1. PARP Inhibition for Ovarian Cancer
GEMSTONE Educational Module
Last Update: June 27, 2018
GEMSTONE, a committee of ovarian cancer experts, provided direction and approval of the material in this educational resource. TESARO, Inc. provided writing and organizational support to GEMSTONE in the generation of this material.

2. Module Objectives Review the mechanism of action of PARP inhibitors
Chronicle recent FDA approvals of PARP inhibitors for patients with ovarian cancer
Review how BRCA mutations can drive treatment decisions with PARP inhibitors
Describe best practices for managing toxicities associated with PARP inhibition
BRCA, breast cancer susceptibility gene; FDA, US Food and Drug Administration; PARP, poly ADP ribose polymerase.

3. Module Outline PARP Inhibitor Mechanism of Action
Summary of Select Clinical Trials Supporting PARP Inhibitor Approvals in United States
PARP Inhibitor Efficacy in Patients Without a BRCA Mutation
Adverse Effects and Dosing
PARP Inhibitor Effect on Quality of Life
Summary of Other Select PARP Inhibitor Trials
Acquired Resistance to PARP Inhibitors
Summary and Unresolved Questions
BRCA, breast cancer susceptibility gene; PARP, poly ADP ribose polymerase.

4. Treatment Landscape for Ovarian Cancer Is Rapidly Changing
Bevacizumaba (platinum- sensitive)
Treatment
Landmark FDA approvals in ovarian cancer therapy1
Maintenance
Rucaparib (platinum- sensitive)
Altretamine
Topotecan
Liposomal Doxorubicin (Full)
Bevacizumab (platinum- resistant)
Bevacizumaba (after initial resection)
Cisplatin2
Carboplatin2
(1L)
1978
1989
1990
1991
1992
1996
1999
2005
2006
2014
2016
2017
2018
Niraparib (platinum- sensitive)
Carboplatin2
(palliative)
Paclitaxel
Liposomal Doxorubicin (Accelerated)
Gemcitabine
Olaparib (BRCAmut carriers)
Olaparib (platinum- sensitive)
Historically, SOC for ovarian cancer has been chemotherapy, with limited FDA approvals for novel therapies
Emerging therapies offer patients new options for a targeted approach to treating ovarian cancer
Rucaparib (somatic + germline BRCAmut)
a In combination with carboplatin and paclitaxel, followed by bevacizumab alone.
FDA, US Food and Drug Administration; L, line; mut, mutation.
1. FDA Approved Drug Products. Accessed March 29, April 9, and June 13, Kelland L. Nat Rev Cancer. 2007;7(8):

5. PARP Inhibitor Mechanism of Action

6. Many Patients With Ovarian Cancer Have Genetic Mutations
Frequently mutated genes in ovarian cancer (germline and somatic)1,2
TP53
CSMD3
PTENa
EMSYa
BRCA1a
RB1
RAD51a
ATM/ATRa
BRCA2a
NF1
CDK12
CCNE1
a Many genes that are abnormal in ovarian cancer regulate DNA repair.
1. Patch AM, et al. Nature. 2015;521(7553): Cancer Genome Atlas Research Network. Nature. 2011;474(7353):

7. PARP Inhibitors Yield Synthetic Lethality in Patients With HRD
PARP inhibitors prevent repair of single-strand breaks, which accumulate and generate double-strand breaks
People with HRD cannot repair double-strand breaks, which triggers cell death
Single-strand break
PARP
PARP inhibitors
Double-strand breaks
Repair by homologous recombination
No homologous recombination or repair
Cell survival
Cell death
DNA repaired
Normal Cell
Cell with HRD
HRD, homologous recombination deficiency; PARP, poly ADP ribose polymerase.
Sonnenblick A, et al. Nat Rev Clin Oncol. 2015;12(1):27-41.

8. DNA Repair Involves a Complex Protein Network
Many enzymes mediate repair of multiple forms of DNA damage via several key pathways1,2
Base mismatches, insertions, deletions
Single-strand breaks
Double-strand breaks
Bulky adducts
Type of damage
Base excision repair
Homologous recombination
Nucleotide excision repair
Repair pathway
Mismatch repair
PARP-1
XRCC1
DNA ligase III
BRCA1/2
ATM
RAD51
ERCC4
ERCC1
MSH2
MLH1
Key repair enzymes
Mutations in the genes that encode these enzymes cause HR deficiency
HR, homologous recombination.
1. Lord CJ, et al. Nature. 2012;481(7381): Hosoya N, et al. Cancer Sci. 2014;105(4):

9. Loss of Heterozygosity (LOH)2
In Addition to HRD, Genomic Instability May Indicate Deficiencies in DNA Repair
Genomic Instability1
Loss of Heterozygosity (LOH)2
Chromosomal alterations, nucleotide substitutions, insertions, and deletions that accumulate in the absence of DNA repair due to DNA repair gene mutations
These genomic changes can alter cell behavior, drive development of malignancy, and influence response to therapy
Loss of a wild-type allele in the presence of a mutated gene allele produces an abnormal or nonfunctional locus
LOH is common in individuals with an inherited cancer predisposition syndrome (eg, BRCA1 or BRCA2)
BRCA, breast cancer susceptibility gene; HRD, homologous recombination deficiency.
1. Lord CJ, et al. Nature. 2012;481(7381): Merajver SD, et al. Clin Cancer Res. 1995;1(5):

10. Summary of Select Clinical Trials Supporting PARP Inhibitor Approvals in United States

11. Summary of FDA-Approved PARP Inhibitors
Drug
Registrational Clinical Trials
Indications
Olaparib1,2
Study 42
Treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with ≥3 prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for olaparib
SOLO-2
Study 19
Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR to platinum-based chemotherapy
Rucaparib3
Study 10
ARIEL2
Monotherapy for treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with ≥2 chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for rucaparib
ARIEL3
Niraparib4
NOVA
BRCA, breast cancer susceptibility gene; CR, complete response; FDA, US Food and Drug Administration; PARP, poly ADP ribose polymerase; PR, partial response.
1. Olaparib package insert. AstraZeneca Pharmaceuticals LP; January FDA. Summary Review for Regulatory Action: Olaparib. Approval date December 19, Accessed April 10, Rucaparib package insert. Clovis Oncology, Inc; April Niraparib package insert. TESARO, Inc; August 2017.

12. Study 42 Supported Initial FDA Approval for Olaparib as Treatment for Patients With Ovarian Cancer, a gBRCA Mutation, and ≥3 Prior Lines of Chemotherapy
Study 42 reported promising responses to olaparib in patients who had recurrent cancer, gBRCA mutation, and progressed after ≥3 prior lines of chemotherapy
Study 42 (NCT )1,2 N
137a
Design
Phase 2
Patients
Advanced solid tumors with gBRCA1/2 mutation (N=298)
Recurrent ovarian cancer cohort (n=193): platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancer
Treatment
Olaparib 400 mg bid
Results
ORR: 34% mPFS: 6.7 mo
Safety: Most common grade ≥3 AEs in ovarian cancer cohort
Anemia (20%)
Abdominal pain (8%)
Fatigue (7%)
a Overall study population: N=298; ovarian cancer cohort n=193; safety and PFS analyses: ovarian cancer patients who received ≥3 prior lines of chemotherapy n=154; ORR analysis: ovarian cancer patients with measurable disease who received ≥3 prior lines of chemotherapy n=137.
AE, adverse event; bid, twice daily; BRCA, breast cancer susceptibility gene; FDA, US Food and Drug Administration; g, germline; mPFS, median progression-free survival; ORR, objective response rate.
1. Kaufman B, et al. J Clin Oncol. 2015;33(3): Domchek SM, et al. Gynecol Oncol. 2016;140(2):

13. Olaparib Tablet Indication for Maintenance Treatment With or Without BRCA Mutation was Supported by Study 19 and SOLO-2
Study 19 reported improved PFS in response to olaparib compared with placebo in patients with platinum-sensitive, relapsed, HGSOC with or without gBRCA mutation
Study 19 (NCT )1,2
Olaparib
Placebo N
136
129
Design
Phase 2
Patients
Platinum-sensitive, recurrent ovarian or fallopian tube or primary peritoneal cancer with high-grade serous features or a serous component, with or without gBRCA1/2 mutation, ≥2 prior lines of platinum-based chemotherapy, CR or PR in response to last chemotherapy
Treatment
400 mg bid
Results: mPFS and HR (95% CI)
8.4 mo
4.8 mo
0.35 (0.25–0.49); P<0.001
Safety: Most common grade 3 or 4 AEs in active treatment group
Fatigue (6.6%)
Anemia (5.1%)
Nausea (2.2%)
Vomiting (2.2%)
Diarrhea (2.2%)
Back pain (2.2%)
Fatigue (3.1%) Anemia (0.8%)
Nausea (0)
Vomiting (0.8%)
Diarrhea (2.3%)
Back pain (0)
AE, adverse event; bid, twice daily; BRCA, breast cancer susceptibility gene; CI, confidence interval; CR, complete response; g, germline; HGSOC, high-grade serous ovarian cancer; HR, hazard ratio; mPFS, median progression-free survival; PR, partial response.
1. Ledermann J, et al. N Engl J Med. 2012;366(15): Ledermann JA, et al. Lancet Oncol. 2016;17(11):

14. 300 mg bid (two 150-mg tablets)
Olaparib Tablet Indication for Maintenance Treatment With or Without BRCA Mutation was Supported by Study 19 and SOLO-2 (continued)
SOLO-2, a double-blind phase 3 clinical trial, reported improved PFS in response to olaparib compared with placebo in patients who had platinum-sensitive, relapsed ovarian cancer and a germline BRCA mutation
SOLO-2 (NCT )
Olaparib
Placebo N
195 99
Design
Phase 3
Patients
Platinum-sensitive, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer including primary peritoneal or fallopian tube cancer, gBRCA1/2 mutation, ≥2 prior lines of platinum-based chemotherapy, in response to last chemotherapy
Treatment
300 mg bid (two 150-mg tablets)
Results: mPFS and HR (95% CI)
19.1 mo
5.5 mo
0.30 (0.22–0.41); P<0.0001
Safety: Most common grade 3 or 4 AEs in active treatment group
Anemia (19%)
Neutropenia (5%)
Fatigue/asthenia (4%)
Anemia (2%)
Neutropenia (4%)
Fatigue/asthenia (2%)
AE, adverse event; bid, twice daily; BRCA, breast cancer susceptibility gene; CI, confidence interval; HR, hazard ratio; mPFS, median progression-free survival.
Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9):

15. Olaparib 300 mg bid (two 150-mg tabs)
Olaparib Is Approved for ≥4L Treatment of Ovarian Cancer With a gBRCA Mutation and for Maintenance Treatment of Recurrent Platinum-Sensitive Ovarian Cancer
Study 42 (NCT )1
Study 19 (NCT )2,3
SOLO-2 (NCT )4 N
154
136
129
195 99
Design
Phase 2
Phase 3
Patients
Recurrent ovarian cancera with gBRCA mutation, ≥3 prior lines of therapy
Platinum-sensitive, relapsed, HGSOCa with or without gBRCA1/2 mutation, ≥2 prior lines of platinum-based chemotherapy
Platinum-sensitive, relapsed HGSOCa with gBRCA1/2 mutation, ≥2 prior lines of platinum-based chemotherapy
Treatment
Olaparib 400 mg bid
Placebo
Olaparib 300 mg bid (two 150-mg tabs)
Results: mPFS
6.7 mo
8.4 mo
4.8 mo
19.1 mo
5.5 mo
Safety: Most common grade ≥3 AEs in active treatment group
Anemia (20%)
Abdominal pain (8%)
Fatigue (7%)
Fatigue (6.6%) Anemia (5.1%)
Nausea (2.2%)
Vomiting (2.2%)
Diarrhea (2.2%)
Back pain (2.2%)
Fatigue (3.1%) Anemia (0.8%)
Nausea (0)
Vomiting (0.8%)
Diarrhea (2.3%)
Back pain (0)
Anemia (19%)
Neutropenia (5%)
Fatigue/asthenia (4%)
Anemia (2%)
Neutropenia (4%)
Fatigue/asthenia (2%)
A deleterious or suspected deleterious gBRCA mutation should be identified with an FDA-approved companion diagnostic for use in ≥4L treatment5
Tablets have been approved for both indications5
a Including primary peritoneal or fallopian tube cancer.
AE, adverse event; bid, twice daily; BRCA, breast cancer susceptibility gene; FDA, US Food and Drug Administration; g, germline; HGSOC, high-grade serous ovarian cancer; L, line of treatment; mPFS, median progression-free survival.
1. Domchek SM, et al. Gynecol Oncol. 2016;140(2): Ledermann J, et al. N Engl J Med. 2012;366(15): Ledermann JA, et al. Lancet Oncol. 2016;17(11): Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9): Olaparib package insert. AstraZeneca Pharmaceuticals LP; January 2018.

16. Advanced solid tumor, progressed on treatment
Study 10 and ARIEL2 Supported Initial Approval for Rucaparib as ≥3L Treatment for Patients With Ovarian Cancer and a Germline or Somatic BRCA Mutation
Study 10 reported promising responses to rucaparib in patients with platinum-sensitive ovarian cancer and a gBRCA mutation, who had received 2–4 prior lines of therapy
Study 10 (NCT )1
Part 1
Part 2 N 56 42
Design
Phase 1 dose escalation
Phase 2 expansion
Patients
Advanced solid tumor, progressed on treatment
Platinum-sensitive, relapsed, high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer, with gBRCA1/2 mutation, 2–4 prior regimens
Treatment
Rucaparib 40–840 mg
daily or bid (3+3)
Rucaparib 600 mg bid
Results
RP2D: 600 mg bid
ORR: 59.5%
Safety: Most common grade 3 or 4 AEs NR
Anemia (38.1%)
Fatigue/asthenia (26.2%)
Neutropenia (16.6%)
AE, adverse event; bid, twice daily; BRCA, breast cancer susceptibility gene; g, germline; L, line of treatment; NR, not reported; ORR, objective response rate; RP2D, recommended phase 2 dose.
Kristeleit R, et al. Clin Cancer Res. 2017;23(15):

17. Study 10 and ARIEL2 Supported Initial Approval for Rucaparib as ≥3L Treatment for Patients With Ovarian Cancer and a Germline or Somatic BRCA Mutation (continued)
ARIEL2 measured PFS in response to rucaparib in patients with platinum-sensitive ovarian cancer who had received 1–4 prior lines of therapy
ARIEL2 stratified patients by BRCAmut status and extent of HRD, as assessed by LOH
LOH occurs when a mutated gene allele is accompanied by loss of wt allele; ARIEL2 subgroups included patients with a BRCAmut, patients with BRCAwt and either a high (LOH high) or low (LOH low) percentage of genome-wide LOH
ARIEL2 (NCT )
BRCAmut (all)
sBRCAmut*
BRCAwt, LOH high
BRCAwt, LOH low N 40 19 82 70
Design
Phase 2
Patients
Part 1: Platinum-sensitive, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer with ≥1 prior line of platinum therapy
Part 2 (ongoing): Platinum-sensitive, -resistant, or -refractory; 3–4 prior lines of chemotherapy
Treatment
Rucaparib 600 mg bid
Results (Part 1)
mPFS: 12.8 mo
Confirmed ORR: 74%
mPFS: 5.7 mo
mPFS: 5.2 mo
HR 0.27, P< vs LOH low
HR 0.62, P=0.011 vs LOH low
Safety (Part 1): Most common grade ≥3 AEs
Anemia (22%)
Elevated ALT/AST (12%)
Fatigue/asthenia (9%)
* Not a primary cohort.
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; bid, twice daily; BRCA, breast cancer susceptibility gene; HR, hazard ratio; HRD, homologous recombination deficiency; L, line of treatment; LOH, loss of heterozygosity; mPFS, median progression-free survival; mut, mutation; ORR, objective response rate; s, somatic; wt, wild-type.
Swisher EM, et al. Lancet Oncol. 2017;18(1):75-87.

18. ARIEL3 Supported Subsequent FDA Approval for Rucaparib as Maintenance Therapy in Patients With Recurrent Ovarian Cancer, With or Without a BRCA Mutation
ARIEL3 (NCT )
Rucaparib
Placebo N
375a
189
Design
Phase 3
Patients
Platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer, ≥2 prior lines of platinum chemotherapy
Treatment
Rucaparib 600 mg bid
Results:
mPFS
HR (95% CI) [P value]
BRCAmut
HRD
BRCAwt LOHlow
ITT (all pts)
16.6 mo
13.6 mo
6.7 mo
10.8 mo
5.4 mo
0.23 (0.16–0.34)
[<0.0001]
0.32 (0.24–0.42)
0.58 (0.40–0.85) [0.0049]
0.36 (0.30–0.45)
Safety: Most common grade ≥3 AEs in active treatment group
Anemia (19%)
Elevated ALT/AST (10%)
Fatigue/asthenia (7%)
Anemia (1%)
Elevated ALT/AST (0)
Fatigue/asthenia (3%)
a Safety population n=372.
AE, adverse event; bid, twice daily; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BRCA, breast cancer susceptibility gene; CI, confidence interval; FDA, US Food and Drug Administration; HR, hazard ratio; HRD, homologous recombination deficiency; ITT, intent-to- treat; LOH, loss of heterozygosity; mPFS, median progression-free survival; mut, mutation; pts, patients; wt, wild-type.
Coleman RL, et al. Lancet. 2017;390(10106):

19. Rucaparib Is Approved for ≥3L Treatment of Ovarian Cancer With a BRCA Mutation and for Maintenance Treatment of Recurrent Platinum-Sensitive Ovarian Cancer
Study 10 (NCT )1
ARIEL2 (NCT )2
ARIEL3 (NCT )3
Part 2
BRCAmut
sBRCAmut*
HRD
ITT N 42 40 19
130
236
375
Design
Phase 2 expansion
Phase 2, Part 1
Phase 3
Patients
Platinum-sensitive, relapsed, high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer, with gBRCA1/2 mutation, 2–4 prior regimens
Platinum-sensitive, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer with ≥1 prior lines of platinum therapy
Platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer, ≥2 prior lines of platinum chemotherapy
Treatment
Rucaparib 600 mg bid
Results
ORR: 59.5%
mPFS: mo
Confirmed ORR: 74%
mPFS: 16.6 mo
mPFS: 13.6 mo
mPFS: 10.8 mo
Safety: Most common grade ≥3 AEs
Anemia (38.1%)
Fatigue/asthenia (26.2%)
Neutropenia (16.6%)
Anemia (22%)
Elevated ALT/AST (12%)
Fatigue/asthenia (9%)
Anemia (19%)
Elevated ALT/AST (10%)
Fatigue/asthenia (7%)
The presence of a deleterious BRCA mutation (germline and/or somatic) should be identified with an FDA-approved companion diagnostic for use in ≥3L treatment3
A complementary diagnostic can be used to determine the status of BRCA mutations and HRD when making treatment decisions for maintenance treatment4
* Not a primary cohort.
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; bid, twice daily; BRCA, breast cancer susceptibility gene; FDA, US Food and Drug Administration; g, germline; HRD, homologous recombination deficiency; L, line of treatment; mPFS, median progression-free survival; mut, mutation; ORR, objective response rate; s, somatic.
1. Kristeleit R, et al. Clin Cancer Res. 2017;23(15): Swisher EM, et al. Lancet Oncol. 2017;18(1): Rucaparib package insert. Clovis Oncology, Inc; April FDA. FDA Approves Rucaparib for Maintenance Treatment of Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. Last updated April 6, Accessed April 10, 2018.

20. NOVA Supported FDA Approval for Niraparib as Maintenance Treatment in Patients With Recurrent Platinum-Sensitive Ovarian Cancer
NOVA, a double-blind phase 3 clinical trial, reported improved PFS in response to niraparib compared with placebo in patients who had platinum-sensitive, relapsed HGSOC
NOVA assessed patients with and without a gBRCA mutation
NOVA (NCT )
gBRCAmut
Non-gBRCAmut N
203
350
Design
Phase 3
Patients
Platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer with predominantly high-grade serous features, ≥2 prior lines of platinum therapy, in CR or PR to most recent platinum therapy
Treatment
Niraparib 300 mg daily
Placebo
Results: mPFS and HR (95% CI)
21.0 mo
5.5 mo
9.3 mo
3.9 mo
0.27 (0.17–0.41); P<0.001
0.45 (0.34–0.61); P<0.001
Safety: Most common grade 3 or 4 AEs in patients treated with niraparib
Thrombocytopenia (33.8%)
Anemia (25.3%)
Neutropenia (19.6%)
Please see Important Safety Information for niraparib on slide 22.
AE, adverse event; BRCA, breast cancer susceptibility gene; CR, complete response; FDA, US Food and Drug Administration; g, germline; HGSOC, high-grade serous ovarian cancer; HR, hazard ratio; HRD, homologous recombination deficiency; mPFS, median progression-free survival; mut, mutation; PR, partial response.
Mirza MR, et al. N Engl J Med. 2016;375(22):

21. NOVA Supported FDA Approval for Niraparib as Maintenance Treatment in Patients With Recurrent Platinum-Sensitive Ovarian Cancer (continued)
Subgroups within the non-gBRCAmut cohort were analyzed to assess outcomes in distinct biomarker populations
NOVA (NCT )
Non-gBRCAmut
HRD-positive
sBRCAmut
HRD-negative N
162 47
134
Treatment
Niraparib 300 mg daily
Placebo
Results: mPFS
and HR (95% CI)
12.9 mo
3.8 mo
20.9 mo
11.0 mo
6.9 mo
0.38 (0.24–0.59); P<0.001
0.27 (0.08–0.90); P=0.02
0.58 (0.36–0.92); P=0.02
Please see Important Safety Information for niraparib on the next slide.
BRCA, breast cancer susceptibility gene; FDA, US Food and Drug Administration; g, germline; HR, hazard ratio; HRD, homologous recombination deficiency; mPFS, median progression-free survival; mut, mutation; s, somatic.
Mirza MR, et al. N Engl J Med. 2016;375(22):

22. Niraparib: Important Safety Information
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including some fatal cases, was reported in 1.4% of patients receiving niraparib vs 1.1% of patients receiving placebo in Trial 1 (NOVA), and 0.9% of patients treated with niraparib in all clinical studies. The duration of niraparib treatment in patients prior to developing MDS/AML varied from <1 month to 2 years. All patients had received prior chemotherapy with platinum and some had also received other DNA damaging agents and radiotherapy. Discontinue niraparib if MDS/AML is confirmed. Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients receiving niraparib. Grade ≥3 thrombocytopenia, anemia and neutropenia were reported in 29%, 25%, and 20% of patients receiving niraparib, respectively. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, in 3%, 1%, and 2% of patients, respectively. Do not start niraparib until patients have recovered from hematological toxicity caused by prior chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically thereafter. If hematological toxicities do not resolve within 28 days following interruption, discontinue niraparib, and refer the patient to a hematologist for further investigations. Hypertension and hypertensive crisis have been reported in patients receiving niraparib. Grade 3–4 hypertension occurred in 9% of patients receiving niraparib vs 2% of patients receiving placebo in Trial 1, with discontinuation occurring in <1% of patients. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with niraparib. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Manage hypertension with antihypertensive medications and adjustment of the niraparib dose, if necessary. Based on its mechanism of action, niraparib can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months after receiving their final dose. Because of the potential for serious adverse reactions from niraparib in breastfed infants, advise lactating women to not breastfeed during treatment with niraparib and for 1 month after receiving the final dose. In clinical studies, the most common adverse reactions (Grades 1–4) in ≥10% of patients included: thrombocytopenia (61%), anemia (50%), neutropenia (30%), leukopenia (17%), palpitations (10%), nausea (74%), constipation (40%), vomiting (34%), abdominal pain/distention (33%), mucositis/stomatitis (20%), diarrhea (20%), dyspepsia (18%), dry mouth (10%), fatigue/asthenia (57%), decreased appetite (25%), urinary tract infection (13%), ALT/AST elevation (10%), myalgia (19%), back pain (18%), arthralgia (13%), headache (26%), dizziness (18%), dysgeusia (10%), insomnia (27%), anxiety (11%), nasopharyngitis (23%), dyspnea (20%), cough (16%), rash (21%) and hypertension (20%). Common lab abnormalities (Grades 1–4) in ≥25% of patients included: decrease in hemoglobin (85%), decrease in platelet count (72%), decrease in white blood cell count (66%), decrease in absolute neutrophil count (53%), increase in AST (36%) and increase in ALT (28%).
Please see Prescribing Information for niraparib here.
ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Niraparib package insert. TESARO, Inc; August 2017.

23. Olaparib: Important Safety Information
CONTRAINDICATIONS There are no contraindications for olaparib. WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to olaparib monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or bone marrow dysplasia. Do not start olaparib until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt olaparib and monitor blood count weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue olaparib if MDS/AML is confirmed. Pneumonitis: Occurred in <1% of patients exposed to olaparib, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt olaparib treatment and initiate prompt investigation. Discontinue olaparib if pneumonitis is confirmed and treat patient appropriately. Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, olaparib can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose. 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 olaparib and to not donate sperm during this time. ADVERSE REACTIONS—Maintenance Setting Most common adverse reactions (Grades 1–4) in ≥20% of patients in clinical trials of olaparib in the maintenance setting for SOLO-2: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%). Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), and decreased appetite (21%).
Olaparib package insert. AstraZeneca Pharmaceuticals LP; January 2018.

24. Olaparib: Important Safety Information (continued)
Most common laboratory abnormalities (Grades 1–4) in ≥25% of patients in clinical trials of olaparib in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%). ADVERSE REACTIONS—Advanced gBRCAm ovarian cancer Most common adverse reactions (Grades 1–4) in ≥20% of patients in clinical trials of olaparib for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%). Most common laboratory abnormalities (Grades 1–4) in ≥25% of patients in clinical trials of olaparib for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), increase in mean corpuscular volume (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%). ADVERSE REACTIONS—gBRCAm, HER2-negative breast cancer Most common adverse reactions (Grades 1–4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%). Most common laboratory abnormalities (Grades 1–4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%). DRUG INTERACTIONS Anticancer Agents: Clinical studies of olaparib in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of olaparib. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during olaparib treatment. CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using olaparib. If a moderate inducer cannot be avoided, be aware of a potential for decreased efficacy of olaparib.
Olaparib package insert. AstraZeneca Pharmaceuticals LP; January 2018.

25. Olaparib: Important Safety Information (continued)
USE IN SPECIFIC POPULATIONS Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with olaparib and for 1 month after receiving the final dose. Pediatric Use: The safety and efficacy of olaparib have not been established in pediatric patients. Hepatic Impairment: No adjustment to the starting dose is required in patients with mild hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment. Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51–80 mL/min), but patients should be monitored closely for toxicity. In patients with moderate renal impairment (CLcr=31–50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min). DOSING AND ADMINISTRATION To avoid substitution errors and overdose, do not substitute olaparib tablets with olaparib capsules on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. Recommended tablet dose is 300 mg, taken orally twice daily, with or without food. Continue treatment until disease progression or unacceptable toxicity. For adverse reactions, consider dose interruption or dose reduction.
Olaparib package insert. AstraZeneca Pharmaceuticals LP; January 2018.

26. Rucaparib: Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with rucaparib, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long term follow-up. Of these, 5 occurred during treatment or during the 28 day safety follow-up (0.5%). The duration of rucaparib treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA damaging agents. Do not start rucaparib 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 rucaparib or reduce dosea 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 rucaparib. Based on its mechanism of action and findings from animal studies, rucaparib can cause fetal harm when administered to a pregnant woman. 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 rucaparib. Most common adverse reactions in ARIEL3 (≥20%; Grade 1–4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distension (46%), rash (43%), dysgeusia (40%), anemia (39%), ALT/AST elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%), and neutropenia (20%). Most common laboratory abnormalities in ARIEL3 (≥25%; Grade 1–4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in ALT (73%), increase in AST (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%), and decrease in lymphocytes (29%). Most common adverse reactions in Study 10 and ARIEL2 (≥20%; Grade 1–4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%). Most common laboratory abnormalities in Study 10 and ARIEL2 (≥35%; Grade 1–4) were increase in creatinine (92%), increase in ALT (74%), increase in AST (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%), and decrease in absolute neutrophil count (35%).
a See Dosage and Administration (2.2) in full Prescribing Information.
ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Rucaparib package insert. Clovis Oncology, Inc; April 2018.

27. Rucaparib: Select Important Safety Information (continued)
Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, 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 frequency of international normalized ratios (INR) monitoring. Because of the potential for serious adverse reactions in breast-fed children from rucaparib, advise lactating women not to breastfeed during treatment with rucaparib and for 2 weeks after the last dose.
Rucaparib package insert. Clovis Oncology, Inc; April 2018.

28. PARP Inhibitor Efficacy in Patients Without a BRCA Mutation

29. Germline BRCA Mutations Are Present in About 14% of HGSOC Cases
When considering the rate of mutations in gBRCA, can PARP inhibitors be applied to tumors with other DNA repair defects?
Germline
BRCAmut
~14%
BRCA, breast cancer susceptibility gene; g, germline; HGSOC, high-grade serous ovarian cancer; mut, mutation; PARP, poly ADP ribose polymerase.
Konstantinopoulos PA, et al. Cancer Discov. 2015;5(11):

30. Patients With BRCAmut (n=136) Patients With BRCAwt(a) (n=118)
Study 19: In an Exploratory Retrospective Analysis, Patients With BRCAwt Treated With Olaparib Had Longer mPFS Compared With Placebo
Patients With BRCAmut (n=136)
Patients With BRCAwt(a) (n=118)
Olaparib
Placebo
Olaparib
Placebo
Number at riskb
Olaparib 74 59 34 15 5
Placebo 62 35 13 2
Number at riskb
Olaparib 57 45 18 9 2
Placebo 61 35 10 4 1
BRCAmut (n=136)
Olaparib
(n=74)
Placebo
(n=62)
Events, n (%)
26 (35)
46 (74)
mPFS, mo
11.2
4.3
HR (95% CI)
P value
0.18 (0.10–0.31)
<
BRCAwt (n=118)
Olaparib
(n=57)
Placebo
(n=61)
Events, n (%)
32 (56)
44 (72)
mPFS, mo
7.4
5.5
HR (95% CI)
P value
0.54 (0.34–0.85)
0.0075
a Wild-type subgroup includes patients with no known BRCAmut and those with a BRCAmut of unknown significance. b Number of remaining patients in the study for each interval.
BRCA, breast cancer susceptibility gene; CI, confidence interval; HR, hazard ratio; mPFS, median progression-free survival; mut, mutation; wt, wild-type.
Ledermann J, et al. Lancet Oncol. 2014;15(8):

31. Study 19: No Clear Difference in OS Was Observed, Especially for BRCAwt Subgroupa
Patients With BRCAmut (n=136)
Patients With BRCAwt(b) (n=118)
Olaparib
Placebo
Olaparib
Placebo
Time From Randomization (Months)
Time From Randomization (Months)
Number at riskc
Olaparib 74 69 65 56 50 39 33 27 25 23 11 1
Placebo 62 58 52 40 34 29 20 19 15 13 10 6
Number at riskc
Olaparib 57 50 39 28 23 19 16 15 14 12 4 1
Placebo 61 60 56 46 37 25 17 11 8 3
BRCAmut (n=136)
Olaparib
(n=74)
Placebo
(n=62)
Events, n (%)
47 (64)
48 (77)
mOS, mo
34.9
30.2
HR (95% CI)
Nominal P value
0.62 (0.41–0.94)
0.025
BRCAwt (n=118)
Olaparib
(n=57)
Placebo
(n=61)
Events, n (%)
43 (75)
56 (92)
mOS, mo
24.5
26.6
HR (95% CI)
Nominal P value
0.83 (0.55–1.24)
0.37
a Study 19 was not designed to show a statistically significant difference in OS. b Wild-type subgroup includes patients with no known BRCAmut and those with a BRCAmut of unknown significance. c Number of remaining patients in the study for each interval.
BRCA, breast cancer susceptibility gene; CI, confidence interval; HR, hazard ratio; mOS, median overall survival; mut, mutation; OS, overall survival; wt, wild-type.
Ledermann JA, et al. Lancet Oncol. 2016;17(11):

32. Non-BRCA HR Deficient ~33%
Beyond BRCA, Other Methods of Characterizing DNA Repair Defects May Allow Determining Potential Benefit
About half of women with HGSOC have known homologous recombination deficiencies
HR Proficient ~47%
Non-BRCA HR Deficient ~33%
Germline
BRCAmut
~14%
Somatic BRCAmut
~6%
BRCA, breast cancer susceptibility gene; HGSOC, high-grade serous ovarian cancer; HR, homologous recombination; mut, mutation.
Konstantinopoulos PA, et al. Cancer Discov. 2015;5(11):

33. ARIEL2: HRD Subgroup Data Suggest Benefit in Assessing Tumor LOH
Along with BRCA1/2 mutations, genomic LOH may represent HRD and predict response to rucaparib
BRCA mutant
BRCA wild-type and LOH high
BRCA wild-type and LOH low
BRCA mutant vs BRCA wild-type and LOH low: HR 0.27 (95% CI, ); P<0.0001
BRCA wild-type and LOH high vs BRCA wild-type and LOH low: HR 0.62 (95% CI, ); P=0.011
Number at riska
BRCA mutant 40 39 36 34 33 27 25 22 20 19 16 12 9 7 5 2
BRCA wild-type and LOH high 82 77 61 56 48 45 31 23 21 18 17 14 10 4 3 1
BRCA wild-type and LOH low 70 69 53 37 15 6
a Number of remaining subjects in the study for each interval.
BRCA, breast cancer susceptibility gene; CI, confidence interval; HR, hazard ratio; HRD, homologous recombination deficiency; LOH, loss of heterozygosity.
Swisher EM, et al. Lancet Oncol. 2017;18(1):75-87.

34. Non-BRCA HR Deficient ~33%
Can Current Biomarkers Identify All Patients Who May Benefit from PARP Inhibitor Treatment?
HR Proficient ~47%
Non-BRCA HR Deficient ~33%
Germline
BRCAmut
~14%
Somatic BRCAmut
~6%
HR, homologous recombination; mut, mutation; PARP, poly ADP ribose polymerase.
Konstantinopoulos PA, et al. Cancer Discov. 2015;5(11):

35. NOVA: PFS Benefit Seen in Pre-Identified Subgroups
Germline BRCA Mutation
HR 0.27 (95% CI, 0.17–0.41) P<0.001
No Germline BRCA Mutation
HR 0.45 (95% CI, 0.34–0.61) P<0.001
Niraparib: mPFS 21.0 mo
Niraparib: mPFS 9.3 mo
Placebo: mPFS 5.5 mo
Placebo: mPFS 3.9 mo
Number at riska
Niraparib
138
125
107 98 89 79 63 44 28 26 16 3 1
Placebo 65 52 34 21 12 8 6 2
Number at riska
Niraparib
234
188
145
113 88 75 57 41 23 21 16 7 3
Placebo
116 52 33 19 10 8 4 1
No Germline BRCA Mutation With HRD Positivity
HR 0.38 (95% CI, 0.24–0.59) P<0.001
No Germline BRCA Mutation With HRD Negativity
HR 0.58 (95% CI, 0.36–0.92) P=0.02
Niraparib: mPFS 12.9 mo
Niraparib: mPFS 6.9 mo
Placebo: mPFS 3.9 mo
Placebo: mPFS 3.8 mo
Number at riska
Niraparib
106 90 75 64 52 46 40 29 16 14 11 4 2
Placebo 56 41 26 9 3 1
Number at riska
Niraparib 92 73 54 35 26 22 11 8 3 2 1
Placebo 42 19 7 6
Please see Important Safety Information for niraparib on slide 22.
a Number of remaining subjects in the study for each interval.
CI, confidence interval; HR, hazard ratio; HRD, homologous recombination deficiency; mPFS, median progression-free survival; PFS, progression-free survival.
Mirza MR, et al. N Engl J Med. 2016;375(22):

36. Adverse Effects and Dosing

37. Adverse Events Associated With Approved PARP Inhibitors in Clinical Trials (Grade 1–4 Occurring in ≥20% of Treated Patients)
Olaparib1,a
Rucaparib2
Niraparib3
N=223
N=377b
N=372c
N=367
Gr 1–4
Gr 3/4
Blood and lymphatic system disorders, % 
Anemia 34 18 44 25 39 21 50
Thrombocytopenia – 5 29 61
Neutropenia 20 8 30
Gastrointestinal disorders, %
Decreased appetite 22 1 3 23
0.3
Nausea 64 77 76 4 74
Vomiting 43 46 37 2
Diarrhea 31 32
0.5
Dyspepsia
Constipation 40
0.8
Abdominal pain/distension
32d 3d 33
Mucositis/stomatitis
28e 1e
Respiratory, thoracic, and mediastinal disorders %
Nasopharyngitis/upper respiratory tract infection 26
23f 0f
Dyspnea
Other disorders, %
Fatigue/asthenia 66 11 73 7 57
Insomnia 27
Rash
Hypertension 9
ALT/AST elevation 38
Nervous system disorders, %
Dysgeusia
Headache
Musculoskeletal disorders, %
Arthralgia/musculoskeletal pain 0 
Myalgia
a Pooled from 6 studies: patients with gBRCAmut ovarian cancer who received 3 or more prior lines of chemotherapy. b Data from Study 10 and ARIEL2. c Data from ARIEL3. d Does not include distension. e Does not include mucositis. f Does not include upper respiratory infection.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; Gr, grade; PARP, poly ADP ribose polymerase.
1. Olaparib package insert. AstraZeneca Pharmaceuticals LP; January Rucaparib package insert. Clovis Oncology, Inc; April Niraparib package insert. TESARO, Inc; August 2017.

38. Laboratory Abnormalities Associated With Approved PARP Inhibitors in Clinical Trials (Grade 1–4 Occurring in ≥35% of Patients)
Olaparib1,a
Rucaparib2
Niraparib3
N=223
N=377b
N=372c
N=367
Gr 1–4
Gr 3/4
Hematology, %
Decrease in hemoglobin 90 15 67 23 88 13 85 25
Decrease in lymphocytes 56 17 45 7 –
Decrease in platelets 39 6 44 2 72 35
Decrease in absolute neutrophil count 10 53 21
Decrease in leukocytes 3
Decrease in neutrophils 38
Decrease in white blood cell count 66
Mean corpuscular volume elevation 57
Chemistry, %
Increase in creatinine 92 1 98
0.3
Increase in ALT 74 73
Increase in AST 5 61 36
Increase in cholesterol 40 84 4
Increase in alkaline phosphatase 37
a Pooled from 6 studies: patients with gBRCAmut ovarian cancer who received 3 or more prior lines of chemotherapy. b Data from Study 10 and ARIEL2. c Data from ARIEL3.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; g, germline; Gr, grade; mut, mutation; PARP, poly ADP ribose polymerase.
1. Olaparib package insert. AstraZeneca Pharmaceuticals LP; January Rucaparib package insert. Clovis Oncology, Inc; April Niraparib package insert. TESARO, Inc; August 2017.

39. Monitor for hematological toxicity at baseline and monthly thereafter
MDS and AML Have Been Reported in Patients Treated With PARP Inhibitors
Olaparib1
Rucaparib2
Niraparib3
Rates of MDS/AML in clinical trials
<1.5%
1.1%
1.4%
MDS/AML incidence in clinical trial(s), n / N
21 / 1680
12 / approx. 1100
5 / 367
Monitoring
Monitor for hematological toxicity at baseline and monthly thereafter
Monitor for hematological toxicity: test CBC weekly for the first month, then monthly for the next 11 months, and then periodically
MDS/AML Monitoring1-3
Do not start PARP inhibitors until patients have recovered from hematological toxicity from prior therapy
For prolonged hematological toxicity, interrupt treatment and monitor CBC weekly until recovery
If no recovery within 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics
If MDS/AML is confirmed, discontinue PARP inhibitor
AML, acute myeloid leukemia; CBC, complete blood count; MDS, myelodysplastic syndrome; PARP, poly ADP ribose polymerase.
1. Olaparib package insert. AstraZeneca Pharmaceuticals LP; January Rucaparib package insert. Clovis Oncology, Inc; April Niraparib package insert. TESARO, Inc; August 2017.

40. General Strategies for Managing Common ARs That May Occur During PARPi Therapy
Adverse Reaction
Characteristics
Treatments
Cancer-related anorexia-cachexia syndrome1
Physical wasting with loss of skeletal and visceral muscle mass
Loss of desire to eat
Reversible causes of anorexia should be addressed
Relief of symptoms that interfere with food intake
Metoclopramide for early satiety
Consider appetite stimulants and/or nutrition consultation
Diarrhea1
Increase in number of stools per day over baseline
Increase in ostomy output
Hydration and electrolyte replacement (oral or IV fluids)
Dietary modifications
Antidiarrheal, antibiotic, and/or anticholinergic medication
Complicated diarrhea may require hospital admission; consider somatostatin analog
Nausea and vomiting2
Vomiting results from stimulation of a multistep reflex pathway
Nausea can be acute or delayed
Oral antiemetic prophylaxis
Cancer-related fatigue3
Distressing and persistent sense of tiredness or exhaustion
Not proportional to recent activity
Interferes with usual functioning
Management of concurrent symptoms and treatable contributing factors
Nonpharmacologic interventions (eg, physical activity, massage therapy, psychosocial interventions, and energy conservation)
Pharmacologic management
AR, adverse reaction; IV, intravenous; PARPi, poly ADP ribose polymerase inhibitor.
1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Palliative Care V © National Comprehensive Cancer Network, Inc All rights reserved. Accessed June 27, To view the most recent and complete version of the guideline, go online to NCCN.org Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V © National Comprehensive Cancer Network, Inc All rights reserved. Accessed June 27, To view the most recent and complete version of the guideline, go online to NCCN.org Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Cancer-Related Fatigue V © National Comprehensive Cancer Network, Inc All rights reserved. Accessed June 27, To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

41. PARP Inhibitor Pharmacology
Olaparib1
Rucaparib2
Niraparib3
Dosage forms
Capsules: 50 mg
Tablets: 100 or 150 mg
Tablets: 200, 250, or 300 mg
Capsules: 100 mg
Dose
Capsulesa: 400 mg bid
Tabletsa: 300 mg bid
600 mg bid
300 mg daily
Starting dose modifications
Moderate renal impairment
CYP3A inhibitor use
None
Metabolized primarily by
CYP3A4/5
CYP2D6
Carboxylesterases
Monitor
CBC at baseline and monthly thereafter
CBC weekly for the first month, then monthly for the next 11 months, and then periodically
BP and heart rate monthly during the first year and periodically
Manage adverse reactions through
Dose interruption or dose reduction
a Olaparib capsules and tablets formulations are not interchangeable.
bid, twice daily; BP, blood pressure; CBC, complete blood count; CYP, cytochrome P450; PARP, poly ADP ribose polymerase.
1. Olaparib package insert. AstraZeneca Pharmaceuticals LP; January Rucaparib package insert. Clovis Oncology, Inc; April Niraparib package insert. TESARO, Inc; August 2017.

42. PARP Inhibitor Effect on Quality of Life
These analyses are exploratory in nature and do not control for Type 1 error; elements more distal to disease and treatment-related symptoms may be influenced by multiple non-drug factors

43. NOVA: Patients Treated With Niraparib Maintained Their QoL as Assessed by FOSI
Analyses of patient-reported outcomes indicated similar outcomes for patients treated with niraparib and placebo
gBRCAmut cohort
Non-gBRCAmut cohort
Niraparib
Placebo
Niraparib
Placebo
Screening
Post prog
Screening
Post prog
Niraparib
Placebo
24.8
24.0
24.6
25.3
25.1
25.2
23.8
24.9
24.5
24.4
24.1
23.7
25.0
24.0
24.3
24.7
25.1
24.9
25.3
22.5
24.6
23.7
24.8
24.4
22.9
Please see Important Safety Information for niraparib on slide 22.
C, cycle; FOSI, Functional Assessment of Cancer Therapy – Ovarian Symptom Index; g, germline; mut, mutation; prog, progression; QoL, quality of life; SE, standard error.
Mirza MR, et al. N Engl J Med. 2016;375(22):

44. SOLO-2: Olaparib Maintenance Did Not Affect Global QoL
HRQoL reported using the TOI of the Functional Assessment of Cancer Therapy – Ovarian
TOI over first 12 months
Olaparib (n=185)
Placebo (n=94)
Change from baseline, adjusted mean
–2.90
–2.87
Estimated difference in adjusted means: –0.03 (95% CI, –2.19 to 2.13; P=0.98)
CI, confidence interval; HRQoL, health-related quality of life; QoL, quality of life; TOI, Trial Outcome Index.
Pujade-Lauraine E, et al. Presented at SGO 2017 Annual Meeting.

45. Summary of Other Select PARP Inhibitor Trials

46. Phase 3 Clinical Development Landscape for PARPi Monotherapy Treatment in Ovarian Cancer
Olaparib
Rucaparib
Niraparib
Talazoparib
Veliparib
Monotherapy in recurrent disease
FDA approved
SOLO-3 gBRCAmut
NCT
ARIEL4
BRCAmut
NCT
First-line monotherapy
Maintenance in recurrent disease
OPINION
Non-gBRCAmut
NCT
First-line maintenance
SOLO-1
NCT
PRIMA
NCT
Maintenance re-treatment
OReO
NCT
FDA, US Food and Drug Administration; g, germline; mut, mutation; PARPi, poly ADP ribose polymerase inhibitor; PSOC, platinum-sensitive ovarian cancer.
Olaparib package insert. AstraZeneca Pharmaceuticals LP; January Rucaparib package insert. Clovis Oncology, Inc; April Niraparib package insert. TESARO, Inc; August ClinicalTrials.gov: NCT , NCT , NCT , NCT , NCT , and NCT Accessed April 10, 2018.

47. Combination Approaches With PARP Inhibitors Are Moving Into the Clinic
Challenges
Opportunities
Potential multiple mechanisms of PARP inhibitors (eg, PARP trapping vs catalytic inhibition)
Identifying combination biomarkers that would direct therapy
Dose-limiting toxicities caused by combinations not observed in single-agent studies
Combination of PARP inhibitors with non-DNA damaging agents
Using combinations to target PARP inhibitor resistance mechanisms
Using PARP inhibitor combinations to enhance mutational load and immunogenicity of tumor
Agent
Synthetic Mechanism
Anti-angiogenic agents
Hypoxia may induce BRCA-like phenotype
Immunotherapy
Mutagenic burden induced by PARP inhibition may improve response to immunotherapy
PARP, poly ADP ribose polymerase.
Dréan A, et al. Crit Rev Oncol Hematol. 2016;108:73-85.

48. Many Clinical Trials Are Investigating PARPi Combination Treatment Approaches for Ovarian Cancer
Combination therapy is being tested in both upfront and maintenance settings in phase 2 or 3 studies
Olaparib
Niraparib
Veliparib
Anti-angiogenic therapy
PAOLA-1 Ph 3 NDOC (stage III/IV)
ICON9 Ph 3 Rec PSOC
NRG-GY004 Ph 3 Rec PSOC
CONCERTO Ph 2 Rec PROC BRCAwt
OCTOVA Ph 2 PROC BRCAmut
AVANOVA Ph 1/2 PSOC
OVARIO Ph 2 NDOC
Concurrent chemotherapy
NCT Ph 2 PSOC
ROLANDO Ph 2 PROC
NCT Ph 3 NDOC (stage III/IV)
NCT Ph 1/2 RROC
Immunotherapy
TOPACIO Ph 2 Rec OC
mut, mutation; NDOC, newly diagnosed ovarian cancer; OC, ovarian cancer; PARPi, poly ADP ribose polymerase inhibitor; Ph, phase; PROC, platinum-resistant ovarian cancer; PSOC, platinum-sensitive ovarian cancer; Rec, recurrent; RROC, relapsed or refractory ovarian cancer; wt, wild-type.
ClinicalTrials.gov: NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , and NCT Accessed April 10, 2018.

49. Acquired Resistance to PARP Inhibitors

50. Multiple Potential Mechanisms of Acquired Resistance to PARP Inhibition in BRCA Mutant Tumors
Fundamental and preclinical research suggests that resistance to PARP inhibitors can be induced by mechanisms beyond genetic reversions that correct or bypass original BRCA-inactivating mutation
Resistance mechanism
Genetic reversion of
Truncating mutation in
BRCA1 or BRCA2 gene
Hypomorphic BRCA1 or BRCA2 activity
DNA Damage Response Rewriting
Drug transport by P-gp
PARPi resistant
BRCA-1 revertant
BRCA1-C61G
BRCA BP1
PARPi sensitive
BRCA1-truncated
BRCA1-C61G
BRCA1 HR HR HR HR
53BP1 3’ 5’ 3’ 5’ 5’ 3’ 5’ 3’ HR HR
BRCA, breast cancer susceptibility gene; i, inhibitor; HR, homologous recombination; PARP, poly ADP ribose polymerase.
Bouwman P, et al. Clin Cancer Res. 2014;20(3):540-7.

51. Summary and Unresolved Questions

52. Module Summary
PARP inhibition is synthetically lethal for tumors with HRD1
Currently, 3 PARP inhibitors are approved for patients with ovarian cancer: olaparib, rucaparib, and niraparib2-4
Several grade 3 to 4 hematological adverse reactions are commonly associated with PARP inhibitors2-4
Ongoing clinical trials are examining the efficacy of PARP inhibition across various lines of therapy and treatment approaches, including combination regimens5
PARP inhibition has shown clinical efficacy in patients without HRD6
HRD, homologous recombination deficiency; PARP, poly ADP ribose polymerase.
1. Konstantinopoulos PA, et al. Cancer Discov. 2015;5(11): Olaparib package insert. AstraZeneca Pharmaceuticals LP; January Rucaparib package insert. Clovis Oncology, Inc; April Niraparib package insert. TESARO, Inc; August ClinicalTrials.gov: NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , and NCT Accessed April 10, Mirza MR, et al. N Engl J Med. 2016;375(22):

53. Unresolved Questions
How do biomarkers drive treatment decisions for patients with ovarian cancer?
Beyond BRCA mutations, is there a role for LOH or HRD status in decisions regarding treatment with PARP inhibitors?
What will be the role of PARP inhibitors as maintenance treatment in the frontline setting?
Which patients would benefit from PARP inhibition in place of SOC chemotherapy in the adjuvant setting?
For platinum-sensitive patients, in which order should anti-angiogenic agents and PARP inhibitors be given for maximal clinical benefit?
What is the role of PARP inhibitors in platinum-resistant patients with wild-type BRCA1/2? How might BRCA, LOH, and HRD be used in this setting?
What will be the effect of novel liquid biopsy technology examining circulating tumor cells and cell-free DNA on biomarker-guided ovarian cancer treatment?
BRCA, breast cancer susceptibility gene; HRD, homologous recombination deficiency; LOH, loss of heterozygosity; PARP, poly ADP ribose polymerase; SOC, standard of care.

54. PARPi: Full Prescribing Information
Niraparib rescribing_Information.pdf
Olaparib
Rucaparib
Click to open the full prescribing information for niraparib (revised 08/2017)
PARPi, poly ADP ribose polymerase inhibitor.

55. GEMSTONE
GEMSTONE, a committee of ovarian cancer experts, provided direction and approval of the material in this educational resource. TESARO, Inc. provided writing and organizational support to GEMSTONE in the generation of this material.
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