Moderator: Paula J. Anastasia RN, MN, AOCN Gyn-Onc Clinical Nurse Specialist Cedars-Sinai Medical Center Los Angeles, CA

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2 Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of May The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Creative Educational Concepts or the supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

3 Usage Rights This slide deck is provided for educational purposes and slides may be used for personal, non-commercial presentations only as long as content and references remain the same. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts.

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5 Moderator: Paula J. Anastasia RN, MN, AOCN Gyn-Onc Clinical Nurse Specialist Cedars-Sinai Medical Center Los Angeles, CA

6 Optimizing DNA Damage Response Targeting Therapies: Focus on Genetic Testing and Counseling Nadine M. Tung, MD Beth Israel Deaconess Medical Center Boston, MA

7 Genetic Testing and Counseling Who should get genetic testing? Which genes should be tested? How does this impact treatment?

8 Who Should be Tested for BRCA1/2 Mutations? BRCA1/2 mutations increase the risk for: Breast cancer EOC/FT/PPC Pancreatic cancer Prostate cancer BRCA2 more aggressive: Gleason score >7, higher stage, more risk metastatic disease BRCA2: Melanoma, biliary?/gastric? not part of criteria for testing NCCN Breast/Ovarian Genetic Assessment Guidelines Version

9 Who Should be Tested for BRCA1/2 Mutations? Ovarian Cancer All EOC/FT/PPC pts NCCN, ASCO, SGO agree Insurance cover appropriate pts NCCN Breast/Ovarian Genetic Assessment Guidelines Version ;

10 Who Should be Tested for BRCA1/2 Mutations? Breast Cancer 45 yrs ( 50 yrs if small family/few women) TNBC 60 yrs Ashkenazi Jewish ancestry Male Bilateral 1 st 50 yrs 50 yrs: 1 relative with breast, pancreatic, or prostate cancer Any age: 2 relatives with breast, pancreatic, or prostate cancer 1 relative with ovarian cancer 1 relative with breast cancer diagnosed 50 yrs 1 male relative with breast cancer NCCN Breast/Ovarian Genetic Assessment Guidelines Version

11 Who Should be Tested for BRCA1/2 Mutations? Other Cancers Pancreatic or prostate cancer (Gleason score 7): 1 relative: breast 50 yrs or ovarian cancer (any age) 2 relatives: breast (any age), pancreatic, or prostate cancer Ashkenazi Jewish pancreatic cancer Family hx of BRCA1/2 mutation Somatic BRCA1/2 mutation identified in tumor NCCN Breast/Ovarian Genetic Assessment Guidelines Version

12 Incidence of BRCA1/2 Germline (Inherited) Mutations Breast Cancer: 3-4% (Overall) 10-20% (TNBC) 10-15% (Ashkenazi Jewish breast cancer) Ovarian Cancer: 15% Gonzalez-Angulo AM, et al. Clin Cancer Res. 2011; Sharma P, et al. Breast Cancer Res Treat. 2014; Rummel S, et al. Breast Cancer Res Treat. 2013; Warner E, et al. J Natl Cancer Inst. 1999; King MC, et al. Science. 2003; Risch HA, et al. J Natl Cancer Inst. 2006; Norquist BM, et al. JAMA Oncol

13 Incidence of BRCA1/2 Germline (Inherited) Mutations Pancreatic Cancer 1-5% (Overall) 12% (Ashkenazi Jewish pancreatic cancer) Prostate Cancer 1-2% (Overall) Metastatic: 6% (BRCA2 5%; BRCA1 1%) Holter S, et al. J Clin Oncol. 2015; Agalliu I, et al. Clin Cancer Res. 2009; Prichard CC, et al. N Engl J Med

14 BRCA1/2 Repair Double Strand Breaks in DNA: Homologous Recombination Pennington KP, et al. Gynecol Oncol

15 Criteria for Panel Testing and Types of Panel Testing No criteria or predictors for mutations in more moderate risk genes Multi-gene panels High risk genes (>5x risk cancer) vs. high and moderate risk (2-5x risk cancer) By cancer type or all cancers Tung N, et al. Nat Rev Clin Oncol

16 Breast/Ovarian Cancer Risks with Novel Genes Gene Breast Ovary PALB2 Y (RR 5.3)? (RR ) ATM Y (RR 2.8) CHEK2 (truncating) Y (RR 3.0) NBN Y (RR 2.7) NF1 Y (RR 2.6) BRIP1 Y (RR ) RAD51C Y (OR 5.2) RAD51D Y (OR 12) Easton DF, et al. N Engl J Med. 2015; Antoniou AC, et al. N Engl J Med. 2014; Norquist BM, et al. JAMA Oncol. 2015; Ramus SJ, et al. J Natl Cancer Inst. 2015; Song H, et al. J Clin Oncol

17 Risk of Breast Cancer Associated with Inherited Mutations Gene Breast Cancer Risk (by age 70) High Penetrance BRCA % BRCA % PALB % Moderate Penetrance ATM 20-30% CHEK % Antoniou AC, et al. N Engl J Med. 2014; Tung N, et al. Nat Rev Clin Oncol. 2016; Graffeo R, et al. Breast Cancer Res Treat

18 Management Guidelines for BRCA1/2 Carriers Screening Clinical breast exam Breast MRI Mammogram Management Option Transvaginal US, CA 125 Prevention Bilateral mastectomy Screening Interval/Comment Q6-12 months beginning age 25 Annually: Begin age 25 Annually: Begin age 30 Insufficient data to recommend; may consider starting age Discuss degree of protection, reconstruction options and risks Bilateral salpingo-oophorectomy BRCA1: age 35-40; BRCA2: by age 45 Consider OCP Consider tamoxifen, raloxifene, or AI NCCN Breast/Ovarian Genetic Assessment Guidelines Version ; Visvanathan K, et al. J Clin Oncol

19 NCCN Guidelines Version Breast/Ovarian Management Based on Genetic Test Results Gene Intervention warranted based on gene and/or risk level Recommended Breast MRI (>20% risk of breast cancer) ATM BRCA1 BRCA2 CDH1 CHEK2 NBN NF1 PALB2 PTEN TP53 Discuss Option of RRM BRCA1 BRCA2 CDH1 PTEN TP53 PALB2* *Consider based on family history NCCN Breast/Ovarian Genetic Assessment Guidelines Version

20 Risk of Ovarian Cancer Gene Estimated Lifetime Risk of Ovarian Cancer Recommended Age for RRSO BRCA % BRCA % By age 45 BRIP1 13% (or lower?) >45 RAD51C 6% >45 RAD51D 14% >45 PALB %?? Unknown or insufficient evidence NCCN Breast/Ovarian Genetic Assessment Guidelines Version ; Hartmann LC, et al. N Engl J Med. 2016; Antoniou AC, et al. N Engl J Med. 2014; Norquist BM, et al. JAMA Oncol. 2015; Ramus SJ, et al. J Natl Cancer Inst. 2015; Song H, et al. J Clin Oncol. 2015; Chen S. Parmigiani G. J Clin Oncol. 2007; Mavaddat N, et al. J Natl Cancer Inst

21 Why Do Genetic Testing of a Cancer Patient? Family members Identify other cancers to screen for/or prevent Treatment Platinum PARP inhibitors

22 The Development of Hereditary Cancer 1 damaged gene 1 normal gene All cells in the body: One functioning BRCA gene 2 damaged genes Cancer cells: No functioning BRCA gene Tumor Develops

23 Platinum Damage DS DNA Break Evans MK, Longo DL. N Engl J Med

24 Platinum is Effective in Cancers in Patients with BRCA1/2 Mutations Platinum causes more DS DNA breaks Cancers without BRCA1 or BRCA2 can t repair these breaks Ovarian cancer patients with BRCA1/2 mutations have a better prognosis In part due to higher sensitivity to platinum BRCA1/2 breast cancer Platinum is effective but less data (most info is for TNBC) Still being studied Evans MK, Longo DL. N Engl J Med. 2014;

25 Why Do Genetic Testing of a Cancer Patient? Family members Identify other cancers to screen for or prevent Treatment Platinum PARP inhibitors

26 Platinum Damage SS DNA Break DS DNA Break Evans MK, Longo DL. N Engl J Med

27 PARP Inhibitors: Synthetic Lethality in BRCA Breast Cancers Inglehart JD, Silver DP. N Engl J Med

28 PARP Inhibition: A Possible Achilles Heel for Solid Tumors? BJ Rimel, MD Cedars-Sinai Medical Center Los Angeles, CA

29 What is PARP? Poly (ADP-Ribose) Polymerase Single Strand Break PARP Unrepaired double strand breaks lead Double Strand Break from radiation or to CELL DEATH!!! chemotherapy Morales J, et al. Crit Rev Eukaryot Gene Expr

30 Olaparib DNA AZ1775 Inactive Mitosis Active Rationale for PARP inhibition: antiangiogenesis and cell cycle inhibition Cediranib Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci

31 Olaparib DNA AZ1775 Inactive Mitosis Active Rationale for PARP inhibition: antiangiogenesis and cell cycle inhibition Cediranib Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci

32 Olaparib DNA AZ1775 Inactive Mitosis Active Rationale for PARP inhibition: antiangiogenesis and cell cycle inhibition Cediranib Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci

33 Olaparib DNA AZ1775 Inactive Mitosis Active Rationale for PARP inhibition: antiangiogenesis and cell cycle inhibition Cediranib Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci

34 Currently Approved PARP Inhibitors Olaparib Rucaparib Niraparib

35 PARP Inhibitors in Clinical Trials Veliparib Talazoparib

36 Olaparib On December 19, 2014, the US Food and Drug Administration (FDA) approved olaparib capsules as monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated (gbrcam) (as detected by an FDAapproved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Concurrent with this action, FDA approved a multiplex PCR companion diagnostic test for the qualitative detection and classification of variants in the BRCA1 and BRCA2 genes. FDA Prescribing Information;

37 Olaparib Indication Olaparib is approved for women with a germline BRCA mutation After failing three prior lines of therapy for ovarian cancer Has a companion diagnostic test, which is a blood test for the presence of a germline BRCA 1 or 2 mutation 400 mg twice daily (16 capsules) FDA Prescribing Information.

38 Olaparib Study 19 Randomized phase II, double blind study of recurrent platinum-sensitive serous ovarian cancer Two prior lines of platinum required with complete or partial response to the prior line of platinum 265 women randomized N=136 (olaparib) N=129 (placebo) 136 patients had deleterious BRCA mutation 400 mg twice daily (16 capsules) Ledermann JA, et al. N Engl J Med. 2012; Ledermann JA, et al. Lancet Oncol

39 Probability of Progression- Free Survival PFS in Randomized Population No. at Risk Olaparib Placebo Olaparib Placebo Months since Randomization Hazard ratio, 0.35 (95% CI, ) P< HUGE difference in PFS No. of Patients/ Median Progressionfree Survival (mo) Total No. (%) 60/136 (44.1) /129 (72.1) 4.8 Adapted from Ledermann JA, et al. N Engl J Med

40 Subgroup Analysis of PFS in Randomized Population Ledermann JA, et al. N Engl J Med

41 Progression-Free Survival (Proportion) Olaparib in Germline BRCA Mutation Tumors Ovarian (median, 7.0 months) Breast (median, 3.7 months) Pancreas (median, 4.6 months) Prostate (median, 7.2 months) Germline BRCA mutation carriers Tumor agnostic Median PFS in ovarian cancer: 7 months 0.2 No. at risk Ovarian Breast Pancreas Prostate Time From First Dose (months) Adapted from Kaufmann B, et al. J Clin Oncol

42 Overall Survival (%) Olaparib in gbrca and BRCAwt Overall Survival Olaparib Placebo Deaths/total patients (%) Median OS, months (95% CI) HR 0.73 (95% CI ); P=.025 Olaparib Placebo 94/136 (69%) 109/129 (84%) 29.8 ( ) 27.8 ( ) All patients randomized (N=265) Did not reach pre-specified statistical significance. Number at Risk Olaparib Placebo (0) 129 (5) 117 (2) 97 (2) 79 (0) 62 (0) 52 (0) 43 (0) 42 (0) 41 (0) 37 (0) 35 (0) 15 (19) 2 (12) 0 (2) 129 (0) 122 (3) 112 (1) 90 (0) 75 (1) 57 (0) 44 (0) 37 (0) 32 (0) 27 (0) 24 (1) 18 (0) 9 (5) 1 (8) 0 (1) Adapted from Ledermann JA, et al. Lancet Oncol

43 Overall Survival (%) Olaparib in gbrca Overall Survival Olaparib Placebo Deaths/total patients(%) Median OS, months (95% CI) HR 0.62 (95% CI ); P=.025 Olaparib Placebo 47/74 (64%) 48/62 (77%) 34.9 ( ) 30.2 ( ) Germline BRCA mutated N=136 Did not reach pre-specified statistical significance. Number at Risk Olaparib Placebo (0) 69 (4) 65 (0) 56 (2) 50 (0) 39 (0) 33 (0) 27 (0) 27 (0) 27 (0) 25 (0) 23 (0) 11 (11) 1 (9) 0 (1) 62 (0) 58 (2) 52 (1) 40 (0) 34 (1) 29 (0) 25 (0) 20 (0) 19 (0) 15 (0) 13 (1) 10 (0) 6 (3) 0 (6) 0 (0) Adapted from Ledermann JA, et al. Lancet Oncol

44 Rucaparib On December 19, 2016, the US Food and Drug Administration granted accelerated approval to rucaparib for treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. Concurrent with this action, the FDA approved a next generation sequencing-based companion diagnostic test for use with rucaparib to detect the presence of deleterious mutations.

45 Rucaparib Indication At least two prior lines of therapy Germline BRCA mutation OR somatic BRCA mutation (tumor specific mutation, methylation or protein loss) 600 mg twice daily (4 tablets) FDA Prescribing Information.

46 Rucaparib ARIEL2 Phase II study of recurrent platinum-sensitive high grade serous ovarian cancer At least one prior platinum therapy 3 pre-specified groups: BRCA mutant (germline or somatic) BRCAwt LOH high BRCAwt LOH low Enrolled N=206 Swisher EM, et al. Lancet Oncol

47 Progression-free Survival Rucaparib in gbrca and BRCAwt PFS BRCA mutant vs. BRCA wild-type and LOH low: HR 0.27 (95% CI ); P<.001 BRCA wild-type and LOH high vs. BRCA wild-type and LOH low: HR 0.62 (95% CI ); P= BRCA mutant BRCA wild-type and LOH high BRCA wild-type and LOH low Number at Risk (number censored) BRCA mutant BRCA wild-type and LOH high BRCA wild-type and LOH low 0 0 Adapted from Swisher EM, et al. Lancet Oncol Time from Start of Treatment (months) 45 (0) 40 (0) 39 (0) 39 (0) 36 (0) 36 (0) 34 (0) 33 (1) 27 (3) 25 (4) 22 (4) 20 (5) 29 (4) 16 (6) 12 (9) 9 (10) 7 (10) 5 (12) 5 (12) 5 (12) 2 (15) 2 (15) 0 (16) 82 (0) 77 (3) 61 (8) 56 (9) 48 (9) 45 (11) 36 (11) 31 (14) 27 (14) 23 (14) 21 (15) 20 (15) 18 (15) 17 (15) 14 (18) 10 (21) 5 (23) 4 (23) 3 (24) 1 (25) 1 (25) 70 (0) 69 (1) 53 (2) 48 (5) 37 (5) 34 (6) 23 (7) 22 (7) 15 (8) 14 (8) 12 (8) 10 (9) 6 (9) 4 (10) 3 (10) 2 (10) 1 (10) 0 (10)

48 Niraparib On March 27, 2017, the US Food and Drug Administration approved niraparib, a poly ADP-ribose polymerase (PARP) inhibitor, for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.

49 Niraparib Indication Maintenance treatment Recurrent ovarian cancer Complete or partial response to platinum chemotherapy 300 mg once daily (3 tablets) FDA Prescribing Information.

50 Niraparib NOVA Randomized, double blind, placebo controlled phase III trial Platinum sensitive epithelial ovarian cancer (majority high grade serous) At least two prior platinum regimens Examination for homologous recombination deficiency (HRD) Randomized 2:1 Enrolled N= gbrca 350 BRCAwt Mirza MR, et al. N Engl J Med

51 Niraparib in gbrca PFS Mirza MR, et al. N Engl J Med

52 Niraparib in non-gbrca with and without HRD Positivity PFS No Germline BRCA Mutation with HRD Positivity No Germline BRCA Mutation Mirza MR, et al. N Engl J Med

53 Selected Toxicity Grade 3 Nausea Vomiting Constipation Anemia Thrombocytopenia Fatigue Olaparib 1 0.5% 2.6% <5% 18.7% <5% 6.2% Rucaparib 2 4% 2% 1% 21% 2% 9% Niraparib 3 3% 1.9% 0.5% 25.3% 33.8% 8.2% 1 Kaufmann B, et al. J Clin Oncol. 2015; 2 Swisher EM, et al. Lancet Oncol. 2017; 3 Mirza MR, et al. N Engl J Med

54 PARPi Response Rates and Toxicities BRCA1/2 Mutant BRCA1/2 Wild Type and Unknown Drug No. Response No. Response Olaparib Rucaparib >100 (mostly platinum resistant) 39 (all platinum sensitive) 30-60% 46 69% 132 Platinum sensitive 50% Platinum resistant 4% LOH high 29% LOH low 13% Predominant toxicity (in order of frequency) GI symptoms, fatigue, anemia GI symptoms, fatigue, anemia, transient ALT/AST elevations Niraparib 20 (9 platinum sensitive) 40% 3 19 Platinum sensitive 67% Platinum resistant 16% Anemia, thrombocytopenia, neutropenia, GI symptoms, fatigue Talazoparib 26 a 46% - - Fatigue, alopecia, GI symptoms, anemia, neutropenia, thrombocytopenia Veliparib 28 a,b 40% 24 a,b 4% Nausea, fatigue, lymphopenia a Platinum responsiveness not known b Includes triple negative breast cancer Brown JS, et al. Br J Cancer

55 PARP Inhibitors in BRCA+ Breast Cancer Nadine M. Tung, MD Beth Israel Deaconess Medical Center Boston, MA

56 PARP Inhibitors: Women with gbrca+ Breast Cancer (Iceberg Trial: Olaparib) 27 metastatic BRCA+ breast cancer at 400 mg twice daily Many patients heavily pre-treated 41% RR 85% responded or had stable disease Responses seen in ER+ and ER-neg (TNBC) Well tolerated, oral therapy Tutt A, et al. Lancet. 2010; Audeh MW, et al. Lancet

57 Randomized PARP Inhibitor Studies in Metastatic Breast Cancer: BRCA1/2 gbrca+ metastatic disease Anthracycline, taxane resistant Randomized PARP inhibitor daily Standard Chemo, MD s choice: Primary Endpoint: PFS BRAVO Trial (NCT ) - Niraparib EMBRACA (NCT ) - Talazoparib OLYMPIAD Trial (NCT ) - Olaparib Capecitabine or Vinorelbine or Eribulin or Gemcitabine

58 Randomized PARP Inhibitor Studies in Metastatic Breast Cancer: BRCA1/2 gbrca+ metastatic disease Anthracycline, taxane resistant BRAVO Trial (NCT ) - Niraparib EMBRACA (NCT ) Talazoparib OLYMPIAD Trial (NCT ) - Olaparib Randomized PARP inhibitor daily OlympiAD Trial: Standard Chemo, MD s choice: Positive : Increased PFS for olaparib vs chemotherapy Capecitabine or Vinorelbine or Eribulin or Gemcitabine Results: ASCO Primary Endpoint: PFS

59 Olaparib in Adjuvant Breast Cancer Setting: OlympiA gbrca+ TNBC or ER+ I. Adjuvant: T2 or N+ II. Neoadjuvant: Residual disease Randomized After chemo and surgery PARP inhibitor daily X 1 yr Placebo X 1 yr Endpoints: DFS DDFS OS NCT

60 Efficacy of PARP Inhibitors may be Lower in Breast Cancer pts with Prior Platinum Study 42: Study of various gbrca+ cancers 62 breast cancer pts 3 prior chemo in metastatic setting ORR 12.9% Response rate differed if prior platinum (20% vs. 9.5%) Kaufman B, et al. J Clin Oncol

61 Reversion Mutations have been described in BRCA+ breast cancers after platinum The new mutation restores the BRCA1 or BRCA2 function in the cancer cell So PARP inhibitor may not work Afghahi A, et al. Clin Cancer Res

62 Select Studies Combining PARPi with Platinum Chemotherapy BROCADE (NCT ) Paclitaxel/carboplatin vs. paclitaxel/carboplatin/veliparib vs. veliparib/temozolomide gbrca+ metastatic breast cancer Study 21 1 (NCT ) Cisplatin/olaparib Advanced solid tumors Carboplatin/olaparib 2 (NCT ) BRCA+ advanced breast, ovarian cancer 1 Balmaña J, et al. Ann Oncol. 2014; 2 Lee JM, et al. J Natl Cancer Inst

63 Hard to Combine Chemo and PARPi Myelosuppression limit dose chemo and PARPi

64 PARP Inhibitors in Additional Solid Tumors

65 Ongoing PARPi Trials in Pancreatic Cancer Trial Phase Treatment Arms Inclusion Primary Outcomes NCT II Olaparib Non-gBRCA1/2 mutation or HRD deficiency NCT II Olaparib Non-gBRCA1/2 mutation ORR POLO NCT III Olaparib Placebo gbrca1/2 mutation NCT I/II Veliparib/mFOLFOX BRCA1/2 mutation NCT NCT II II Veliparib Veliparib/gemcitabine/ cisplatin Gemcitabine/cisplatin Veliparib/FOLFIRI FOLFIRI BRCA1/2 or PALB2 mutation Metastatic pancreatic cancer ORR PFS Dose limiting toxicities ORR FOLFIRI: Fluorouracil, irinotecan, leucovorin; mfolfox: Modified 5-fluorouracil and oxaplatin OS

66 Ongoing PARPi Trials in Prostate Cancer Trial Phase Treatment Arms Inclusion PROfound NCT III Olaparib Enzalutamide Abiraterone NCT II Olaparib TRITON3 NCT TRITON2 NCT GALAHAD NCT NCT III II II II Rucaparib Enzalutamide Abiraterone Docetaxel Rucaparib Niraparib Veliparib/abiraterone Abiraterone mcrpc, progression on androgen receptor targeted therapy HRR deficiency in tumor tissue Malignant solid tumor (including prostate) gbrca1/2 mcrpc, progression on androgen receptor targeted therapy BRCA1/2 or ATM mutation mcrpc, progression on 1 androgen receptor targeted therapy and 1 taxane BRCA1/2, ATM or other HR deficiency mcrpc, progression on >1 taxane and >1 androgen receptor targeted therapy Tumor w/ DNA repair anomalies mcrpc, progression on androgen deprivation therapy Primary Outcomes rpfs Tumor response rate rpfs ORR PSA response ORR PSA response

67 Improving Patient Outcomes with PARP Inhibitors: Case-based Treatment Strategies for the Oncology Nurse Lisa Arvine, RN, MSN, ANP-BC, WHNP-BC Dana-Farber Cancer Institute Boston, MA

68 Overview Procuring PARP inhibitors for patients Understand adverse events associated with PARP inhibitors Dosing of PARP inhibitors How to manage adverse effects and discuss ways the oncology nurse can optimize therapy Understand ways nurses can improve adherence to PARP inhibitors Patient based cases

69 How Do I Procure PARP Inhibitors for My Patients? Rucaparib FDA approved for patients with advanced ovarian cancer who have BRCA gene mutations, either inherited (germline) or acquired (somatic) Two or more prior lines of chemotherapy Next generation sequencing-based companion diagnostic approved to test for deleterious mutations Olaparib FDA approved for patients with advanced ovarian cancer who have BRCA gene mutation (germline) Three or more prior lines of chemotherapy Multiplex PCR companion diagnostic approved to detect germline mutation Niraparib Maintenance treatment in recurrent ovarian, fallopian or primary peritoneal who have had a complete or partial response to platinum based therapy FDA Prescribing Information.

70 Somatic vs. Germline Mutations Somatic (Acquired) Mutations Occur in non-germline tissues Are not inherited Germline (Inherited) Mutations Present in egg or sperm Can be inherited from either parent Can cause cancer family syndrome Not Inheritable Inheritable Mutation only found in tumor Unaffected children Mutation in egg or sperm All cells affected in children Adapted from

71 Common Adverse Effects of PARP Inhibitors Fatigue Nausea and/or vomiting Decreased appetite Dysgeusia Abdominal pain Myelosuppression Changes in kidney function tests Shortness of breath Anemia Arthralgias/mylagias Rash Myelodysplastic syndrome (MDS) or Acute Myeloid Leukemia (AML)* FDA Prescribing Information. *Although rare, can be delayed and life threatening

72 Drug Specific Adverse Effects Rucaparib Constipation and/or diarrhea Changes in liver function tests Increased cholesterol levels Olaparib Indigestion/heartburn Rhinorrhea Pneumonitis Niraparib Palpitations Mucositis/dry mouth Increase in AST/ALT Urinary tract infections Hypertension Headache/dizziness FDA Prescribing Information.

73 Dosing Rucaparib 600 mg (two 300 mg tablets) taken orally twice daily Rucaparib is available in 300 mg and 200 mg tablets Olaparib 400 mg (eight 50 mg capsules) taken orally twice daily Niraparib 300 mg (three 100 mg capsules) taken once daily FDA Prescribing Information.

74 Other Important Safety Information Females who are able to become pregnant should use birth control during treatment and for six months after last dose. Do not breast feed during treatment and one month (niraparib/olaparib) or two weeks (rucaparib) after last dose. Avoid grapefruit, grapefruit juice and Seville oranges during treatment with olaparib. FDA Prescribing Information.

75 How Do I Manage Hematologic Adverse Effects Associated with PARP Inhibitors? Prior to initiating PARP inhibitor, prior chemotherapy adverse effects should have resolved to <Grade 1 Anemia Rule out other causes of anemia (iron deficiency) Transfuse as needed Dose interruption or dose reduction Thrombocytopenia First occurrence: Hold until platelets >100,000/µL. Resume at same or reduced dose Second occurrence: Hold until platelets >100,000/µL. Resume at reduced dose Discontinue if platelets have not returned to acceptable levels after 28 days Transfuse as needed Monitor closely for MDS FDA Prescribing Information; NCCN Anemia Guidelines Version

76 How Do I Manage Adverse Effects Associated with PARP Inhibitors? Monitor for MDS Check CBC/d prior to starting PARPi (olaparib, rucaparib) and monthly thereafter Check CBC/d weekly x 1 month, then monthly for the next 11 months and longer as indicated (niraparib) If hematological toxicities are noted: Interrupt PARP inhibitor and monitor blood counts weekly until Grade 1 or less If hematological profile recovers, consider restarting drug at a reduced dose If hematological profile has not recovered to Grade 1 or less after 4 weeks, refer to hematologist (bone marrow analysis, cytogenics) Discontinue drug if MDS/AML is confirmed FDA Prescribing Information.

77 How Do I Manage Adverse Effects Associated with PARP Inhibitors? Nausea/Vomiting Use PARP inhibitor sooner in disease course. GI symptoms often become more prominent later in disease course Consider starting PARP inhibitor at lower dose to allow patient to acclimate to drug. Increase dose as tolerated Prophylactic antiemetics 30 minutes prior to dosing Encourage small meal prior to dosing Consider dose reduction if not originally started at lower dose Try behavioral modifications GI Toxicity Small frequent meals Behavioral modifications (avoid carbohydrates, heavy meals) Work on effective bowel regimen

78 How Do I Manage Adverse Effects Associated with PARP Inhibitors? Pneumonitis Symptoms include cough, shortness of breath, fatigue and weight loss Discontinue drug Fatigue Monitor for anemia Encourage periods of rest and activity Maintain good nutrition Stay well hydrated Manage stress Consider dose interruption or dose reduction FDA Prescribing Information; NCCN Cancer-Related Fatigue Guidelines Version ;

79 Ensuring Patient Compliance Empower the patient Provide behavioral support Incorporate the medication regimen into daily regimen Adherence aids Medication boxes Patient alarms Patient drug diary Patient communication (Telephone calls, scheduled appointments) Manage side effects

80 Case Study 1: JG Ms. JG is a 65 year old woman with a BRCA germline mutation Diagnosed with a stage IIA papillary serous ovarian cancer. Underwent cytoreductive surgery followed by adjuvant carboplatin and paclitaxel x 6 cycles. December 2013 Diagnosed with recurrent disease. Underwent a secondary cytoreductive surgery followed by adjuvant carboplatin and gemcitabine x 6 cycles. Completed May July 2014 Enrolled in the SOLO2 trial evaluating olaparib 300 mg BID as maintenance therapy.

81 Case Study 1: JG August 26, 2014 Presented with Grade 3 anemia (Hct of 18) with low reticulocyte count. Leukopenia noted. Platelets normal. Olaparib interrupted 2 units of PRBC given Rule out other sources of anemia: Iron studies ordered Guaiac test done Hemolysis panel August 29, 2014 Repeat labs revealed anemia improved to Grade 2. Referred to Hematology to rule out aplastic anemia. Per Hematology, anemia related to olaparib.

82 Case Study 1: JG September 5, 2014 Patient presented with Grade 2 fatigue and Grade 1 anemia. Continued to hold olaparib September 23, 2014 Olaparib restarted at 300 mg BID CBC/d weekly October 16, 2014 Patient presented with Grade 2 fatigue and Grade 2 anemia (Hct 26.5). Olaparib discontinued given concern for potential MDS. November 2016 Rising CA 125, CT with recurrent disease

83 Case Study 2: DS DS is a 45 year old woman with a BRCA germline mutation and high grade serous adenocarcinoma. December 2013 Underwent a cytoreductive surgery in China. She subsequently received cycle 1 of carboplatin and paclitaxel but developed skin itching and declined further chemotherapy. She was managed with traditional Chinese medicine. May 2014 CT scan revealed recurrent disease. Received carboplatin and docetaxel x 4 cycles. August 2015 Repeat imaging revealed an isolated splenic lesion. She underwent an ex-lap, splenectomy with no residual disease. September 15, 2015 Initiated on single agent carboplatin x 6 given positive washings. November 2016 CA 125 elevated. CT revealed multiple new hepatic lesions. CT guided biopsy of liver mass. December 28, 2016 Initiated on olaparib 400 mg BID

84 Case Study 2: DS December 28, 2016 Initiated on olaparib 400 mg BID January 11, 2017 Patient presented with fatigue, nausea, vomiting, weakness, and abdominal pain Advised patient to hold drug x 3 days Restarted olaparib 400 mg BID Added prochlorperazine 10 mg 30 minutes prior to dosing Behavior modifications reviewed January 25, 2017 Patient presented with similar symptoms despite recommendations as above Dose reduced to 300 mg BID

85 Summary Patients with ovarian cancer often have multiple recurrences and many lines of therapy. All patients with ovarian cancer should have BRCA testing and genetic counseling (and certain patients with breast, prostate or pancreatic cancers). Patients with germline and somatic BRCA mutations may benefit from a PARPi with the goal of increased survival. There are three PARPi choices approved for recurrent ovarian cancer, all with separate indications. PARPi s are also being studied in breast, prostate, and pancreatic cancers. PARPi tolerability is achieved with early identification and assessment of hematological adverse effects and proactive prevention of nausea.

86