NEW AGENTS ON THE HORIZON: IMPLICATIONS FOR PHASE I, II & III TRIALSDNA Repair and PARP inhibitorsCarol Aghajanian, Nicoletta Colombo & Amit OzaAcknowledgements: Stan Kaye and AZ for slides

Amit M. OzaProfessor of Medicine,

Princess Margaret Hospital,University of Toronto

Co-Chair Gynecology, NCIC CTG

Base excision

repair

Types of DNA damage and repair

Type of damage:

Bulky adducts

Insertions& deletions

O6-alkylguanine

Repairpathway:

Nucleotide-excision

repair

Mismatch repair

Directreversal

Repairenzymes:

Double-strandbreaks(DSBs)

Single-strand breaks(SSBs)

Poly ADP

Ribose Polymer

ase

Recombinationalrepair

ATM DNA-PK

HR NHEJ

XP, poly-

merases

MSH2,MLH1

AGT

BRCA

PARP-1 is a key enzyme involved in the repair of single-strand DNA breaks

PAR chains are degraded via PARG

RepairedDNA

PARPDNA damage

Binds directly to SSBs

Repair enzymes

PAR

Nicotinamide+pADPr

NAD+

Once bound to damaged DNA, PARP modifies itself producing large branched chains of PAR

Inhibiting PARP-1 increases double-strand DNA damage

PARP

Inhibition of PARP-1 prevents recruitment of repair factors to repair SSB

XRCC1

LigIII

PNK 1

pol β

Replication (S-phase)

DNA DSB

DNA SSB

Cellsurvival

Normal cell

Deficient HR pathway – DSB not repaired

Selective effect of PARP-1 inhibition on cancer cells with BRCA1 or BRCA2 mutation

DSB repaired

effectively via HR

pathway

DSB in DNA

Cancer cell death

BRCA-deficient cancer cell

Lethality

Tumour Selective Synthetic Lethality

Error prone repairGenomic instabilityCell death

DNA DAMAGE DNA DAMAGE

HR deficient e.g. BRCA1/2-/-

HR NHEJ SSA BER NER etc HR NHEJ SSA BER NER etcx xx

PARPi PARPi

Normal or heterozygotefor HR defect

  TotalPlatinum sensitive

Platinum resistant

Platinum refractor

y

No. of evaluable patients

46 10 25 11

Responders by RECIST 13 (28%) 5 (50%) 8 (32%) 0 (0%)

Responders by GCIG CA125

18 (39%) 8 (80%) 8 (32%) 2 (18%)

Responders by either RECIST or GCIG criteria

21 (46%) 8 (80%) 11 (44%) 2 (18%)

SD (> 4 cycles) 9 (15%) 1 (10%) 4 (16%) 1 (9%)

Median duration of response in weeks (range)

31 (10-96) 31 (16-96) 29 (10-84) 39 (27-51)

RESPONSE TO AZD 2281, Parp inhibitor - OLAPARIB BY PLATINUM-FREE INTERVAL

23 mm

Strong family history

Ovarian BRCA1-/-

21.05.07

12 mm 6.8 mm

03.04.07

Breast BRCA?

Ovarian BRCA1-/-

6.5 mm 3 mm

0

6

12

18

24

CR/PR SD >4 months PD

Pla

tin

um

-fre

e in

terv

al (

mo

nth

s)

Sensitive Resistant Refractory

CORRELATION OF PLATINUM SENSITIVITY WITH RESPONSE TO OLAPARIB

SINGLE AGENT TREATMENT WITH OLAPARIB

Well tolerated oral therapy not associated with the typical toxicities of chemotherapy

Clear evidence of beneficial tumour response in BRCA mutated ovarian cancer patients

• 46% (21/46 pts) response rate (RECIST or GCIG CA125)

• 15% meaningful disease stabilisation

• Total clinical benefit rate of 61%

• Median response duration: 8 m

Randomized trials now underway

Question: What proportion of ovarian cancer patients will have BRCA1/2 dysfunction, either due to mutation of either gene or for other reasons, e.g. methylation of this or related genes?

Answer: • approx 15% of sporadic ovarian cancers have mutation of either gene; in serous histological subtypes, proportion is 18%• approx 15-20% more cases have BRCA dysfunction, through methylation, etc.• approx 10% have FANCF methylation

Therefore: potentially half the cases of serous ovarian ca could benefit from targeted single agent treatment - how can these be identified?

POTENTIAL OF PARP INHIBITOR (SINGLE AGENT) IN SPORADIC OVARIAN CANCER

Phase I-II studies

Phase I: Combination with - platinum, topotecan

Phase II: Single agent BRCA +/-

Randomized Phase II/III Post chemo consolidation/maintenance Combination/maintenance

Carbo/taxol +/- Parp inhibitor

Parp Inhibition

Compelling efficacy data in hereditary ovarian cancer patients

Studies in hereditary ovarian cancer.

High grade serous histology – “BRCAness”

Without BRCA mutations

Combination studies

Chemotherapy

Targeted agents

PARP Inhibitors in Clinical Trials

Agent Company Strategy Administration

AG014699 Pfizer Combination* IV

KU59436 AstraZeneca-Kudos

Single Oral

ABT-888 Abbott Single Oral

BSI-201 BiPar SingleCombinations

IV

INO-1001 Inotek-Genentech

Combination* IV

MK Merck Single agent and combination

Oral

GPI 21016 MGI Pharma Combination* Oral

Adapted Ratnam K, Low JA Clin Cancer Res 2007;13: 1383-1388

FURTHER DEVELOPMENT OF OLAPARIB - 1

RANDOMISE

Patients with advanced ovarian cancer with BRCA-1 or 2 mutations, relapsed within 12 months of platinum-based chemotherapy

olaparib 400 mg bd cont

olaparib 200 mg bd cont

caelyx/doxil 50 mg/m2 q4 weekly

n = 90, recruitment completeprimary end point = PFS

statistical analysis: combined olaparib arms vs caelyx/doxil, aimed at detecting incr. in PFS from 4 m to 7.3 m (HR 0.55, 80% power)

FURTHER DEVELOPMENT OF OLAPARIB - 2

RANDOMISE

Patients with serous ovarian cancer, responding to 2nd or 3rd line platinum-based chemo, with CR/PR (penultimate treatment-free interval >6 m)

olaparib 400 mg bduntil PD

- BRCA mutation not necessary

placebo until PD

n = 250

Primary end point: progression-free survival

Recruitment now underway

PATIENT SELECTION FOR SINGLE AGENT

Predictive biomarker:

• immunohistochemistry, with BRCA 1/2 antibodies

• functional (ex vivo) test for loss of HR (RAD 51 foci-formation)

• molecular signature (gene array)

and/or: background of •repeated response to platinum-based chemo

•prolonged survival (>5 yrs)

•serous histology