The role of PARP inhibitors in high grade serous ovarian cancers

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1 The role of PARP inhibitors in high grade serous ovarian cancers Jonathan Ledermann UCL Cancer Institute University College London ANZGOG-ASGO, Canberra, March 214 Cancer Research UK UCL Centre

2 DNA Repair Lee J-m et al Ann Oncol 214

3 INCREASED SENSITIVITY of BRCA1 -/- and BRCA2 -/- CELLS to PARP INHIBITION BRCA1 +/+ BRCA1 +/- BRCA1 -/- BRCA2 +/+ BRCA2 +/- BRCA2 -/- No difference in sensitivity between heterozygous and wild-type BRCA cells Targeted inhibition selective and less toxic therapy Farmer et al. Nature 25; 434:917-21

4 PARP inhibitor: Olaparib (AZD 2281) DNA SSBs occur all the time in cells and PARP detects and repairs them PARP Olaparib 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 Olaparib No effective repair (No HR pathway) Cell death

5 Olaparib: An orally active PARP inhibitor Olaparib Phase I and BRCA mutation expansion studies 1,2 Olaparib phase II BRCA Olaparib phase II BRCA Olaparib dose 2 mg bid 4 mg bid 1 mg bid RECIST CR/PR SD Median duration of response 14/5 (28%) 11/33 ( 33%) 3/24 ( 13%) 3/5 (6%) ( 4 months) 12/33 ( 36%) (8 weeks) 14/24 (58%) (8 weeks) ~214 d 29 d 269 d 1. Fong PC et al. N Engl J Med 29;361: ; 2. Fong PC et al. J Clin Oncol 21;28: Audeh MW et al. Lancet 21;376:

6 The HR phenotype and the potential of PARP inhibitors in sporadic ovarian cancer Other 34% BRCA1 germline 8% BRCA2 germline 6% BRCA1 somatic 3% BRCA2 somatic 3% BRCA1 methylation 11% MMR germline 2% CCNE1 amplification 15% Not HR deficient Levine D. The Cancer Genome Atlas, Molecular profiling of serous ovarian cancer, 211 EMSY amplification 6% PTEN loss 5% Other HRD 7% Homologous recombination (HR) deficient

7 Best change from baseline in size of target lesion (%) Best change from baseline in size of target lesion (%) Olaparib in BRCA and non-brca 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 Gelmon KA, et al. Lancet Oncol 211;12:852 61

8 Randomized trial of maintenance olaparib in platinumsensitive high grade serous relapsed ovarian cancer - Study 19 Study aim and design 265 patients 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 4 mg po bid Randomized 1:1 Placebo po bid Treatment until disease Progression Primary end point : PFS Ledermann J, et al. N Engl J Med 212;366:

9 Proportion of patients progression free Progression-free survival No. of events: Total patients (%) Median PFS (months) Olaparib 6:136 (44.1) 8.4 Placebo 93:129 (72.1) 4.8 Hazard ratio.35 (95% CI,.25.49) P<.1 At risk (n) Olaparib Placebo Randomized treatment Placebo Olaparib 4 mg bid Time from randomization (months) Ledermann J et al. N Engl J Med 212;366:

10 Interim Overall survival (OS) and subgroup analysis* Interim OS analysis (38% maturity): HR=.94; 95% CI, ; P=.75 BRCA1/2 mutation (BRCAm) status was not required for study entry, but was known for 97/265 patients (36.6%) Overall gbrca positive gbrca negative gbrca status unknown HR (olaparib:placebo) and 95% CIs Olaparib 4 mg bd Placebo 52/136 (38%) 49/129 (38%) 8/31 (26%) 12/28 (43%) 11/18 (61%) 5/2 (25%) 33/87 (38%) 32/81 (4%) Favours olaparib Size of circle is proportional to number of events Purple band represents 95% CI for overall population Hypothesis: olaparib 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 gbrcam, germline BRCA1/2 mutation

11 gbrca Results: BRCA testing tbrca Mutated Wild type* Not available TOTAL Mutated Wild type* Not available (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 The number of patients with a known BRCAm status increased from 97 (36.6%) to 254 (95.8%) out of 265 *Wild-type group: includes patients with no known BRCAm or a mutation of unknown significance (a non-deleterious mutation) 265 Ledermann et al ASCO; J Clin Oncol 31, 213 (suppl; abstr 555)

12 Proportion of patients progression-free PFS by BRCAm status Number at risk Olaparib BRCAm Placebo BRCAm Olaparib BRCAm Placebo BRCAm BRCAm (n=136) Olaparib Placebo Events: total pts (%) 26:74 (35.1) 46:62 (74.2) Median PFS, months Time from randomization (months) HR=.18 95% CI (.11,.31); P< % reduction in risk of disease progression or death with olaparib Presented by: Jonathan Ledermann

13 Proportion of patients progression-free PFS by BRCAm status Number at risk Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt BRCAm (n=136) BRCAwt (n=118) Olaparib Placebo Olaparib Placebo Events: total pts (%) 26:74 (35.1) 46:62 (74.2) 32:57 (56.1) 44:61 (72.1) Median PFS, months Time from randomization (months) HR=.18 95% CI (.11,.31); P< HR=.53 95% CI (.33,.84); P=.7 BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance) Presented by: Jonathan Ledermann

14 Proportion of patients alive Study 19 updated overall survival: all patients Number at risk Randomized treatment Placebo Olaparib 4 mg bd Time from randomization (months) Overall population (n=265) Olaparib 4 mg bd 48 Placebo Deaths: total pts (%) 77:136 (56.6) 77:129 (59.7) Median OS, months HR=.88 95% CI (.64, 1.21); 8% CI (.72, 1.9) P=.438 Placebo Olaparib 4 mg bd At the interim OS data cut-off (26 Nov 212), 154/265 (58.1%) patients had died Presented by: Jonathan Ledermann

15 Proportion of patients alive OS in BRCAm patients Number at risk Olaparib BRCAm Placebo BRCAm Randomized treatment Olaparib BCRAm Placebo BRCAm Time from randomization (months) Olaparib 48 BRCAm (n=136) Placebo Deaths: total pts (%) 37:74 (5.) 34:62 (54.8) Median OS, months HR=.74 95% CI (.46, 1.19) P=.28 OS in BRCAwt patients: HR=.98; 95% CI, ; P=.946 Median OS: olaparib, 24.5 months; placebo, 26.2 months 14/62 (22.6%) placebo patients switched to a PARP inhibitor Presented by: Jonathan Ledermann

16 Intermediate clinical endpoints PFS: Primary endpoint Olaparib monotherapy Intermediate clinical endpoints TDT TFST PFS2 TSST OS PSR Chemo Maintenance treatment Chemo Chemo First subsequent treatment response PSR, platinum-sensitive relapse PFS, progression-free survival TDT, time to discontinuation of treatment (or death) TFST, time to first subsequent treatment (or death) PFS2, time to second progression (or death) TSST, time to second subsequent treatment (or death) OS, overall survival

17 Proportion of patients receiving study treatment or first subsequent therapy Time to second subsequent therapy (PFS2) Number at risk Olaparib BRCAm Placebo BRCAm Olaparib BRCAm Placebo BRCAm Time from randomization (months) BRCAm (n=136) Olaparib Placebo Events: total pts (%) 42:74 (56.8) 49:62 (79.) Median PFS, months HR=.46 95% CI (.3,.7); P< Presented by: Jonathan Ledermann

18 Proportion of patients receiving study treatment or first subsequent therapy Time to second subsequent therapy (PFS2) Number at risk Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt Time from randomization (months) BRCAm (n=136) BRCAwt (n=118) Olaparib Placebo Olaparib Placebo Events: total pts (%) 42:74 (56.8) 49:62 (79.) 42:57 (73.7) 55:61 (9.2) Median PFS, months HR=.46 95% CI (.3,.7); P<.3 HR=.64 95% CI (.42,.96); P=.32 BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance) Presented by: Jonathan Ledermann

19 Tolerability - long term use Fatigue, nausea and anemia main adverse effectsgenerally low grade 3 % patients on olaparib had a dose interruption ( 9% placebo) 19% needed dose reduction (2 % placebo) As of Nov More than 45 months after closure of study (~1%) patients remain on study treatment (olaparib, n=23; placebo, n=3) 33/136 patients (24%) have received >3 years of olaparib treatment, of whom 22 had a known BRCAm

20 Resistance to PARPi in BRCAm population ORR ( RECIST) ORR ( RECIST+ CA125) Platinum-based 4% ( 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 J-E et al Clin Cancer Res 213

21 PARP inhibitors with chemotherapy Should PARP inhibitors be compared to chemotherapy? Will additional benefit be obtained by adding PARP inhibitors to chemotherapy? Is there interaction between PARP inhibitors and chemotherapy?

22 Comparison of olaparib with Pegylated Liposomal Doxorubicin Study 12 Olaparib (2) Olaparib (4) PLD Confirmed RECIST response and/or CA-125 response 12 (38) 19 (59) 13 (39) efficacy of olaparib (4 mg bd) was as predicted, with response (RECIST/CA125 ) in 59% and median PFS of 8.8 m. HR.88 p =.66 PLD was more effective than anticipated (response 39%; median PFS 7.1 m), thus no significant difference in primary end-point overall, both treatments well tolerated (<1% discontinuation) Kaye SB et al, J.Clin. Onc

23 Randomised Phase II Study of Carboplatin/Paclitaxel ± Olaparib in Platinum-Sensitive Recurrent Ovarian Cancer- Study sites, 12 countries 162 patients recruited Feb - July 21 Serous histology 3 previous platinumbased regimes > 6 months progression-free after last platinum R A N D O M I S E N = 81 N = 81 Paclitaxel 175mg/m² Carboplatin AUC 4 & olaparib 2mg bd for 1 days q 21 Paclitaxel 175mg/m² carboplatin AUC 6 q 21 N=66 N =55 Maintenance olaparib 4mg bd until progression No maintenance treatment Primary end point: PFS BRCA mutation positive 12 (14%) in each arm Oza et al ASCO 212

24 Proportion of patients progression free Progression-free survival*: Study Olaparib + P + C (AUC4) P + C (AUC6) Events: Total patients (%) Median (months) O + P + C 47:81 (58.) Time from randomization (months) Number of patients at risk O + P + C P + C P + C 55:81 (67.9) Hazard ratio =.51 95% CI (.34,.77) p=.12 *Central review data Oza, et al. J Clin Oncol 3, 212 (suppl; abstr 51)

25 GOG 9923: Phase I study of veliparib (ABT-888) for first-line therapy in ovarian cancer Phase A: (Cycle repeated every 21 days for a total of 6 cycles) Phase B Eligible patients Newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer FIGO Stage II IV defined surgically Regimen I Continuous Paclitaxel 175 mg/m 2, Day 1 Carboplatin AUC 6, Day 1 Bevacizumab 15 mg/kg, Day 1* ABT-888 twice daily, Days 1 21** Regimen II Continuous Paclitaxel 175 mg/m 2, Days 1,8,15 Carboplatin AUC 6, Day 1 Bevacizumab 15 mg/kg, Day 1* ABT-888 twice daily, Days 1 21** Stage II IV: ovarian, peritoneal, fallopian tube cancers; Post-surgery: all histologies *Bevacizumab from cycle 2 **ABT-888 to be dose escalated through cohorts or or Regimen III Continuous Paclitaxel 135 mg/m 2, Day 1 Cisplatin 75 mg/m 2 IP, Day 1 OR 2 Paclitaxel 6 mg/m 2 IP, Day 8 Bevacizumab 15 mg/kg, Day 1* ABT-888 twice daily, Days 1 21** or Regimen I Intermittent Paclitaxel 175 mg/m 2, Day 1 Carboplatin AUC 6, Day 1 Bevacizumab 15 mg/kg, Day 1* ABT-888 twice daily, Days 1 21** Regimen II Intermittent Paclitaxel 8 mg/m 2, Days 1,8,15 Carboplatin AUC 6, Day 1 Bevacizumab 15 mg/kg, Day 1* ABT-888 twice daily, Days 2 5** Regimen III Intermittent Paclitaxel 135 mg/m 2, Day 1 Cisplatin 75 mg/m 2 IP, Day 1 OR 2 Paclitaxel 6 mg/m 2, IP Day 8 Bevacizumab 15 mg/kg, Day 1* ABT-888 twice daily, Days 2 5** Bevacizumab will be continued as maintenance for Cycles 7 22 every 21 days NCT989651

26 Predictive markers of Response to PARPi Lee J-m et al Ann Oncol 214) 25:32

27 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 For ovarian cancer: repeated response to platinum-based chemotherapy prolonged survival (>5 yrs) high grade serous histology 1 Mukhopadhay et al, Clin Cancer Res, 21, 16, Graeser et al, Clin Cancer Res, 21; epub 3 Konstantinopoulos et al, J Clin Oncol, 21, 28,

28 Gene expression profiling for BRCAness and correletion with outcome Konstantinopoulos et al J Clin Oncol 21

29 PARP inhibitors in ovarian cancer Agent Sponsor Status Olaparib (AZD-2281) Veliparib (ABT-888) Niraparib (MK4827) Rucaparib (AG14699, PF ) AstraZeneca (Kudos) Abbott Pharma Tesaro (Merck) Clovis (Pfizer) Completed randomized maintenance Phase II trials. Application of Marketing Authorisation with EMA. Reformulation: Now in phase III SOLO-1 & SOLO-2 maintenance programme NCI-CTEP, Phase I concurrent chemotherapy trials in progress, non-randomized Phase II study in BRCAmutated ovarian cancer: Phase III under consideration Phase I/II data show comparable activity to olaparibperhaps more potent with high response in platinumresistant population: NOVA Phase III maintenance trial in progress Phase I/II chemotherapy trial completed with oral compound. Phase II and phase III trials - ARIEL 2 and ARIEL 3 in progress BMN-637 Biomarin Confirmed activity in phase I trial

30 SOLO-1 & SOLO 2 Programme BRCAm population only First-line maintenance or maintenance in platinumsensitive setting Response to platinum-based chemotherapy Randomisation 2:1 Olaparib Placebo SOLO patients 2 years PFS/PFS2/OS + QoL SOLO patients to progression PFS/PFS2/OS + Qol

31 NOVA and ARIEL3 Programmes Both studies include a BRCAm and High Grade Serous wild type subsets Platinum-sensitive ovarian cancer responding to platinum-based therapy Randomisation 2:1 PARPi Placebo Niraparib 36 patients 2 cohorts - BRCAm & BRACwt Rucaparib 54 patients 2 cohorts BRCAm & BRCAwt Identification of companion diagnostic marker to select patients with HRD, most likely to benefit

32 How common is BRCA mutation in HGSOC? Australian Ovarian Cancer Study Group: 11 patients with nonmucinous carcinomas studied 14.1% had germline mutation- 16.6% of serous, 22.6% of high-grade serous 44% had NO family history of ovarian or breast cancers Alsop et al. J Clin Oncol 212;3:2654 Should we now be testing all patients with high-grade serous ovarian cancer? NICE UK Familial Breast Cancer Guidance CG164, June 213

33 Conclusions PARP inhibitor maintenance phase III programme in ovarian cancer is in progress More work needed to study role in combination with chemotherapy or other targeting agents Discovery and validation of predictive markers of response ( eg HRD) are a top priority Emergence of PARPi resistance is usual and mechanisms poorly understood. Tumours may remain sensitive to retreatment with chemotherapy Some patients super responders with remission lasting several years Position in treatment pathway needs careful consideration

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