1. Maintenance Therapy for Ovarian Cancer – Do the Benefits Outweigh the Risks? Bradley J. Monk, MD, FACS, FACOG Professor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, a Dignity Health Member University of Arizona Cancer Center-Phoenix Arizona USA bradley.monk@chw.edu

2. Newly Diagnosed Advanced Ovarian Cancer

3. Maintenance: The Stakes are High! Symptoms Diagnosis Chemotherapy #1 Staging Evaluation ? SLL Progression Chemo #2 Chemo #3+ Supportive Care SecondarySurgery Maintenance What we know… Rate of response is high (CR + PR) >75% Second assessment operations find disease > 40% of CR’s Clinical CR’s have >50% recurrence risk at 2 years Pathological CR’s have >40% risk at 2 years Option applies to CR’s and documented PR’s

4. Maintenance Strategies in Epithelial Ovarian Cancer Anti-angiogenesis Chemotherapy Clinical trial – PARP inhibitor

5. B-2 What Are the Promising Targets for Future Therapeutic Approaches? The most promising targets in clinical trials are angiogenesis and homologous recombination deficiency. Int J Gynecol Cancer 2011: 21; 756-762 4 th Ovarian Cancer Consensus Conference 25 – 27 June 2010 UBC Life Sciences Institute, Vancouver, British Columbia

6. Maintenance Strategies in Epithelial Ovarian Cancer Anti-angiogenesis Chemotherapy Clinical trial – PARP inhibitor

7. GOG#218 ICON-7

8. GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic)Stage III optimal (macroscopic) Stage IIIStage III suboptimal suboptimal Stage IVStage IV n=1800 (planned) Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic)Stage III optimal (macroscopic) Stage IIIStage III suboptimal suboptimal Stage IVStage 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)GOG performance status (PS) Stage/debulking statusStage/debulking status RANDOMRANDOMIIZEZERANDOMRANDOMIIZEZEI RANDOMRANDOMIIZEZERANDOMRANDOMIIZEZEI 1:1:1 15 months Paclitaxel (P) 175 mg/m 2 Carboplatin (C) AUC 6 Placebo IArm Cytotoxic (6 cycles) BEV 15 mg/kg Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 III Maintenance (16 cycles)

9. GOG-0218 CA-125 To Determine Progression Protocol-defined PFS analysis CA-125-censored PFS analysis Median PFS CP (Arm I)10.3 months12.0 months CP + BEV  BEV (Arm III) 14.1 months18.0 months Absolute diff. median PFS3.8 months6.0 months Hazard ratio0.7170.645 Censored for CA125, % CP (Arm I)020 CP + BEV  BEV (Arm III) 029

10. GOG-0218 Ad Hoc Survival Analysis in Stage IV Overall Survival (months) Proportion Surviving CPP (n=153) CPB (n=165) CPB+B (n=165)) 0 72 1.0 0.8 0.6 0.4 1224364860 0.2 0.0 CPPCPBCPB+B Median OS (months) 32.832.940.6 HR 0.72, 95% confidence interval 0.53-0.97 NEJM Data cut-off date August 26, 2011 (ASCO 2010 cut-off date February 5, 2010) Randall LM et al SGO 2013

11. 11 ICON7: a phase III Gynaecologic Cancer InterGroup (GCIG) trial of adding bevacizumab to standard chemotherapy in women with newly diagnosed epithelial ovarian, primary peritoneal or fallopian tube cancer Tim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Philip Beale, Andreas Cervantes, Amit Oza on behalf of GCIG ICON7 collaborators (MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG, GEICO, NCIC-CTG) ESMO 2010 N Engl J Med. 2011 Dec 29;365(26):2484-96.

12. ICON7: Study Design Stratification variables: Stage/surgery Stage/surgery Time since surgery Time since surgery GCIG group GCIG group *Might vary based on GCIG group ** Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m 2 Carboplatin AUC 6* AVASTIN Paclitaxel 175 mg/m 2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC)Stage I-IIA (Gr 3 or CC) Stage IIB/CStage IIB/C Stage IIIStage III Stage IVStage IVn=1528 Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC)Stage I-IIA (Gr 3 or CC) Stage IIB/CStage IIB/C Stage IIIStage III Stage IVStage IVn=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness,translational No IRC present Perren, et al. ESMO 2010

13. Number at risk CP764723693556464307216143915025 CPB7.5+764748715647585399263144733619 1.00 0.75 0.50 0.25 0 Proportion alive without progression Time (months) 036912151821242730 CPCPB7.5+ Events, n (%) 392 (51)367 (48) Median, months 17.319.0 Log-rank test p=0.0041 HR (95% CI)0.81 (0.70–0.94) 17.3 19.0 CP CPB7.5+ ICON 7 PFS Benefit: Academic Analysis Perren, et al. ESMO 2010

14. ICON 7 Summary of Updated Results Parameter Protocol-Defined Analysis Bulk Disease Analysis PFSHR = 0.87, P =.039 CP17.4 months CP + BEV  BEV 19.8 months OSHR = 0.84, P =.099HR = 0.64, P =.002 CP28.8 months CP + BEV  BEV 36.6 months Kristensen G, et al. J Clin Oncol.2011;29: (suppl; abstr LBA5006)

15. Phase III randomized, placebo-controlled, double-blind, multicenter N=940 patients randomized (1:1) from June 2009 to August 2010 Pazopanib administered at 800 mg daily for up to 24 months* ICF Survival follow-up (post-PD) First-line surgery and chemotherapy (allowed: dose- dense, IP, neoadjuvant) Placebo 24 months Pazopanib 24 months RANDOMIZERANDOMIZE Observation (to PD) If not PD + tumor < 2 cm Median 7 months from diagnosis to randomization *Original design was for 12 months and later amended to 24 months AGO-OVAR 16 Du Bois A et al J Clin Oncol 31, 2013 (suppl; abstr LBA5503)

16. Primary Endpoint: Progression-free Survival (RECIST) (months) Δ= 5.6 months Median time from Diagnosis: 7 months Du Bois A et al J Clin Oncol 31, 2013 (suppl; abstr LBA5503) AGO-OVAR 16

17. Adverse Events Grade 3-4 per Patient occurring in at least 1% in the Pazopanib Arm Grade 3/4 adverse events Placebo (N=461) Pazopanib (N=477) Δ Hypertension26 (6%)147 (31%)121 (25%) Hypertension (including Grade 2)80 (17%)248 (52%)168 (35%) Liver-related toxicity 3 (<1%)45 (9%)42 (9%) Neutropenia7 (2%) 47 (10%)40 (8%) Diarrhea5 (1%)39 (8%)34 (7%) Asthenia / Fatigue 1 (<1%)13 (3%)12 (3%) Thrombocytopenia 3 (<1%)12 (3%)9 (2%) Palmar-plantar erythrodysesthesia 1 (<1%) 9 (2%)8 (2%) Headache 3 (<1%) 8 (2%)5 (1%) Abdominal pain5 (1%) 8 (2%) 3 (<1%) Proteinuria 2 (<1%) 6 (1%) 4 (<1%) Arthralgia 3 (<1%) 5 (1%) 2 (<1%) Du Bois A et al J Clin Oncol 31, 2013 (suppl; abstr LBA5503) AGO-OVAR 16

18. OCEANS Stratification variables: Time to recurrenceTime to recurrence Cytoreductive surgeryCytoreductive 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 ClinicalTrials.gov Identifier: NCT00434642 Aghajanian C et al J Clin Oncol 29: 2011 (suppl; abstr LBA5007)

19. 242177451130CG + PL OCEANS: Primary analysis of PFS CG + PL (n=242) CG + BV (n=242) Events, n (%) 187 (77)151 (62) Median PFS, months (95% CI) 8.4 (8.3–9.7) 12.4 (11.4–12.7) Stratified analysis HR (95% CI) Log-rank p-value 0.484 (0.388–0.605) <0.0001 Months No. at risk 2422039233110CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0612182430 ASCO 2011 Aghajanian C et al J Clin Oncol 29: 2011 (suppl; abstr LBA5007)

20. 1.0 Proportion surviving OCEANS: OS Analyses a Data cutoff date: Sept 17, 2010. Median follow-up of 24 months in both arms, with 141 deaths (29% of patients). b Data cutoff date: Aug 29, 2011. Median follow-up 33.7 months in PL arm and 35.4 months in BV arm, with 235 deaths (49% of patients). GC + PL (n=242) GC + BV (n=242) No. events (%)78 (32.2)63 (26.0) Median OS, mo29.935.5 HR (95% CI)0.751 (0.537–1.052) Log-rank P value.0944 GC + PL (n=242) GC + BV (n=242) No. events (%)112 (46.3)123 (50.8) Median OS, mo35.233.3 HR (95% CI)1.027 (0.792–1.331) Log-rank P value.8422 06121824303642 Months 1.0 0.8 0.6 0.4 0.2 0.0 Proportion surviving GC + PL (n=242) GC + BV (n=242) First Interim Analysis a Second Interim Analysis b 061218243036424854 Months 0.8 0.6 0.4 0.2 0.0

21. Maintenance Strategies in Epithelial Ovarian Cancer Anti-angiogenesis Chemotherapy Clinical trial – PARP inhibitor

22. Maintenance Chemotherapy: GOG 178 EOC, FT, PP Stage III/IV Prior chemo 5–6 cycles Register 3–8 wks CCR Neuropathy ≤ grade II Paclitaxel (3 hrs) 175 mg/m 2 q28days x 12 Paclitaxel (3 hrs) 175 mg/m 2 q28days x 3RANDOMIZE N = 450 anticipated Accrual closed 9/6/01 N = 277; 222 with FU 54 progression events End points PFS OS FU = follow-up. Markman et al, J Clin Oncol 2003.

23. Unadjusted Log Rank p (1-sided) =.0035 Adjusted Log Rank p (1-sided) =.0023 Markman et al, J Clin Oncol 2003. Maintenance Chemotherapy: GOG 178

24. GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL OPEN TO PATIENT ENTRY MARCH, 2005 CLOSED TO ENROLLMENT JANUARY, 2014 www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin ( N = 1100) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses

25. Maintenance Strategies in Epithelial Ovarian Cancer Anti-angiogenesis Chemotherapy Clinical trial – PARP inhibitor

26. PARP recruitment PARP DNA damage PARP activation and assembly of repair factors NAD+ poly (ADP-ribose) PARP PAR degradation via PARG PARG PARP End processing, gap filling, and ligation PNK 1 pol β XRCC1 LigIII pol β XRCC1 LigIII PNK 1 Vergote, ND; Khanna et al, 2001; Sanchez-Perez, 2006; Kennedy et al, 2006. PARP and Base Excision Repair

27. DNA Repair Inhibitors in Cancer Cells: 2 Modes of Action Potentiation –Inhibition of DNA repair following DNA-damaging agents –Original hypothesis Synthetic lethality –Selected cancer cells lose DNA repair pathways, whereas normal cells remain unaffected –Targeting these defective cells may cause selective cell kill with an increased therapeutic ratio –May allow for a novel targeted approach to cancer treatment Bentle MS et al J Mol Histol. 2006 Sep;37(5-7):203-18

28. PARPi in Phase III Development in Ovarian Cancer 1.AZD 2281 (KU-0059436) = Olaparib 2. MK-4827 = Niraparib 3.CO-338 (AG014699, PF-01367338) = Rucaparib  Others with randomized trials in devleopment  ABT-888 = Veliparib  BMN 673 No direct clinical comparisons!

29. Dual Activities of PARP Inhibitors  Cell cytotoxicity greatest with niraparib  Dual mechanisms include catalytic inhibition of PARP and PARP trapping on DNA DT40: avian line with only PARP1: facilitates assessment of role of PARP trapping Murai J, et al.Cancer Res. 2012 Nov 1;72(21):5588-99.

30. PARPi in Phase III Development in Ovarian Cancer 1.AZD 2281 (KU-0059436) = Olaparib 2. MK-4827 = Niraparib 3.CO-338 (AG014699, PF-01367338) = Rucaparib

31. Olaparib Development Oral small molecule PARPi (low nM) Escalation Phase (N = 46) –All tumors –BRCA mutation not required (11 BRCA ovarian ca’s) –10 Dose levels; administration 2 of 3 weeks up to bid continuously PK and PD determined DLT: Myelosuppression, N/V, CNS (mood changes) MTD: 400 mg bid Expansion Phase (N=52) –All confirmed BRCA mutation carriers (39 Ovarian ca’s) –DLT: fatigue, thrombocytopenia, somnolence –Administration 200 mg bid continuously 1 Fong, ASCO 2006, 2007 2 Yap, ASCO 2007

32. Phase I: AZD 2281 (Olaparib)

33. Clinical Activity: RECIST + GCIG (cont.) Fong et al, 2008.

34. Phase II: AZD 2281 (Olaparib)

35. Phase II: BRCA Mutation Ovarian Cohort Audeh et al, 2009.

36. Who Will Benefit From PARPi Treatment? Sporadic tumors with intact BRCA function Courtesy of Robert Coleman, MD. Adapted from Coleman, 2009.

37. Even Wider Catch: BRCAness “Profile” Konstantinopoulos PA, et al. J Clin Oncol. 2010;28:3555.

38. BRCAness and Response to Chemotherapy Disease Free SurvivalOverall Survival Konstantinopoulos PA, et al. J Clin Oncol. 2010;28:3555. 34 v 15 mo P = 0.01 72 v 41 mo P = 0.006

39. Phase II study of the oral PARP inhibitor olaparib (AZD2281) versus liposomal doxorubicin in ovarian cancer patients with BRCA1 and/or BRCA2 mutations Stan Kaye, 1 Bella Kaufman, 2 Jan Lubinski, 3 Ursula Matulonis, 4 Charlie Gourley, 5 Beth Karlan, 6 Dianna Taylor, 7 Mark Wickens, 7 James Carmichael 7 1. Royal Marsden Hospital, Sutton, Surrey, UK 2. Chaim Sheba Medical Center, Tel Hashomer, Israel 3. Pomeranian Medical University, Szczecin, Poland 4. Dana-Farber Cancer Institute, Boston, MA, USA 5. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK 6. Cedars-Sinai Medical Center, Los Angeles, CA, USA 7. AstraZeneca, Alderley Park, Macclesfield, UK Clinicaltrials.gov number, NCT00628251 ESMO 2010 Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.

40. Randomized 1:1:1 Olaparib 200 mg bid in 28-day cycles PLD 50 mg/m 2 IV every 4 weeks PD or withdrawal from treatment for other reason As above or max lifetime cumulative dose reached Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib (200 mg and 400 mg bid) with pegylated liposomal doxorubicin (PLD) Study Design Olaparib 400 mg bid in 28-day cycles BRCA1/2 germline carriers with Ovarian Ca Progressive or recurrent disease < 12 months after previous platinum- based chemotherapy Patients in PLD group were allowed to cross over to olaparib 400 mg bid on confirmed PD Stats: HR 0.55 (median PFS of 4 to 7.3 mos) N planned: 90 (30/arm) Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.

41. Progression-Free Survival Olaparib 200 mg: 6.5 (5.6-8.0) months Median PFS (80% CI) Olaparib 400 mg: 8.8 (6.3-9.2) months PLD 50 mg/m 2 : 7.1 (5.5-7.8) months HR* vs PLD (80% CI) Olaparib 200 mg: 0.91 (0.60-1.39); P = 0.78 Olaparib 400 mg: 0.86 (0.56-1.30); P = 0.63 Olaparib 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66 Time From Randomization (months) Proportion of Patients Progression Free 0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 12 108 64 2 *HR < 1 favors olaparib. 32 0 38 1321 24 32 0 112 1721 28 33 0 38 1518 25 Number of patients at risk: Olaparib 200 mg Olaparib 400 mg PLD Stats: HR 0.55 (median PFS of 4 to 7.3 mos) N planned: 90 (30/arm) Olaparib 400 mg Olaparib 200 mg PLD Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.

42. Maintenance Olaparib: Study design (Study 19) Placebo (n=129) Olaparib 400mg bid, orally (n=136) Patients Platinum-sensitive high-grade serous ovarian cancer ≥2 previous platinum regimens Maintained PR or CR following last platinum regimen Primary endpoint PFS by RECIST Secondary endpoints TTP by CA-125 (GCIG criteria) or RECIST, OS, safety Randomized 1:1 82 sites in 16 countries Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med. 2012 Apr 12;366(15):1382-92.

43. Study 19: Progression-free survival 0 Time from randomization (months) 1361045123600 12972237100 At risk (n) Olaparib Placebo 0.6 0.8 0.9 0 0.1 0.2 0.3 0.4 0.5 0.7 1.0 369121518 No. of events: Total patients (%) Median PFS (months) Olaparib 60:136 (44.1) 8.4 Placebo 93:129 (72.1) 4.8 Hazard ratio 0.35 (95% CI, 0.25–0.49) P<0.00001 Olaparib 400 mg bid Placebo Randomized treatment Proportion of patients progression free Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med. 2012 Apr 12;366(15):1382-92.

44. Study 19: Common Adverse Events* Placebo (n=128) *Adverse events graded according to maximum CTCAE version 3.0 grade, experienced by >15% of patients in either treatment group. Adverse event Any event Nausea Fatigue Vomiting Diarrhea Headache Decreased appetite Abdominal pain Anemia Dyspepsia Grade 1/2 61 66 42 29 21 18 16 12 16 Olaparib 400 mg bid (n=136) Grade 3/4 35 2 7 2 0 2 5 0 Grade 1/2 70 35 34 13 20 11 13 23 4 9 Grade 3/4 20 0 3 1 2 1 0 3 1 0 Percentage of Patients Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med. 2012 Apr 12;366(15):1382-92.

45. Study 19: PFS by BRCAm status Presented by: Jonathan Ledermann et al at ASCO 2013 0 Time from randomization (months) 0 1.0 Proportion of patients progression-free 3691215 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 82% reduction in risk of disease progression or death with olaparib Olaparib BRCAm Placebo BRCAm Number at risk Olaparib BRCAm Placebo BRCAm 7459331440 623513200 BRCAm (n=136) OlaparibPlacebo Events: total pts (%)26:74 (35.1)46:62 (74.2) Median PFS, months11.24.3 HR=0.18 95% CI (0.11, 0.31); P<0.00001

46. Study 19: PFS by BRCAm status 0 Time from randomization (months) 0 1.0 Proportion of patients progression-free 3691215 Olaparib BRCAm Olaparib BRCAwt 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 BRCAm (n=136)BRCAwt (n=118) OlaparibPlaceboOlaparibPlacebo Events: total pts (%)26:74 (35.1)46:62 (74.2)32:57 (56.1)44:61 (72.1) Median PFS, months11.24.35.65.5 HR=0.18 95% CI (0.11, 0.31); P<0.00001 HR=0.53 95% CI (0.33, 0.84); P=0.007 Placebo BRCAm Placebo BRCAwt Number at risk Olaparib BRCAm Olaparib BRCAwt Placebo BRCAm Placebo BRCAwt 7459331440 574417920 623513200 613510410 BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance) Presented by: Jonathan Ledermann et al at ASCO 2013

47. Study 19: OS in BRCAm patients 0 Time from randomization (months) 0 48 1.0 Proportion of patients alive 369121518212427303336394245 Number at risk 62 5852504639363329 2721124 Placebo BRCAm 74716967656257545048393626127 Olaparib BRCAm Randomized treatment Placebo BRCAm Olaparib BCRAm 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 BRCAm (n=136) OlaparibPlacebo Deaths: total pts (%)37:74 (50.0)34:62 (54.8) Median OS, months34.931.9 HR=0.74 95% CI (0.46, 1.19) P=0.208 OS in BRCAwt patients: HR=0.98; 95% CI, 0.62–1.55; P=0.946 –Median OS: olaparib, 24.5 months; placebo, 26.2 months 14/62 (22.6%) placebo patients switched to a PARP inhibitor Presented by: Jonathan Ledermann et al at ASCO 2013

48. Study 19: Time to second subsequent therapy (PFS2) 0 Time from randomization (months) 0 1.0 Proportion of patients receiving study treatment or first subsequent therapy 10203040 Olaparib BRCAm 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Placebo BRCAm Number at risk Olaparib BRCAm Placebo BRCAm 74 62 515253545 70 60 65 46 50 31 38 21 33 18 30 11 23 9 9 2 0 0 BRCAm (n=136) OlaparibPlacebo Events: total pts (%)42:74 (56.8)49:62 (79.0) Median PFS, months23.815.3 HR=0.46 95% CI (0.30, 0.70); P<0.0003 Presented by: Jonathan Ledermann et al at ASCO 2013

49. 0 Time from randomization (months) 0 1.0 Proportion of patients receiving study treatment or first subsequent therapy 1020304050 Olaparib BRCAm Olaparib BRCAwt 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Placebo BRCAm Placebo BRCAwt Number at risk Olaparib BRCAm Olaparib BRCAwt Placebo BRCAm Placebo BRCAwt 74 57 62 61 515253545 70 56 60 58 65 48 46 48 50 34 31 28 38 20 21 18 33 16 18 8 30 14 11 6 23 11 9 4 9 3 2 2 0 0 0 1 0 0 0 0 BRCAm (n=136)BRCAwt (n=118) OlaparibPlaceboOlaparibPlacebo Events: total pts (%)42:74 (56.8)49:62 (79.0)42:57 (73.7)55:61 (90.2) Median PFS, months23.815.317.114.7 HR=0.46 95% CI (0.30, 0.70); P<0.0003 HR=0.64 95% CI (0.42, 0.96); P=0.032 BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance) Presented by: Jonathan Ledermann et al at ASCO 2013 Study 19: Time to second subsequent therapy (PFS2)

50. ORR post-olaparib = 36% (24/67) by RECIST  Platinum = 40% (19/48) by RECIST ORR post-olaparib = 45% (35/78) by RECIST + GCIG No evidence of secondary BRCA1/2 mutations detected in tumor samples of 6 PARPi-resistant patients

51. Front-Line Olaparib Maintenance Therapy A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Olaparib Maintenance Monotherapy in Patients with BRCA Mutated Advanced (FIGO Stage III-IV) Ovarian Cancer following First Line Platinum Based Chemotherapy (GOG 3004) ClinicalTrials.gov (identifier: NCT01844986

52. Olaparib Maintenance Therapy in Platinum Sensitive Ovarian Cancer A Phase III, Randomized, Double Blind, Placebo Controlled, Multicenter Study of Olaparib Maintenance Monotherapy in Patients with BRCA Mutated Relapsed Ovarian Cancer Following Complete or Partial Response Following Platinum Based Chemotherapy: SOLO-2 ClinicalTrials.gov (identifier: NCT01874353

53. PARPi in Phase III Development in Ovarian Cancer 1.AZD 2281 (KU-0059436) = Olaparib 2. MK-4827 = Niraparib 3.CO-338 (AG014699, PF-01367338) = Rucaparib

54. Niraparib: Phase 1/2 Ovarian Cancer Anti-tumor Activity  At recommended dose (290/300 mg), 3/4 (75%) platinum sensitive patients achieved RECIST response  RECIST response rate in platinum-sensitive patients was 46% (6/13)  Response rate (by RECIST and/or GCIG Ca125 criteria) in evaluable platinum- resistant patients was 22% (6/27) * BRCA1/2 mutation carriers † Reduction in overall sum of measurable disease but new lesion seen (overall: PD) -Refractory patient (BRCA mutated) not included Percentage change from baseline in size of target lesions Platinum Resistant Platinum SensitivePlatinum Sensitive @ Recommended Dose * * * * * * * * * * * * * * * * * * * † † Michie Co et al. J Clin Oncol 31, 2013 (suppl; abstr 2513)

55. NOVA Study Design ClinicalTrials.gov Identifier:NCT01847274

56. PARPi in Phase III Development in Ovarian Cancer 1.AZD 2281 (KU-0059436) = Olaparib 2. MK-4827 = Niraparib 3.CO-338 (AG014699, PF-01367338) = Rucaparib

57. A Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer (ARIEL-3) ClinicalTrials.gov Identifier:NCT01968213

58. Summary: PARPi in Phase III Development as Maintenance Therapy in Ovarian Cancer 1.AZD 2281 (KU-0059436) = Olaparib –SOLO-1 = Front-line HGS maintenance in BRCAmut –SOLO-2 = Platinum sensitive HGS maintenance in BRCAmut 2. MK-4827 = Niraparib –NOVA = Platinum sensitive HGS maintenance in BRCAmut and BRCAwt 3.CO-338 (AG014699, PF-01367338) = Rucaparib –ARIEL-3 = Platinum sensitive HGS and endometrioid maintenance in BRCAmut and BRCAwt HGS = High grade serous

59. Thank You Bradley.monk@chw.edu