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New Directions in the Management of Recurrent Ovarian Cancer: Focus on PARP Inhibitors


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New Directions in the Management of Recurrent Ovarian Cancer: Focus on PARP Inhibitors

  1. 1. New Directions in the Management of Recurrent Ovarian Cancer: Focus on PARP Inhibitors Ursula A. Matulonis, MD Chief, Division of Gynecologic Oncology Brock-Wilson Family Chair Dana-Farber Cancer Institute Professor of Medicine Harvard Medical School
  2. 2. Disclosures Dr. Matulonis discloses the following commercial relationships: Consultant: 2X Oncology, Clearity Foundation, FujiFilm, Geneos, Immunogen, Merck, Myriad Genetics Research Grant: Merck
  3. 3. Learning Objectives Describe the pathophysiology of ovarian cancer and the scientific foundation for PARP inhibitors Evaluate predictive and prognostic markers that can inform personalized care plans for patients with recurrent ovarian cancer Apply emerging data on PARP inhibitors in selection of maintenance and later line treatment for patients with recurrent ovarian cancer PARP = poly ADP(adenosine diphosphate)-ribose polymerase.
  4. 4. Ovarian Cancer and Importance of Genetics Increasingly recognized that hereditary mutations contribute to ovarian cancer risk Most commonly associated genes: BRCA1 and BRCA2 BRCA1 associated with ~40% lifetime risk of ovarian cancer BRCA2 associated with ~15% lifetime risk of ovarian cancer 9 other genes have been identified as high risk: MSH2, MLH1, PMS2, MSH6, PALB2, BARD1, RAD51C, RAD51D, and BRIP1 ~10-15% of ovarian cancers may have BRCA1 or BRCA2 mutations Up to 40% of patients with germline BRCA1/2 mutations may not have a suggestive family history All women with a diagnosis of ovarian cancer should undergo genetic counseling regarding germline high-risk gene testing: panel testing is preferred BRCA = breast cancer gene type. NCCN, 2017; Norquist et al, 2016; SGO, 2014; Konstantinopoulos et al, 2015; TCGA, 2011.
  5. 5. BRCA1/2 Mutations in Ovarian Cancer: Who Should Be Tested? Leading oncology societies recommend testing all women with ovarian cancer NCCN Genetic counseling and testing should be considered in women with a history of ovarian carcinoma, fallopian tube, or primary peritoneal cancer SGO Women diagnosed with epithelial ovarian, tubal, and peritoneal cancers should receive genetic counseling and be offered genetic testing, even in the absence of family history ASCO Genetic counseling and testing should be considered in women with epithelial ovarian, fallopian tube, or primary peritoneal cancer even in the absence of family history NCCN = National Comprehensive Cancer Network; SGO = Society of Gynecologic Oncology; ASCO = American Society of Clinical Oncology. Lancaster et al, 2015; Lu et al, 2014; NCCN, 2017.
  6. 6. BRCA1/2 Mutations Can Be Germline or Somatic • Blood- or saliva-based diagnostics that do not test tumor DNA cannot detect somatic BRCA mutations • BRCA testing of the tumor, including archival tumor tissue, can detect both germline and somatic BRCA mutations Germline Mutations Inherited and present in every cell in the body Somatic Mutations Acquired and found only within tumor cells DNA = deoxyribonucleic acid. Moschetta et al, 2016; Petrucelli et al, 2016; Myriad MyChoice, 2018.
  7. 7. 50% of High-Grade Serous Cancers Harbor HRD HR = homologous recombination; HRD = homologous recombination deficiency; miRNAs = micro RNAs. Konstantinopoulos, 2015.
  8. 8. Two Main HRD Genomic Scar Tests Have Been Developed BRCAm = BRCA mutation; BRCAwt = BRCA wild type. Swisher et al, 2014; Foundation Medicine, 2014; Swisher et al, 2017; Jenner et al, 2016. Myriad HRD Provides a score based on an assessment of three genomic scars: LOH Telomeric allelic imbalance: a chromosomal abnormality characterized by an unequal contribution of maternal and paternal DNA sequences Large-scale state transitions: a chromosomal break between adjacent regions that is at least 10 Mb long A score of ≥42 (on a scale of 0- 100) represents a + score (loss of DNA repair function) A score of <42 reflects a negative score (intact DNA repair function) Genomic loss of heterozygosity (LOH) Foundation Medicine has developed a test in collaboration with Clovis Oncology that assesses HRD status using an algorithm comprising two elements Tumor BRCAm status Genomic LOH (high or low) A tumor is defined as HRD negative if it is BRCAwt with low genomic LOH LOH cutoff score was 14% of genomic LOH in tissue
  9. 9. PARP Has Several Functions IL = interleukin; STING = stimulator of interferon genes. Konstantinopoulos & Matulonis, 2018.
  10. 10. Synthetic Lethality A combination of mutations resulting in cell death Cell viability maintained if only 1 mutation present Can be achieved pharmacologically by inactivation of a second gene/protein function Dedes et al, 2011. Synthetic lethality (eg, BRCA and PARP) ✓Gene/protein functional ✘Gene/protein dysfunctional or inhibited 1-Gene/protein 2-Gene/protein cell survives ✓ ✓ cell survives ✓ ✘ cell survives ✓ ✘ synthetic lethality ✘ ✘
  11. 11. PARP Inhibitors and Homologous Recombination Repair PARPi = PARP inhibitor. Dedes et al, 2011. Survival Normal cell Repair by homologous recombination DNA single-strand breaks (SSBs) occur all the time in cells, and PARP detects and repairs them During the replication process, unrepaired SSBs are converted into double-strand breaks (DSBs) Replicating cells PARP No effective repair (No homologous recombination pathway) Cell death Cancer cell with homologous recombination deficiency Tumor-specific killing by PARPis
  12. 12. How Do PARP Inhibitors Work? Farmer et al, 2005. PARP trapping PARP enzyme trapped on DNA lesions, leading to cell death Inhibition of PARP1 Leads to loss of base excision repair and alternative end joining as DNA-repair mechanisms (PARP1 is damage sensor) Promotes non-homologous end-joining as a repair pathway (error prone) Other DNA-repair proteins not recruited Inhibit PARP enzymes and cause PARP trapping Log surviving fraction BRCA-/+ and BRCA wt BRCA-/-
  13. 13. Single-Agent Olaparib Has Activity in gBRCAm Ovarian Cancer gBRCAm = germline BRCA-mutant. Audeh, et al, 2010.
  14. 14. ARIEL2 Part 1 Designed to Assess Rucaparib Efficacy in 3 Prospectively Defined HRD Subgroups BID = twice a day; NGS = next-generation sequencing; OC = ovarian cancer; ORR = overall response rate; PFS = progression-free survival; PK = pharmacokinetics. Swisher et al, 2016.
  15. 15. ARIEL2 Final Efficacy Analysis: PFS in BRCAm and LOH-High vs LOH-Low Patients CI = confidence interval; HR = hazard ratio. Swisher et al, 2016.
  16. 16. Response and Duration of Response of PARP Inhibitors in BRCAm Ovarian Cancer Pts = patients; RR = response rate; IRR = independent radiologic review. Lynparza™ prescribing information, 2014; Rubraca® prescribing information, 2018; Moore et al, 2018. Olaparib approved as single agent for treatment for gBRCAm ovarian cancer in 12/2014 and rucaparib for BRCAm cancer in 5/2017 Olaparib Rucaparib Niraparib # of pts 137 106 55 # of lines of prior therapy ≥3 ≥2 (43% had ≥3) ≥4 Objective RECIST RR 34% 54% (IRR 42%) 31% Median duration of response 7.9 months 9.2 months (IRR 6.7 months) 9.4 months
  17. 17. Predictors of Response to PARP Inhibitors: Should PARP Inhibitors Be Used Earlier? pop = population. Matulonis et al, 2016. Presence of a BRCA mutation (either germline or somatic) Platinum sensitivity Number of prior lines of treatment Olaparib response by platinum sensitivity and # of prior lines
  18. 18. Rationale for maintenance: Ovarian cancer has a high rate of relapse and agents such as PARP inhibitors and bevacizumab can delay recurrence when used at the completion of chemotherapy Study 19 was a positive study Phase 3 bevacizumab maintenance studies OCEANS GOG213 Phase 3 studies of PARP inhibitor maintenance ENGOT-OV16/NOVA (niraparib) SOLO2/ENGOT-OV21 (olaparib) ARIEL3 (rucaparib) Maintenance Therapy Aghajanian et al, 2012; Aghajanian et al, 2015; Coleman, Brady et al, 2017; Ledermann et al, 2012; Mirza et al, 2016; Pujade-Lauraine et al, 2017.
  19. 19. Maintenance Strategies for Platinum-Sensitive Recurrent Ovarian Cancer PARP inhibitor maintenance: Bevacizumab maintenance: Platinum chemotherapy PARP inhibitor maintenance Platinum chemotherapy + bevacizumab Bevacizumab maintenance Aghajanian et al, 2012; Aghajanian et al, 2015; Coleman, Brady et al, 2017; Ledermann et al, 2012; Mirza et al, 2016; Pujade-Lauraine et al, 2017.
  20. 20. Important Differences Between PARP Inhibitor and Bevacizumab Maintenance Trials OS = overall survival. Aghajanian et al, 2012; Aghajanian et al, 2015; Coleman, Brady et al, 2017; Ledermann et al, 2012; Mirza et al, 2016; Pujade-Lauraine et al, 2017. Maintenance schedule and timing: For OCEANS and GOG213, bevacizumab initiated with chemotherapy and used as maintenance post-chemotherapy PARP inhibitor maintenance studies: PARP inhibitor started after chemotherapy has been completed (aka “switch maintenance”) in a documented platinum-sensitive population Histology: All PARP inhibitor studies required high-grade serous carcinoma Bevacizumab studies allowed all histologies # of prior lines of treatment: Both bevacizumab trials only enrolled first recurrence For PARP inhibitor studies, no limit on # of prior platinum treatments, but patients needed to be continuously sensitive Trial maturity: No OS yet on PARP inhibitor trials; OS available on bevacizumab studies
  21. 21. Bevacizumab Maintenance Studies Aghajanian et al, 2012; Coleman, Brady et al, 2017. PFS OS OCEANS Carboplatin/gemcitabine 8.4 32.9 Carbo/gem/bevacizumab + bevacizumab maintenance 12.4 33.6 HR 0.484 0.95 GOG213 Carboplatin/paclitaxel 10.4 37.3 Carbo/paclitaxel/bev + bevacizumab maintenance 13.8 42.2 HR 0.63 0.83
  22. 22. Olaparib: Study 19 Design CR = complete response; PR = partial response. Ledermann et al, 2012. Randomization1:1 Olaparib Oral 400mg BID n=136 Placebo Oral BID n=129 • Platinum-sensitive advanced OC • High-grade (grade 2- 3) serous histology or serous component • ≥ 2 previous platinum regimens • CR or PR to just- completed platinum regimen and the penultimate platinum regimen N=265 Treat until progression or death Primary end point: PFS
  23. 23. Study 19: Progression-Free Survival HGSOC = high-grade serous ovarian carcinoma. Ledermann et al, 2012; Ledermann et al, 2014. Whole population with HGSOC Subpopulation with BRCA mutation
  24. 24. SOLO2/ENGOT-OV21 Study Schema Pujade-Lauraine et al, 2017. Placebo n=99 Olaparib 300 mg BID n=196 Primary end point Investigator-assessed PFS Patients • BRCA1/2 mutation • Platinum-sensitive relapsed ovarian cancer • At least 2 prior lines of platinum therapy • CR or PR to most recent platinum therapy Randomized2:1
  25. 25. Olaparib (n=196) Placebo (n=99) Events (%) 107 (54.6) 80 (80.8) Median PFS, months 19.1 5.5 HR 0.30 95% CI 0.22-0.41 P<0.0001 SOLO2/ENGOT-OV21: Olaparib Maintenance Significantly Improves PFS in BRCAm Platinum-Sensitive Ovarian Cancer Pujade-Lauraine et al, 2017. No. at risk Olaparib Placebo 196 99 182 70 156 37 134 22 118 18 104 17 89 14 82 12 32 7 29 6 3 0 2 0 0 0 90 80 70 60 50 40 30 20 10 0 Progression-freesurvival(%) Months since randomization 0 3 6 9 12 15 18 21 24 27 30 3 3 3 6 19.1 Olaparib Placebo 5.5 PFS by Investigator Assessment 100
  26. 26. ENGOT-OV16/NOVA Trial Schema gBRCA = germline BRCA. Mirza et al, 2016. gBRCAm (n=203) Treat until progression of disease Niraparib 300 mg once daily Placebo Non-gBRCAm (n=350) Treat until progression of disease Niraparib 300 mg once daily Placebo 2:1 Randomization 2:1 Randomization Platinum-sensitive recurrent high-grade serous ovarian cancer Response to platinum treatment Treatment with at least 4 cycles of platinum-based therapy Primary end point: PFS by central, blinded review; results for both gBRCA and non-gBRCA groups analyzed simultaneously Non-gBRCA group was subjected to retrospective HRD testing
  27. 27. ENGOT-OV16/NOVA Primary Analysis Demonstrates PFS Improvement Across All Patients Subsets Mirza et al, 2016. gBRCAm Niraparib Placebo Non-gBRCAm HRDpos Non-gBRCAm Overall HR=0.38 Niraparib: 12.9 Placebo: 3.8 HR=0.45 Niraparib: 9.3 Placebo: 3.9 Median PFS (months) HR=0.27 Niraparib: 21.0 Placebo: 5.5
  28. 28. Niraparib Effects on PFS in Patients Without Germline BRCA Mutations Most Notable in HRD-Positive Subset sBRCAm = somatic BRCA-mutant. Mirza et al, 2016. 0 2 4 6 8 10 12 14 16 18 20 22 24 0 25 50 75 100 Months Since Randomization PFS(%) Exploratory Analyses HRD-positive HRD-negative HR=0.27 Niraparib: 20.9 Placebo: 11.0 HR=0.38 Niraparib: 9.3 Placebo: 3.7 HR=0.58 Niraparib: 6.9 Placebo: 3.8 sBRCAm BRCAwt 0 2 4 6 8 10 12 14 16 18 20 22 24 0 25 50 75 100 Months Since Randomization PFS(%) 0 2 4 6 8 10 12 14 16 18 20 22 24 0 25 50 75 100 Months Since Randomization PFS(%) Median PFS (months) Niraparib Placebo
  29. 29. Niraparib Dose Level by Month on Treatment 100 49 36 28 23 22 22 22 21 22 23 23 49 50 47 47 46 44 41 40 40 40 40 3 15 26 30 32 34 36 39 38 37 37 0% 20% 40% 60% 80% 100% Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Month 7 Month 8 Month 9 Month 10Month 11Month 12 Patientsremainingon treatmentbydose 100 mg 200 mg 300 mg After dose modification, 200 mg was the most commonly administered dose. Berek et al, 2018; Mirza et al, 2016.
  30. 30. Dose Modifications Result in Decreased Incidence of Adverse Events Grade 3/4 AE 300 mg (n=367) 200 mg (n=254) 100 mg (n=128) Dose Discontinuations (n=367) Thrombocytopenia 33.2% 5.9% 2.3% 3.3% Anemia 15.3% 16.1% 6.3% 1.4% Neutropenia 18.0% 8.3% 2.3% 1.9% AE = adverse event. Berek et al, 2018; Mirza et al, 2016.
  31. 31. Estimated PFS Probability by Dose Level Measured After Month 3 Berek et al, 2018; Mirza et al, 2016. Dose reduction from 300 mg did not appear to compromise efficacy in this retrospective analysis From month 4: HR (300 vs 200): 1.01 (95%CI: 0.69, 1.48) HR (300 vs 200): 1.01 (95%CI: 0.69, 1.48) ■ 200 mg ■ 100 mg ■ 300 mg Time (months) 4 0.0 0.2 0.4 0.6 0.8 1.0 PFSProbability 8 12 16 20 24
  32. 32. ARIEL3: Study Design ECOG = Eastern Cooperative Oncology Group; HRR = homologous recombination repair. Coleman, Oza et al, 2017. High-grade serous or endometrioid epithelial OC, primary peritoneal, or fallopian tube cancers Sensitive to penultimate platinum Responding to most recent platinum (CR or PR)a Excludes patients without assessable disease following second surgery CA-125 within normal range No restriction on size of residual tumor ECOG PS ≤1 No prior PARP inhibitors Patient eligibility HRR status by NGS mutation analysis gBRCA1 or BRCA2 Non-BRCA HRR geneb None of the above Response to recent platinum CR PR Progression-free interval after penultimate platinum 6 to <12 months ≥12 months Randomization2:1 Placebo BID n=189 Rucaparib 600 mg BID n=375 aCR (defined by RECIST v1.1) or PR (defined by RECIST v1.1 and/or a GCIG CA-125 response [CA-125 within normal range]) maintained until entry to ARIEL3 (≤8 weeks of last dose of chemotherapy). bATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RPA1.
  33. 33. ARIEL3: Investigator-Assessed PFS Coleman, Oza et al, 2017. At risk (events) Rucaparib 130 (0) 93 (23) 63 (46) 35 (58) 15 (64) 3 (67) 0 (67) Placebo 66 (0) 24 (37) 6 (53) 3 (55) 1 (56) 0 (56) Rucaparib, 48% censored Placebo, 15% censored Median (months) 95% CI Rucaparib (n=130) 16.6 13.4–22.9 Placebo (n=66) 5.4 3.4–6.7 HR, 0.23; 95% CI, 0.16–0.34; P<0.0001 BRCA mutant
  34. 34. Median (months) 95% CI Rucaparib (n=236) 13.6 10.9–16.2 Placebo (n=118) 5.4 5.1–5.6 HR, 0.32; 95% CI, 0.24–0.42; P<0.0001 At risk (events) Rucaparib 236 (0) 161 (55) 96 (104) 54 (122) 21 (129) 5 (134) 0 (134) Placebo 118 (0) 40 (68) 11 (95) 6 (98) 1 (101) 0 (101) Rucaparib, 43% censored Placebo, 14% censored Coleman, Oza et al, 2017. HRD ARIEL3: Investigator-Assessed PFS (cont.)
  35. 35. Median (months) 95% CI Rucaparib (n=375) 10.8 8.3–11.4 Placebo (n=189) 5.4 5.3–5.5 HR, 0.36; 95% CI, 0.30–0.45; P<0.0001 At risk (events) Rucaparib 375 (0) 228 (111) 128 (186) 65 (217) 26 (226) 5 (234) 0 (234) Placebo 189 (0) 63 (114) 13 (160) 7 (164) 2 (167) 1 (167) 0 (167) Rucaparib, 38% censored Placebo, 12% censored ITT = intent-to-treat. Coleman, Oza et al, 2017. ITT ARIEL3: Investigator-Assessed PFS (cont.)
  36. 36. Phase 3 PARP Inhibitor Maintenance Studies Show Strikingly Similar Results BICR = blind independent central review; NR = not reached; NA = not applicable. Pujade-Lauraine et al, 2017; Coleman, Oza et al, 2017; Mirza et al, 2016. Trial ITT BRCAm HRD Positive BRCAwt and HRD Negative PFS OS PFS OS PFS OS PFS OS NOVA (BICR) Niraparib Pts were separated into gBRCA and non-BRCA groups 21.0 NR 12.9 NR 6.9 NR Placebo 5.5 NR 3.8 NR 3.8 NR Hazard ratio 0.27 0.38 0.58 SOLO2 (Investigator-Assessed) Olaparib Only patients with BRCAm cancers eligible 19.1 NR NA NA Placebo 5.5 NR Hazard ratio 0.30 ARIEL3(Investigator-Assessed) Rucaparib 10.8 NR 16.6 NR 13.6 NR 6.7 NR Placebo 5.4 NR 5.4 NR 5.4 NR 5.4 NR Hazard ratio 0.36 0.23 0.32 0.58
  37. 37. PARP Inhibitor Characteristics Inform Treatment Choices Given comparable efficacy of the 3 agents available for ovarian cancer treatment, other characteristics will need to inform choice: Toxicities Drug-drug interactions Schedule Price Special clinical situations (eg, treatment of central nervous system disease)
  38. 38. PARP Inhibitors Differ in Terms of Biochemical Properties Lynparza™ prescribing information, 2014; Zejula™ prescribing information, 2017; Rubraca® prescribing information, 2018. PARP Inhibitor Bioavailability Tissue Distribution (L) Half-Life (h) Niraparib 73 1220 36 Olaparib NA 167 11.9 ±4 Rucaparib 36 113-262 17
  39. 39. Differences in Metabolism and Drug-Drug Interactions Exist Among PARP Inhibitors CYP = cytochrome P450 enzymes. Lynparza™ prescribing information, 2014; Zejula™ prescribing information, 2017; Rubraca® prescribing information, 2018. PARP Inhibitor CYP Enzymes Used for Metabolism Drug‒Drug Interactions Effect on CellTransporters Niraparib • Carboxylesterases (non-CYP) • Can induceCYP1A2 (weak) • No interaction with the major hepatic or renal uptake transporters • Inhibits BCRP (weak) • Substrate of P- glycoprotein and BCRP Olaparib • CYP3A4 • Reduce dosage if strong or moderate CYP3A inhibitors are co-administered • Inhibits CYP3A4 and inducesCYP2B6 • Inhibits MDR1, BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1, MATE2-K • Substrate of P- glycoprotein Rucaparib • CYP2D6 (predominant) • CYP1A2 andCYP3A4 (lesser extent) • Reversibly inhibits CYP1A2,CYP2C19, CYP2C9,CYP3A and inducesCYP1A2 • Inhibits MATE1 and MATE2-K,OCT1 • Substrate of P- glycoprotein
  40. 40. Key Grade 3/4 Toxicities From Phase 3 Maintenance Studies AML = acute myelogenous leukemia; MDS = myelodysplastic syndromes. Coleman, Oza et al, 2017; Mirza et al, 2016; Pujade-Lauraine et al, 2017; Rubraca® prescribing information, 2018. Toxicity NOVA SOLO2 ARIEL3 Niraparib Placebo Olaparib Placebo Rucaparib Placebo Anemia 25.3% 0 19% 2% 19% 1% Thrombocytopenia 33.8% 0.6% 1% 1% 5% 0% Neutropenia 19.6% 1.7% 5% 4% 7% 2% Nausea 3.0% 1.1% 3% 0% 4% 1% Vomiting 1.9% 0.6% 3% 1% 4% 1% Constipation 0.5% 0.6% 0% 3% 2% 1% Dyspepsia 0% 0% 0% 0% <1% 0% Abdominal pain 1.1% 1.7% 3% 3% 2% 1% Diarrhea 0.3% 1.1% 1% 0% 1% 1% Increase in SGOT or SGPT 0% 0% 0% 1% 10% 0% Increase in serum creatinine NR NR 0% 0% <1% 0% Elevated cholesterol NR NR NR NR 4% 0% Hypertension 8.2% 2.2% 0% 0% NR NR Fatigue 8.2% 0.6% 4% 2% 7% 3% Risk of AML/MDS: NOVA: 1.4% (niraparib) 1.1% (placebo) ARIEL3: 1% (rucaparib) 0% (placebo) SOLO2: 2% (olaparib) 4% (placebo)
  41. 41. Central Nervous System Penetration: PARP Inhibitors Olaparib, niraparib,and veliparib all cross the blood- brain barrier Rucaparib has limited penetration across the blood- brain barrier Meehan & Chen, 2016; Mikule & Wilcoxen, 2015; NCRI, 2017; Zejula™ prescribing information; Parrish et al, 2015.
  42. 42. Opportunity: PARPi Will Have Activity in Cancers Harboring Mutations in DNA Damage/Response/Repair Genes Other Than BRCA1/2
  43. 43. OC With Damaging Mutations in Some HR Genes Responded to Rucaparib SD = standard deviation. Swisher et al, 2017.
  44. 44. Swisher et al, 2017. Rucaparib Is Active in BRCA1- and RAD51C-Methylated OC Confirmed investigator-assessed RECIST responses: 52.4% (11/21) of BRCA1-methylated cases 75.0% (3/4) of RAD51C-methylated cases 29% of BRCAwt/LOH high Duration of response: Median 6.1 months (95% CI, 4.8-8.9) for BRCA1-methylated cases Median 9.5 months (95% CI, 5.2-9.8) for RAD51C-methylated cases Progression-free survival: Median 7.4 months (95% CI, 5.3-9.7) for BRCA1-methylated cases Median 11.1 months (95% CI, 3.2-14.1) for RAD51C-methylated cases
  45. 45. PARP Inhibitor Resistance Konstantinopoulos et al, 2017. Patients who receive PARP inhibitors for recurrent cancer will develop PARP inhibitor resistance and have cancer progression CLINICAL CHALLENGE: What leads to PARP inhibitor resistance? What rational therapies can we offer patients who have developed PARP inhibitor resistance?
  46. 46. Evolution of HR-Proficiency in Ovarian Cancer Konstantinopoulos et al, 2017. Approximately 50% are de novo HR-proficient Approximately 50% are de novo HR-deficient Platinum or PARPi therapy Tumors with acquired HR- proficiency RESISTANCE TO PARP INHIBITION
  47. 47. Mechanisms of PARP-Inhibitor Resistance: Restoration of HR Proficiency 1. 2. 3. ORF = open reading frame. Bouwman & Jonkers, 2014; Edwards et al, 2008; Norquist et al, 2016; Patch et al, 2015; Sakai et al, 2008.
  48. 48. Additional Mechanisms of PARP Inhibitor Resistance PgP = phosphorylated glycoprotein. Bouwman & Jonkers, 2014; Chaudhuri et al, 2016; Edwards et al, 2008; Norquist et al, 2016; Patch et al, 2015; Sakai et al, 2008. 4. P glycoprotein (PgP) drug efflux 53BP1 or REV7 PARP1 PARP1-/- 1. Loss of PARP1 expression 53BP1-/- or REV7- /-2. Loss of end resection regulation; Increased HR capacity CHD4 CHD4-/- 3. Activation of translesion synthesis; Enhanced DNA damage tolerance TLS TLS 5. Replication fork stabilization
  49. 49. Opportunity: Extending PARP Inhibitor Use in HR-Proficient Tumors and Overcoming PARP Inhibitor Resistance HR-PROFICIENT HR-DEFICIENT PARP Inhibitor Another agent that inhibits HR PARPi + CDKi PARPi + PI3Ki PARPi + PD-1 blockade PARPi + HSP90i PARPi + antiangiogenic PARPi + Chk1i Konstantinopoulos et al, 2015.
  50. 50. Scientific Rationale for Niraparib in Combination With PD-1 Inhibitor IFN = interferon; NK cells = natural killer cells. Mouw & Konstantinopoulos, 2018; Jiao et al, 2017; Sato et al, 2017. Unrepaired DNA damage resulting from niraparib treatment leads to the abnormal presence of DNA in the cytoplasm, which activates the STING pathway Activation of the STING pathway leads to: Increased expression and release of type 1 interferons Subsequent induction of γ- interferon Intratumoral infiltration of effector T cells
  51. 51. Niraparib + PD-1 Inhibitor Treatment Resulted in Clinical Activity Across a Broad Study Population Konstantinopoulos, 2018.
  52. 52. The addition of pembrolizumab to niraparib in BRCAwt and HRDneg led to ORR similar to PARPi efficacy in the BRCAm population HRD status does not correlate with response to this combination in platinum-resistant/refractory disease Clinical Activity Is Observed Across Biomarker Populations in Patients with Platinum-Resistant/Refractory Disease Response All (%) BRCAm (%) HRDposa (%) BRCAwt (%) HRDneg (%) ORR 11/47 (23%) 2/8 (25%) 4/16 (25%) 9/37 (24%) 7/26 (27%) DCR 30/47 (64%) 5/8 (63%) 11/16 (69%) 24/37 (65%) 15/26 (58%) aHRDpos includes BRCA mutation or HRD score ≥42 per Myriad assay. Patients with inconclusive biomarker results were not included in the biomarker subpopulations. Responses include confirmed and unconfirmed responses. DCR = disease control rate. Konstantinopoulos et al, 2018.
  53. 53. Treatment-Related Adverse Events Occurring in ≥10% of Patients, Phase 2 Konstantinopoulos et al, 2018. Adverse Event Any Grade (N=53) n (%) Grade ≥3 (N=53) n (%) Fatigue 28 (53%) 2 (4%) Nausea 22 (42%) 2 (4%) Constipation 19 (36%) 1 (2%) Anemia 18 (34%) 11 (21%) Thrombocytopenia 14 (26%) 5 (9%) Decreased appetite 12 (23%) 1 (2%) Vomiting 11 (21%) 2 (4%) Decreased platelet count 8 (15%) 3 (6%) Headache 7 (13%) 1 (2%) Decreased neutrophil count 7 (13%) 2 (4%) Insomnia 7 (13%) 0 Diarrhea 7 (13%) 1 (2%) Hypothyroidism 7 (13%) 1 (2%) Decreased body weight 6 (11%) 1 (2%) Rash 6 (11%) 0 Dyspnea 6 (11%) 1 (2%)
  54. 54. Case Study 1 q3w = every 3 weeks; CT = computed tomography. Mrs. DJ is a 52-year-old woman diagnosed with advanced stage IIIC high-grade serous ovarian cancer Undergoes initial optimal cytoreductive surgery followed by 6 cycles carboplatin IV q3w Has no germline nor somatic deleterious BRCA mutation Has residual grade 1 peripheral neuropathy 14 months after completion of initial platinum chemotherapy, she develops recurrent ovarian cancer Elevated CA-125 of 200 U/mL CT scan shows omental caking and thickening and new enlarged retroperitoneal adenopathy
  55. 55. Case Study 1 (cont.) How would you treat this patient? a. Platinum-based chemotherapy, and if responsive to this, PARP inhibitor maintenance b. Platinum-based chemotherapy alone c. Single-agent PARP inhibitor d. Carboplatin/gemcitabine/bevacizumab with bevacizumab maintenance e. Carboplatin/paclitaxel/bevacizumab with bevacizumab maintenance
  56. 56. Case Study 1 (cont.) You elect to prescribe a PARP inhibitor after Mrs. DJ has had a partial response to carboplatin and pegylated liposomal doxorubicin. Which PARP inhibitor would you select? a. Rucaparib b. Olaparib c. Niraparib d. Talazoparib
  57. 57. Case Study 2 Ms. LC is a 60-year-old woman with high-grade serous ovarian cancer who has a deleterious germline BRCA2 mutation She has previously received: Carboplatin/paclitaxel as initial chemotherapy Carboplatin/gemcitabine for platinum-sensitive recurrence Most recently, single-agent pegylated liposomal doxorubicin
  58. 58. Case Study 2 (cont.) Ms. LC wants to begin PARP inhibitor therapy, and you counsel her about the different PARP inhibitor choices. Which of the following would you NOT tell Ms. LC? a. Olaparib and rucaparib are twice daily oral formulations, and niraparib is a once daily administration b. Rucaparib use can lead to transient liver function test elevation c. Rucaparib, olaparib, and niraparib can cause elevated serum creatinine d. Olaparib is metabolized by CYP enzymes and niraparib by carboxylesterases e. Toxicities of niraparib include hypertension and tachycardia
  59. 59. Key Takeaways How to decide: PARP inhibitor versus bevacizumab maintenance If PARP inhibitor maintenance, which one? Need to use clinical judgement Benefits in specific patient populations Toxicities (PARPi vs bevacizumab) Others such as drug-drug interactions, metabolism Several ongoing studies are examining maintenance combinations All may/will influence treatment decisions for maintenance therapy SOLO 1 met its primary end point in favor of olaparib; full results to be presented at ESMO 2018
  60. 60. Key Takeaways PARP inhibitor development has been transformative for ovarian cancer drug development PARP inhibitor resistance is an important clinical problem and post-treatment strategies need to be defined PARP inhibitor combination testing has promise but also challenges such as: Deciding which combinations to move forward Drug-drug interactions Registration strategy Teams are necessary to do these studies: expertise in DNA repair/basis science, translational medicine, pathology, ovarian cancer, and trial design, etc.
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