New Treatments for Early Ovarian Cancer. Jonathan Ledermann UCL Cancer Institute University College London

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1 New Treatments for Early Ovarian Cancer Jonathan Ledermann UCL Cancer Institute University College London Lucerne Oct 213

2 Progression-free survival in first-line trials of platinum-based chemotherapy 1998 Pt. numbers PFS months ICON ICON ICON 5/GOG OVAR OVAR

3 Treatment strategies Initial primary debulking surgery Removal of part of the tumour Six cycles of platinum-based chemotherapy Three cycles of platinum-based neoadjuvant chemotherapy, following tumour biopsy Interval debulking surgery Three cycles of platinum-based chemotherapy

4 Surgical outcome as a prognostic factor in advanced ovarian cancer Aim: complete resection du Bois A et al. Cancer 29;115:

5 Ovarian Cancer not one disease 874 patients from 7 Randomised trials Mackay et al Int J Gyn Cancer 21

6 Tumour-specific therapy Type I tumours Low grade serous Low Grade Endometrioid Clear Cell Mucinous Type II tumours High Grade serous High Grade Endometrioid Undifferentiated Carcinosarcomas Systemic therapy for Clear Cell Cancer Irinotecan/cisplatin versus Carboplatin/Paclitaxel Systemic therapy for Advanced Mucinous Cancer (meoc/gog 241) Oxaliplatin/Capecitabine versus Carboplatin/paclitaxel ( +/- bevacizumab) Low Grade tumours poor sensitivity to chemotherapy MEK inhibitors- most promising systemic agents

7 Moving Forward Intraperitoneal chemotherapy Dose-dense chemotherapy Molecular Targeted therapies

8 Intraperitoneal therapy X2 heterogeneity (5 d.f.)= 3.1, p=.68 Is the observed effect real? Do carboplatin and cisplatin have an equivalent effect when given i.p.? What is the contribution of weekly paclitaxel?

9 Intraperitoneal Therapy GOG-172 Cisplatin 75 mg/m2 Paclitaxel 135 mg/m2 Day1: IV Paclitaxel 135 mg/m2 Day 2: IP Cisplatin 1mg/m2 Day 8: IP Paclitaxel 6 mg/m2 Armstrong et.al. N Engl J Med 26;354:34 43

10 Long-term survival following IP therapy GOG 114 & patients. 1.7 years median FU IP Micro IP IV Macro IP IV IP OS improved from 51 to 62 months (p=.48) 17% decreased risk of death (AHR.83) D. Tewari et al SGO 213

11 ipocc JGOG trial Epithelial ovarian cancer Stages II IV Including bulky tumour RANDOMIZATION Paclitaxel 8 mg/m2 IV Day 1,8,15 Carboplatin AUC 6 IV Q21, 6 8 cycles Paclitaxel 8 mg/m2 IV Day 1,8,15 Carboplatin AUC 6 IP Q21, 6 8 cycles Dose dense TCiv Dose dense TCip Primary endpoint: PFS Secondary endpoints: OS, toxicity, QoL Accrual goal: 746 patients / 511 events

12 NCIC OV21/ PETROC/SWOG Intraperitoneal therapy after interval debulking surgery Patients with EOC 3-4 cycles neoadjuvant chemotherapy Initial surgery: < 1 cm residual 3 cycles standard IV carboplatin/paclitaxel 3 cycles IP/IV platinum and paclitaxel Phase II evaluating IP carboplatin v cisplatin IP Platinum and IP paclitaxel (Day 8) All arms have D1/D8 Paclitaxel

13 Ongoing intraperitoneal therapy studies Arm GOG 252 IV carboplatin AUC 6 q3w Weekly IV paclitaxel 8 Ovarian (epithelial), primary peritoneal, or fallopian tube cancer Stage II IV optimal No prior anti-vegf therapy n=125 (target) R A N D O M I S E Primary endpoint: PFS Secondary endpoints: OS, QoL, safety Closed Oct 211: Primary Analysis 214 I mg/m2 Bevacizumab 15 mg/kg q3w IP carboplatin AUC 6 q3w II Weekly IV paclitaxel 8 mg/m2 Bevacizumab 15 mg/kg q3w IP cisplatin 75 mg/m2 d2 IV paclitaxel 135 mg/m2 d1 IP paclitaxel 6 mg/m2 d8 III Bevacizumab 15 mg/kg q3w 22 cycles

14 Dose-dense paclitaxel Stage II-IV EOC/FTC/PPC n=637 1:1 randomisation Carboplatin AUC6 q3w Paclitaxel 18mg/m2 q3w Carboplatin AUC6 q3w Paclitaxel 8mg/m2 q1w 66% stage III 98% ECOG PS -2 89% primary debulking, 1% delayed debulking 55% residual disease >1cm 56% serous, 12% endometrioid, 11% clear cell, 5% mucinous JGOG 316 Katsumata et al; Lancet 29

15 JGOG 316- Outcome Progression-free survival Overall survival Katsumata et al; Lancet 29

16 JGOG 316 NOVEL trial Progression-Free Survival >1 cm median 17 6 months vs 12 1 months; HR 71 p= 29 < 1cm median not reached v 6.9 months HR.74 p=.8 Overall Survival >1 cm 51.2 vs 33 5 months; HR 75; p= 27; < 1cm median not reached. HR.76; p=.23 Katsumata et al Lancet Oncol 213

17 GOG 262- Dose dense chemotherapy Stage III suboptimal debulking Stage IV ovarian cancer Carboplatin AUC5 IV d1 Paclitaxel 175mg/m2 +/- Bev. 15mg/kg ( 2-6) at investigator s discretion* 1:1 n = 625 Closed Feb 212 Carboplatin AUC5 IV d1 Paclitaxel 8 mg/m2 IV d1, 8, 15 +/- Bev. 15mg/kg ( 2-6) at investigator s discretion* Bevacizumab 15mg/kg q21 x 16 at investigator s discretion* * 85% of patients received bevacizumab

18 Diagnosis of Stage IC-IV EOC/PPC/FTC Immediate Primary Surgery (IPS) Delayed Primary Surgery (planned) Randomise 1:1:1 Randomise 1:1:1 Arm 1 6 cycles Arm 1 (control) Arm 2 6 cycles Arm 3 6 cycles Carboplatin AUC 5 Paclitaxel 175mg/m2 Arm 1 3 cycles Arm 2 3 cycles Arm 3 3 cycles Cycle 3 d15 omitted q3w q3w Delayed Primary Surgery (DPS) Arm 2 Carboplatin AUC 5 Paclitaxel 8mg/m2 q3w q1w Arm 3 Carboplatin AUC 2 Paclitaxel 8mg/m2 q1w q1w Arm 1 3 cycles Arm 2 3 cycles Single trial with a pre-specified stratification for IPS vs. DPS 159 patients Arm 3 3 cycles

19 Angiogenesis is an important driver of ovarian cancer growth Increased expression of angiogenic cytokines and receptors Associated with development of ascites High expression associated with poor prognosis

20 Two front-line trials with similar but not identical designs Carboplatin AUC 6 (C) Paclitaxel 175 mg/m2 (P) GOG-2181 Placebo Stage III optimal (macroscopic) Stage III suboptimal Stage IV (Oct 5 Jun 9) I II R Bev 15 mg/kg Placebo III Bevacizumab 15 mg/kg 15 months ICON72 High-risk stage I IIA (grade 3 or clear cell) Stage IIB IV Carboplatin AUC 5 or 6 Paclitaxel 175 mg/m2 R (Dec 6 - Feb 9) Bevacizumab 7.5 mg/kg q3w 12 months 1. Burger et al. ASCO 21; 2. Perren et al ESMO 21;

21 GOG-218: Outcome Primary endpoint: PFS Secondary endpoint: OS 14.1 months 1.3 months HR.717 ( ); P<.1 Burger RA, et al. N Engl J Med 211;365: HR.88 ( ); P=.45

22 ICON 7: Outcome Primary endpoint: PFS Secondary endpoint: OS 19. months 17.3 months HR.81 (.7-.94); P=.4 Perren TJ, et al. N Engl J Med 211;365: Erratum in N Engl J Med 212;366:284. HR.85 ( ); P=.11

23 ICON 7: high risk of progression subset PFS in patients at high-risk for progression OS in patients at high-risk for progression 16. months 1.5 months HR=.73 (.6.93); P=.2 HR.64 ( ); P=.2 Increment of 7.8 months in median OS Kristensen G, et al. J Clin Oncol 211;29(Suppl.);Abstract LBA56 and oral presentation; Perren TJ, et al. N Engl J Med 211;365: Erratum in N Engl J Med 212;366:284.

24 GO218: Stage IV Subpopulation Proportion Surviving 1. CPB+B vs CPP HR (95% C) =.72 (.53.97) CPP (n=153) CPB (n=165) CPB+B (n=165) Months on Study Randell LM, et al. SGO 213

25 25 Final OS by risk groups 1. Interaction: p=.1 Non-high risk HR 1.14 ( ) 37% events Proportion alive.75 Control Research.5 Control Research Research Control High risk HR.78 (.63.97) 66% events.25 BEV exposure Time (months) Oza et al ECCO-ESMO, ECC 213

26 Summary of safety: GOG-218 and ICON7 GOG-218 a ICON7 CP + Pla Pla (N=61) CP + Bev 15 Bev (N=67) CP (N=763) CP + Bev 7.5 (N=746) Hypertension GI perforation Fistula/abscess Proteinuria Wound-healing complication Non-CNS bleeding ATE VTE Neutropeniab Febrile neutropenia CHF RPLS Grade 3 adverse event, % CNS bleeding aregulatory analysis; bincludes laboratory abnormality for GOG-218. Roche data on file

27 OCTAVIA: Single-arm, Phase II trial of first-line carboplatin/weekly paclitaxel plus bevacizumab Newly diagnosed FIGO stage I IV ovarian cancer* Carboplatin AUC 6 q3w (6 8 cycles) Paclitaxel 8 mg/m2 Days 1, 8 and 15 (6 8 cycles) Bevacizumab 7.5 mg/kg q3w (total 1 year) Eligibility criteria designed to recruit a population similar to ICON7 Initial surgery within the preceding 8 weeks No prior chemotherapy or radiotherapy for ovarian cancer Aged 18 years and ECOG 2 No contraindication for bevacizumab administration *Epithelial ovarian, primary peritoneal or fallopian tube cancer; Switch to cisplatin permitted in patients with hypersensitivity to carboplatin. Gonzalez-Martin A, et al. Int J Gynecol Cancer 212;22(Suppl. 3):E98 and oral presentation.

28 OCTAVIA: Efficacy results Median duration follow-up: 26.3 months (range months) 1. n=189 Estimated probability of PFS Events, n (%) (52.4) 12-month PFS rate, % 85.6 Median PFS, months (9% CI) (95% CI) 23.7 ( ) ( ) Patients at risk Time (months) 19 Gonzalez-Martin A, et al. Int J Gynecol Cancer 212;22(Suppl. 3): E98 and oral presentation

29 B Diagnosis Diagnosisof ofstage StageIIIC-IV IC-IV EOC/PPC/FTC EOC/PPC/FTC Immediate Primary SurgerySurgery (IPS) and(ips) residual >1cm Immediate Primary Delayed Primary Surgery (planned) Randomise 1:1:1 Arm 11 Arm cycles 66 cycles Arm 2 6 cycles Randomise 1:1:1 Arm 3 6 cycles Arm 1 * 3 cycles Arm 2 3 cycles Arm 3* 3 cycles Cycle 3d15 PTX omitted Delayed Primary Surgery (DPS) Arm 1* 3 cycles Arm 2 3 cycles Arm 3* 3 cycles *- Bevacizumab omitted from cycles 3 and 4 Bevacizumab maintenance to continue for maximum of 16 cycles in arms 1 and 3

30 Anti-VEGFR: Anti-angiogenic therapy in ovarian cancer Drug VEGFR PDGFR FGR C-kit Other Pazopanib 1,2,3 α, β 1,3 Cediranib 1,2,3 α, β 1 Nintedanib (BIBF 112) 1,2,3 α, β 1,2,3 Sorafenib 2,3 β Ras/Raf Flt-3 Sunitinib 2 β RET Flt-3 Cabozantinib (XL-184) 2 RET MET Src, Flt-3

31 Randomised Clinical Trials With VEGFR-TKIs Agent Outline Sorafenib Pazopanib Pharma/ OVAR16 Nintedanib (BIBF112) Pharma/ AGO-OVAR12 Cediranib ICON6 (GCIG study) Maintenance after carbo/pax Maintenance only To 2 years after carbo/pax Concurrent with C/pax, then 2 years Platinum-based to progression/18 months Primary Line of Therapy Endpoint First Line Therapy 2 arm Phase II Status HR =1.9 PFS (95% CI.72, 1.63) p=.665 Med PFS 12.7 v 15.7 months First line 2-arm Placebo controlled First line 2-arm Placebo controlled Recurrent 3-arm Placebo controlled PFS ASCO 213 PFS ESGO 213 PFS and OS ECCO-ESMO 213

32 AGO-OVAR 16 Study Design Phase III randomized, placebo-controlled, double-blind, multicenter N=94 patients randomized (1:1) from June 29 to August 21 Pazopanib administered at 8 mg daily for up to 24 months* First-line surgery and chemotherapy (allowed: dosedense, IP, neoadjuvant) If not PD + tumor < 2 cm R A N D O M I Z E Pazopanib 24 months Observation (to PD) Placebo 24 months Survival follow-up (post-pd) Median 7 months from ICF diagnosis to randomization *Original design was for 12 months and later amended to 24 months Presented by: Andreas du Bois on behalf of the AGO led Intergroup consortium

33 AGO-OVAR 16 1st Endpoint: Progression-free Survival (RECIST) Median time from 1 Diagnosis: 7 months Pazopanib: 472 pts. / 237 events median 17.9 ( ) mos Placebo: 468 pts. / 273 events median 12.3 ( ) mos Δ= 5.6 months.5 HR =.766 (95% CI: ) Stratified log-rank test: P =.21 Patients at risk (months) Presented by: Andreas du Bois on behalf of the AGO led Intergroup consortium

34 AGO-OVAR 16 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 Hypertension 26 (6%) 147 (31%) 121 (25%) Hypertension (including Grade 2) 8 (17%) 248 (52%) 168 (35%) Liver-related toxicity 3 (<1%) 45 (9%) 42 (9%) Neutropenia 7 (2%) 47 (1%) 4 (8%) Diarrhea 5 (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 pain 5 (1%) 8 (2%) 3 (<1%) Proteinuria 2 (<1%) 6 (1%) 4 (<1%) Arthralgia 3 (<1%) 5 (1%) 2 (<1%) Presented by: Andreas du Bois on behalf of the AGO led Intergroup consortium

35 Study schema Relapse > 6 months after completion of first line platinum-based chemotherapy ICON6: Cediranib with platinum-based chemotherapy in platinum-sensitive relapsed ovarian cancer Randomise 2:3:3 6 Cycles platinum-based Chemotherapy Carboplatin/paclitaxel Carboplatin/gemcitabine Single agent platinum Maintenance phase Ledermann et al 213 Eur Cancer Conf Arm A (Chemo only) Arm B (Concurrent) Arm C (Maintenance) Chemotherapy + placebo Chemotherapy + cediranib Chemotherapy + cediranib Continue placebo Switch to placebo Maintenance cediranib Treatment continued to 18 months or until progression (>18 for patients continuing to benefit)

36 Progression-free survival arms A vs. C 1. Maintenance PFS events, n (%) Chemo. Maint. 112 (94.9) 139 (84.8) Median, months Chemotherapy.75 Log-rank test p=.1 HR (95% CI).57 (.45.74) Test for non-proportionality p=.24 Restricted means, months Restricted mean survival time increases by 3.1 months with maintenance treatment Months Chemo. 118 Maint Ledermann et al 213 Eur Cancer Conf

37 Overall survival Maintenance 1. Restricted mean survival time increases by 2.7 months with maintenance treatment (over two years) Chemotherapy.75 Chemo. Maint. OS events, n (%) 63 (53.3) 75 (45.7) Median, months Log-rank test p=.42 HR (95% CI).7 (.51.99) Test for non-proportionality p=.42. Restricted means, months Months. Chemo. 118 Maint Ledermann et al 213 Eur Cancer Conf

38 Angiopoietin Axis Ang1 and Ang2 Interact With Tie2 Receptor to Mediate Vascular Remodeling Trebananib (AMG 386) Peptide-Fc fusion (Peptibody) that binds and neutralizes Ang1 and Ang2 Single-agent activity in relapsed ovarian cancer in a phase 1 study1 Prolongation of PFS in a randomized phase 2 study in combination with paclitaxel in recurrent ovarian cancer2 1. Herbst RS, et al. J Clin Oncol. 29;27: Karlan BY, et al. J Clin Oncol. 212;3:

39 TRINOVA-1 Trial Design Recurrent EOC 3 prior anticancer regimens Evaluable or measurable disease R GOG Performance Status of or 1 1:1 Weekly Paclitaxel + Placebo Treat to PD/toxicity Weekly Paclitaxel + Trebananib Treat to PD/toxicity PFI < 12 months Paclitaxel 8 mg/m2 IV on days 1, 8, 15 Q4W Trebananib 15 mg/kg IV QW Stratification factors ClinicalTrials.gov Identifier: NCT Platinum-free interval (PFI) ( 6 vs. > 6 months) Measurable disease (Yes/No) Region (North America, Western Europe/Australia, Rest of World) EOC = epithelial ovarian cancer including primary peritoneal, or fallopian tube cancer; PD = progressive disease Presented by Monk BJ at European Cancer Congress European Journal of Cancer 49; suppl 3, Sept 213 LBA 41

40 Progression-free Survival (Primary Analysis) Events, n (%) 1. Pac + Trebananib (n = 461) 361 (79) 31 (67) Median PFS, months.9 HR =.66 (95% CI,.57.77) P (stratified log rank) <.1.8 Event-free Probability Pac + Placebo (n = 458) Study Month Patients at risk: Presented by Monk BJ at European Cancer Congress European Journal of Cancer 49; suppl 3, Sept 213 LBA

41 TRINOVA-1 Partial Plat sensitive or Resistant Weekly paclitaxel + AMG 386 1:1 Primary endpoint: PFS N=9 1:2 TRINOVA-3 First line OC, PPC, TC Primary endpoint: PFS N=2 TRINOVA-2 PLD+ placebo Partial Plat sensitive or Resistant PLD + AMG 386 1:1 Primary endpoint: PFS N=38 Paclitaxel-carbo + placebo Paclitaxel-carbo + AMG 386 Placebo 18 months AMG months Until progression Weekly paclitaxel + placebo Until progression TRINOVA programme with AMG 386 (trebananib)

42 Anti-angiogenic targeted therapy for First-line treatment Significant increase in PFS with bevacizumab How long should bevacizumab be given? BOOST trial compares 15 v 3 months VEGFR TKI similar results with pazopanib and nintedanib expected this year. Which to choose? Which patients? Poorer prognosis - residual disease/ stage IV- survival benefit in ICON 7 What dose? 7.5 mg/kg as effective as 15 mg/kg Should therapy be incorporated with dose dense chemotherapy? Better first line or later line?: trade off between PFS increase and adverse QoL

43 Anti-angiogenic targeted therapy for First-line treatment Significant increase in PFS with bevacizumab How long should bevacizumab be given? BOOST trial compares 15 v 3 months VEGFR TKI similar results with pazopanib and nintedanib expected this year. Which to choose? Which patients? Poorer prognosis - residual disease/ stage IV- survival benefit in ICON 7 What dose? 7.5 mg/kg as effective as 15 mg/kg Should therapy be incorporated with dose dense chemotherapy? Better first line or later line?: trade off between PFS increase and adverse QoL

44 Poly(ADP-ribose) polymerase A key regulator of DNA damage repair processes Involved in DNA base-excision repair (BER) Binds directly to DNA damage Produces large branched chains of poly(adp-ribose) Attracts and assists BER repair effectors XRCC1 PNK padpr padpr,, poly(adp-ribose) Lig3 Polß

45 PARP inhibitor: Olaparib (AZD 2281) DNA SSBs occur all the time in cells and PARP detects and repairs them During the replication process unrepaired SSBs are converted into DSBs Normal cell Repair by Homologous Recombination Survival PARP Olaparib Replicating cells Cancer cell with HRD Tumour specific killing by Olaparib No effective repair (No HR pathway) Cell death

46 Olaparib: An orally active PARP inhibitor Olaparib Phase I and BRCA mutation expansion 1,2 studies Olaparib multicentre Phase II BRCA mutation ovarian cancer study3 Olaparib dose 2 mg bid 4 mg bid RECIST CR/PR 14/5 (28%) 11/33 (33%) 3/5 (6%) 12/33 (36%) 17/5 (34%) 23/33 (69%) 7. months 9.5 months SD 4 months Overall Median duration of response Most common toxicities: CTCAE grade 1 and 2 nausea and fatigue 1. Fong PC, et al. N Engl J Med 29;361:123 34; 2. Fong PC, et al. J Clin Oncol 21;28:2512 9; 3. Audeh MW, et al. Lancet 21;376:245 51

47 Best change from baseline in size of target lesion (%) Olaparib in BRCA and non-brca ovarian cancer patients Ovarian BRCA Ovarian non-brca Best change from baseline in size of target lesion (%) BRCA, platinum resistant or refractory Gelmon KA, et al. Lancet Oncol 211;12: BRCA, platinum sensitive Non-BRCA, platinum resistant or refractory Non-BRCA, platinum sensitive

48 Potential of PARP inhibitors in sporadic ovarian cancer BRCA1 germline 8% BRCA2 germline 6% BRCA1 somatic 3% Other 34% BRCA2 somatic 3% BRCA1 methylation 11% MMR germline 2% CCNE1 amplification 15% Not HR deficient Levine D. The Cancer Genome Atlas, Molecular profiling of serous ovarian cancer, 211 Other HRD 7% PTEN loss 5% EMSY amplification 6% Homologous recombination (HR) deficient

49 Study 19: olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer Study aim and design Patients: Platinum-sensitive high-grade serous ovarian cancer 2 previous platinum regimens Last chemotherapy was platinum-based to which they had a maintained PR or CR prior to enrolment Stable CA patients Olaparib 4 mg po bid Randomised 1:1 Placebo po bid Treatment until disease progression Primary end point: PFS Total of 265 recruited: 64% BRCA unknown 22% BRCA positive 14% BRCA negative Ledermann et al. N Engl J Med 212

50 Study 19: PFS in total population Patients were randomised after response to platinum-based chemotherapy Probability of progression-free free survival Median PFS, months.5.4 Olaparib Placebo HR.35 (95% CI.25,.49); P<.1.3 Randomised treatment* Placebo (n=129) Olaparib 4 mg bid monotherapy (n=136).2.1 Primary analysis (58% maturity; n=154/265) Time from randomisation (months) Interim OS analysis (38% maturity): HR.94 (95% CI.63, 1.39); P=.75 *Patients were treated until disease progression Ledermann et al. N Engl J Med 212

51 Study 19: PFS by BRCAm status The number of patients with a known BRCAm status increased from 97 (36.6%) to 254 (95.8%) out of (51.3%) patients had a known deleterious BRCAm Events: total patients (%) Median PFS, months 1. Proportion of patients progression-free.9.8 BRCAm (n=136) Olaparib Placebo 26:74 (35.1) 46:62 (74.2) HR.18 (95% CI.11,.31); P< Olaparib BRCAm.2 Placebo BRCAm Time from randomisation (months) Number at risk Olaparib BRCAm Placebo BRCAm Ledermann et al. ASCO 213

52 Proportion of patients progression progressionfree PFS in BRCA wt 1. BRCAwt (n=118) Olaparib Placebo Events: total pts (%) 32:57 (56.1) 44:61 (72.1) Median PFS, months HR=.53 95% CI (.33,.84); P= Olaparib BRCAwt.1 Placebo BRCAwt Time from randomization (months) Number at risk Olaparib BRCAwt Placebo BRCAwt BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance) Ledermann et al. ASCO 213

53 Study 19: OS in BRCAm patients BRCAm (n=136) Proportion of patients alive 1..9 Deaths: total patients (%).8 Median OS, months 37:74 (5.) 34:62 (54.8) HR.73 (95% CI.45, 1.17); P= Randomised treatment Olaparib BCRAm Placebo BRCAm Olaparib BRCAm Placebo BRCAm Time from randomisation (months) Number at risk OS in BRCAwt patients: HR.99 (95% CI.63, 1.55); P=.957 Placebo.7 Olaparib Median OS: olaparib, 24.5 months; placebo, 26.2 months 14/62 (22.6%) placebo patients switched to a PARP inhibitor Ledermann et al. ASCO 213

54 Phase III trials with PARP inhibitors Recruiting: SOLO 1 and SOLO 2 (olaparib) Randomised maintenance trials in first-line and platinum-sensitive recurrent BRCAm ovarian cancer NOVA (niraparib) Randomised maintenance trial following platinum-based chemotherapy in BRCAm and BRCAwt high-grade serous cancer Planned: ARIEL 3 (rucaparib) Randomised maintenance trial following platinum-based chemotherapy in BRCAm and BRCAwt high-grade serous cancer with companion diagnostic

55 The Future Anti-angiogenic agents and PARP inhibitors likely to change practice in treating ovarian cancer Selecting the right drug for the appropriate phase of disease will be challenging Absence of predictive markers is a major obstacle to the efficient identification of patients likely to benefit from precision medicine

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