Nombre de la sesión Papel de los Inhibidores del PARP en el tratamiento del cáncer de ovario Antonio González Martín Clinica Universidad de Navarra GEICO & ENGOT

Disclosure Information Employment: NO Consultant or Advisory Role: AZ, TESARO. CLOVIS, MSD, ROCHE, Pfizer/MERCK, INMUNOGEN, GENMAB Stock Ownership: NO Research Funding: TESARO, ROCHE Speaking: ROCHE, TESARO, AZ, PHARMAMAR Grant support: NO Other: Travel and accommodation: TESARO, AZ

Disclaimer: de cara a dar una vision balanceada, completa y actualizada de la situación del tratamiento del cancer de ovario, se incluyen en algunas partes de esta presentación datos de ensayos clínicos de diferentes moléculas, en proceso de aprobación por la EMA.

Agenda Mechanisms of action Clinical development update Papel de los inhibidores de PARP en cáncer de ovario Agenda Mechanisms of action Clinical development update Future directions

Mechanisms of action

DNA Damage Response DNA DAMAGE Cell death MAJOR DNA REPAIR PATHWAYS Environmental factors (UV, radiation, chemicals) DNA DAMAGE Normal physiology (DNA replication, ROS) Cell death Chemotherapy (alkylating agents, antimetabolites) Radiotherapy MAJOR DNA REPAIR PATHWAYS Replication lesions Base excision repair PARP1/PARP 2 Single strand breaks Mismatch repair (MMR) Nucleotide excision repair (NER) Base excision repair (BER) PARP1/PARP 2 PARP, poly(adenosine diphosphate ribose) polymerase; ROS, reactive oxygen species; UV, ultraviolet.   Double strand breaks Nonhomologous end-joining Homologous recombination BRCA1/BRCA2 Fanconi anemia pathway Endonuclease-mediated repair DNA adducts/base damage Alkyltransferases Nucleotide excision repair Base excision repair PARP1/PARP 2 Helleday T, et al. Nat Rev Cancer. 2008;8:193-204. O’Shaughnessy J, et al. ASCO 2009. Abstract 3. Reproduced with permission.

Synthetic Lethality “Phenomenon in which 2 non- lethal genetic mutations are innocuous when they occur individually, but which result in lethality to a cell in combination” Theodosius Dobzhansky, 1946

20% HGSOC are BRCA 1/2 mut BRCA1/2 germline mutation 14% Homologous recombination (HR) deficient Not HR deficient BRCA1 germline 8% BRCA2 6% somatic 3% methylation 11% EMSY amplification PTEN loss 5% Other HRD 7% CCNE1 amplification 15% MMR 2% Other 34% BRCA1/2 germline mutation 14% BRCA1/2 somatic mutation 6% Total 20% Levine D. The Cancer Genome Atlas, Molecular profiling of serous ovarian cancer, 2011

PARP catalytic cycle Tens of thousands of endogenous SSBs form transiently every day, and PARP1 and PARP2 are critical for their repair

PARP inhibitor and Homologous Recombination Repair DNA SSBs occur all the time in cells and PARP detects and repairs them During the replication process unrepaired SSBs are converted into DSBs Replicating cells Survival Normal cell Repair by Homologous Recombination No effective repair (No HR pathway) Cell death Cancer cell with HRD Tumour specific killing by PARP Inhibitors

PARP inhibitor Trapping (vii) Several clinical PARPi, each of which binds the catalytic site, prevent the release of PARP1 from DNA, “trapping” PARP1 at the site of damage, potentially removing PARP1 from its normal catalytic cycle.

PARP inhibitors

Presented By Elise Kohn at 2015 ASCO Annual Meeting Trapping potency of PARPi Slide 15 Presented By Elise Kohn at 2015 ASCO Annual Meeting

Clinical development update

RR 50% (8/16) in OC and BRCA mut Clinical Development Phase I Expansion cohort Non-BRCA mutated RR 43% (23/50) OC and BRCA mut RR 24% (11/46) OC and BRCA wt RR 50% (8/16) in OC and BRCA mut Dose up to 400 bid Fong P et al. New Eng J Med 2009 Fong P et al. J Clin Oncol 2010 Gelmon KA, et al. Lancet Oncol 2011;12:852–61

Desarrollo clínico de inhibidores de PARP en monoterapia Monoterapia BRCAmut Study 42 (O) Study 10 & ARIEL-2 (R) QUADRA (N) Mantenimiento 1ª Línea SOLO1 (O) (BRCA) PRIMA (N) (All comers) Mantenimiento > 2ª línea Study-19 (O) SOLO-2 (O)(BRCA) NOVA (N) (All comers ARIEL-3 (R) (All comers) O: olaparib; N: niraparib; R: rucaparib

PARPi as single agent in BRCAmut Olaparib1 Study 42 Rucaparib2 Study-10 & ARIEL-2 Niraparib3 QUADRA Prior number of lines > 3 lines > 2 lines N 137 106 (74.5% Plat-S) 463 (68% plat-R) ORR 34% 53.8% 29% Median PFS (months) 7 10 - Median DOR (months) 7.9 9.2 9.4 Approval FDA FDA and EMA (Plat-S) Kaufman B et al.. J Clin Oncol 2015; 33(3): 244–250. 2. Oza et al. Gyn Oncol 2017; 147 (2017) 267–275 3. Moore K et al. Lancert Oncol 2019 Apr 1. pii: S1470-2045(19)30029-4

Ledermann J, et al. N Engl J Med 2012;366:1382–92 Platinum combination followed by iPARP maintenance Olaparib study-19 design and results Study-19 aim and design Study-19 PFS 265 patients Olaparib 400 mg po bid 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 Randomized 1:1 Placebo po bid 11.2 vs 4.3 months HR 0.18 (95% CI: 0.10-0.31) Primary end point : PFS Ledermann J, et al. N Engl J Med 2012;366:1382–92 Ledermann et al. Lancet Oncol. 2014;15(8):852–861

Long-term outcome with olaparib in Study-19 15% 11% Lederman et al. Lancet Oncol 2016; 17: 1579–89

Clinical Trials Designs and Patient’s Characteristics 1SOLO-2 2ENGOT-OV16 / NOVA 3ARIEL-3 Random 2:1 with placebo Olaparib 300 mg bid Niraparib 300 mg once daily Rucaparib 600 mg bid BRCA status BRCAmut gBRCA Non-gBRCA All comers Histology HGS/HGEOC HGSOC TFIp prior line > 6 months Prior lines 2 > 2 56% 44% 51% 49% 66% 34% 62% 38% Best response CR PR 46% 54% 50% 66%* Lesion > 2 cm 15% 0% 19% *Normal CA125 required 1. Pujade et al. Lancet Oncol 2017; 18: 1274–84 2. Mirza et al. N Eng J Med 2016;375(22):2154-2164.; 3. Coleman et al. Lancet 2017; 390: 1949–61

Efficacy of PARPi in BRCA mutant patients Primary endpoint: PFS 1SOLO-2 2NOVA 3ARIEL-3 19.1 vs 5.5 months HR 0.3 (95% CI: 0.22-0.41) 21.0 vs 5.5 months HR 0.27 (95% CI: 0.17-0.41) 16.6 vs 5.4 months HR 0.23 (95% CI: 0.16-0.34) 1. Pujade et al. Lancet Oncol 2017; 18: 1274–84 2. Mirza et al. N Eng J Med 2016;375(22):2154-2164.; 3. Coleman et al. Lancet 2017; 390: 1949–61

…what if gBRCA is wild-type? Is HRD a biomarker?

myChoice HRD test (Myriad Genetics) Genomic LOH HRD test (Foundation) Hypothesis: HRD may explain long term outcome with PARPi in BRACwt Consequently: HRD may be a potential predictive biomarker beyond BRCA myChoice HRD test (Myriad Genetics) Genomic LOH HRD test (Foundation) HRD is a numerical score (0- 100) resulting from the sum of three components scores LOH: loss of heterozygosity TAI: Telomeric Allelic Imbalance LST: large-scale state Transition A cut off point of 42 is able to capture 95% of BRCA mut and was used to identify BRCAwt HRD+ tumors Wilcoxen et al. ASCO 2015. Poster #5532

Efficacy of PARPi in non-gBRCAmutant patients ENGOT-ov16/NOVA PFS: non-gBRCAmut PFS: HRD positive PFS: HRD negative Treatment PFS Median (95% CI) (Months) Hazard Ratio (95% CI) p-value Niraparib (N=234) 9.3 (7.2, 11.2) 0.45 (0.338, 0.607) p<0.0001 Placebo (N=116) 3.9 (3.7, 5.5) Treatment PFS Median (95% CI) (months) Hazard Ratio (95% CI) P value Niraparib (N=106) 12.9 (8.1, 15.9) 0.38 (0.243, 0.586) P<0.0001 Placebo (N=56) 3.8 (3.5, 5.7) Treatment PFS Median (95% CI) (Months) Hazard Ratio (95% CI) p-value Niraparib (N=92) 6.9 (5.6, 9.6) 0.58 (0.361, 0.922) p=0.0226 Placebo (N=42) 3.8 (3.7, 5.6) Mirza et al. N Eng J Med 2016;375(22):2154-2164.

Efficacy of PARPi in BRCAwt patients ARIEL-3 PFS: BRCAwt LOH high PFS: BRCAwt LOH low 9.7 months vs 5.4 months HR 0.44 (0.29–0.66); p<0.0001 6.7 months vs 5.4 months HR 0.58 (0.40–0.85); p=0.0049 Coleman et al. Lancet 2017; 390: 1949–61

Safety Profile of PARPi Olaparib (SOLO-2) Niraparib (ENGOT OV-16/NOVA) Rucaparib (ARIEL 3) Discontinuation 11% 14.7% 13.4% Dose reduction 25% 66.5% 54.6% Related SAE 17.9% 16.9% - Nausea/vomiting, grade >3 2.6% 3% 7.8% Fatigue, grade >3 4.1% 8% 6.7% Anemia, grade >3 19.5% 25 % 18.8% Thrombocytopenia, grade >3 1% 33 % 5.1% Neutropenia, grade >3 19% MDS 4 (2.1%) 5 (1.4%) 3 (0.8%) GOT/GPT, grade >3 10.5% MDS, myelodysplastic syndrome; SAE, serious adverse event 1. Pujade et al. Lancet Oncol 2017; 18: 1274–84 2. Mirza et al. N Eng J Med 2016;375(22):2154-2164.; 3. Coleman et al. Lancet 2017; 390: 1949–61

Stratified by response to platinum-based chemotherapy SOLO-1: Study design Primary endpoint Investigator-assessed PFS (modified RECIST 1.1) Secondary endpoints PFS using BICR PFS2 Overall survival Time from randomization to first subsequent therapy or death Time from randomization to second subsequent therapy or death HRQoL (FACT-O TOI score) Newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid ovarian, primary peritoneal or fallopian tube cancer Germline or somatic BRCAm ECOG performance status 0–1 Cytoreductive surgery* In clinical complete response or partial response after platinum-based chemotherapy Olaparib 300 mg bd (N=260) Study treatment continued until disease progression Patients with no evidence of disease at 2 years stopped treatment Patients with a partial response at 2 years could continue treatment HR 0.62 2:1 randomization Stratified by response to platinum-based chemotherapy Placebo (N=131) From September 3, 2013, to March 6, 2015, a total of 391 patients underwent randomization 2 years’ treatment if no evidence of disease *Upfront or interval attempt at optimal cytoreductive surgery for stage III disease and either biopsy and/or upfront or interval cytoreductive surgery for stage IV disease. BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology Group; FACT-O, Functional Assessment of Cancer Therapy – Ovarian Cancer; FIGO, International Federation of Gynecology and Obstetrics; HRQoL, health-related quality of life; PFS2, time to second progression or death; RECIST, Response Evaluation Criteria in Solid Tumours; TOI, Trial Outcome Index

SOLO-1: Patients September 2013 to March 2015 391 patients 260 Olaparib 131 Placebo 85% ovary 80% ECOG 0 80-85% FIGO III 2/3 PDS 75% R0 1/3 NACT (IDS) 80% R0 82% CR 18% PR

PFS by investigator assessment Olaparib (N=260) Placebo (N=131) Events (%) [50.6% maturity] 102 (39.2) 96 (73.3) Median PFS, months NR 13.8 HR 0.30 95% CI 0.23, 0.41; P<0.0001 PFS by investigator assessment 100 60% 90 80 70 60 Olaparib progression-free survival (%) Investigator-assessed 50 40 30 20 27% 10 Placebo 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Months since randomization 131 103 82 65 56 53 47 41 39 38 31 28 22 6 5 1 118 No. at risk Placebo 260 229 221 212 201 194 184 172 149 138 133 111 88 45 36 4 3 240 Olaparib Olaparib 260 240 229 221 212 201 194 184 172 149 138 133 111 88 45 36 4 3 NR, not reached

SOLO-1: Subgroup analysis CR HR 0.35 Residual HR 0.44 FIGO III HR 0.32 PR HR 0.19 No-Resid HR 0.33 FIGO IV 0.49

Summary of efficacy endpoints HR 0.30 95% CI 0.23, 0.41; P<0.0001 Median PFS Median time to first subsequent therapy or death HR 0.30 95% CI 0.22, 0.40; P<0.0001 HR 0.50 95% CI 0.35, 0.72; P=0.0002 Median PFS2 Median time to second subsequent therapy or death HR 0.45 95% CI 0.32, 0.63; P<0.0001

Health-related quality of life: FACT-O TOI score* Olaparib Placebo Change from baseline in TOI score Weeks since randomization 218 115 204 114 No. at risk Olaparib Placebo 35 30 25 20 15 10 5 -40 -35 -30 -25 -20 -15 -10 -5 13 37 49 61 73 85 97 191 104 186 91 179 75 163 61 144 51 141 49 137 42 The difference between olaparib and placebo in the mean change from baseline in TOI score over 24 months (−3.00; 95% CI −4.779, −1.216) was not clinically meaningful *TOI scores range from 0 to 100, with higher scores indicating better HRQoL and a clinically meaningful difference defined as ±10 points Figure reproduced from: Moore K et al. N Engl J Med 2018; 379(26):2495–505

Most common treatment-emergent adverse events Olaparib (N=260) Placebo (N=130) Nausea 77.3 0.8 37.7 Fatigue/asthenia* 63.5 3.8 1.5 41.5 Vomiting 40.0 0.4 0.8 14.6 Anaemia* 38.8 21.5 1.5 10 Diarrhoea 34.2 3.1 24.6 All grades (frequency ≥25%) Constipation 27.7 19.2 Grade ≥3 (frequency ≥5%) Dysgeusia 26.2 3.8 All grades (frequency ≥25%) Arthralgia 25.4 26.9 Grade ≥3 (frequency ≥5%) Neutropenia* 23.1 8.5 4.6 11.5 100 75 50 25 25 50 75 100 Adverse events (%) *Grouped terms. All-grade thrombocytopenia (grouped term) occurred in 11.2% of patients in the olaparib group and 3.8% of patients in the placebo group and grade ≥3 thrombocytopenia (grouped term) occurred in 0.8% and 1.5%, respectively

New algorithm in front line After SOLO-1 SoC CT ± BEV BRCAmut gBRCA sBRCA BRCA non-mutant CT  Ola CT ± BEV

ENGOT ov26 / PRIMA Study pre-enrollment screening: Platinum responsive ovarian cancer Stage III or IV ovarian CR or PR with front line platinum-based chemotherapy HRDpos or HRDneg/not determined (nd) tumor pre-enrollment screening: centralized HRD testing for all patients local sBRCA and/or gBRCA test results are allowed 2:1 Randomization Stratification factors: Use of NACT: yes or no Best tumor response: CR or PR HRD status: pos or neg/nd Niraparib 300 mg Placebo Patients with sBRAC or tBRCAmut will be stratified as HRDpos Patients with unknown or wild type BRCA will be stratified based on HRD test results Endpoint assessment Estimated enrollment = 490 Study Design: Double-blind, 2:1 randomized, placebo-controlled Treatment setting: maintenance following response Patients Platinum-sensitive disease Known gBRCAmut or a tumor with high-grade serous histology At least 2 previous courses of platinum-based regimens No measurable disease <2 cm and normal CA-125 (or 90% decrease) and response following their last treatment Endpoints Primary: PFS in each cohort gBRCA: patients with deleterious gBRCA mutations Non-gBRCA: patients without such gBRCA mutations Secondary PRO OS Safety and tolerability CFI Concordance with BRCA genetic testing CA125 PFS2 Primary Endpoint PFS in HRDpos patients; hierarchical analysis for all patients regardless of HRD status Key Secondary Endpoints Overall survival (OS), patient reported outcomes (PRO’s), time to first subsequent treatment, progression- survival-2 , time to CA-125 progression, safety and tolerability of study therapy HRD=homologous recombination deficiency; CR=complete response; PR=partial response; PFS=progression-free survival; CONFIDENTIAL

Future Directions

(Olaparib Retreatment in late recurrent Ovarian cancer) OReO – ENGOT-Ov38 (Olaparib Retreatment in late recurrent Ovarian cancer) R A N D OM I Z A T O Eligible patients Relapsed non-mucinous EOC Documented BRCA1/2 status Treatment with one course of PARPi maintenance therapy PR/CR after≥4 cycles of platinum-based chemo Olaparib tablets 300 mg bid or last tolerable dose Placebo PFS Primary endpoint (RECIST 1.1) PFS, OS, TTP ‡, TDT, TFST, TSST, HRQoL, Safety Stratification factors: Prior bevacizumab ≤3 vs ≥4 prior lines of chemotherapy 136 patients with a germline or somatic mutation in BCRA1/2 Exposure for ≥18 months after first-line Cx or ≥12 months after second-/later-line chemotherapy Cohort 1 BRCAm 280 patients Exposure for ≥12 months after first-line Cx or ≥6 months after second-/later-line chemotherapy Cohort 2 non-BRCAm PR or CR to most recent course of platinum-based chemotherapy (no bevacizumab) How stable are the mechanisms of resistance is something that OREO could potentially answered

Optimizing PARPi efficacy: Combinations Anti-angiogenic iPARP

Combination of PARPi and anti-angiogenic agent Olaparib Olaparib Cediranib N 46 44 PFS all 8.2 m 16.5 m HR 0.5 (p 0.007) PFS BRCAwt 5.7 m 23.7 m P 0.002 OS BRCAwt 23 m 37.8 m P 0.047 Hypothesis Hypoxia induced by antiangiogenic agents may (re)create homologous recombination repair deficiency, thus enhancing the effect of PARP inhibition Liu et al. Ann Oncol 2019

Combination of PARPi and anti-angiogenic agent STUDY LEAD GROUP COMBINATION SETTING ICON-9 MRC Olaparib vs Cediranib - Olaparib Maintenace 1st platinum-sensitive relapse GY-004 NRG Cediranib - Olaparib vs TPC Platinum-sensitive AVANOVA NSGO Niraparib vs Niraparib - Bevacizumab GY-005 Cediranib vs Olaparib vs Olaparib – Cediranib vs Non-Platinum TPC Platinum-resistant

PAOLA 1 / ENGOT OV-25 Phase III randomized, placebo-controlled, double-blind, multicenter Olaparib tablets administered at 600 mg daily for up to 2 years. ) Stratification factors: First-line treatment outcome (complete resection after initial surgery and NED at screening, complete resection at interval debulking surgery and NED at screening, incomplete resection at initial or interval debulking surgery and in CR at screening, PR at screening) & gBRCA status (yes, no, unknown) 42

Combination of PARPi and immunetherapy Preclinical data PARPi upregulates PD-L1 in BC xenograft Sinergy of PARPi and anti-PD-L1 Jiao et al. Clin Can Res 2017

TOPACIO/Keynote-162 (PROC) Niraparib 200 mg/d + pembrolizumab 200 mg/21d 60 evaluable patients ORR: 25% ORR BRCAmut: 42% ORR in PR: 23% ORR in PRf: 24% Kostantinopoulos et al. ESMO 2017 and ASCO 2018

ENGOT-OV41/GEICO 69-O/ANITA N= 414 patients A Niraparib+ Placebo until disease progression, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor Platinum doublet+ Placebo 6 cycles Recurrent high- grade serous or endometrioid, or undifferentiated ovarian, primary peritoneal or tubal carcinoma TFIp >6 months ≤ 2 prior lines Measurable disease ECOG≤ 1 RECIST v1.1 CT SCAN RANDOMIZATION 1:1 If CR, PR or SD B Platinum-doublet + Atezolizumab 6 cycles Niraparib+ Atezolizumab disease progression, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor Primary Endpoint: PFS by RECIST v.1.1 Secondary endpoints: Safety and tolerability TFST, TSST,PFS2,OS ORR, DOR QoL/PRO The addition of atezolizumab is expected to increase the median PFS of Arm A from 16 months to 22.9 months, corresponding to a 30% reduction of the risk of progression (average HR of 0.70)   Stratification factors: Platinum based regimen selected PFI (6-12 months vs > 12 months) BRCA mutation status (mutated vs. non-mutated)

Front line for Stage III/IV with PARPi / IO /Bev TRIAL Setting Patient selection Arms AGO / DUO-O ENGOT Ov46 Front line PDS or IDS Any residual LGSOC excluded Bev mandatory CP-Bev CP-Bev-Durvalumab CP-Bev-Durvalumab-Olaparib BGOG /ENGOT Ov43 BRCA non-mut*, Any histotype Bev optional CP-Placebo-Placebo CP- Pembro-Placebo CP- Pembro-Olaparib GINECO/ FIRST ENGOT Ov44 PDS (high risk) or IDS Mucinous excluded CP-Placebo-Niraparib CP-TSR042-Niraparib ATHENA GOG3020/ ENGOT OvXX Maintenance after front line PDS or IDS Response to platinum Ruca-Nivo Ruca-Placebo Nivo-Placebo Placebo-Placebo * Clinical trial with NACT for BRACmut under discussion

Summary PARPi therapy is one of the most important advances for ovarian cancer patients in the last decades Maintenance with PARPi improves significantly the PFS and the time to subsequent therapy in platinum-responders patients in front line and in the recurrent setting. BRCA mutated patients benefit most, but no biomarker is good enough to rule out the benefit in BRCAwt patients as maintenance in recurrent setting Several ongoing trials are addressing different combinations in different settings

Muchas Gracias! Antonio González Martín Clínica Universidad de Navarra, Madrid GEICO (Grupo Español de Investigación en Cáncer de Ovario) ENGOT (European Network of Gynecological Oncological Trials groups)