PARP INHIBITORS IN OVARIAN CANCER. A 2011 PERSPECTIVE

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1 PARP INHIBITORS IN OVARIAN CANCER. A 2011 PERSPECTIVE Prof S.B. Kaye Royal Marsden Hospital, London MD Anderson Cancer Centre December 2011

2 DISCLOSURES Received honoraria as member of Advisory Boards to AstraZeneca, Sanofi Aventis, Merck

3 PARP INHIBITORS: A STEP FORWARD IN OVARIAN CANCER TREATMENT Mrs BS: 62-year-old with BRCA-1 mutation linked ovarian cancer after 22 months of treatment with single agent olaparib 1500 CA-125 (U/ml) this is nothing like chemotherapy Time (Days) on AZD2281 The reason: tumour selective synthetic lethality PARP: poly(adp)ribose polymerase

4 PARP INHIBITION AND TUMOUR-SELECTIVE SYNTHETIC LETHALITY γh2ax Normal BRCA1/BRCA2 SSB PARPi DNA replication fork arrest and collapse DSB BRCA1/BRCA2 failure RAD51 Impaired HR repair Alternative error prone repair HR-based repair Chromosome stability Cell survival Chromosomal instability Cell death HR, homologous recombination; SSB, single-strand break; DSB, double-strand break Farmer H et al. Nature 2005;434: ; Bryant HE et al. Nature 2005;434: Slide provided by Andrew Tutt

5 IS SINGLE AGENT PARP INHIBITOR OR COMBINATION APPROACH PREFERABLE? Single agent treatment utilizes tumour selective synthetic lethality, without toxicity of chemotherapy Chemo/PARPi combination enhances chemo effect in exptl. models, particularly in HR-deficient cells, e.g with temozolomide, topo I inhibitor, platinum But: clinically, myelotoxicity is usually enhanced by chemo/parpi combination, and optimal duration of PARPi not yet defined

6 OLAPARIB, A NOVEL, ORALLY ACTIVE AND WELL TOLERATED PARP INHIBITOR A Phase I trial identified olaparib (AZD2281; KU ) 400 mg b.d.as the maximum tolerated dose 1 with significant PARP inhibition and tumour response at mg bd Most common toxicities: CTCAE grade 1 and 2 nausea and fatigue 46% (23/50 pts) combined response rate (RECIST and CA125) in BRCA-mutated ovarian cancer 2, in cohort expansion at 200 mg bd, with median response duration of 8 months 1. Fong P et al. N Engl J Med, 2009; 361, ; 2. Fong P et al. J Clin Oncol, 2010; 28,

7 INTERNATIONAL PHASE II TRIAL OF OLAPARIB IN BRCA ASSOCIATED OVARIAN CANCER 57 pts (BRCA 1 39; BRCA 2 18) received either 400 mg bd or 100 mg bd in two sequential cohorts (med. 3 prior CT) Audeh MW et al., 2010, Lancet 376: pts at 400 mg bd 24 pts at 100 mg bd RECIST response Clinical benefit (incl. CA125 response) RECIST response Clinical benefit (incl. CA125 response) 11 (33%) 22 (66%) 3 (13%) 10 (42%) Conclusion: Level of efficacy confirmed, med. response duration 9.5 m Favourable toxicity profile confirmed 400 mg bd appears to be more active than 100 mg bd Key issues for olaparib in BRCA-mutated ovarian cancer: what is the optimal dose (200 mg bd or 400 mg bd)? how does this compare with standard therapy, e.g. liposomal doxorubicin (Caelyx)?

8 WHAT IS THE OPTIMAL DOSE OF OLAPARIB, AND HOW DOES IT COMPARE WITH CAELYX? efficacy of olaparib (400 mg bd) was as predicted, with response (RECIST/CA125 ) in 59% and median PFS of 8.8 m. Caelyx was more effective than anticipated (response 39%; median PFS 7.1 m), thus no significant difference in primary end-point HR 0.88 p = 0.66 overall, both treatments well tolerated (<10% discontinuation) further studies certainly warranted in BRCA-associated ovarian cancer, including those previously treated with Caelyx. additional evaluation in high grade sporadic serous ovarian cancer is a high priority. Kaye et al, J Clin Oncol., 2011, in press

9 POTENTIAL OF PARP INHIBITORS IN SPORADIC OVARIAN CANCER The Cancer Genome Atlas, Molecular profiling of serous ovarian cancer, D. Levine 2011 Other 34% MMR Germline 2% CCNE1 Amplification 15% BRCA1 Germline 8% BRCA2 Germline 6% BRCA1 Somatic 3% BRCA2 Somatic 3% BRCA1 Methylation 11% EMSY Amplification 6% PTEN Loss 5% Other HRD 7% Gelmon et al., Lancet Onc Best % change in target lesion size: high grade serous ovarian/undifferentiated tuboovarian; unknown or BRC ve at entry Single agent olaparib 400 mg b.d. cont. in 48 cases of relapsed ovarian cancer Not HR deficient Homologous recombination (HR) deficient

10 CORRELATION BETWEEN OLAPARIB RESPONSE AND PRIOR PLATINUM SENSITIVITY Germline BRCA status BRCA mutation positive Response to prior platinum Platinum sensitive Platinum resistant RECIST response to olaparib 6/13 (46%) 1 8/24 (33%) 1 Ref BRCA mutation negative Platinum sensitive Platinum resistant 10/20 (50%) 2 1/28 (4%) 2 1. Fong et al, J Clin Oncol 28, , Oza et al, presented at IGCS 2010

11 RANDOMIZED TRIAL OF MAINTENANCE OLAPARIB 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-125 Olaparib 400 mg po bid Randomized 1:1 Placebo po bid Treatment until disease progression Total of 265 recruited: 64% BRCA unknown 22% BRCA positive 14% BRCA negative Ledermann et al., ASCO 2011

12 RANDOMIZED TRIALS OF MAINTENANCE OLAPARIB IN PLATINUM-SENSITIVE RELAPSED OVARIAN CANCER Total of 265 randomized patients: - well balanced for key prognostic criteria, Note: 21-22% BRCA mutation positive 13-16% BRCA known negative 63-64% BRCA unknown Toxicity profile for olaparib 400 mg bd in keeping with previous studies (grade 3 anaemia/fatigue in 5/7%) No significant difference in quality of life measures

13 PROGRESSION-FREE SURVIVAL But what impact on overall survival? Ledermann et al., ASCO 2011

14 PREPLANNED SUBGROUP ANALYSIS OF PFS Overall BRCA mutation BRCA status known BRCA unknown Age <50 Age 50 to <65 Age 65 Race, white Non-Jewish descent CR at baseline PR at baseline TTP penultimate platinum-based regimen 6 12 mo TTP penultimate platinum-based regimen >12 mo Hazard ratio (olaparib:placebo) and 95% CIs Favors olaparib Global interaction test showed no evidence of inconsistency across the subgroups (P=0.282) Size of circle is proportional to number of events; grey band represents 95% confidence intervals (CIs) in overall population; Subgroups with <20 events not statistically analyzed (BRCA negative, Jewish decent)

15 SINGLE AGENT THERAPY WITH OLAPARIB IN OVARIAN CANCER What we know now: Single agent olaparib has significant clinical activity in both BRCA-mutated and sporadic ovarian cancer, with favourable toxicity profile and particular potential as maintenance therapy What we still need to know: Long-term toxicity Impact on subsequent chemo and overall survival Nature of reliable predictive biomarker Potential for combination with other maintenance approach, e.g. bevacizumab Optimal dose of new formulation

16 CHEMOSENSITIVITY POST OLAPARIB CA125 levels (U/ml) Anecdote: Olaparib Days Carbo. +Caelyx 98% CA125 decline 86% CA125 decline initial prolonged response to olaparib, then radiological and CA125 progression subsequent response to carboplatin/caelyx In 61 evaluable olaparib-treated patients, response to subsequent chemotherapy seen in 24 (39%) weekly taxol and/or platinum 13/24 resp carbo/caelyx or gen or taxol 7/23 resp caelyx 3/9 resp other 1/5 resp Further follow up needed to assess response duration and correlation with prior chemo sensitivity Ang et al, ASCO 2010 (updated 2011)

17 Patient selection for treatment with PARP inhibitors Predictive biomarker: functional test for loss of HR (RAD 51 foci-formation) 1,2 molecular signature (gene array) 3 and/or background of: repeated response to platinum-based chemo prolonged survival (>5 yrs) high grade serous histology 1 Mukhopadhay et al, Clin Cancer Res, 2010, 16, Graeser et al, Clin Cancer Res, 2010; epub 3 Konstantinopoulos et al, J Clin Oncol, 2010, 28,

18 COMBINATION APPROACH WITH PARP INHIBITORS AND CHEMOTHERAPY DRUG Olaparib ABT-888 MK-4827 PF CEP 9722 Iniparib COMBINED WITH Carboplatin/paclitaxel, topotecan, weekly paclitaxel, and others Temozolomide, topotecan, carboplatin/paclitaxel and bevacizumab Carboplatin Carboplatin/paclitaxel Temozolomide Gemcitabine/carboplatin

19 INIPARIB AND GEMCITABINE/CARBOPLATIN IN RELAPSED OVARIAN CANCER Penson et al, ASCO 2011, Birrer et al, ASCO 2011al, Birrer et al) Separate cohorts of patients with platinum-sensitive and platinumresistant ovarian cancer Carboplatin AUC 4 day 1 Gemcitabine 1000 mg/m 2 day 1, 8 Iniparib 5.6 mg/kg day 1, 4, 8, 11 q 21 days up to 10 cycles, then continue maintenance iniparib until PD 2 stage response assessment Note: carboplatin AUC 4 q 21 days Instead of carboplatin AUC 2 d 1, 8 (as in O Shaughnessy breast ca study Does this matter?

20 INIPARIB WITH GEMCITABINE/CARBOPLATIN IN RELAPSED OVARIAN CANCER PHASE II STUDIES Platinum sensitive Penson et al BRCA 1/2 RECIST response Med PFS 26/40 (65%) 9.5 m 8/12 Platinum resistant Birrer et al BRCA 1/2 RECIST response Med PFS 8/32 (25%) 6.4 m 4/10 Responses seen in BRCA mutant and wild type in both studies Safety profile consistent with previous gem/carbo trials in similar pts (grade 3/4 myelotoxicity in 26-59%)? How does efficacy compare with gem/carbo alone? Preclinical data now indicate mechanism of action of iniparib differs from other PARP inhibitors

21 COMBINATION OF PARP INHIBITORS AND CHEMOTHERAPY IN OVARIAN CANCER What we know now Combination of PARPi with chemo is feasible, usually leads to increased myelosuppression (iniparib excepted) and may lead to increase in efficacy; most likely in platinum-sensitive disease What we still need to know Impact on PFS/OS in ongoing/completed randomized trials (both 1 st and 2 nd line) Optimal dose/schedule of PARP inhibitor Predictive biomarker to select optimal patient subgroup, does BRCA status matter? Any difference in potential of different PARP inhibitors

22 PARP INHIBITORS IN OVARIAN CANCER Future studies What is the role of PARPi in combination with chemo and as maintenance in patients most likely to benefit, i.e. high grade serous ovarian ca First (or second) line high grade serous sporadic ovarian cancer R A N D O M I Z E Carboplatin combination + placebo Carboplatin combination + PARPi placebo PARPi placebo PARPi

23 WHAT IS THE ROUTE TO REGISTRATION FOR SINGLE AGENT PARPi in BRCA MUTATION POSITIVE PATIENTS? BRCA mutation pos Relapsed ovarian ca Prev treated with Caelyx OR in Caelyx naïve patients BRCA mutation pos Relapsed ovarian ca * Recently completed feasibility study - Caelyx 40mg/m 2 plus Olaparib 400mg bd. R A N D O M I Z E R A N D O M I Z E PARPi inhibitor Investigator choice Caelyx Caelyx + PARPi *

24 PARP INHIBITORS IN CLINICAL TRIAL PF (Rucaparib) Clovis/Pfizer i.v./oral Olaparib AZ oral ABT 888 (Veliparib) Abbott oral INO-1001 Inotek i.v. GP1201 Eisai oral CEP 9722 Cephalon Oral MK 4827 Merck oral BMN 673 BioMarin oral

25 PHASE I TRIAL OF MK 4827 Sandhu et al, ASCO 2010 first-in-man Phase I trial (updated data, 2011) MK-4827 highly selective PARP 1/2 inhibitor ( nm IC50) 56 pts: received mg o.d. cont. in 2 phases dose escalation dose expansion included 37 pts with ovarian cancer 19 BRCA mutation positive 18 BRCA unknown/negative MTD: 300 mg o.d. DLT: thrombocytopenia G4 in 2 pts

26 ANTITUMOUR ACTIVITY OF MK 4827 IN PATIENTS WITH OVARIAN CANCER Total number of RECIST evaluable patients RECIST and / or Ca125 responses (%) Stable disease 4 months (%) BRCA1/2 mutation carriers Ovarian / Primary Peritoneal Cancer 19 9(47%) 2 (11%) Sporadic Ovarian Cancer (platinum sensitive) Ovarian Cancer (platinum resistant) 5 2 (40%) (15%) 1(6%) Median response duration: 12 months for BRCA pts

27 54-yr-old BRCA mutation positive, RECIST PR to MK 4827 for 14 m

28 BMN-673 (BioMarin) A NEW PARP INHIBITOR IN EARLY CLINICAL DEVELOPMENT The most potent and selective PARPi so far reported. IC50 for PARP1 is 0.57 nm) Up to 700-fold more active in vitro in BRCAdefective cell lines compared to olaparib, with substantial increase in efficacy in vivo in MX xenograft

29 BMN-673 Is Potent and Selective for Tumor Cells with Defects in DNA Repair CELL LINE MDA-MB- 231 MDA- MB-468 (PTEN-) IC 50 (µm) Capan-1 (BRCA2-/-) MX-1 (BRCA1-/-) MRC-5 (Normal) ABT-888 ND ND >10 ND >10 AG AZD BMN

30 MX-1 TUMOUR MODEL STUDY: MONOTHERAPY EFFICACY MX-1 MX-1 intratumoral tumor: PAR level MX-1: breast tumour xenograft with BRCA1 deletion and BRCA 2 mutation pg PAR/mg protien AZD hr 8 hr 24 hr BMN 673 2hr 8 hr 24 hr

31 PHASE I TRIAL OF BM 673 Dose escalation in solid tumours, dose expansion planned in BRCA associated disease Dose escalation continuing after 5 steps Preliminary results encouraging, both in terms of toxicity and signs of efficacy

32 PARP INHIBITORS IN OVARIAN CANCER Proof-of-principle of tumour synthetic lethality confirmed in the clinic Efficacy of PARPi confirmed in both BRCA positive and sporadic high grade serous ovarian cancer Single agent development likely to incorporate maintenance study; strategy for specific registration in BRCA positive disease requires urgent consideration Combinations with chemotherapy are promising, but results of randomized trials awaited Combinations with other targeted approaches under active consideration A robust predictive biomarker for HR deficiency remains a priority

33 ACKNOWLEDGEMENTS Johann de Bono Peter Fong Tim Yap Shahneen Sandhu Alan Ashworth AstraZeneca Merck BioMarin Colleagues at NKI Co-investigators on study 12 Patients and families with ovarian cancer

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35 PHASE I TRIAL OF BIOMARIN BM yr-old BRCA mutation diagnosis October 2008, 2 prior lines of carbo/taxol, with 6 m platinum-free interval After 2 m of BM μg o.d. CA125: complete response RECIST: partial response 29 June Tumour size 2355 m 2 5 October Tumour size 1204 m 2

36 PHASE I TRIAL OF BIOMARIN BM yr-old BRCA mutation diagnosis October 2008, 2 prior lines of carbo/taxol, with 6 m platinum-free interval After 2 m of BM μg o.d. CA125: CR RECIST: