Overview and future horizons of PARP inhibitors in BRCAassociated. Judith Balmaña

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2 Overview and future horizons of PARP inhibitors in BRCAassociated breast cancer Judith Balmaña

3 PARP inhibitors: Mechanism of action Clinical development: Monotherapy In combination with chemotherapy Ongoing clinical trials Future horizons: When and who?

4 Mechanism of action: Synthetic lethality in DNA repair defective backgrounds 10,000 s DNA SSBs occur each day in cells During replication unrepaired SSBs bound by PARP result in fork collapse and DNA DSBs PARP PARPi Replicating cells PARPi traps PARP on the DNA single strand break preventing repair and effectively generating a protein-dna adduct Combination with DNA damaging therapies (chemotherapy and IR) Normal cell Cancer cell with HRD Repair by Homologous Recombination Survival Tumour-specific killing by single agent PARPi (Synthetic Lethality) No effective repair (No HRR pathway) Cell death

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6 Current development of PARPi in BC PARPi Olaparib (AZD2281) Rucaparib (AGO14699) Veliparib (ABT888) Niraparib (MK-4827) Talazoparib BMN 673 Company, First trial Astra Zeneca 2005 Pfizer/Clovis 2003 Abbott 2006 Tesaro 2010 Biomarin 2011 IC 50 phase route 5nM (PARP1) 1nM (PARP2) 1.5 µm (Tankyrase 1) II-III oral 1.4nM (PARP1) I-II-III oral 5.2nM (PARP1) 2.9nM (PARP2) I-II oral 3.8nM (PARP1/2) I-III oral 0.57nM (PARP1) I-III oral

7 Proof of Concept for synthetic lethal targeting first shown with Olaparib in BRCA1/2 carriers Tutt et al The Lancet (9737):235-44

8 PARPi Monotherapy in heavily treated gbrca mutated breast cancer and in sporadic TNBC Best % change from baseline 120 TNBC BRCA 100 TNBC non-brca 80 Non-TNBC BRCA 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 K Gelmon et al Lancet Oncology 2011

9 Talazoparib (BMN 673) in gbrca mutated cancer. Phase I data Ramanathan et al Abst 29LBA ECCO 2013

10 Niraparib (MK-4827) in gbrca mutated cancer. Phase I data Sandhu SK, Lancet Oncol 2013; 14:882-92

11 Veliparib (ABT 888) in gbrca mutated cancer. Phase I data At the MTD 400mg BID, 28 BRCA+ patients were evaluable for response: ORR 40% CBR 68% Puhalla S, J Clin Oncol 32:5s, 2014 (suppl; abstr 2570))

12 Registration Trial Designs for advanced BRCA mutated breast cancer patients gbrca1 / BRCA2 Carriers with advanced cancer Anthracycline and/or taxane pre-treated Niraparib BRAVO Trial TESARO/EORTC/BIG NCT BMN 673 EMBRACA Trial - NCT R Potent PARP inhibitor at MTD as continuous exposure Physician Choice within SOC options Capecitabine Vinorelbine Eribulin (Gemcitabine) Primary endpoint PFS Olaparib OlympiAD NCT

13 A Phase 2, 2-Cohort Study of Talazoparib (BMN 673), in Locally Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (ABRAZO, NCT ) Cohort 1: Prior PR or CR to platinum-based regimen, with PD at least 8 weeks after last dose of platinum Metastatic/locally advanced BC-BRCA mutated Talazoparib 1mg PO QD Cohort 2: >2 chemotherapy regimens and who have had no prior platinum Treatment until PD Primary Objective: ORR Secondary Objective: CBR, DOR, PFS, OS, safety, PK

14 Platinum chemotherapy PARP inhibitors Interstrand crosslink repair Target BRCA and HR deficient cancers SSB Replication fork collapse Xenograft studies with BRCA deficient models suggest additive effects maintaining doses in combination Rottenberg PNAS 2008, Drew JNCI 2011 Single agent PARP inhibitor Well tolerated Large therapeutic window synthetic lethality PARP inhibitor Platinum combo Potential for improved response But chemo-sensitization is nonspecific May not enhance therapeutic window

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17 Randomization 1:1:1 Phase 2: veliparib + temozolomide, vs placebo+carboplatin/paclitaxel, vs veliparib+carboplatin/paclitaxel in advanced BC patients with BRCA mutation Patient Population Endpoints Men and women 18 years of age Measureable metastatic breast cancer Locally recurrent breast cancer not amenable to therapy with curative intent Documented BRCA1 or BRCA2 deleterious germline mutation N = mg Veliparib BID + Temozolomide N = 85 Placebo + Carboplatin/Paclitaxel N = mg Veliparib BID + Carboplatin/Paclitaxel Primary Endpoint Progression Free Survival Secondary Endpoints Overall Survival Clinical Benefit Rate Objective Response Rate Safety and Tolerability CIPN Veliparib- BROCADE- NCT

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19 Randomization 2:1:1 M14-011:BRIGHTNESS Study, NCT Patient Population Women 18 years of age with early stage breast cancer amenable to surgical resection Tumors must be triplenegative (confirmed by histology) Tumors must be clinical stage T2-4 N0-2, or T1 N1-2 Pac / Carbo / Veliparib BID followed by AC Pac / Carbo / Placebo followed by AC Pac / Placebo followed by AC Endpoints Primary Complete pathologic response (pcr) of breast and axillary tumor Secondary Breast Conservation Rate (BCR) Tertiary EFS, OS, CRR, Residual Cancer Burden (RCB)*, ECOG and QoL Primary Analysis pathologic response assessment Secondary Analyses Subjects will be followed for event-free survival (absence of local recurrence, distant recurrence, new primary breast tumor, other malignancy, or death) for up to 10 years following neoadjuvant therapy and surgery Stratification factors: BRCA status Lymph node status

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21 How much of the tumour retains targetable DNA repair deficiency in advanced disease? Serena Nik-Zainal et al Cell 2012

22 Sakai et al. (2008). Nature 451, ; Dhillon et al. (2011). Cancer Sci 102, ; Norquist et al. (2011). J Clin Oncol,

23 Would the use of a PARPi earlier in high risk BRCA mutated cancers be more efficient than in advance disease (ie, less risk of resistant mechanisms activated under selective pressure?)

24 Adjuvant trial rationale PARP inhibition has strong proof of concept in BRCA1/2 carriers Treatment early in disease minimizes therapy induced resistance TNBC has few other targets

25 BRCA1 mutation carriers with >T2 or node +ve disease have high risk despite adjuvant / neo-adjuvant chemotherapy Huzarski et al JCO 2013

26 OlympiA: Adjuvant olaparib in TNBC breast cancer patients with gbrca mutations at high risk of recurrence Distant DFS; OS Post neoadjuvant gbrca TNBC Non-pCR patients Post adjuvant gbrca TNBC patients with node positive disease (any tumour size) or node negative (primary tumour > 2cm) Randomisation 1:1 Double-blind 12 months Olaparib 300 mg BID Placebo Follow up 10 years IDFS

27 PARPi RESISTANCE MECHANISMS: SUMMARY PRECLINICAL & CLINICAL DATA secondary mutations in BRCAs restoring the gene and HR x x (2 BC) loss of 53BP1 x x x up-regulation of P-glycoproteins -efflux pumps- x loss of PARP1 expression x Hypomorphic BRCA1 RING mutation (C61G) x Hsp90-mediated BRCA1 stabilization (BRCT domain mut) x x (cisplatin) Edwards, Nature 2008; Norquist, J Clin Oncol 2011; Bowman, Nat Struc Mol Biol 2010; Petitt, PLOS One 2013; Johnson, PNAS 2013; Jaspers, Cancer Discovery 2013; Nordquist, JCO 2011; Drost, Cancer Cell 2011; Barber, J Pathol 2013

28 Preclinical models, and especially PATIENT-DERIVED XENOGRAFT MODELS, will be instrumental to develop: 1) methods for adequate patient stratification 2) treatment sequentiality that prevent or counteract resistance to PARPi.

29 Take home messages Several PARP inhibitors have shown clinical efficacy in gbrca advanced breast cancer, both in monotherapy and in combination with chemotherapy Ongoing phase 3 trials in metastatic setting will define the role of PARPi in monotherapy for the therapeutic management of these patients Current efforts are focused on developing these agents in earlier stages of the disease Further work is ongoing to select which patients may benefit most