, then day 1 of each new cycle
PK – day 15 of cycle 1, then day 1 of cycle 2,3,4; as close to 12h post dose
Swisher EM, et al. Lancet Oncol

15. Rubraca™ - Rucaparib Literature Review
Inclusion Criteria:
Exclusion Criteria
High-grade carcinoma of ovary, fallopian tube
≥ 1 platinum therapy
Adults ≥ 18 years old
No prior PARP
Progression after 6 months following platium treatment
ECOG 0-1
Active second malignancy
CNS metastasis
Anticancer therapy with 14 days of trial
Subgroups
--BRCA mutant
--LOH High
--LOH Low
Swisher EM, et al. Lancet Oncol

16. Rubraca™ - Rucaparib Literature Review
Patient Characteristics:
BRCA-mutant
LOH
High
Low
Unknown
Number 40 82 70 12
Age
58.5 yrs
65.0 yrs
69.5 yrs
ECOG 0
65%
63%
67%
75%
Ovarian Cancer
95%
83%
70%
Serous Histology
98%
94%
100%
Platinum-based Treatments
1 Regimen
2 Regimens
43%
58%
55%
45%
30%
17%
PFI after Prior Treatments
6-12 months
≥12 months
44%
56%
42%
LOH = Loss of Heterozygosity
ECOG = Eastern Cooperative Oncology Group
PFI = Progression Free Interval
Swisher EM, et al. Lancet Oncol

17. Rubraca™ - Rucaparib Literature Review
Results
BRCA-mutant
LOH
High
Low
Unknown
Number 40 82 70 12
Median PFS
12.8 mo
5.7 mo
5.2 mo
n/a
Hazard Ratio
0.27
p<0.001
0.62
p=0.011
Reference
OR – RECIST
80%
29%
p=0.0033
10%
33%
OR – RECIST + CA-125
85%
44%
p=0.0018
20%
58%
Median Duration of Response
9.2 mo
p=0.013
10.8 mo
p=0.022
5.6 mo
Primary – PFS (progression free survival
Secondary – OR (Objective response (complete or partial)) duration of response, safety, PK
LOH = Loss of Heterozygosity
ECOG = Eastern Cooperative Oncology Group
Swisher EM, et al. Lancet Oncol

18. Rubraca™ - Rucaparib Literature Review
Treatment-Emergent Adverse Events
Grade 1-2
Grade 3
Grade< 4
Grade 5
Nausea
75% 4%
Asthenia/Fatigue
69% 9%
Constipation
45% 1%
Vomiting
42% 2%
Dysgeusia
43%
ALT/AST Increased
30%
12%
<1%
Decreased Appetite
39%
Anemia
14%
21%
Diarrhea 3%
Abdominal Pain
27%
39% of patients had dose reductions
Only 9% of patients withdrew due to adverse events
Anemia
Most common Grade 3 TEAE
Treated with transfusions and dose reductions
Similar to other PARP studies
LFT Increases
Asymptomatic, Reversible; normalized over time
Did NOT lead to dose reductions
Creatinine Increases
Occurred in first few weeks
Potentially due to inhibition of MATE1 and MAE2-K transporters which secreate Cr
Swisher EM, et al. Lancet Oncol

19. Rubraca™ - Rucaparib Literature Review
Treatment-Emergent Adverse Events
Grade 1-2
Grade 3
Grade< 4
Grade 5
Dyspnea
23%
<1%
Abdominal Distension
21%
Dizziness
18%
UTI
16% 2%
Creatinine Increased
17%
Headache
Cough
Back Pain
15% 1%
Platelet Decreased
12%
Photosensitivity
13%
Primary – PFS (progression free survival
Secondary – OR (Objective response (complete or partial)) duration of response, safety, PK
LOH = Loss of Heterozygosity
ECOG = Eastern Cooperative Oncology Group
Swisher EM, et al. Lancet Oncol

20. Rubraca™ - Rucaparib Literature Review
Treatment-Emergent Adverse Events
Selected Serious TEAEs
Grade 1-2
Grade 3
Grade< 4
Grade 5
Neutrophils Decreased 5% 4% 3%
Malignant Neoplasm Prog.
<1% 1%
Sepsis
Lymphocyte Decreased
Febrile Neutropenia
MDS/AML
Primary – PFS (progression free survival
Secondary – OR (Objective response (complete or partial)) duration of response, safety, PK
LOH = Loss of Heterozygosity
ECOG = Eastern Cooperative Oncology Group
Other TEAEs: Insomnia, pyrexia, abdominal pain (upper), peripheral edema, alopecia, stomatitis, URTI, AP increased, dyspepsia, pain, weight loss, dehydration, myalgia, ascites, cholesterol increased, HypoK, WBC decreased, small bowel obstruction, hydronephrosis, bilirubin increased, mucosal inflammations, hypotension, AKI, bronchitis, GGT increased, hypercholesterolemia, hyperglycemia, hyperPhos, rectal hemorrhage, fall, hypoNa, transaminases increased, malaise, leucopenia, presyncopy, PE, syncope, food poisoning, hyperBili, lymphoedema, tachycardia, pneumonia, agitation, bile duct obstruction, cataract, dyspareunia, emphsema, granulocytopenia, hyperMg, intestinal obstruction, LFT abnomality, lymphangitis, AMS, peritonitis, granulocyte decreased, intestinal perforation, large bowel obstruction, congenital long QT syndrome,
Swisher EM, et al. Lancet Oncol

21. Rubraca™ - Rucaparib Literature Review
Conclusions:
Rucaparib has activity against relapse, Pt-sensitive, high-grade ovarian cancer
Benefits seen in BRCA mutation and High LOH groups
Limitations – LOH needs to be further studied, unknown benefit for Pt-resistant cancers
ARIEL2 Part 2 provides positive results for specific population, more studies needed for extending indication
Swisher EM, et al. Lancet Oncol

22. Rubraca™ - Rucaparib Summary
Rucaparib is a new PARP inhibitor for the treatment of advanced ovarian carcinoma with BRCA mutations after 2 or more chemotherapies
Initiate at 600 mg BID
Reduce dose for toxicities
Monitor CBC monthly
Rucaparib has no contraindications, but warnings include myelodysplatic syndrome, acute myeloid leukemia, and potential embryo-fetal harm

23. Rubraca™ - Rucaparib References
Rubraca (rupacarib) [package insert]. Boulder, CO: Clovis Oncology, Inc; 2016
Swisher E, Lin K, Oza A, Scott C, Giodano H, Sun J, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicenter, open-label, phase 2 trial. Lancet Oncol 2017;18:75-87