Management of BRCA mutated ovarian cancer

Transcription

1 Management of BRCA mutated ovarian cancer Jonathan A Ledermann UCL Cancer Institute University College London, UK

2 BRCA mutations BRCA mutated ovarian cancer Epidemiology PARP inhibitors in BRCA mutated ovarian cancer Clinical Activity of PARP inhibitors in ovarian cancer PARP inhibitors beyond BRCA mutated ovarian cancer Indications for use of PARP inhibitor in ovarian cancer Future strategies for the development of PARP inhibitors

3 BRCA mutations and ovarian cancer Germline mutations of BRCA1 or BRCA2, cancer susceptibility genes, are inherited as an autosomal dominant gene leading to a life-time risk of ovarian cancer 11-40% Deletion of normal allele leads to cancer susceptibility through loss of function of homologous DNA repair, genomic stability, translational regulation, protein ubiquitination, chromatin remodelling and cell cycle control A mutation is found in approximately 1 in 400 of the population but it is much higher in certain ethnic groups (e.g. Ashkenazi Jews - 1 in 40) Epidemiological data estimate that a BRCA mutation is found in about 17% women with high grade ovarian/fallopian tube/ peritoneal cancers

4 Survival (%) Clinical phenotype of BRCA mutated ovarian cancer Pooled analysis, 26 observational studies, 1213 EOC patients with germline BRCA1 (n=909) or BRCA2 (n=304) mutations, and 2666 non-carriers Carriers BRCA2 BRCA1 Noncarriers Phenotypic features of BRCAmut ovarian cancer Platinum-sensitive Often responds to multiple rounds of chemotherapy Years from diagnosis BRCA BRCA Noncarriers Survival better than in non carriers Adapted and redrawn from: Bolton KL et al. JAMA 2012;307:

5 PARP inhibitors - Mode of action A key regulator of DNA damage repair processes Involved in DNA baseexcision repair (BER) Binds directly to DNA damage Produces large branched chains of poly(adp-ribose) Attracts and assists BER repair effectors Illustration courtesy of AstraZeneca

6 Increased sensitivity of BRCA1 -/- and BRCA2 -/- cells to PARP (poly ADP ribose polymerase) inhibition BRCA1 +/+ BRCA1 +/- BRCA2 +/+ BRCA2 +/- BRCA1 -/- BRCA2 -/- No difference in sensitivity between heterozygous and wild-type BRCA cells Farmer H et al. Nature 2005; 434: Reprinted by permission from Macmillan Publishers Ltd: Nature, copyright 2005.

7 PARP inhibitor and homologous recombination repair DNA SSBs occur all the time in cells and PARP detects and repairs them PARP During the replication process unrepaired SSBs are converted into DSBs Replicating cells Normal cell Cancer cell with HRD Repair by homologous recombination Survival Tumour specific killing by No effective repair (No HR pathway) Cell death Courtesy of Andrew Tutt

8 : An orally active PARP inhibitor Phase I and BRCA mutation expansion studies 1,2 phase II BRCA phase II BRCA dose 200 mg bid 400 mg bid 100 mg bid RECIST CR/PR 14/50 (28%) 11/33 ( 33%) 3/24 ( 13%) SD Median duration of response 3/50 (6%) ( 4 months) 12/33 ( 36%) (8 weeks) 14/24 (58%) (8 weeks) ~214 d 290 d 269 d 1. Fong PC et al. N Engl J Med 2009;361: ; 2. Fong PC et al. J Clin Oncol 2010;28: Audeh MW et al. Lancet 2010;376:

9 Development strategies for PARP inhibitors in ovarian cancer How do PARP inhibitors compare with chemotherapy? Will PARP inhibitors have additive effects to chemotherapy? Maintenance therapy with PARP inhibitors

10 Comparison of olaparib with Pegylated Liposomal Doxorubicin (PLD) Relapsed BRCAm ovarian cancer ( progression 12 months post platinum) Compare efficacy of two dose levels olaparib with pegylated liposomal doxorubicin (PLD) Primary endpoint PFS 200 mg bid Investigator choice of therapy 97 patients randomised 400 mg bid Investigator choice of therapy PLD 50 mg/m 2 every 4 weeks Investigator choice of therapy May receive olaparib 400 mg PFS (primary endpoint) Follow up for OS Kaye SB et al. J Clin Oncol 2012;30:

11 Proportion of patients progression-free STUDY 12: Progression-free survival Time from randomisation (months) Number of patients at risk 400 mg: mg: PLD CI, confidence interval; HR, hazard ratio. HR 80% CI p-value 200 mg vs PLD , mg vs PLD , Events 200 mg 400 mg PLD Median PFS 6.5 months 8.8 months 7.1 months 12 Adapted and redrawn from: Kaye SB et al. J Clin Oncol 2012;30:

12 Study 12 Conclusions The efficacy of olaparib (400 mg bd) was as predicted, with a response (RECIST/CA125 ) in 59% The median PFS was 8.8 months PLD was more effective than anticipated: Response 39% Median PFS 7.1 month Both doses of olaparib were well tolerated with <10% discontinuation rate. No significant difference in HRQoL although a higher improvement rate was seen with olaparib 400 mg bd compared with PLD Conclusions: No significant difference in primary end-point but olaparib performed as well as PLD

13 Randomised phase II study of carboplatin/ paclitaxel ± olaparib in platinum-sensitive recurrent ovarian cancer: Study 41 Patients non selected for BRCAm Adjustments to both carboplatin dose and olaparib (dose and duration) during chemotherapy phase due to myelotoxicity Maintenance was open label with observation in the control arm n=162 Platinum-sensitive Serous histology Measurable disease 3 previous platinum-containing regimens n=81 Randomisation (1:1) n= mg bid* (days 1 10 every 21 days) + paclitaxel 175 mg/m 2 (iv, day 1) + carboplatin AUC 4 (iv, day 1) For 6 x 21-day cycles Paclitaxel 175 mg/m 2 (iv, day 1) + carboplatin AUC 6 (iv day 1) For 6 x 21-day cycles n=66 n=55 Maintenance phase 400 mg bid continuously No further study treatment Primary endpoint: PFS by central review (RECIST 1.1) Secondary endpoints: OS ORR Safety Oza AM et al. Lancet Oncol. 2015;16:87 97 Multinational study: 43 sites in 12 countries

14 Proportion of patients progression free Study 41: Progression-free survival P + C (AUC4) P + C (AUC6) Events: Total patients (%) O + P + C 47:81 (58.0) Time from randomisation (months) Number of patients at risk O + P + C P + C P + C 55:81 (67.9) Median (months) Hazard ratio = % CI (0.34, 0.77) p= Oza AM et al. J Clin Oncol 2012; 30(suppl):5001

15 Study 41: Conclusions No evidence of an additive effect of olaparib on carboplatin and paclitaxel Dose reductions of both drugs needed Retrospective testing for BRCAm identified 38% positive PFS Hazard ratio for BRCAm population was 0.21 (95% CI ; p=0.0015) Benefit of olaparib appeared during the maintenance phase Statistically significant improvement in median progression-free survival from 9.6 to 12.2 months

16 Best change from baseline in size of target lesion (%) Best change from baseline in size of target lesion (%) in BRCA and non-brca ovarian cancer Activity of PARP inhibitors in non BRCA mutated ovarian cancer Ovarian BRCA Ovarian non-brca BRCA, platinum resistant or refractory BRCA, platinum sensitive Non-BRCA, platinum resistant or refractory Non-BRCA, platinum sensitive Reprinted from The Lancet Oncol, 12, Gelmon KA et al, in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study, , Copyright (2011), with permission from Elsevier

17 The Cancer Genome Atlas (TCGA) Project in high grade serous ovarian cancer Other 34% MMR germline 2% CCNE1 amplification 15% Not HR deficient BRCA1 germline 8% BRCA2 germline 6% BRCA1 somatic 3% BRCA2 somatic 3% BRCA1 methylation 11% EMSY amplification 6% PTEN loss 5% Other HRD 7% Homologous recombination (HR) deficient The Homologous Recombination Deficient phenotype extends beyond germline BRCA mutation up to 50 % of high grade serous ovarian cancers Is olaparib active in a broad population of high-grade serous ovarian cancer? How should this be assessed in a clinical trial in patients with platinum-sensitive disease? Courtesy of Levine D. The Cancer Genome Atlas, Molecular profiling of serous ovarian cancer, 2011

18 Design of a randomised maintenance trial End of therapy for relapse Restart chemotherapy for clinical progression Placebo PARP inhibitor (olaparib) PFS and restart chemotherapy

19 Randomised trial of maintenance olaparib in platinum-sensitive high-grade serous relapsed ovarian cancer study 19 Aim: To assess the efficacy and safety of oral olaparib as a maintenance treatment Design: Randomised, double-blind, placebo-controlled Phase II maintenance study 265 patients in 82 investigational sites in 16 countries 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 mg po bid Randomised 1:1 Placebo po bid Treatment until disease progression Sept 2008 Feb 2010 Primary end point: PFS Ledermann J et al. N Engl J Med 2012;366:

20 Patient characteristics 400 mg bid (n=136) Placebo (n=129) Median age, years (range) 58 (21 89) 59 (33 84) Prior chemotherapy regimens Median (range) 3 (0 11)* 3 (2 8) TTP on penultimate platinum regimen, n (%) >6 12 months >12 months Objective response to last platinum, n (%) CR PR BRCA mutation status, n (%)* BRCA1 BRCA2 BRCA1 & BRCA2 Known negative Unknown 53 (39) 83 (61) 57 (42) 79 (58) 25 (18) 6 (4) 0 18 (13) 87 (64) 54 (42) 75 (58) 63 (49) 66 (51) 20 (16) 7 (5) 1 (1) 20 (16) 81 (63) Ledermann J et al. N Engl J Med 2012;366:

21 Proportion of patients progression free Progression-free survival in Study 19 trial Placebo Placebo Events/total patients (%) 60/136 (44.1) 93/129 (72.1) Median PFS, months HR=0.35 (95% CI: 0.25, 0.49) P< After 153 progression events 0.5 (57.7% of patients) the study 0.4 met its primary endpoint of a statistically significant PFS 0.3 benefit in the overall study 0.2 Randomised treatment population 0.1 Placebo 400 mg bid At risk (n) Time from randomisation (months) CI, confidence interval; HR, hazard ratio. From: New Engl J Med, Lederman J et al, Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer, Volume 366., Page No Copyright (2012) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

22 Interim overall survival and subgroup analysis Interim OS analysis (38% maturity): HR=0.94; 95% CI ; P=0.75 BRCA1/2 mutation (BRCAm) status was not required for study entry, but was known for 97/265 patients (36.6%) Overall BRCAm positive BRCAm negative BRCAm status unknown 400 mg bid Placebo 52/136 (38%) 49/129 (38%) 8/31 (26%) 12/28 (43%) 11/18 (61%) 5/20 (25%) 33/87 (38%) 32/81 (40%) HR (olaparib:placebo) and 95% CIs Favours olaparib Size of circle is proportional to number of events Blue band represents 95% CI for overall population Hypothesis: maintenance therapy may lead to a greater PFS and OS benefit vs. placebo in patients with a known BRCAm *Subgroup analysis pre-specified in study protocol. OS, overall survival. Ledermann J et al. N Engl J Med 2012;366: ; AstraZeneca data on file

23 Proportion of patients progression-free Study 19: Progression-free survival in patients with BRCAm ovarian cancer 136 (51.3%) patients had a known deleterious BRCAm (BRCAm dataset) 118 (44.5%) patients were defined as BRCA1/2 wild type for this analysis 11 (4.2%) patients had neither a tumour nor a germline result available Patients with a known BRCAm status increased from 98 (37%) to 254 (95.8%) out of 265 Number at risk BRCAm Placebo BRCAm BRCAm Placebo BRCAm Events/total patients (%) Median PFS, months (95% CI) Time from randomisation (months) BRCAm (n=136) 26/74 (35%) 11.2 (8.3, NC) NC, not calculable. Placebo 46/62 (74%) 4.3 (3.0, 5.4) HR= % CI: 0.10, 0.31; P< Reprinted from Lancet Oncol, 15/8, Lederman J et al, 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, Pages No , Copyright (2014), with permission from Elsevier

24 Proportion of patients progression-free Study 19: Progression-free survival by mutation status Number at risk BRCAm Placebo BRCAm BRCAwt Placebo BRCAwt BRCAm Placebo BRCAm BRCAwt Placebo BRCAwt Events/total patients (%) Median PFS, months (95% CI) BRCAm (n=136) BRCAwt (n=118) Placebo Placebo 26/74 (35%) 11.2 (8.3, NC) 46/62 (74%) 4.3 (3.0, 5.4) HR= % CI: 0.10, 0.31; P< Time from randomisation (months) /57 (56.%) 7.4 (5.5, 10.3) 44/61 (72%) 5.5 (3.7, 5.6) HR= % CI: 0.34, 0.85; P= Reprinted from Lancet Oncol, 15/8, Lederman J et al, 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, Pages No , Copyright (2014), with permission from Elsevier

25 Proportion of patients alive Study 19: Updated survival in BRCAm population (52% maturity) BRCAm (n=136) Placebo Number at risk BRCAm Placebo BRCAm BRCAm Placebo BRCAm Deaths/total patients (%) Median OS, months (95% CI) Time from randomisation (months) /74 (50%) 34.9 (29.2, NC) 34/62 (55%) 31.9 (23.1, 40.7) HR= % CI: 0.45, 1.17 P=0.19 Reprinted from Lancet Oncol, 15/8, Lederman J et al, 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, Pages No , Copyright (2014), with permission from Elsevier

26 Time to further therapy- a new exploratory endpoint TSST (time from randomisation to second subsequent therapy or death) PFS2 (time from randomisation to second objective disease progression or death)* Progression Intermediate clinical endpoints maintenance monotherapy PFS TFST PFS2 TSST OS Chemo Chemo First subsequent treatment response Progression Progression All patients who received treatment were included in exploratory endpoint analyses *PFS2 is a surrogate for TSST Ledermann J et al. Lancet Oncol 2014;15:

27 Not on first subsequent therapy (%) 100 Number at risk Placebo Placebo STUDY 19: Time to first subsequent therapy (TFST) in patients with BRCA mut ovarian cancer Events/total patients (%) Median TFST, months (95% CI) Time from randomisation (months) /74 (62%) 15.6 (12.3, 28.2) Placebo TFST was significantly improved in the olaparib group vs. placebo in the overall population, irrespective of BRCA mutation status (BRCAm group data shown here) 54/62 (87%) 6.2 (5.3, 9.2) HR=0.33 (95% CI: 0.22, 0.50); P< Reprinted from Lancet Oncol, 15/8, Lederman J et al, 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, Pages No , Copyright (2014), with permission from Elsevier

28 Proportion of patients receiving study treatment or first subsequent therapy Number at risk BRCAm Placebo BRCAm 0 Placebo Study 19: Time to second subsequent therapy (TSST) in patients with BRCA mut ovarian cancer Time from randomisation (months) BRCAm (n=136) Placebo Events/total patients (%) 42/74 (57%) 49/62 (79%) Median TSST, months (95%CI) 23.8 (17.7, NC) 15.2 (13.9, 18.7) HR= % CI: 0.29, 0.67; P< TSST is a surrogate for PFS2 Reprinted from Lancet Oncol, 15/8, Lederman J et al, 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, Pages No , Copyright (2014), with permission from Elsevier

29 Proportion of patients not on second subsequent therapy Time to second subsequent therapy (TSST) in BRCA wt patients Number at risk BRCAwt Placebo BRCAwt Randomised treatment BRCAwt Placebo BRCAwt Time from randomisation (months) BRCAwt (n=118) Placebo Events: total pts (%) 42:57 (73.7) 55:61 (90.2) Median TSST, months HR % CI (0.42, 0.96) P=0.033 BRCAwt, wild-type (includes patients with no known BRCAm or a variant of unknown significance); Patients were treated until disease progression Reprinted from Lancet Oncol, 15/8, Lederman J et al, 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, Pages No , Copyright (2014), with permission from Elsevier

30 Overview of efficacy analyses in patients with a BRCA1/2 mutation PFS month difference 11.2 HR: 0.18 (95% CI 0.10, 0.31), P< Primary endpoint TFST (Exploratory) TSST (Exploratory) month difference 15.6 HR: 0.33 (95% CI 0.22, 0.50), nominal P< month difference 23.8 Placebo 400 mg bid HR: 0.44 (95% CI 0.29, 0.67), nominal P= OS month difference 34.9 HR: 0.73 (95% CI 0.45, 1.71), P= Month 35 Chemo Maintenance treatment Chemo Chemo TFST, time from randomisation to first subsequent therapy or death; TSST, time from randomisation to second subsequent therapy or death Ledermann J et al. Lancet Oncol 2014;15: (Supplementary Appendix, p 5)

31 Evaluation of toxicity of long-term therapy with PARP inhibitors CTCAE toxicity grading Short term Long-term Dose reductions Dose discontinuation due to AEs Health-related Quality of Life

32 STUDY 19: Tolerability profile in maintenance treatment Adverse events (%) (N=136) Overall Placebo (N=128) (N=74) BRCAm Placebo (N=62) Any AE 132 (97%) 119 (93%) 72 (97%) 58 (94%) Any AE Grade 3 55 (40%) 28 (22%) 28 (38%) 11 (18%) Any serious AE 25 (18%) 11 (9%) 11 (21%)* 3 (7%)* Any AE leading to discontinuation 7 (5%) 2 (2%) 5 (9%)* 0* Any AE leading to death 2 (1%) 0 1 (2%)* 0* Ledermann J et al. Lancet Oncol 2014;15: ; AstraZeneca data *Data cut off: 26 November 2012., N=53; Placebo, N=43. Ledermann J et al. Lancet Oncol 2014;15: ; AstraZeneca data on file

33 STUDY 19: Safety profile in BRCAm population BRCAm (N=96) Preferred term (%) (N=74) All grades Placebo (N=62) Nausea 54 (73%) 20 (32%) Fatigue 40 (54%) 23 (37%) Vomiting 27 (36%) 5 (8%) Diarrhoea 22 (30%) 12 (19%) Abdominal pain 17 (23%) 18 (29%) Anaemia 19 (26%) 3 (5%) Constipation 14 (19%) 7 (11%) Decreased appetite 14 (19%) 6 (10%) Abdominal pain upper 14 (19%) 4 (6%) (N=74) Grade 3 Placebo (N=62) 1 (1%) 0 5 (7%) 1 (2%) 2 (3%) 0 2 (3%) 1 (2%) 0 2 (3%) 4 (5%) 1 (2%) Toxicity of BRCAm population consistent with the overall population Ledermann J et al. Lancet Oncol 2014;15:

34 Rare complications of olaparib Important identified risks Myelodysplasia/acute myeloid leukaemia Rare 0.76% patients monotherapy, all had prior chemotherapy Pneumonitis Rare 0.5% patients, no clinical pattern New primary malignancies Rare 0.9% 10/19 were non-melanoma skin cancer All had prior chemotherapy

35 LSM and 95% CI LSM and 95% CI Quality of Life during treatment Placebo Overall population Patients with BRCAm (MMRM analysis) Placebo Placebo 1 Time point (months) HRQoL, as measured by Treatment Outcome Index. TOI, a component of FACTO-O was similar for olaparib and placebo and remained consistent over time Not measured beyond progression Compliance 85% but fell in the placebo group at 6 months due to progression (68%) Similar for BRCAm and all patients Ledermann J et al. ESMO, Madrid, Spain, 2014, poster 885PD Placebo Time point (months) LSM, least squares mean; MMRM, mixed model repeated measures.

36 Duration of treatment on Study 19 in BRCAm Group 25% Treated for 2 years 80% 70% 60% (N=53) Placebo (N=43) Median duration (months) 11.1 Placebo % 45% 40% 30% 25% 20% 17% 10% 9% 7% 5% 0% 1 year 2 years 3 years Data on file courtesy of ASTRA Zeneca BRCAm (N=96) Data cut off: 26 November 2012

37 Response in patients with a BRCA mut to subsequent treatment following a PARPi ORR (RECIST) ORR (RECIST+ CA125) Platinum-based 40% (n=48) 49% (n=53) Non-platinum 26 % (N=19) 36% (n=25) Pl-resistant Pl-partial sensitive Pl- sensitive ORR 36% (n=14) 62% (n=26) 38% (n=13) PFS (weeks) OS (weeks) All Platinum-rechallenge Ang JE et al. Clin Cancer Res 2013;19:

38 Landscape of PARP inhibitors in clinical development PARP inhibitor Company Target PARP Summary (AZD2281) AstraZeneca PARP1/2/3 Licensed in EU for maintenance BRCAm; 3 rd line (FDA) in BRCAm. Phase III trials with tablet formulation - 1 st line and recurrence (SOLO-1; SOLO-2) Rucaparib (AG ; CO-338) Clovis Oncology PARP1/2 Ongoing phase II studies and III studies in BRCAm, BRCAwt (ARIEL2; ARIEL3) Veliparib (ABT-888) Abbvie PARP1/2 1 st line phase III planned with chemotherapy Niraparib (MK4827) Tesaro PARP1/2 Ongoing phase III ( NOVA) maintenance in BRCAm and BRCAwt; plans for 1 st line Talazoparib (BMN-673) BioMarin Pharmaceutical PARP1/2 Ovarian cancer strategy unclear

39 Patient selection for treatment with PARP inhibitors - Identifying HRD in the non BRCAm For ovarian cancer: Repeated response to platinum-based chemotherapy Prolonged survival (>5 yrs) High grade serous histology Functional test for loss of HR (RAD 51 foci-formation) 1,2 Molecular signature (gene array) 3,4 1. Mukhopadhay A et al. Clin Cancer Res 2010;16(8): Graeser M et al. Clin Cancer Res 2010;16(24): Konstantinopoulos PA et al. J Clin Oncol 2010;28(22): Walsh T et al. Proc Natl Acad Sci U S A 2011;108:

40 Beyond BRCA-germ line mutations leading to HRD Proportions of patients germ-line loss-of-function mutations in BRCA1 (red); BRCA2 (blue); BARD1, BRIP1, CHEK2, MRE11, NBN, PALB2, RAD50, or RAD51C (green); MSH6 (purple); or p53 (yellow) Walsh T et al. Proc Natl Acad Sci U S A 2011;108: , Reprinted with permission from Proc Natl Acad Sci U S A

41 Homologous recombination deficiency HR genetic defects Other HR defects Mutations Homozygous deletions Gene expression mirna Methylation Defective HR protein Defective HR pathway expression HR deficiency Ovarian cancer Genomic scarring A large proportion of HGSOC has genomic Loss of Heterozygosity (LOH) 3 The majority of, but not all, BRCA1/2 mutant tumours exhibit high genomic LOH Swisher EM et al. J Clin Oncol 2014(suppl; abstr TPS5619);32:5s ASCO 2014 abstract

42 HRD causes genome-wide loss of heterozygosity (LOH) that can be measured by comprehensive genomic profiling based on NGS BRCA mut BRCA wt BRCA wt Chromosome No. mut=mutation; NGS=next-generation sequencing; wt=wild type. Hypothesis 1: Ovarian cancer patients with high genomic LOH suggesting BRCA-like signature will respond to PARPi. Hypothesis 2: Ovarian cancer patients who are biomarker negative (ie, with low genomic LOH) will not respond to PARPi. Swisher EM et al. Eur J Cancer 2014;50(suppl. 6):73 [abstract from 26th EORTC-NCI-AACR Symposium on Molecular Targeted therapy]

43 HRD biomarker- BRCA-like based on genomic scarring. Response to rucaparib Clinical activity observed in BRCAwt patients with BRCA-like signature (n=25) 32% ORR (RECIST) 40% ORR (RECIST & CA-125) 52% of patients continuing on treatment (+) Few responses observed in BRCAwt patients without BRCA-like signature (n=13) 8% ORR (RECIST) 8% ORR (RECIST & CA-125) 38% of patients continuing on treatment (+) +=ongoing. Swisher EM et al. Eur J Cancer 2014;50(suppl. 6):73 [abstract from 26th EORTC-NCI-AACR Symposium on Molecular Targeted therapy]

44 Combining PARP inhibitors with anti-angiogenic agents Preclinical data suggest a synergy between PARP inhibitors and anti-angiogenic drugs Phase 2 open-label randomised study Platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer ± cediranib continued to progression Platinumsensitive recurrent ovarian cancer capsules 400 mg BID Randomise 1:1 Cediranib 30 mg daily + capsules 200 mg BID Disease progression by RECIST v1.1 criteria Liu JF et al. Lancet Oncol 2014;15:

45 Figure 2 PFS: Cediranib and olaparib in platinum-sensitive ovarian cancer Ced/Olap PFS events Median PFS 9.0 mo 17.7 mo p=0.005 HR 0.42 (95% CI: ) Reprinted from Lancet Oncol, 15, Liu JF et al, Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study, Pages No , Copyright (2014), with permission from Elsevier

46 Figure 3 PFS: Cediranib/olaparib in BRCAm carriers PFS BRCA mutation carrier Cediranib/olaparib Events Median 16.5 mo 19.4 mo p=0.16 HR 0.55 (95% CI: ) PFS BRCA non-carrier/unknown Cediranib/olaparib Events 15 9 Median 5.7 mo 16.5 mo p=0.008 HR 0.32 (95% CI: ) Reprinted from Lancet Oncol, 15, Liu JF et al, Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study, Pages No , Copyright (2014), with permission from Elsevier

47 PARP inhibitors for routine care of BRCAmut ovarian cancer? Clear benefit in BRCAmut as maintenance post platinum for platinum-sensitive ovarian cancer Germline and somatic included in EMA licence Approval of olaparib as a single agent by FDA in patients who have received 3 or more prior lines of therapy Establishment of routine BRCA testing is needed but is not straightforward Testing of germline or tumour, or both and in which order?

48 Possible treatment pathways for maintenance olaparib First line chemotherapy Option 1 Option 2 Option 3 Bevacizumab 1 st platinum-sensitive relapse 2 nd platinum-sensitive relapse Platinum-resistant relapse Bevacizumab If PR/CR Bevacizumab If suitable

49 Single-agent activity of olaparib in platinum-resistant ovarian cancer with a BRCA mutation Reprinted with permission. (2014) American Society of Clinical Oncology Kaufman B et al. J Clin Oncol 2015;33:

50 for recurrent BRCA mut ovarian cancer Pooled analysis of 300 patients who received olaparib in 6 studies involving BRCA mut recurrent disease (273 with measurable disease) All but one study nonrandomised Data on a subgroup of 137 patients who received 3 lines of chemo presented to FDA for accelerated approval Response rate 34%; response duration 7.9 months Accelerated approval granted by the FDA in ovarian cancer with germline BRCA mut

51 Testing for BRCA mutations in women with ovarian cancer Frequency in high grade serous About 16-18% germ line BRCA mutations About 6-8% somatic BRCA mutations Frequency of germ line BRCA mutations in other types 7% endometrioid/clear cell Family history About 30-40% no family history Age at presentation About 25% patients with BRCA mutations are diagnosed >60 years Risch HA et al. J Natl Cancer Inst 2006;98: Walsh T et al. Proc Natl Acad Sci U S A 2011;108: Alsop K et al. J Clin Oncol 2012;30:

52 New pathways for testing Counselling and testing pathways vary throughout Europe. Historically referrals are made to cancer geneticists and the focus has been on identifying unaffected relatives, not for treatment decisions of a patient Testing should no longer be dependent on family history as this is unreliable New pathways are needed, either through gynaecological oncology, or by a modified genetics pathways, taking into consideration patient numbers and need for rapid assessment and testing Training of gynaecologists and oncologists in providing information and obtaining consent for germline BRCA testing is needed 6-8 % of patients have a somatic BRCA mutation- testing tumours for both somatic and germ line mutations should be considered, and it may become the most appropriate first phase of testing Patients who carry a germline mutation should be referred to cancer geneticists for family tracing, counselling and advance about prophylactic treatments for ovarian and breast cancer

53 Pathway of testing for BRCA mutations Diagnosis & first-line treatment 1 st platinum-sensitive relapse Knowledge of BRCA status allows for increased treatment choices 1. May decide to use bevacizumab first-line in BRCA negative patients 2. BRCA positive knowledge allows preparation for first recurrence if it occurs Post 1 st line Treatment 1. Allows patient to cope with all the physical and emotional issues of first line treatment before having to deal with a positive BRCA test 2. Decisions can be made about including bevacizumab in secondline setting 3. Applies currently to prevalent undiagnosed population During 2 nd line treatment 1. Should be done when patient is clearly responding. If response is poor patient may not need a test 2. Applies currently to prevalent undiagnosed population.

54 Future directions Combination studies: With chemotherapy: veliparib in first-line treatment (NRG/GOG) With bevacizumab maintenance in first-line therapy (PAOLA-1) Combinations of cediranib/olaparib in platinum-sensitive disease (primary or maintenance treatment [NRG/NCI; ICON 9 in development]) Establishing and validating HRD testing Platinum-resistant disease? Which drug? Which line of therapy?

55 THANK YOU!