1. Personalized therapy in ovarian cancer Dragos Median “Filantropia” Clinical Hospital, Bucharest

2. Conflicts of interest None

3. Ovarian cancer – data and facts From Annual Report on the Results of Treatment in Gynecological Cancer, Vol 22. Stockholm, International Federation of Gynecology and Obstetrics, 1994

4. Ovarian cancer – data and facts

5. Ovarian cancer - landmarks surgical bulk reduction can improve outcome 1,2 identifying activity of cisplatin and carboplatin 3,4,5 expanding the therapeutic armamentarium to include over 20 additional active agents 6-10 demonstrating the efficacy of intravenous paclitaxel or docetaxel plus carboplatin, which now constitutes the international standard for initial treatment of ovarian carcinoma 4,5 pinpointing potentially enhanced activity of the intraperitoneal route of administration of chemotherapy in patients with minimal residual disease 11 developing targeted therapy for the tumor microenvironment, particularly the antiangiogenic agent bevacizumab 12-15 1. N Engl J Med 1995;332:629–34; 2. Gynecol Oncol 1992;47:159–66; 3. Cancer 1986;57:1725–30; 4. J Clin Oncol 2003;21:3194–200; 5. J Natl Cancer Inst 2003;95:1320–9; 6. J Clin Oncol 2011;29 (Abstract 5008); 7. J Clin Oncol 2012;30:372–9; 8. Am J Clin Oncol 1995;18:19–22; 9. J Clin Oncol 2011;29:69–75; 10.J Clin Oncol 2009;27:5601–6; 11.N Engl J Med 2006;354:34–43; 12.N Engl J Med 2011; 365:2473–83; 13.J Clin Oncol 2011;29 (Abstract LBA5006); 14.N Engl J Med 2011;365:2484–96; 15.J Clin Oncol 2012;30:2039–45

6. Ovarian cancer - landmarks surgical bulk reduction can improve outcome 1,2 identifying activity of cisplatin and carboplatin 3,4,5 expanding the therapeutic armamentarium to include over 20 additional active agents 6-10 demonstrating the efficacy of intravenous paclitaxel or docetaxel plus carboplatin, which now constitutes the international standard for initial treatment of ovarian carcinoma 4,5 pinpointing potentially enhanced activity of the intraperitoneal route of administration of chemotherapy in patients with minimal residual disease 11 developing targeted therapy for the tumor microenvironment, particularly the antiangiogenic agent bevacizumab 12-15 1. N Engl J Med 1995;332:629–34; 2. Gynecol Oncol 1992;47:159–66; 3. Cancer 1986;57:1725–30; 4. J Clin Oncol 2003;21:3194–200; 5. J Natl Cancer Inst 2003;95:1320–9; 6. J Clin Oncol 2011;29 (Abstract 5008); 7. J Clin Oncol 2012;30:372–9; 8. Am J Clin Oncol 1995;18:19–22; 9. J Clin Oncol 2011;29:69–75; 10.J Clin Oncol 2009;27:5601–6; 11.N Engl J Med 2006;354:34–43; 12.N Engl J Med 2011; 365:2473–83; 13.J Clin Oncol 2011;29 (Abstract LBA5006); 14.N Engl J Med 2011;365:2484–96; 15.J Clin Oncol 2012;30:2039–45

7. Targeting angiogenesis VEGF – Promotes proliferation and survival of vascular endothelial cells – Induces vascular permeability and angiogenesis Endocr. Rev. 25, 581–611.

8. VEGF-dependent angiogenesis inhibitors TypeDrugTarget Monoclonal antibodies BevacizumabCirculating VEGF RamucirumabVEGFR2 Soluble VEGFR decoy receptors AfliberceptCirculating VEGF Tyrosine kinase inhibitors (TKIs) PazopanibVEGFR, PDGFR, c-kit, FGFR CediranibVEGFR, PDGFR, c-kit NintedanibVEGFR, PDGFR, FGFR SunitinibVEGFR, PDGFR SorafenibVEGFR, PDGFR, Raf, c-kit Critical Reviews in Oncology/Hematology 84 (2012) 314–326

9. Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE 1:1:1 15 months Paclitaxel (P) 175 mg/m 2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) BEV 15 mg/kg Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 III Maintenance (16 cycles) Systemic treatment for advanced stages Antiangiogenic agents GOG-0218: Study Design Burger RA et al. Proc ASCO 2010;Abstract LBA1.

10. GOG 0218 - Results 1.0 0 Proportion surviving progression free Months since randomization CP (Arm I) 123624 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 + Bev (Arm II) + Bev  Bev maintenance (Arm III) Arm I CP (n = 625) Arm II CP + Bev (n = 625) Arm III CP + Bev  Bev (n = 623) Median PFS, months 10.311.214.1 Hazard ratio0.9080.717 One-sided p-value0.080<0.0001 Median OS, months 39 Engl J Med. 2011 Dec;365(26):2473-83.

11. Systemic treatment for advanced stages Antiangiogenic agents N. Engl J Med. 2011 Dec;365(26):2484-96.

12. Definition of high-risk subgroup.N Engl J Med. 2011 Dec;365(26):2484-96.

13. ICON 7 - Results PFS (High-risk)OS (High-risk) N Engl J Med. 2011 Dec;365(26):2484-96. All ptsHigh-risk CHTCHT + BevCHTCHT + Bev mOS (mo.)58.658.030.239.7 p0.850.03 HR0.990.78 95% CI0.85-1.140.63-0.97 Lancet Oncol 2015; 16: 928–36

14. ICON 7 - Results OS (All patients)OS (High-risk) Lancet Oncol 2015; 16: 928–36 All ptsHigh-risk CHTCHT + BevCHTCHT + Bev mOS (mo.)58.658.030.239.7 p0.850.03 HR0.990.78 95% CI0.85-1.140.63-0.97

15. Stratification variables: Time to recurrence Cytoreductive surgery Gemcitabine 1000 mg/m 2 d1/8 Carboplatin AUC 4 Gemcitabine 1000 mg/m 2 d1/8 Arm A Arm B Placebo to progression Bevacizumab 15 mg/kg to progression Platinum- sensitive, recurrent OC, PP, FTC No prior bevacizumab n=480 Platinum- sensitive, recurrent OC, PP, FTC No prior bevacizumab n=480 Primary endpoint: PFS Secondary endpoints: ORR, OS, DR, safety Exploratory endpoints: IRC, CA 125 response, ascites IRC present J Clin Oncol 29: 2011 (suppl; abstr LBA5007) Medical treatment of relapsed disease Platinum-sensitive OCEANS

16. J Clin Oncol. 2012;30(17):2039.

17. AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC) Recurrent EOC platinum resistant ≤ 2 prior therapies no clinical or radiologic evidence of bowel involvement Non-Platinum Chemotherapy RANDOMIZERANDOMIZE Non-Platinum Chemotherapy + Bevacizumab 15 mg/kg Chemotherapy Options Paclitaxel 80 mg/m 2 d 1,8,15, 22 q28 Topotecan 4 mg/m 2 d 1, 8,15 q28 or Topotecan 1.25 mg/m 2 d 1-5 q21 PLD 40 mg/m 2 d 1 q28 Stratified chemotherapy PFI (< 3 vs 3-6 mo) prior anti-angiogenesis Treat to progression N = 361 J Clin Oncol. 2012; Suppl. Abstract LBA5002.

18. Medical treatment of relapsed disease Platinum-resistant AURELIA J Clin Oncol. 2014;32(13):1302.

19. Medical treatment of relapsed disease Platinum-sensitive ICON 6 Arm A Reference arm 6 cycles of chemotherapy plus Placebo No Progressive disease Maintenance cediranib after chemotherapy Maximum 18 months from randomisation PFS-12.5 mo OS-20.3 mo Arm B Chemotherapy Plus cediranib during Chemotherapy Arm C Chemotherapy plus cediranib during Chemotherapy No Progressive disease Placebo Maximum 18 months from randomisation No Progressive disease Placebo Maximum 18 months from randomisation PFS-9.4 mo OS-17.6 mo

20. ICON 6 7th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress in Amsterdam (Abstract E17-7020)

21. ICON6 7th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress in Amsterdam (Abstract E17-7020)

22. ICON6 7th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress in Amsterdam (Abstract E17-7020)

23. Gynecologic Oncology 138 (2015) 223–226

24. Targeting angiogenesis Bevacizumab combined with chemotherapy provides a statisti- cally and clinically significant improvement in PFS in the primary and recurrent advanced ovarian cancer settings OS benefit in subgroups of patients defined according to residual disease and/or disease stage Angiogenesis is a valid target for the treatment of ovarian cancer Biomarkers predictive of treatment response to anti- angiogenic therapies are needed

26. Functioning PARP enzyme PARP enzyme inhibited Walsh CS, Two decades beyond BRCA1/2: Homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.017

27. . J Clin Oncol 2012;30:372–9.

28. Progression Free Survival Overall Survival. J Clin Oncol 2012;30:372–9. OS: 6.5 mo 8.8 mo 7.1 mo The primary end point: investigator-assessed PFS for Olaparib versus PLD Secondary end points: overall survival (OS);

29. Phase 2 – combined with chemotherapy

30. 173 pts - Pt-sensitive HGS Ov. Ca. - up to 3 cycles of Pt-Tx - PFS ≥ 6 mo before RDS 162 pts RDS 1:1 81 pts Ola 200 mg bid, D1-10, q3w Tax 175 mg/m2, D1, q3w CBDCA AUC 4, D1, q3w 66 pts Ola 400 mg bid 75pts Tax 175 mg/m2, D1, q3w CBDCA AUC 6, D1, q3w The primary endpoint: progression-free survival Secondary endpoints were: overall survival; percentage change in tumour size; the proportion of patients with an objective response according to RECIST; cancer antigen 125 (CA-125) response; portion of patients with a RECIST or CA125 response. Lancet Oncol 2014; http://dx.doi.org/10.1016/S1470-2045(14)71135-0

31. Olaparib – combined with chemotherapy Overall Survival Lancet Oncol 2014; http://dx.doi.org/10.1016/S1470-2045(14)71135-0

32. Olaparib – combined with chemotherapy Progression Free Survival Lancet Oncol 2014; http://dx.doi.org/10.1016/S1470-2045(14)71135-0

33. Olaparib – Maintenance therapy

34. N Engl J Med 2012;366:1382–92. Study design

35. Phase 2 – Maintenance therapy Patients characteristics Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012;366:1382–92.

36. Phase 2 – Maintenance therapy Patients characteristics Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012;366:1382–92.

37. Olaparib – Maintenance therapy Results N Engl J Med 2012;366:1382–92.

38. Olaparib – Maintenance therapy Results N Engl J Med 2012;366:1382–92.

39. Olaparib – Maintenance therapy Adverse events N Engl J Med 2012;366:1382–92.

40. Olaparib – Maintenance therapy

41. Phase 2 – Maintenance therapy Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014;15:852–61.

42. Progression Free Survival Olaparib – Maintenance therapy Lancet Oncol 2014;15:852–61.

43. Overall Survival Olaparib – Maintenance therapy. Lancet Oncol 2014;15:852–61.

44. Time to first subsequent therapy Phase 2 – Maintenance therapy Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014;15:852–61.

45. Time to second subsequent therapy Phase 2 – Maintenance therapy Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014;15:852–61.

46. Olaparib – US indication

47. Patients characteristics J Clin Oncol 2014;33(3):244–50.

48. Olaparib – US indication Results.J Clin Oncol 2014;33(3):244–50.

49. Olaparib – US indication Progression Free SurvivalOverall Survival.J Clin Oncol 2014;33(3):244–50.

50. Olaparib – US indication Adverse events.J Clin Oncol 2014;33(3):244–50.

51. Cediranib and Olaparib PFS O: 9.0 mo C/O: 17.7 mo HR: 0.42 (95% CI 0.23-0.76) p:0.005 Lancet Oncol 2014; 15: 1207–14

52. Cediranib and Olaparib PFS O: 5.7 mo C/O: 16.5 mo HR: 0.32 (95% CI 0.14-0.74) p:0.008 PFS O: 16.5 mo C/O: 19.4 mo HR: 0.55 (95% CI 0.24-1.27) p:0.19 Lancet Oncol 2014; 15: 1207–14

53. Olaparib Olaparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum- sensitive relapsed BRCA- mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy. Olaparib indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

54. Intraperitoneal chemotherapy Rationale Higher concentration of cytotoxic agents Lower systemic toxicity Enhanced cytotoxic effects of chemotherapy Diminished the resistance to chemotherapy

55. Intraperitoneal vs. Intravenous cisplatin N Engl J Med 1996;335: 1950-5.

56. 3 Major Frontline IP Studies  GOG Protocol 104 (SWOG 8501) 1  GOG Protocol 114 2  GOG Protocol 172 3 1. Alberts DS, et al. N Eng J Med. 2006;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong D, et al. N Eng J Med. 2006;354:34-43.

57.  Trial conducted among patients with stage III minimal residual < 1.0 cm GOG Protocol 172: Schema N Eng J Med. 2006;354:34-43. Regimen I (n = 210) Paclitaxel 135 mg/m 2 /24 hrs IV Cisplatin 75 mg/m 2 IV Every 3 wks for 6 cycles Regimen II (n = 205) Paclitaxel 135 mg/m 2 /24 hrs IV Day 1 Cisplatin 100 mg/m 2 IP Day 2 Paclitaxel 60 mg/m 2 IP Day 8 Every 3 wks for 6 cycles

58. GOG 172: Ovarian (Optimal III) N Engl J Med. 2006;354:34-43. 0 0.2 0.4 0.6 0.8 1.0 PFS 01224364860 Mos on Study 24 vs 18 mos PFS CDDP (IP) Paclitaxel (IP + IV) (n = 206) CDDP (IV) Paclitaxel (IV) (n = 210) PFS: 18.3mo vs. 23.8mo, HR: 0.80 (0.64–1.00), p:0.05

59. GOG 172: Ovarian (Optimal III) 0.0 0.2 0.4 0.6 0.8 1.0 OS 01224364860 Mos on Study CDDP (IV) Paclitaxel (IV) (n = 210) CDDP (IP) Paclitaxel (IP + IV) (n = 206) 66 vs 50 mos survival N Engl J Med. 2006;354:34-43. OS: 49.7mo vs. 65.6mo, HR: 0.75 (0.58–0.97), p:0.03

60.  Trial conducted among patients with stage III minimal residual < 1 cm  Each regimen given every 3 wks for 6 cycles GOG Protocol 15 Schema and Results J Clin Oncol. 2003;21:3194-3200. Regimen I (n = 400) Paclitaxel 135 mg/m 2 /24 hrs Cisplatin 75 mg/m 2 Regimen II (n = 392) Paclitaxel 175 mg/m 2 /3 hrs Carboplatin AUC 7.5 Parameter, Median MosPaclitaxel/Cisplatin (n = 400) Paclitaxel/Carboplatin (n = 392) PFS19.420.7 Survival48.757.4

61. 0 20 40 60 80 100 120 140 160 Pretreatment4th CyclePosttreatment 3-6 Wks Posttreatment 12 Mos IVIP P =.03P <.001P =.009P = NS Patient-Reported Outcomes GOG 172: Quality of Life.J Clin Oncol. 2007;25:437-443.

62. Courses Completed GOG 172: IP Courses Completed Gynecol Oncol. 2006;100:27-32. 0 10 20 30 40 50 60 70 80 90 Patients (%) 0123456 100 8 92 74 59 52 47 42 % Received

63. PFS: IP vs. IV Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.: CD005340. DOI: 10.1002/14651858.CD005340.pub4.

64. OS: IP vs. IV Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.: CD005340. DOI: 10.1002/14651858.CD005340.pub4.

65. Adverse events Infection Pain Fever Gastro-intestinal Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.: CD005340. DOI: 10.1002/14651858.CD005340.pub4.

66. Complications of IP chemotherapy catheter-related complications – 10% inflow obstruction – 6.3% Infection – 3.6% cessation of chemotherapy 7% Gynecol Oncol. 2001 Apr;81(1):77-81.

67. Ports and complications for IP chemotherapy delivery Port complications: 6.8–40.5%  failure to complete chemotherapy: 1.9-26.2% (12.6%)  discontinuation: 9.1-70% Infection: 0–20.5%  discontinuation: 31.4% Obstruction: 2.1 -22%  discontinuation: 37.6% Access issues: 3-7.9% Retraction 1% Bowel perforation: 1.2–3.6% Pain and discomfort: 2.3 -85.7% Leakage: 1.3-11.9% BJOG 2012;119:150–159.

68. Intraperitoneal chemotherapy The results support the use of IP chemotherapy IP chemotherapy increases both overall survival and progression-free survival in women with advanced ovarian cancer The potential for catheter-related complications and complications relating to toxicity need to be taken into consideration

69. Personalizing treatments IP/IV therapy is preferred adjuvant systemic approach for women diagnosed with advanced ovarian cancer optimally debulking Bevacizumab treatment is associated with improved PFS in first line or relapsed ovarian cancer setting (Pt sensitive/resistant) Bevacizumab improved OS in first line setting for high-risk ovarian cancer patients Olaparib improved PFS in maintenance setting for high-grade serous, mBRCA, Pt-sensitive which experienced CR/PR to Pt-based chemotherapy ovarian cancer Olaparib improved PFS in germline mBRCA advanced ovarian cancer who have been treated with ≥ 3 lines of chemotherapy