PARP Inhibitors and DNA Damage Repair

Transcription

1 Breakthrough in Triple Negative Breast Cancer PARP Inhibitors and DNA Damage Repair Seock-Ah Im M.D. PhD. Department of Internal Medicine Seoul National University Hospital

2 Contents Introduction Hallmark of Cancer & DNA Damage Repair Action Mechanism of PARP inhibitor Synthetic Lethality gbrcamt PARP inhibitor Clinical Trials Early Clinical Trial Pivotal Randomized III Clinical Trials : OlympiAD & EMBRACA PARP inhibitor Combination Clinical Trials Challenges and Future Works Conclusion

3 Abnormal DNA repair An enabling Hallmark of Cancer Hanahan and Weinberg Cell March 211

4 DNA damage repair mechanism Non-homologous end joining Homologous Recombination Branzei,D & Foiani, M 28, Nature review

5 Homologous recombination-based DNA repair H2AX SSB PARPi Normal BRCA1/BRCA2 DNA replication fork arrest and collapse BRCA1/BRCA2 failure RAD51 HR-based repair Impaired HR repair Alternative error prone repair Chromosome Stability Cell Survival Chromosomal Instability Cell Death Farmer H et al. Nature 25;434: ; Bryant HE et al. Nature 25;434:

6 DNA damage responsive enzymes of poly (ADP-ribose) (PAR) metabolism PARP rapidly recognize DNA strand interruptions Binding to damaged DNA activates these PARPs to synthesize poly(adp-ribose) on themselves (auto modification) This results in the local relaxation of chromatin and the recruitment of DNA repair enzymes. PARG catalyzes poly(adp-ribose) degradation Poly(ADP-ribosyl)ated PARP-1 andparp-2 lose affinity for DNA, thus allowing access to repair proteins. Current Opinion in Cell Biology 18: , 26

7 Synthetic Lethality Gene A Gene B Cell survival Synthetic lethality arises when a combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes does not, and by itself is said to be viable +

8 Targeting BRCA for tumor selective killing

9 Targeting BRCA for tumor selective killing BRCA1 or BRCA2 Carrier Normal tissue BRCA1 or BRCA2 Carrier Tumor tissue DNA DAMAGE DNA DAMAGE HR NHEJ SSA BER NER etc x HR NHEJ SSA BER NER etc x x Tumor-specific lethality Tutt A et al. Cold Spring Harb Symp Quant Biol 25;7: ; McCabe N et al. Cancer Res 26;66:

10 Synthetic Sickness Combining rational chemotherapy with PARP inhibition Selective tumor cell killing Increased normal tissue toxicity Predicted Degree of PARP trapping of inhibitor may be relevant

11 9 PARP Inhibitors Riffell JL, et al. Nat Rev Drug Discovery 212

12 PARP Inhibitors and Status of Current Clinical trials Agent Olaparib AZD2281 Veliparib ABT888 First Trial (year) Company 25 AstraZeneca /Kudos Route oral Phase III in mbc gbrcamt, adj. gbrca 26 Abbott / Abbvie oral Phase III in neoadj. In combination with carboplatin & SOC in TNBC Phase III in gbrcamt mbc with CTx combination Iniparib BSI BiPar/ Sanofi-Aventis iv Phase III in TNBC in combination with Gem + Cisplatin Niraparib MK TESARO oral Phase III in gbrcamt mbc Phase II in gbrca intact mbc E Eisai oral Talazoparib BMN673 Rucaparib AG Medivation /Biomarin/Pfizer oral Phase III in mbc gbrcamt 23 Clovis iv (oral) Phase II in gbrcamt mbc and solid tumor Phase II adj. in TNBC or gbrcamt CEP-9722 TEVA Phase II in solid tumor

13 gbrca1 BRCA2 : Most important biomarker for PARP inhibitor Hereditary breast cancer hereditary breast ovarian cancer syndrome and BRCA1 deleterious mutation : 5% ~ 65%, triple-negative ovarian cancer ; 35%~46%

14 BRCA mutations are associated with increased risk for cancer Lifetime risk for breast and ovarian cancer is substantially increased among women harbouring mutations in BRCA1 or BRCA2 Lifetime risk for developing cancer General female population Women harbouring BRCA1 mutation Women harbouring BRCA2 mutation Breast 12.4% 1 65% 3 (95% CI 44-78) 45% 3 (95% CI 31-56) Ovarian 1.3% 2 39% 3 (95% CI 18-54) 11% 3 (95% CI ) CI=confidence interval 1. SEER Stat Fact Sheets: Breast cancer SEER Stat Fact Sheets: Ovary Cancer Balmaña J, et al. Ann Oncol 211;22(Suppl. 6):vi31 vi34

15 However, the overall prevalence of BRCAm in breast cancer is not well defined It has been estimated that approximately 7% of breast cancers are associated with gbrcam and additional 3% have sbrcam. 1 However, founder mutations in certain geographical locations do skew these data BRCAm and HR+ BC Estimated prevalence of BRCAm within mbc segments Based on Winter et al, While BRCAm are widely associated with TNBC, the clinical community are less likely to assess BRCAm in HR+ disease However, evidence suggest that HR+ patients account for at least half all BRCAm carriers: ~1 in 17 HR+ patients are gbrcam (~65% of BC gbrcam population) 1 the majority of these will be BRCA2 mutations 2,3 ~1 in 6 TNBC patients are gbrcam (3% of BC gbrcam population) 1 the majority of these will be BRCA1 mutations 4 Calculations based on Winter et al, 216 TNBC=triple negative breast cancer, HER=human epidermal growth factor, mbc=metastatic breast cancer 1. Winter et al. Ann Oncol. 216 Aug; 27(8): ; 2. Atchley DP et al. J Clin Oncol 28; 26: ; 3.Mavaddat N et al. Cancer Epidemiol Biomarkers Prev 212;21: ; 4. Couch FJ et al J Clin Oncol 33:34-311; 3.

16 BRCA1m are strongly associated with TNBC and BRCA2m with HR+/HER2- breast cancer Triple negative breast cancer is the predominant subtype in individuals with a germline BRCA1 mutation 1 The majority of breast cancers in individuals harbouring a germline BRCA2 mutation are HR+/HER2-2,4 6-8% of tumours in women carrying a BRCA1 mutation have a triple negative phenotype 3 >75% of breast cancers among women with BRCA2 mutations can be classified as luminal A or luminal B 2,5 Asian subgroup BRCA mutation prevalence in OlympiAD trial The prevalence of a deleterious or suspected deleterious BRCA mutation in patients with unknown BRCA status, who were screened for the study using a Myriad test, was 13.5% (121/895) in Asian patients, compared with 11.4% (11/888) in Caucasian patients and 1.4% (14/135) in other patients in OlympiAD trial. 1. Robertson L et al British Journal of Cancer (212) 16, ; 2. Atchley DP et al. J Clin Oncol 28; 26: ; 3. Couch FJ et al J Clin Oncol 33:34-311; 4. Mavaddat N et al. Cancer Epidemiol Biomarkers Prev 212;21: ; 5. Larsen MJ et al PLoS One. 213 May 21;8(5):e Im SA et al. SABCS 217 Abst P

17 Current gbrca test Insurance Reimbursement in Korea (since 212) BRCA(BReast CAncer Gene) Breast cancer or Ovarian cancer patients with close family member (relatives within the second degree) also have breast cancer or ovarian cancer Metachronous or Synchronous breast cancer and ovarian cancer in one patient Breast cancer diagnosed before age of 4 Bilateral breast cancer Male breast cancer Serous epithelial ovarian cancer BRCA1 Sequencing BRCA2 Sequencing BRCA1/2 sequencing of family members

18 NCCN Guidelines for Breast Cancer Genetic Assessment 18

19 Mean number of chromatid aberrations per cell Pre-clinical proof of concept PARP inhibition in BRCA deficient cells : Olaparib Log survivin g fraction-1 Increased levels of chromosomal aberrations in PARP inhibitor treated BRCA2 -/- cells Complex aberrations -3 Wild type BRCA2 +/- BRCA2 -/- 2 1 Chromatid breaks PARP inhibitor concentration (M) WT WT BRCA -/- + PARPi BRCA2 -/- + PARPi Olaparib (AZD2281; KU59436) Farmer et al, Bryant et al., Nature 25

20 Cell Cycle Arrest at the G2 Stage followed by apoptosis of BRCA1- or BRCA2-Deficient Cells after Treatment with KU58684 (Olaparib)

21 Proof of Concept for synthetic lethal targeting via PARPi first shown with Olaparib Phase I in gbrca1/2mutation carriers * Dose of olaparib : 1 mg daily for 2 of every 3 weeks to 6 mg twice daily continuously. Reversible dose-limiting toxicity (DLT) 1/8 pts receiving 4 mg twice daily (grade 3 mood alteration and fatigue) 2/5 pts receiving 6 mg twice daily (grade 4 thrombocytopenia and grade 3 somnolence). No obvious increase in AEs in the mutation carriers. Fong P. et al. N Engl J Med 29;361:123-34

22 Olaparib phase I : gbrca1/2 mt cohort olaparib 2 mg bid Antitumor Activity as Evidence of Synthetic Lethality 19 BRCA carriers had ovarian, breast, or prostate cancers. 12 of the 19 (63%) had a clinical benefit from treatment with olaparib, with radiologic or tumor-marker responses or meaningful disease stabilization (stable disease for a period of 4 months or more). Nine BRCA carriers (47.3%) had a response according to RECIST, with the response sustained for more than 76 weeks in one patient Fong P. et al. N Engl J Med 29;361:123-34

23 Olaparib phase I : Evidence of PARP Inhibition Pharmacokinetic pharmacodynamic analyses. Samples of peripheral- blood mononuclear cells (PBMCs) were collected before and after administration of olaparib for each patient. Poly(adenosine diphosphate [ADP] ribose) polymerase (PARP) activity was determined through an ex vivo PARP-activation assay

24 Pharmacodynamic assays using γh2ax foci formation in eyebrow-hair follicles : Significant induction of γh2ax Percentage of cell nuclei with at least 1 small or 3 large foci of γh2ax, the phosphorylated form of histone H2A histone family, member X (H2AX) at serine 139 is shown before and after olaparib administration (left), and the peak γh2ax induction during the first cycle is shown for the cohort of patients receiving each dose of olaparib. There was significant induction of γh2ax for each dose shown.

25 Phase II : Olaparib For BRCA-Deficient MBC Multicenter, phase II, single arm, sequential trial Cohort 1 (enrolled first) Confirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer (stage IIIB, C/IV) after failure of 1 prior chemotherapy Olaparib 4mg BID, 28-days cycle (N=27) Cohort 2 Olaparib 1mg BID, 28-days cycle (N=27) First report of clinical trial targeting BRCA1/2 BC. Tutt et al, Lancet 376(9737)July 21,

26 Best change from baseline (%) Best change from baseline (%) OIaparib Phase II Trials: Monotherapy Clinical proof of concept for targeting BRCA in both breast and ovarian cancer in non comparative studies: Advanced breast cancer (Tutt et al): Substantial single-agent activity (4mg bid) in heavily pre-treated BRCA1/BRCA2 carriers Objective response rate ITT (RECIST): 11/27 (41%), CR 1/27 (4%) Toxicity mainly mild in severity Advanced ovarian cancer (Audeh et al): Confirmed single-agent activity (4mg bid) in heavily pre-treated BRCA1 or BRCA2 carriers Objective response rate (RECIST): 33% Toxicity mainly mild in severity 4 mg superior to 1 mg dose in both studies The Lancet 6 July gbrca Breast Cancer Olaparib 4 mg bid Increasing tumour shrinkage gbrca Ovarian Cancer Olaparib 4 mg bid BRCA1 BRCA2 BRCA1 BRCA2 Increasing tumour shrinkage

27 Before After Lancet 376(9737) 21,

28 Best % change from baseline PARPi Monotherapy in heavily treated gbrca mutated breast cancer and in sporadic TNBC treated patients with target lesions identified at baseline 22 had at least one follow-up assessment 1 patient had no follow-up tumour size assessment 1 due to missing / incomplete post-baseline assessments TNBC BRCA TNBC non-brca Non-TNBC BRCA BRCAness sufficient for synthetic lethality uncommon in advanced TNBC? Mutations present in 2% TNBC Gonzalez- Angulo Clin Cancer Res; 17(5) 211 BRCA1 methylation in 4% Grushko T Olopade F ASCO 21 Small sample of a heavily pretreated heterogeneous disease K Gelmon et al Lancet Oncology 211

29 Single agent PARP inhibitors in gbrca mutated cancer Olaparib BMN 673 Breast Breast Ramanathan et al Abst 29LBA ECCO 213 Niraparib Ovary Ovary Breast Tutt et al The Lancet (9737): Ledermann et al ASCO 213 Michie et al Abst 2513 ASCO 213

30 Olaparib data in advanced pre-treated breast cancer patients

31 Pivotal Phase III Trials : gbrca advanced Breast Cancer Registration Trial Designs gbrca1 / BRCA2 Carriers Advanced anthracycline taxane resistant breast cancer Niraparib BRAVO Trial TESARO/EORTC/BIG NCT Olaparib Registration Phase III- OlympiAD Talazoparib (BMN 673) Biomarin - NCT EMBRACA R Potent PARP inhibitor at MTD as continuous exposure Physician Choice within SOC options Capecitabine or Vinorelbine or Eribulin or Gemcitabine Primary endpoint PFS

32 OlympiAD is a Phase III study investigating olaparib vs TPC in gbrcam HER2-negative metastatic breast cancer 1 gbrcam MBC TNBC or HER2-negative, ER/PR positive 2 prior chemotherapy lines for MBC Previous treatment must include anthracycline and taxane Hormone receptor positive (HR+) disease progressed on 1 endocrine therapy, or not suitable If patients have received platinum therapy there should be: No evidence of progression during treatment in the advanced setting At least 12 months since (neo)adjuvant treatment and randomisation ECOG PS -1 At least one lesion that can be assessed by RECIST v1.1 FSI May Global Study in 19 countries and approximately 141 sites 1 Randomise 2:1 N=32 4 Stratification by 2 Prior chemotherapy regimens for metastatic breast cancer Hormonal receptor (HR) status Prior platinum therapy Olaparib 3mg*po bid Treatment of Physician s Choice (TPC) Primary endpoint PFS (RECIST 1.1, Independent Review) Secondary endpoints OS PFS2 ORR PFS, PFS2 and OS based on Myriad gbrcam status HRQoL (EORTC-QLQ-C3) Safety and tolerability * Tablet formulation (2 tablets twice daily) M=metastatic breast cancer, HER2=human epidermal growth factor 2, TNBC=triple negative breast cancer, TPC=treatment of physician s choice, OS=overall survival, PFS=progression-free survival, PFS2=progression-free survival 2, ORR=objective response rate, HRQoL=health-related quality of life, FSI=first subject in, RECiST= Response Evaluation Criteria in Solid Tumors, ER=oestrogen receptor, PR=progresterone receptor, ECOG PS= Eastern Cooperative Oncology Group Performance Status, gbrcam=germline BRCA mutation; po=oral Robson et al. Poster OT1-1-4, San Antonio Breast Cancer Symposium 214; 3. AZ data on file (217), 4. Robson et al. N Engl J Med. 217; Epub ahead of print

33 OlympiAD recruited patients between March 214 and October Over 3 patients enrolled over a period of 19 months in 19 countries 1-3 Region olaparib 3mg N (%) chemother apy N (%) Total N (%) Asia 59 (28.8) 28 (28.9) 87 (28.8) Europe 97 (47.3) 45 (46.4) 142 (47.) North and South America 49 (23.9) 24 (24.7) 73 (24.2) 1. AZ data on file (217); Robson et al. N Engl J Med. 217; Epub ahead of print

34 Baseline patient characteristics were generally well balanced 1 Patients had a median age of 44, and generally had good performance status 1 olaparib N=25 n (%) TPC N=97 n(%) Total N=32 n (%) Median age (min, max) 44 (22, 76) 45 (24, 68) 44 (22, 76) Male 5 (2.4) 2 (2.1) 7 (2.3) ECOG PS 148 (72.2) 62 (63.9) 21 (69.5) 1 57 (27.8) 35 (36.1) 92 (3.4) White 134 (65.4) 63 (64.9) 22 (66.9) Race Asian 66 (32.2) 28 (28.9) 94 (31.1) Other 5 (2.4) 6 (6.2) 11 (3.6) 1. Robson et al. N Engl J Med. 217; Epub ahead of print ; 2. AZ data on file (217)

35 Baseline characteristics by stratification factor were well balanced between arms 1 There was an equal split of patients with HR+ or TNBC. Approximately two-thirds of patients had received chemotherapy in the metastatic setting, and nearly one-third had received prior platinumbased therapy for breast cancer 1 olaparib N=25 n (%) TPC N=97 n(%) Total N=32 n (%) Received previous chemotherapy for MBC Hormonal receptor status Received prior platinum therapy for breast cancer Yes 146 (71.2) 69 (71.1) 215 (71.2) No 59 (28.8) 28 (28.8) 87 (28.8) HR+ 13 (5.2) 49 (5.5) 152 (5.3) TNBC 12 (49.8) 48 (49.5) 15 (49.7) Yes 6 (29.3) 26 (26.8) 86 (28.4) No 145 (71) 71 (73) 216 (71.5) Adapted with permission 1 1. Robson et al. N Engl J Med. 217; Epub ahead of print

36 Other baseline disease characteristics were also well balanced between arms 1 The majority of patients had two or more metastatic lesions and had progressive disease on randomisation 1 Number of metastatic sites Sites of metastatic lesions BRCA mutation status olaparib N=25 n (%) TPC N=97 n(%) Total N=32 n (%) 1 46 (22.4) 25 (25.8) 71 (23.5) 2 or more 159 (77.6) 72 (74.2) 231 (76.5) Bone & locomotor only 16 (7.8) 6 (6.2) 22 (7.3) CNS 17 (8.3) 8 (8.2) 25 (8.3) BRCA1 117 (57.1) 51 (52.6) 168 (55.6) BRCA2 84 (41.) 46 (47.4) 13 (43.) Both 4 (1.9) 4 (1.3) De novo metastatic BC 26 (12.7) 12 (12.4) 38 (12.6) Progressive disease at randomisation 159 (77.6) 73 (75.3) 232 (76.8) Adapted with permission 1,2 1. Robson et al. N Engl J Med. 217; Epub ahead of print; 2. AZ data on file (217) 36

37 Approximately 3% of patients were receiving study treatment as their first-line chemotherapy for metastatic disease 1 Virtually all HR+ patients had previously received endocrine therapy 2 Received prior endocrine therapy* Adjuvant/ neoadjuvant olaparib N=25 n (%) TPC N=97 n(%) Total N=32 n (%) 71 (68.9) 36 (73.5) 17 (7.4) Metastatic 66 (64.1) 28 (57.1) 94 (61.8) Total 97 (94.2) 45 (91.8) 142 (93.4) Lines of previous cytotoxic chemotherapy for metastatic breast cancer Received prior platinum therapy for BC 68 (33.2) 31 (32.) 99 (32.8) 1 8 (39.) 42 (43.3) 122 (4.4) 2 57 (27.8) 24 (24.7) 81 (26.8) Metastatic 43 (21.) 14 (14.4) 57 (18.9) Adjuvant/ neoadjuvant 15 (7.3) 7 (7.2) 22 (7.3) Adapted with permission 1,2 * Reported as the proportion of patients with HR+ disease Patients may appear under more than one previous treatment modality 1. Robson et al. N Engl J Med. 217; Epub ahead of print; 2. AZ data on file (217)

38 Probability of progression-free survival Olaparib treatment significantly improved PFS assessed by BICR compared to TPC 1 The risk of progression or death over the course of the study was reduced by over 4% Olaparib 3 mg bd (N=25) TPC (N=97) Olaparib TPC n Events (%) 163 (79.5%) 71 (73.2%).7 Median (m) HR = % CI (.43,.8) p=.9.3 PFS free at 6m (%) PFS free at 12m (%) Olaparib Chemotherapy Number of patient s at risk Time from randomisation (months) Median PFS was improved by 69% with olaparib treatment compared to standard of care chemotherapy 2 BICR: blind independent centralised review - FAS; Maturity rate: 234/32=77% Stratified log rank test, stratified by previous chemotherapy for MBC (yes/no) and HR+ versus TNBC. 2 sided p value 1. Robson et al. N Engl J Med. 217; Epub ahead of print; 2. AZ data on file (217)

39 Probability of overall survival OS data are immature and there is no indication of detriment 1 1. Olaparib TPC n Events (%) 94 (45.9%) 46 (47.4%) Median (m) HR =.9 95 % CI (.63, 1.29) p= Number of patient s at risk Olaparib Chemotherapy Olaparib 3 mg bd (N=25) TPC (N=97) Time from randomisation (months) Currently 8 patients in the TPC ar m received subsequent treatment with PARP inhibitors 1 Maturity rate: 14/32=46% 2 sided p value 8 control arm patients have received a subsequent PARPi 1. Robson et al. N Engl J Med. 217; Epub ahead of print

40 Doubling of ORR in the olaparib arm compared to further supports the PFS findings 1 ORR was 6% in the olaparib arm versus 29% in the TPC arm 1 Olaparib TPC Response Evaluable Population, n ORR, n (%) 1 (59.9) 19 (28.8) Complete Response, n (%) 15 (9.) 1 (1.5) Partial Response, n (%) 85 (51.) 18 (27.3) Median Duration of Response, months (95%CI) 6.4 ( ) 7.1 ( ) Median Time to Onset of Response, days Adapted with permission 1 BICR Review 1. Robson et al. N Engl J Med. 217; Epub ahead of print

41 Summary of time to event efficacy endpoints PFS BICR 4.2 Month HR:.58 (95% CI.43.8), p=.9 7. Month 2.8 month difference in median TPC Olaparib PFS Inv 3.8 Month HR:.5 (95% CI.36.68), p< Month 4. month difference in median PFS2 9.3 Month HR:.57 (95% CI.4.83), p= Month 3.9 month difference in median OS 19.6 Month 19.3 Month HR:.9 (95% CI ), p= month difference in median Not Yet Fully Mature Month PFS: Progression-free survival; TFST: Time to first subsequent therapy (or death); PFS2: Time from start of randomisation to second progression (or death); TSST: Time to second subsequent therapy (or death); OS: Overall survival 2 sided p value 1. Robson et al. N Engl J Med. 217; Epub ahead of print

42 Reduction in the risk of progression or death was observed across all pre-specified subgroups with olaparib treatment compared with TPC 1 All patients Prior chemotherapy for metastatic breast cancer Yes No Receptor status ER and/or PgR positive ER and PgR negative Prior platinum for breast cancer Yes No Measureable versus non-measurable disease Measureable Non-measurable Progressive disease at time of randomization Yes No BRCA mutation type BRCA1 BRCA2 Age (years) <65 65 Region Asia Europe North and South America Race White Other Hazard ratio (95% CI) Olaparib : TPC, n (%) NC.58 (.43 to.8).65 (.47 to.91).56 (.34 to.98).82 (.55 to 1.26).43 (.29 to.63).67 (.41 to 1.14).6 (.43 to.84).58 (.43 to.8).57 (.3 to 1.12).6 (.43 to.83).72 (.41 to 1.3).54 (.37 to.79).68 (.45 to 1.7).65 (.49 to.88) Not calculated.57 (.34 to.97).71 (.48 to 1.8).39 (.22 to.73).67 (.48 to.95).51 (.32 to.85) 163 (79.5) : 71 (73.2) 119 (81.5) : 51 (73.9) 44 (74.6) : 2 (71.4) 82 (79.6) : 31 (63.3) 81 (79.4) : 4 (83.3) 5 (83.3) : 21 (8.8) 113 (77.9) : 5 (7.4) 139 (84.2) : 56 (77.8) 24 (6.) : 15 (6.) 127 (79.9) : 53 (72.6) 36 (78.3) : 18 (75.) 94 (82.5) : 41 (82.) 64 (76.2) : 3 (66.7) 154 (79.4) : 67 (72.) 9 (81.8) : 4 (1.) 46 (78.) : 21 (75.) 77 (79.4) : 34 (75.6) 4 (81.6) : 16 (66.7) 19 (81.3) : 47 (74.6) 54 (76.1) : 24 (7.6) IVRS, BICR 1. Robson et al. N Engl J Med. 217; Epub ahead of print Olaparib better TPC better Adapted with permission 1

43 Probability of progression-free survival Probability of progression-free survival Risk of progression was also reduced in olaparib treated patients with HR+ disease and TNBC compared to TPC 1 Patients with HR+ MBC 2 Patients with TNBC 2 Olaparib TPC Olaparib TPC n Events (%) 82 (79.6) 31 (63.3) Median (m) HR=.82 95% CI (.55, 1.26) n Events (%) 81 (79.4) 4 (83.3) Median (m) HR=.43 95% CI (.29,.63).5.4 Olaparib 3 mg bd (N=13) Chemotherapy (N=49).5.4 Olaparib 3 mg bd (N=12) Chemotherapy (N=48) Time from randomisation (months) Time from randomisation (months) Number of patient s at risk Number of patient s at risk Olaparib Chemotherapy Olaparib Chemotherapy Robson et al. N Engl J Med. 217; Epub ahead of print; 2. Robson et al. J Clin Oncol 35, 217 (presentation associated with abstr LBA4)

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47 Common subsequent therapies included chemotherapy, endocrine therapy and targeted biologics 1 18% of patients that discontinued study treatment have received no subsequent treatment 1 Olaparib (N=25) n (%) TPC (N=97) n (%) No subsequent therapy 36 (17.6) 18 (18.6) PARP inhibitors 1 (.5) 8 (8.2) Platinum chemotherapy 6 (29.3) 41 (42.3) Other cytotoxic chemotherapy 11 (53.7) 62 (63.9) Endocrine therapy 27 (13.2) 19 (19.6) Targeted biologics 22 (1.7) 16 (16.5) Other 8 (3.9) 2 (2.1) Adapted with permission 1 1. Robson et al. N Engl J Med. 217; Epub ahead of print 49

48 Talazoparib (BMN673)

49 Median Tumor Volume (mm 3 ) Potent Anti-Tumor Effect in BRCA-deficient Xenograft Tumors Single-Agent Activity in MX-1 Model (Human Breast Cancer line, BRCA1-/-) p=.367 p=.1 Days after 1 st Treatment Similar Effect was seen in Capan-1 and HBCx-17 xenograft tumors (BRCA2 -/-) Shen et.al, poster #3514, AACR 21

50 PARP inhibitors have different mechanisms of action..parp inhibitors act in part as poisons that trap PARP enzyme on DNA. the potency in trapping PARP differed markedly among inhibitors., a pattern not correlated with the catalytic inhibitory properties for each drug.

51 BMN 673 Traps PARP-DNA Complexes Greater Potency Than Olaparib and Rucaparib

52 San Antonio Breast Cancer Symposium, December 5-9, 217 Talazoparib Preclinical & Phase II Talazoparib (TALA) is a highly potent dual-mechanism PARP inhibitor 1-3 Inhibits the PARP enzyme Traps PARP on single-stranded DNA breaks 4 Prevents repair of DNA damage, resulting in cell death Phase 1 trial established a tolerable dose of 1 mg/day for continuous dosing (fed or fasting) 5 Single-agent activity in other tumor types (prostate, ovarian, SCLC) The phase 2 ABRAZO trial showed encouraging efficacy and safety in patients with germline BRCA1/2 mutations and prior platinum therapy or at least 3 prior cytotoxic regimens 6 Confirmed ORR, % (95% CI) PFS, mo (95% CI) CBR24, % (95% CI) Phase 1 Prior Platinum (n = 14) a (n = 48) 5% 21% (1, 35) (2.8, 5.4) 86% 38% (24, 53) ABRAZO 3 Lines, No Platinum (n = 35) 37% (22, 55) 5.6 (5.5, 7.8) 66% (48, 81) a Data shown for the phase 1 study is only in breast cancer patients. Abbreviations: CI, confidence interval; CBR24, clinical benefit rate at 24 weeks; HR, homologous recombination; PARP, poly(adp-ribose) polymerase; ORR, objective response rate; PFS, progression-free survival; SCLC, small cell lung cancer; SSB, single-strand break. 1. Ashworth A. J Clin Oncol. 28;26: Jalve M, Curtin NJ. Ther Adv Med Oncol. 2113: Helleday T. Mol Oncol. 211;5: Lord CJ, Ashworth A. Science. 217;355: de Bono J et al. Cancer Discov. 217;7: Turner NC et al. Presented at ASCO; June 3, 217; Chicago, IL. Abstract 17. This presentation is the intellectual property of the author/presenter. Contact her at jlitton@mdanderson.org for permission to reprint and/or distribute.

53 San Antonio Breast Cancer Symposium, December 5-9, 217 A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician s choice of therapy in patients with advanced breast cancer and a germline BRCA-mutation Jennifer K. Litton, Hope S. Rugo, Johannes Ettl, Sara Hurvitz, Anthony Gonçalves, Kyung-Hun Lee, Louis Fehrenbacher, Rinat Yerushalmi, Lida A. Mina, Miguel Martin, Henri Roché, Young-Hyuck Im, Ruben G. W. Quek, Iulia Cristina Tudor, Alison L. Hannah, Wolfgang Eiermann, Joanne L. Blum This presentation is the intellectual property of the author/presenter. Contact her at jlitton@mdanderson.org for permission to reprint and/or distribute. Litton JK et al. SABCS, 217

54 San Antonio Breast Cancer Symposium, December 5-9, 217 Talazoparib (BMN673) Phase III trial : EMBRACA Patients with locally advanced or metastatic HER2-negative breast cancer and a germline BRCA1 or BRCA2 mutation* Stratification factors: Number of prior chemo regimens ( or 1) TNBC or hormone receptor positive (HR+) History of CNS mets or no CNS mets R 2:1 Talazoparib 1 mg PO daily Treatment (21-day cycles) continues until progression or unacceptable toxicity Physician's choice of therapy (PCT) : capecitabine, eribulin, gemcitabine, or vinorelbine Phase 3, international, open-label study randomized 431 patients in 16 countries and 145 sites Primary endpoint Progression-free survival by RECIST by blinded central review Key secondary efficacy endpoints Overall survival (OS) ORR by investigator Safety Exploratory endpoints Duration of response (DOR) for objective responders Quality of life (QoL; EORTC QLQ-C3, QLQ-BR23) Abbreviations: CNS, central nervous system; EORTC, European Organisation for Research and Treatment of Cancer; HER2, human epidermal growth factor receptor 2; mets, metastases; PO, orally (per os); QLQ-BR23, Quality of Life Questionnaire breast cancer module; QLQ-C3, Quality of Life Questionnaire Core 3; R, randomized; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1; TNBC, triple-negative breast cancer. *Additional inclusion criteria included: no more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease; prior treatment with a taxane and/or anthracycline unless medically contraindicated. HER2-positive disease is excluded. Physician's choice of therapy must be determined prior to randomization. (NCT ) This presentation is the intellectual property of the author/presenter. Contact her at jlitton@mdanderson.org for permission to reprint and/or distribute. Litton JK et al. SABCS, 217

55 San Antonio Breast Cancer Symposium, December 5-9, 217 Baseline Characteristics (ITT Population) TALA (n = 287) This presentation is the intellectual property of the author/presenter. Contact her at jlitton@mdanderson.org for permission to reprint and/or distribute. Overall PCT (n = 144) Age, median (range), y 45 ( ) 5 ( ) <5 y, no. % 182 (63.4%) 67 (46.5%) Gender, % female 98.6% 97.9% ECOG = / 1 / 2, % 53.% / 44.% / 2.% 58.% / 4.% / 1.% Measurable disease by investigator, no. (%) 219 (76.3%) 114 (79.2%) History of CNS metastasis, no. (%) 43 (15.%) 2 (13.9%) Visceral disease, no. (%) 2 (69.7%) 13 (71.5%) Hormone receptor status, no. (%) TNBC 13 (45.3%) 6 (41.7%) HR+ 157 (54.7%) 84 (58.3%) BRCA status, no. (%) BRCA (46.3%) 63 (43.8%) BRCA (53.7%) 81 (56.3%) Disease free interval (initial diagnosis to abc) <12 months 18 (37.6%) 42 (29.2%) Abbreviations: abc, advanced breast cancer; ITT, intent to treat. Litton JK et al. SABCS, 217

56 Talazoparib (BMN673) Phase III trial : EMBRACA_PFS At a median follow-up of 11.2 months, Median progression-free survival (PFS) was 8.6 months (95% CI, ) with talazoparib compared with 5.6 months (95% CI, ) with physician s choice of therapy (HR,.54; 95% CI, ; P <.1). Litton JK et al. SABCS, 217

57 Talazoparib (BMN673) PIII EMBRACA_PFS Subgroup PFS : CNS Metastases Subgroup Litton JK et al. SABCS, 217

58 Talazoparib (BMN673) Phase III trial : EMBRACA_OS Median OS was 22.3 months (95% CI, ) with talazoparib compared with 19.5 months (95% CI, ) with physician s choice of therapy (HR,.76; 95% CI, ; P <.15). Litton JK et al. SABCS, 217

59 Talazoparib (BMN673) Phase III trial : EMBRACA The objective response rate (ORR) was 62.6% (95% CI, ) versus 27.2% (95% CI, ), respectively (odds ratio, 4.99; 95% CI, ; 2-sided P value <.1). In the talazoparib group, 37.6% of patients had a disease-free interval (initial diagnosis to advanced breast cancer) of under 12 months versus 29.2% in the chemotherapy arm. Litton JK et al. SABCS, 217

60 Talazoparib (BMN673) PhIII : EMBRACA_AE

61 San Antonio Breast Cancer Symposium, December 5-9, 217 No deterioration, % EMBRACA : Time to Deterioration in EORTC QLQ-C3: GHS/QoL Statistically significant delay in the time to clinically meaningful deterioration* in GHS/QoL favoring TALA TALA 1 mg PO daily (n = 262) PCT (n = 114) Events, no. (%) 76 (29%) 48 (42%) Median, mo (95% CI) 24.3 (13.8, NR) 6.3 (4.9, 12.2) Hazard ratio,.38, 95% CI,.26,.55 P <.1 TALA Overall PCT Abbreviation: NR, not reached. * 1-point decrease and no subsequent observation with a < 1-point decrease from baseline. This presentation is the intellectual property of the author/presenter. Contact her at jlitton@mdanderson.org for permission to reprint and/or distribute. Litton JK et al. SABCS, 217

62 San Antonio Breast Cancer Symposium, December 6-1, 216 Veliparib CTx combination BROCADE: PhII Study Design Locally recurrent or metastatic breast cancer with deleterious BRCA1/2 mutation N = 29 (86 sites, 2 countries) Stratification factors for randomization ER and PgR status (positive or negative) Prior cytotoxic therapy (yes or no) ECOG status ( 1 or 2) 1:1:1 Veliparib 12 mg D1 7 BID + Carboplatin AUC 6/Paclitaxel 175 mg/m 2 Q3W* N = 97 Placebo + Carboplatin AUC 6/Paclitaxel 175 mg/m 2 Q3W* N = 99 Veliparib 4 mg D1 7 BID + TMZ 15 to 2 mg/m 2 QD, D1 5 N = 94 *Carboplatin/Paclitaxel administered on D3, 21-day cycle. 28-day cycle. Patients were treated until progression or unmanageable toxicity. If both carboplatin and paclitaxel or if TMZ was discontinued, placebo/veliparib was discontinued. Veliparib + TMZ results ; SABCS program number: P Han HS et al. SABCS 216 S-2-5 AUC, area under the concentration-time curve; BID, twice daily; D, day; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; PgR, progesterone receptor; Q, every; TMZ, temozolomide. This presentation is the intellectual property of the authors/presenter. Contact them at Hyo.Han@moffitt.org for permission to reprint and/or distribute. 64

63 Probability of Progression-Free Survival San Antonio Breast Cancer Symposium, December 6-1, 216 BROCADE : Progression-Free Survival 1. Placebo + C/P N = 98 Veliparib + C/P N = 95 HR P value *.8 Median PFS, months (95% CI) 12.3 ( ) 14.1 ( ).789 ( ) Statistical Hypothesis : PFS HR.58 OS HR.61 Number at risk Placebo + C/P Veliparib + C/P Months Since Randomization Placebo + C/P Veliparib + C/P 82 8 *From Cox proportional hazard model, stratified by ER/PgR status and prior cytotoxic therapy use. Efficacy population includes all randomized patients who had a deleterious BRCA1/2 mutation per the core lab. CI, confidence interval; HR, hazard ratio Median (95% CI) PFS, Veliparib + TMZ: 7.4 ( ) months; HR = ( ), P =.1. (SABCS program number: P4-22-2) This presentation is the intellectual property of the authors/presenter. Contact them at Hyo.Han@moffitt.org for permission to reprint and/or distribute Han HS et al. SABCS 216 S-2-5

64 Probability of Survival San Antonio Breast Cancer Symposium, December 6-1, 216 BROCADE : Overall Survival 1..8 Median OS, months (95% CI) Placebo + C/P N = ( ) Veliparib + C/P N = (24.9 NR) HR P value *.75 ( ) Statistical Hypothesis : Number at risk Placebo + C/P Veliparib + C/P Placebo + C/P Veliparib + C/P Months Since Randomization *From Cox proportional hazard model, stratified by ER/PgR status and prior cytotoxic therapy use. OS data shown are from an updated interim analysis in October 216, performed after final PFS analysis. Final OS analysis will occur after 194 deaths on the 3 study arms or 136 deaths on the carboplatin/paclitaxel arms, whichever is later. Efficacy population includes all randomized patients who had a deleterious BRCA1/2 mutation per the core lab. NR, not reached This presentation is the intellectual property of the authors/presenter. Contact them at Hyo.Han@moffitt.org for permission to reprint and/or distribute PFS HR.58 OS HR.61 Han HS et al. SABCS 216 S-2-5

65 PARP inhibitor enhances PD-L1 expression in vivo Domcheck SM et al. SABCS 217; PD6-11

66 Combination with PD-L1 blockade sensitizes PARPi therapy PARP inhibition enhances cancer-associated immunosuppression through upregulation of PD-L1 PD-L1 blockade potentiates PARPi therapy

67 Challenges & Future Work What line of Tx? Will it be the same for ER+ and TNBC? Only gbrcamt carriers? ATM? PALB2? CHEK? Etc.. Does BRCAness exist? How can we identify? HRD? TNBC PARPi : better tolerated than iv CTx and beneficial PARPi combined with CTx : Not superior PARPi + DDRi? : VIOLETTE PARPi + IO? : MEDI_OLA showed promising future trial Luminal BRCAmt Better option than iv single agent CTx, but no data available for sequencing Hormone Therapy + CDKi vs PARPi? Hormone Therapy + PARPi? PARPi + IO? : MEDI_OLA showed promising future trial

68 Conclusion gbrca 1/2 mutation testing should be considered for both TNBC and/or HR+HER2- mbc Olaparib and Talazoparib monotherapy resulted in prolonged progression free survival vs physician s choice of therapy in randomized phase III trial for gbrcamt breast cancer Olaparib and Talazoparib were generally well tolerated with few adverse events resulting in treatment discontinuation PARP inhibitor combination therapies are currently on clinical trial

69 Thank you!

70 Olaparib : Monotherapy Study Name NCT NCT NCT NCT NCT Phase Tumor type No. of Pts (Total/BC) (BRCAmt BC) Investigation arm 1 Solid tumors 6/9 (3) Olaparib (1 6 mg bid) 1 Solid tumors 12/4 (NK) Olaparib (1 4 mg bid) 2 BRCAm BC 54/54 (54) C1: olaparib (4 mg bid) C2: olaparib (1 mg bid) 2 TNBC or BRCAm BC, HGSOC or BRCAm OC 2 BRCAm Solid tumors 9/26 (1) Olaparib (4 mg bid) 317/62 (62) Olaparib (4 mg bid) Primary end point PK, PD, safety and tolerability Safety and tolerability Overall Results Resuls in BRCAmt BC Additional Findings ORR: 15 % ORR 33 % One CR in BRCAm BC lasting more than 6 weeks ORR: 8 % ORR ORR C1: 41 % ORR C2: 22 % ORR ORR in BC: % ORR in OC: 29 % 5 % of unconfirmed PR (by RECIST) ORR ORR: 26 % ORR: 13 % DS 8 weeks: 47 % One patient with BC and family history of BC had PR for 13 months Evidence of activity in non-brcam OC and platinum-resistant OC Mean number of previous regimens for advanced disease: 4.6

71 Other PARPi : Monotherapy Study Name Phase Tumor type No. of Pts (Total/BC) (BRCAmt BC) Veliparib NCT Talazoparib NCT TNBC, HGSOC and BRCAm BC and OC Investigation arm 98/35 (14) Veliparib (5 5 mg) 1 Solid tumors 39/8 (6) Talazoparib (25 11 μg) Primary end point Overall Results Results in BRCAm tolerability PK, PD, safety and anti-tumor activity ORR in BRCAm: 24 % ORR in BRCA wt: 4 % ORR: 65 % in BRCAm OC ORR: 29 % CBR: 57 % ORR: 33 % Talazoparib (ABRAZO) 2 BRCAmt Breast cancer Prior platinum N=48 No platinum N=35 ORR in prior plat 21 % (PFS 4 m ORR in no platinu lines) 37 % (PFS 5. Niraparib NCT Solid tumors 1/12 (4) Niraparib (3 4 mg) Safety and tolerability ORR: 18 % in overall population, 4 % in BRCAm OC ORR: 5 % Rucaparib NCT BRCAm BC and OC 56/27 (27) Rucaparib (18 mg/m2) ORR Data mixed between OC and BC, at RP2D ORR: 8 % (4/5) -

72 Olaparib : Combination Therapy Study Name Phase Tumor type No. of Pts (Total/BC) (BRCAmt BC) Investigation arm Primary end point Overall Results Resuls in BRCAmt BC Additional Findings NCT TNBC 19/19 (NK) Olaparib (2 mg bid) + PTX (9 mg/m2 ) Safety and tolerabilit y ORR: 37 % - First- or secondline treatment only NCT Solid tumors 12/3 (NK) Olaparib (1 4 mg bid) + BEV (1 mg/kg) Safety and tolerabilit y - No grade 3 or 4 hematologic toxicities NCT BC, OC, peritoneal cancer, pancreatic cancer 54/42 (17) Olaparib (5 2 mg bid continuously vs. intermittent) + CDDP (75 mg/m2 ) Safety and tolerabilit y ORR: 41 % ORR : 71 % Continuous olaparib schedules not tolerable (hematologic toxicity) NCT TNBC or OC 28/8 (3) Olaparib (1 4 mg bid) + cediranib (2 3 mg) Safety and tolerabilit y Overall ORR: 29 % ORR: % BC ORR: % BC CBR: 29 % ORR: % BC NCT BRCAm BC and OC 45/8 (8) Olaparib (1 4 mg bid) + CBDCA (AUC 3 5) Safety and tolerabilit y ORR: 52 % ORR: 88 % One CR in BRCAm BC for 3 months

73 Veliparib : Combination Therapy Study Name Phase Tumor type No. of Pts (Total/BC) (BRCAmt BC) Investigation arm Primary end point Overall Results Results in BRCAmt BC Additional Findings NCT Solid tumors 68/14 (NK) Veliparib (2 12 mg) + CBDCA (AUC 5 6) + PTX (15 2 mg/m2 ) PK, Safety and tolerabilit y ORR: 19 % - One CR in BC NCT Solid & Hematologic tumors 18/14 (5) Veliparib (5 15 mg) + DOX (6 mg/m2 ) + CYC (6 mg/m2 ) Safety and tolerabilit y - ORR: 6 % No grade 3 or 4 hematologic toxicities NCT Solid tumors 59/1 (NK) Veliparib (25 mg bid) + CBDCA (AUC 4) + GEM (8 mg/m2 ) PK, Safety, tolerabilit y ORR: 22 % - Continuous olaparib schedules not tolerable (hematologic toxicity) NCT TNBC or BRCAmt BC 45/45 (12) Veliparib (2 3 mg) + CDDP (75 mg/m2 ) + VNR (25 mg/m2 Safety and tolerabilit y ORR: 55 % ORR: 73 % NCT BC 44/44 (16) Veliparib (5 2 mg) + CBDCA (AUC Safety and tolerabilit ORR: 19 % ORR: 25 %

74 Veliparib : Combination Therapy Study Name Phase Tumor type No. of Pts (Total/BC) (BRCAmt BC) Investigation arm Primary end point Overall Results Results in BRCAmt BC Additional Findings NCT Solid tumors And lymphoma 35/12 (NK) Veliparib (2 8 mg) + CYC (5 mg) PK, Safety and tolerabilit y ORR: 2 % - NA 1 BRCAm BC 26/26 (26) Veliparib (5 2 mg) + CBDCA (AUC 5 6) Safety and tolerabilit y - ORR: 46 % CBF: 74 % NCT Solid tumors 3/24 (5) Veliparib (5 2 mg) + PTX (8 mg/m2 ) + CBDCA (AUC 5 6) PK, Safety, tolerabilit y ORR: 48 % ORR: 6 % ORR in nonmutated BRCA BC: 67 % NCT BC 41/41 (8) Veliparib (4 mg bid) + TMZ (15 mg/m2 ) Safety and tolerabilit y ORR: 13 % ORR: 5 % CBF: 63 % Expansion cohort with additional 2 patients with BRCA1/2 mutations: ORR 15 %, CBR: 45 %