What Clinicians Want to Know: - PowerPoint Presentation

1. What Clinicians Want to Know: Understanding the Factors Affecting the Optimal Diagnosis and Management of Ovarian CancerThursday, February 18, 20215:00 PM – 6:00 PM ETMichael J Birrer, MD, PhDKathleen Moore, MDDavid M O'Malley, MDModeratorNeil Love, MDFaculty

2. FacultyMichael J Birrer, MD, PhDDirector, Winthrop P Rockefeller Cancer InstituteUniversity of Arkansas for Medical SciencesLittle Rock, ArkansasDavid M O'Malley, MDProfessorDivision Director, Gynecologic OncologyCo-Director, Gynecologic Oncology Phase I ProgramThe Ohio State University and The James Cancer CenterColumbus, OhioKathleen Moore, MDThe Virginia Kerley Cade Endowed Chair in Cancer DevelopmentAssociate Director, Clinical ResearchDirector, Oklahoma TSET Phase I ProgramStephenson Cancer CenterAssociate Professor, Section of Gynecologic OncologyDirector, Gynecologic Oncology FellowshipDepartment of Obstetrics and GynecologyUniversity of Oklahoma Health Sciences CenterOklahoma City, Oklahoma

3. Commercial SupportThis activity is supported by educational grants from AstraZeneca Pharmaceuticals LP and Merck.

4. Dr Love — DisclosuresDr Love is president and CEO of Research To Practice. Research To Practice receives funds in the form of educational grants to develop CME activities from the following commercial interests: AbbVie Inc, Acerta Pharma — A member of the AstraZeneca Group, Adaptive Biotechnologies Corporation, Agendia Inc, Agios Pharmaceuticals Inc, Amgen Inc, Array BioPharma Inc, a subsidiary of Pfizer Inc, Astellas, AstraZeneca Pharmaceuticals LP, Aveo Pharmaceuticals, Bayer HealthCare Pharmaceuticals, Biodesix Inc, bioTheranostics Inc, Blueprint Medicines, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Clovis Oncology, Daiichi Sankyo Inc, Dendreon Pharmaceuticals Inc, Eisai Inc, EMD Serono Inc, Epizyme Inc, Exact Sciences Inc, Exelixis Inc, Five Prime Therapeutics Inc, Foundation Medicine, Genentech, a member of the Roche Group, Genmab, Gilead Sciences Inc, GlaxoSmithKline, Grail Inc, Guardant Health, Halozyme Inc, Helsinn Healthcare SA, ImmunoGen Inc, Incyte Corporation, Infinity Pharmaceuticals Inc, Ipsen Biopharmaceuticals Inc, Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC, Jazz Pharmaceuticals Inc, Karyopharm Therapeutics, Kite, A Gilead Company, Lexicon Pharmaceuticals Inc, Lilly, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, Merck, Merrimack Pharmaceuticals Inc, Myriad Genetic Laboratories Inc, Natera Inc, Novartis, Novocure Inc, Oncopeptides, Pfizer Inc, Pharmacyclics LLC, an AbbVie Company, Prometheus Laboratories Inc, Puma Biotechnology Inc, Regeneron Pharmaceuticals Inc, Sandoz Inc, a Novartis Division, Sanofi Genzyme, Seagen Inc, Sirtex Medical Ltd, Spectrum Pharmaceuticals Inc, Sumitomo Dainippon Pharma Oncology Inc, Taiho Oncology Inc, Takeda Oncology, Tesaro, A GSK Company, Teva Oncology, Tokai Pharmaceuticals Inc and Verastem Inc.

5. Research To Practice CME Planning Committee Members, Staff and ReviewersPlanners, scientific staff and independent reviewers for Research To Practice have no relevant conflicts of interest to disclose.

6. Dr Birrer — DisclosuresAdvisory CommitteeAstraZeneca Pharmaceuticals LP, Clovis Oncology, Tesaro, A GSK CompanyData and Safety Monitoring Board/CommitteeOncoQuest Pharmaceuticals Inc (QPT-ORE-005), VBL Therapeutics (VB-111-701/GOG-3018).

7. Dr Moore — DisclosuresConsulting AgreementsAravive Inc, AstraZeneca Pharmaceuticals LP, Eisai Inc, Elevar Therapeutics, Genentech, a member of the Roche Group, ImmunoGen Inc, Merck, Mersana Therapeutics, Myriad Genetic Laboratories Inc, Sorrento Therapeutics, Tarveda Therapeutics, Tesaro, A GSK Company, VBL TherapeuticsContracted ResearchPTC Therapeutics, US Department of Defense

8. Dr O'Malley — DisclosuresAdvisory Committee and Consulting Agreements (Personal Fees)AbbVie Inc, Agenus Inc, Ambry Genetics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Clovis Oncology, Eisai Inc, Elevar Therapeutics, Genentech, a member of the Roche Group, GOG Foundation Inc, ImmunoGen Inc, Iovance Biotherapeutics, Janssen Biotech Inc, Johnson & Johnson Pharmaceuticals, Merck, Mersana Therapeutics, Myriad Genetic Laboratories Inc, Novartis, Novocure Inc, Regeneron Pharmaceuticals Inc, Rubis, Seagen Inc, Tarveda Therapeutics, Tesaro, A GSK CompanyContracted Research(All Funding to Institution)AbbVie Inc, Agenus Inc, Ajinomoto Co Inc, Amgen Inc, Array BioPharma Inc, a subsidiary of Pfizer Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Daré Bioscience, Eisai Inc, EMD Serono Inc, Ergomed Plc, Genentech, a member of the Roche Group, Genmab, GOG Foundation Inc, ImmunoGen Inc, Iovance Biotherapeutics, Janssen Biotech Inc, Johnson & Johnson Pharmaceuticals, Ludwig Institute for Cancer Research Ltd, Merck, National Cancer Institute, New Mexico Cancer Care Alliance, Novocure Inc, PRA Health Sciences, Regeneron Pharmaceuticals Inc, Seagen Inc, Stemcentrx, Syneos Health, Tesaro, A GSK Company, TRACON Pharmaceuticals Inc, VentiRx Pharmaceuticals Inc, Yale UniversityContracted Research (Personal Fees)Clovis Oncology, Mersana TherapeuticsData and Safety Monitoring Board/CommitteeWatermark Research Partners Inc

9. Consulting Healthcare ProfessionalsCourtney Arn, CNPThe James Cancer Hospital and Solove Research Institute Columbus, OhioSaurinkumar Shah, MDTrinity Family HealthcarePort Richey, FloridaJaclyn Shaver, MS, APRN, CNP, WHNPStephenson Cancer CenterOklahoma City, Oklahoma Paula J Anastasia, MN, RN, AOCNUniversity of California, Los AngelesLos Angeles, CaliforniaTarak S Choksi, MD MyCare MedicalTrinity, FloridaWanda Torres, MDSunCoast Women’s CareTrinity, Florida

10. AgendaModule 1: Ms Arn – Symptoms of ovarian cancerModule 2: Ms Shaver – Implications of genetic testingModule 3: Ms Anastasia – Evaluation of an ovarian massModule 4: Dr Choksi – An 80-year-old woman with ovarian cancer and a BRCA2 germline mutationModule 5: Dr Torres – A 74-year-old woman with a 9.6-cm complex ovarian massModule 6: Dr Shah – A woman in her 60s who speaks Gujarati and has a suspicious ovarian mass

11. AgendaModule 1: Ms Arn – Symptoms of ovarian cancerModule 2: Ms Shaver – Implications of genetic testingModule 3: Ms Anastasia – Evaluation of an ovarian massModule 4: Dr Choksi – An 80-year-old woman with ovarian cancer and a BRCA2 germline mutationModule 5: Dr Torres – A 74-year-old woman with a 9.6-cm complex ovarian massModule 6: Dr Shah – A woman in her 60s who speaks Gujarati and has a suspicious ovarian mass

12. Courtney Arn, CNPThe Ohio State UniversityThe James Cancer Hospital and Solove Research Institute Columbus, Ohio

13. AgendaModule 1: Ms Arn – Symptoms of ovarian cancerModule 2: Ms Shaver – Implications of genetic testingModule 3: Ms Anastasia – Evaluation of an ovarian massModule 4: Dr Choksi – An 80-year-old woman with ovarian cancer and a BRCA2 germline mutationModule 5: Dr Torres – A 74-year-old woman with a 9.6-cm complex ovarian massModule 6: Dr Shah – A woman in her 60s who speaks Gujarati and has a suspicious ovarian mass

14. Jaclyn Shaver, MS, APRN, CNP, WHNPSection of Gynecologic OncologyStephenson Cancer CenterOU HealthOklahoma City, Oklahoma 

15. Germline DNA sequenced from women with OC (N = 1,915) using a targeted capture and multiplex sequencing assayUniversity of Washington GYN tissue bank (n = 570)GOG-218 (n = 788) and GOG-262 (n = 557)Norquist BM et al. JAMA Oncol 2016;2(4):482-90.Overall population(not selected for age or family history)N = 1,915Patients with identified mutations in OC genesN = 347Summary of Germline DNA Mutations in OC* BRCA-Fanconi anemia-associated genes: BRIP1, PALB2, RAD51C, RAD51D, BARD1

16. BRCA1/2 Mutations in Ovarian Cancer: Who Should Be Tested?NCCN1Genetic counseling and testing should be considered for women with a history of ovarian carcinoma, fallopian tube or primary peritoneal cancerSGO2Women diagnosed with epithelial ovarian, tubal and peritoneal cancers should receive genetic counseling and be offered genetic testing even in the absence of family historyASCO3Genetic counseling and testing should be considered for women with epithelial ovarian, fallopian tube or primary peritoneal cancer even in the absence of family historyNCCN = National Comprehensive Cancer Network; SGO = Society of Gynecologic Oncology; ASCO = American Society of Clinical Oncology1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian V2.2019. 2. Lancaster JM et al. Gynecol Oncol 2015;136(1):3-7.3. Lu KH et al. J Clin Oncol 2014;32(8):833-40.

17. Multigene Panel TestingAdvantagesMore “diagnoses”More cost effective More time efficientHigher mutational detection rateEfficient use of single specimenDecrease in testing fatigue for patients and providersDisadvantagesCancer risk and management options often not well defined for low- and moderate-penetrance genesHigh uncertain variant rateLonger turnaround timePanels may include genes that patients don’t want to test forUnexpected findings such as “off-phenotypic-target” gene mutationIncreased prevalence of VUS (variant of uncertain significance)Lynce F, Isaacs C. ASCO Educational Book 2016:72-8.

18. AgendaModule 1: Ms Arn – Symptoms of ovarian cancerModule 2: Ms Shaver – Implications of genetic testingModule 3: Ms Anastasia – Evaluation of an ovarian massModule 4: Dr Choksi – An 80-year-old woman with ovarian cancer and a BRCA2 germline mutationModule 5: Dr Torres – A 74-year-old woman with a 9.6-cm complex ovarian massModule 6: Dr Shah – A woman in her 60s who speaks Gujarati and has a suspicious ovarian mass

19. Paula J Anastasia, MN, RN, AOCNGyn Oncology Advanced Practice NurseUniversity of California, Los AngelesLos Angeles, California

20. Biomarkers and Biomarker-Based AlgorithmsKumari S. Ind J Clin Biochem 2018;33(4):382-6.

21. Clinical Application of OVA1®https://www.slideshare.net/AspiraLabs1/understanding-new-changes-to-the-ova1-results-reportIDENTIFY1. ASSESS2. EDUCATE3. STRATIFY4. MANAGEClinical impressionAdnexalmassesPlanned for surgeryHistoryImagingPATIENTIncreasesensitivityIncreasesatisfactionMinimizeUncertaintyMinimize patient anxiety, wait time, and costsIncrease appropriatestaging and debulkingLow RiskElevated RiskOb/Gyn:TreatGyn Onc:Consult or Refer

22. OVA1 Results Report1 Bristow RE et al. Gynecol Oncol 2013;128:252-9; 2 Goodrich ST et al. Am J Obstet Gynecol 2014;211:65e1-11.OVA1 measures a panel of 5 biomarkers that assesses risk of malignancy across all stages and subtypes of OC. CA-125 is included in the panel of 5 biomarkers.Combining powerful tools like an ultrasound can aid in the detection of OC. The 2014 Goodrich et al study found that imaging and the OVA1 score work together to better identify patients at higher risk of malignancy. The OVA1 report now includes the Goodrich graph and risk of malignancy based on levels of risk and menopausal status.

23. AgendaModule 1: Ms Arn – Symptoms of ovarian cancerModule 2: Ms Shaver – Implications of genetic testingModule 3: Ms Anastasia – Evaluation of an ovarian massModule 4: Dr Choksi – An 80-year-old woman with ovarian cancer and a BRCA2 germline mutationModule 5: Dr Torres – A 74-year-old woman with a 9.6-cm complex ovarian massModule 6: Dr Shah – A woman in her 60s who speaks Gujarati and has a suspicious ovarian mass

24. What is the approximate median time to disease progression for a patient with Stage III ovarian cancer and a BRCA mutation who receives surgery and chemotherapy?1 year3 years2 yearsSurvey of live webinar audienceN = 785 yearsI don’t know

25. What is the approximate median time to disease progression for a patient with Stage III ovarian cancer and a BRCA mutation who receives surgery and chemotherapy followed by a PARP inhibitor?1 year3 years2 yearsSurvey of live webinar audienceN = 665 yearsI don’t know

26. Which of the following adverse events are common class effects of PARP inhibitors?Gastrointestinal (GI) symptomsHepatic toxicitiesCytopeniasSurvey of live webinar audienceN = 59Both GI symptoms and cytopeniasAll of the aboveI don’t know

27. Tarak S Choksi, MD Medical DirectorMyCare MedicalTrinity, Florida

28. Mechanism of Cell Death from Synthetic Lethality Induced by PARP InhibitionCourtesy of Jenny C Chang, MD

29. Current FDA-Approved and Investigational PARP Inhibitors: DifferencesPARP inhibitorIC50PARP trapping potencyPARPi target selectivity(strength of binding)Half lifeDoseOlaparib6 nM1Potent PARP1 inhibitor, less selective11.9 hours300 mg BIDRucaparib21 nM1Potent PARP1 inhibitor, less selective18 hours600 mg BIDNiraparib60 nM~2Selective inhibitor of PARP1 and 236 hours300 mg qdVeliparib30 nM<0.2Potent PARP1 inhibitor, less selective5 hours400 mg BIDTalazoparib4 nM~100Potent PARP1 inhibitor, less selective50 hours1 mg qdLim JSJ, Tan DSP. Cancers 2017;9(8):pii:E109.

30. Phase III First-Line PARPi Maintenance TrialsStudy DesignSOLO-1 (N=451)PAOLA-1 (N=612)PRIMA (N=620)VELIA(N=1140)Treatment arms vs placeboOlaparib (n=260)Bevacizumab ± OlaparibNiraparibVeliparibPatient PopulationBRCA mutationAll comersAll comersAll comersTreatment Duration 24 months15 months for Bev24 months for Olaparib36 months or until PD24 monthsaResidual disease based on stage was not reported. bStage III and IV eligible, but requirements for prior surgery not reported (NR) on clinicaltrials.govCourtesy of Shannon N Westin, MD, MPHBurger RA, N Engl J Med 2011; Norquist B Clin Cancer Res 2018; Bevacizumab prescribing information; Moore K, NEJM 2018; Gonzalez-Martin NEJM 2019; Ray-Coquard NEJM 2019; Coleman NEJM 2019

31. SOLO-1: A Phase III Trial of Maintenance Olaparib in OC with BRCA MutationPrimary endpoint: Investigator-assessed progression-free survivalREligibilityNewly diagnosed ovarian, fallopian tube or primary peritoneal cancerFIGO Stage III-IVHigh-grade serous or endometrioid histologyDeleterious or suspected deleterious BRCA1 or BRCA2 mutation Maintenance olaparib300 mg BID(n = 260)Placebo (n = 131)www.clinicaltrials.gov; Moore KN et al. ASCO 2014;Abstract TPS5616; Moore K et al. N Engl J Med 2018;379(26):2495-505.(2:1)CR or PR and no clinical evidence of PD after completing first-line platinum-based therapyNCT01844986

32. SOLO-1: Updated PFS (60 Months Follow-Up)Banerjee S et al. ESMO 2020; Abstract 811MO.Olaparib(N=260)Placebo(N=131)Events, n (%)118 (45)100 (76)Median PFS, months56.013.8Difference, months42.2HR 0.33 (95% CI 0.25–0.43)Median treatment duration:Olaparib, 24.6 monthsPlacebo†, 13.9 monthsPatients free from disease progression and death (%)PlaceboOlaparibNo. at riskPlaceboOlaparib2601312291032126519453173411403812930115241012391225816303200Months since randomization51%88%35%74%27%60%22%52%21%48%2-year treatment cap*100908070605040302010006121824303642485460667278

33. FDA Approves Olaparib as First-Line Maintenance Therapy for Advanced Ovarian Cancer with BRCA MutationsPress Release: December 19, 2018“On December 19, 2018, the FDA approved olaparib for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Patients with gBRCAm advanced epithelial ovarian, fallopian tube or primary peritoneal cancer should be selected for therapy based on an FDA-approved companion diagnostic.”The FDA also approved the ­­­­BRACAnalysis CDx test to identify patients with gBRCAm advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are eligible for olaparib, based on the effectiveness of the test in the SOLO-1 trial population.” https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm628876.htm

34. PRIMA Trial: Maintenance Niraparib for Advanced Ovarian Cancer After Response to Front-Line Platinum-Based ChemotherapyPrimary endpoint: Progression-free survivalREligibility (N = 620)Newly diagnosed ovarian cancerAdvanced-stage (FIGO III or IV) disease Completion of first-line platinum-based therapyCR or PR to most recent platinum chemotherapy NiraparibPlacebo(2:1)Gonzalez-Martin A et al. N Engl J Med 2019;381:2391-402.Maintenance

35. PRIMA Primary Endpoint: Progression-Free SurvivalGonzalez-Martin A et al. N Engl J Med 2019;381:2391-402.Niraprib(n = 487)Placebo(n = 246)Hazard ratioMedian PFS (ITT)13.8 mo8.2 moHR: 0.62(p<0.001)--BRCA mut, HRD+22.1 mo10.9 moHR: 0.40--BRCA WT, HRD+19.6 mo8.2 moHR: 0.50

36. FDA Approves Niraparib for First-Line Maintenance Therapy for Advanced Ovarian CancerPress Release – April 29, 2020“The Food and Drug Administration approved niraparib for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.Efficacy was investigated in PRIMA (NCT02655016), a double-blind, placebo-controlled trial that randomized 733 patients to niraparib or matched placebo. Patients were in a complete or partial response to first-line platinum-based chemotherapy.”  https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-niraparib-first-line-maintenance-advanced-ovarian-cancer

37. PAOLA-1 Trial: Maintenance Olaparib with Bevacizumab for Advanced Ovarian Cancer After Response to Front-Line Platinum-Based Chemotherapy and BevacizumabNewly diagnosed FIGO Stage III or IV high-grade serous/endometrioid ovarian, fallopian tube or primary peritoneal cancerRSurgery (up-front or interval) Platinum-taxane-based chemotherapy≥3 cycles of bevacizumab Olaparib (300 mg BID) x 2 years+ bevacizumabPlacebo x 2 years+ bevacizumab(2:1)Ray-Coquard I et al. ESMO 2019;Abstract LBA2.Maintenance therapyN = 806NED/CR/PRFirst-line therapy

38. PAOLA-1: Progression-Free Survival (ITT)Gonzalez Martin A et al. ESMO 2020;Abstract LBA33.Months since randomizationPatients free from disease progression and death (%)71%29%89%66%Olaparib +bevacizumab(n = 537)Placebo +bevacizumab(n = 269)Hazard ratioMedian PFS (ITT)22.1 mo16.6 mo0.59 BRCAmut37.2 mo17.7 mo0.33 BRCAwt, HRD+28.1 mo16.6 mo0.43

39. FDA Approves Olaparib with Bevacizumab as Maintenance Therapy for Ovarian, Fallopian Tube or Primary Peritoneal CancerPress Release – May 28, 2020“The Food and Drug Administration expanded the indication of olaparib to include its combination with bevacizumab for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. FDA also approved the Myriad myChoice® CDx as a companion diagnostic for olaparib.Efficacy of this new indication was investigated in PAOLA-1 (NCT03737643), a randomized, double-blind, placebo-controlled, multi-center trial comparing olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy and bevacizumab.”https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-plus-bevacizumab-maintenance-treatment-ovarian-fallopian-tube-or-primary

40. VELIA/GOG-3005: Integration of Veliparib with Front-Line Chemotherapy and Maintenance in Women with High-Grade Serous Carcinoma of Ovarian, Fallopian Tube, or Primary Peritoneal OriginColeman RL et al.SGO 2020;Abstract 36.

41. VELIA/GOG-3005: A Phase III Trial of Veliparib with Front-Line Chemotherapy and as Maintenance Therapy for High-Grade Serous Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer Coleman RL et al. SGO 2020;Abstract 36.Primary endpoint: Progression-free survival for “veliparib throughout” versus controlREligibility (N = 620)High-grade serous cancerFIGO Stage III or IVNo prior systemic therapyNo CNS metastases(1:1:1) Veliparib throughout (N = 382)Veliparib combination only (N = 383)Control (N = 375)Veliparib150 mg BIDVeliparib400 mg BIDVeliparib150 mg BIDPlaceboPlaceboPlaceboMaintenanceCycles 7-36CombinationCycles 1-6Carboplatin (q3w) +paclitaxel (qw or q3w) +

42. VELIA/GOG-3005: Progression-Free Survival (ITT)Coleman RL et al. SGO 2020;Abstract 36.Veliparib-throughout(n = 382)Control(n = 375)Hazard ratioMedian PFS (ITT)23.5 mo17.3 mo0.68 BRCAmut34.7 mo22.0 mo0.44 BRCAwt, HRD+31.9 mo20.5 mo0.57ITTMonths from randomizationPatients free from diseaseprogression or death (%)ITT HR 0.6895% CI [0.56-0.83], P < 0.001N = 757

43. Adverse Events: Class Effects and Specific Drug DifferencesNotesOlaparibNiraparibRucaparibTalazoparibVeliparibFatigue50%-70%, mainly Gr1-2✓✓✓✓✓Hematologic AEsAnemia40%-60%✓✓✓✓✓--ThrombocytopeniaNiraparib dose adjustment, based on platelet counts✓✓++✓✓✓Neutropenia~20%✓✓✓✓✓Gastrointestinal AEsNausea/vomitingModerately emetic >30%✓✓✓✓✓Diarrhea~33%✓✓✓✓✓Laboratory abnormalitiesALT/AST elevation5%-10% olaparib, niraparib; 34% rucaparib✓--✓--✓++✓++?Creatinine elevation10%-12%✓✓✓NRNROlaparib PI, rev 5/2020; Niraparib PI, rev 4/2020; Rucaparib PI, rev 5/2020; Talazoparib PI, rev 3/2020; Madariaga A et al. Int J Gyn Cancer 2020 April 9;[Online ahead of print]; Litton JK et al. NEJM 2018;379:753-63.NR = not reported

44. Adverse Events: Class Effects and Specific Drug DifferencesNotesOlaparibNiraparibRucaparibTalazoparibVeliparibRespiratory disordersDyspnea +/- cough10%-20%, usually Gr 1-2✓✓✓✓NRNasopharyngitis~10%✓✓✓✓NRNervous system and psychiatric disordersInsomnia/headache10%-25%, usually Gr 1-2✓✓✓✓✓Dermatologic toxicityRash, photosensitivity<1%✓✓++NRNRCardiovascular toxicityHypertension, tachycardia, palpitation1%✓++NRNRNRRare AEsMDS/AML~1% of pts✓✓✓✓✓Olaparib PI, rev 5/2020; Niraparib PI, rev 4/2020; Rucaparib PI, rev 5/2020; Talazoparib PI, rev 3/2020; Madariaga A et al. Int J Gyn Cancer 2020 April 9;[Online ahead of print]; Litton JK et al. NEJM 2018;379:753-63.NR = not reported

45. FDA Prescribing Information.Olaparib dose reductionsDose (tablet) Starting dose300 mg BIDFirst dose reduction250 mg BID Second dose reduction200 mg BIDNiraparib dose reductionsDoseStarting dose300 mg dailyFirst dose reduction200 mg dailySecond dose reduction100 mg dailyRucaparib dose reductionsDoseStarting dose600 mg twice dailyFirst dose reduction500 mg twice dailySecond dose reduction400 mg twice dailyThird dose reduction300 mg twice dailyCourtesy, Shannon N Westin, MD, MPHDose Adjustments for Adverse Events

46. Biologic Rationale for the Combination of a PARP Inhibitor with an Immune Checkpoint InhibitorKonstantinopoulos P et al. ASCO 2018;Abstract 106.Preclinical data demonstrate synergy with PARPi and anti-PD-1 combinations. Preclinical models indicate synergy between PARPi + anti-PD-1 agents regardless of BRCA mutation status or PD-L1 statusError-prone repairPoint mutationsNeoantigensCytosolic DNASTING pathway activationType I IFN responseATM/ATR/CHK1 activationSTAT1/3 activationIRF1 activationPD-L1 upregulationImmune activatingImmune suppressingPARP inhibitorsDSBprocessing(EXO1, BLM1, etc)DSBcheckpoint activation(ATM, ATR, CHK1)

47. Select Ongoing or Planned Phase III Trials of PARP Inhibitors in Combination TherapyTrial name(Trial identifier)NSettingTreatment armsATHENA(NCT03522246)1,012Maintenance therapy after 1L platinum-based chemoRucaparib + NivolumabRucaparib + PlaceboNivolumab + PlaceboPlaceboDUO-O(NCT03737643)1,056Maintenance therapy after 1L platinum-based chemo/Bev ± DurvalumabBevBev + DurvalumabBev + Durvalumab + OlaparibNRG-GY004(NCT02446600)549Recurrent, platinum-sensitivePlatinum-based chemoOlaparibOlaparib + CediranibANITA(NCT03598270)414Recurrent, platinum-sensitivePlacebo + Platinum-based chemo  NiraparibATEZO + Platinum-based chemo  Niraparib + ATEZO NSGO/AVANOVA-Triplet (NCT03806049)337Recurrent, platinum-sensitiveNiraparib + Bev + DostarlimabNiraparib + BevCarboplatin + Paclitaxelwww.clinicaltrials.gov. Accessed January 2021Bev = bevacizumab; ATEZO = atezolizumab

48. AgendaModule 1: Ms Arn – Symptoms of ovarian cancerModule 2: Ms Shaver – Implications of genetic testingModule 3: Ms Anastasia – Evaluation of an ovarian massModule 4: Dr Choksi – An 80-year-old woman with ovarian cancer and a BRCA2 germline mutationModule 5: Dr Torres – A 74-year-old woman with a 9.6-cm complex ovarian massModule 6: Dr Shah – A woman in her 60s who speaks Gujarati and has a suspicious ovarian mass

49. Wanda Torres, MDSunCoast Women’s CareTrinity, Florida

50. AgendaModule 1: Ms Arn – Symptoms of ovarian cancerModule 2: Ms Shaver – Implications of genetic testingModule 3: Ms Anastasia – Evaluation of an ovarian massModule 4: Dr Choksi – An 80-year-old woman with ovarian cancer and a BRCA2 germline mutationModule 5: Dr Torres – A 74-year-old woman with a 9.6-cm complex ovarian massModule 6: Dr Shah – A woman in her 60s who speaks Gujarati and has a suspicious ovarian mass

51. Saurinkumar Shah, MDFamily PhysicianTrinity Family HealthcarePort Richey, Florida