Conclusion Dr Antonio González Martín Head of Medical Oncology MD Anderson Cancer Centre, Madrid, Spain Associate Professor of Medicine Francisco de Vitoria University, Madrid, Spain Adjunct Professor University of Texas, USA ESMO 2018 Munich, Germany

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PARPi maintenance therapy traditional Watch & Wait A paradigm shift with the introduction of PARP inhibitor maintenance therapy PARPi maintenance therapy Debulking surgery Chemotherapy traditional Watch & Wait Tumour volume Treatment-free interval Recurrence Symptoms Point of decision Maintenance Time

Pharmacokinetic and -dynamic profiles of PARP inhibitors Absorption Distribution Metabolism Elimination F (%) Papp (10-6 cm/s) Vd/F (L) Major enzyme t1/2 (h) Niraparib 731 12-182 1,0741 CE1 48-511 Olaparib NA3 4-84 1675 CYP3A45 11.95 Rucaparib 366 6-87 113-2626 CYP2D66 17-196 Niraparib is characterised by: High tumour penetration – largest volume of distribution No relevant drug-drug interaction Once daily dosing with or without food1 F, bioavailability; Papp, apparent permeability; t1/2, half-life; Vd, volume of distribution; CE, carboxyl esterase; CYP, cytochrome p450 oxidase 1. ZEJULA® Summary of Product Characteristics, Nov 2017; 2. TESARO Inc., Data on File; 3. CHMP Assessment Report: Lynparza (EMA/CHMP/789139/2014). Available at: http://www.ema.europe.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003726/WC500180154.pdf. Accessed Jan 2018. 4. Clinical pharmacology and biopharmaceutics review: Lynparza. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf. Accessed Jan 2018; 5. Lynparza Summary of Product Characteristics, July 2017; 6. Rubraca package leaflet, Dec 2016; 7. Durmus S, et al. Pharm Res 2015;32(1):37-46. 8. Zhang ZY, et al. Oral presentation at ISSX 2015, Oct 18-22, 2015, Orlando, USA.

PFS, non-gBRCA cohort (N=350) Niraparib significantly increased PFS vs placebo – in gBRCA and non-gBRCA cohorts PFS, gBRCA cohort (N=203) PFS, non-gBRCA cohort (N=350) 1.0 0.8 0.6 0.4 0.2 PFS probability Time (months) 6 12 18 24 HR = 0.27 (95% CI: 0.17–0.41) p < 0.001 1.0 0.8 0.6 0.4 0.2 PFS probability Time (months) 6 12 18 24 HR = 0.45 (95% CI: 0.34–0.61) p < 0.001 Niraparib Niraparib PFS 21.0 months PFS 9.3 months Placebo Placebo PFS 5.5 months PFS 3.9 months PFS, progression free survival; HR, hazard ratio; CI, confidence interval; BRCA, breast cancer gene; gBRCA, germline BRCA mutation; non-gBRCA, no germline BRCA mutation Mirza MR, et al. N Engl J Med 2016;375(22):2154-2164.

Dose individualisation Dose individualisation based on body weight and platelets does not impact efficacy Baseline body weight: <77 kg Baseline platelets: <150,000/µL OR Time (months) 1.0 0.8 0.6 0.4 0.2 4 8 12 16 20 24 ■ 200 mg ■ 100 mg ■ 300 mg PFS Starting dose Dose individualisation Patients <77 kg or platelets <150,000 200 mg (Two 100 mg capsules, QD) 300 mg 200 mg 100 mg Patients ≥77 kg and platelets ≥150,000 300 mg (Three 100 mg capsules, QD) From Month 4: HR (300 vs 200): 1.01 (95%CI: 0.69, 1.48) From Month 4: HR (300 vs 100): 1.05 (95%CI: 0.84, 1.31) *With dose modifications HR, hazard ratio; PFS, progression free survival; QD, once daily 1. Moore KN, et al. Gynecol Oncol 2018: https://doi.org/10.1016/j.ygyno.2018.01.011 2. Lord R, et al. SGO 2018.

Individualised dosing reduces haematological adverse events in PRIMA study Haematological toxicities Grade Pre-amendment, fixed starting dose 300 mg QD (Pooled niraparib & placebo) Post-amendment, individualised starting dose 300 + 200 mg QD N=480 N=247 Thrombocytopenia Any grade, n (%) 164 (34.2) 50 (20.2) ≥Grade 3, n (%) 110 (22.9) 22 (8.9) Grade 4, n (%) 76 (16.5) 8 (3.2) Anaemia† 229 (47.7) 77 (31.2) 101 (21.0) 27 (10.9) Neutropenia‡ 148 (30.8) 57 (23.1) 75 (15.6) 23 (9.3) *†Anaemia events included anaemia and haemoglobin decrease ‡Neutropenia events included neutropenia, febrile neutropenia, and neutrophil count decrease QD, once daily Gonzalez-Martin A, et al. PRIMA. Presented at ESMO 2018.

PRIMA patient population reflects clinical practice SOLO 1 (olaparib)1,2 PRIMA (niraparib)3 Patient population N=391 (randomised to olaparib [n=260] or placebo arm [n=131]) High-grade (stage III-IV) ovarian, fallopian tube, or primary peritoneal cancer Stage III patients must have had one debulking surgery One attempt at optimal debulking, upfront or IDS Stage IV patients must have had either biopsy and/or debulking surgery Biopsy and/or upfront or interval debulking Completed 1L platinum-based chemo 6-9 cycles of front-line chemotherapy, per protocol CR/PR or NED to 1L platinum regimen Some patients had residual macroscopic disease BRCAmut (mostly germline, 2 patients had somatic mutations) Randomised within 8 weeks of last dose of chemo N=733 (LPI 13JUN18; increase from 468) Stage III patients required to have visible residual disease after primary surgery Stage IV patients are eligible, irrespective of residual disease, after primary or interval debulking Patients with inoperable Stage III or IV disease are eligible CR/PR to 1L platinum regimen All comers Randomised within 12 weeks of last dose of chemo Dosing 300 mg BID Dose reduction to 250 mg and 200 mg permitted 200 mg QD starting dose for low body weight (<170 lb) or low baseline platelet count (<150,000 uL) 300 mg QD for all other patients Primary endpoint PFS; investigator-assessed RECIST [scans every 12 weeks up to 3 years; every 24 weeks thereafter until radiological disease progression] PFS; central review RECIST [scans every 12 weeks until progression] Hierarchical testing: HRD+; ITT Key secondary endpoints OS; HRQoL; time to earliest progression by RECIST or CA-125; PFS2; TFST; TSST; TDT; safety OS; PRO (HRQoL); PFS2; Time to CA-125 progression; safety & tolerability For reference only, cross-trial comparisons are inappropriate ClinicalTrials.gov Identifier: NCT01844986. Moore K, et al. N Engl J Med 2018; DOI: 10.1056/NEJMoa1810858. ClinicalTrials.gov. NCT02655016. BID, twice daily; BRCA, breast cancer gene; CR, complete response; HRQoL, health-related quality of life; HRD, homologous recombination deficiency; ITT, intention to treat; OS, overall survival; PFS, progression free survival; PR, partial response; PRO, patient-reported outcomes; QD, once daily; TDT, time to treatment discontinuation; TFST, time to first subsequent therapy; TSST, time to second subsequent therapy

Stratification factors FIRST: Phase 3, randomised, placebo-controlled comparison of platinum-based therapy with TSR-042 and niraparib vs. standard of care as first-line treatment Concurrent bevacizumab use BRCA/HRD status Disease burden: Stage III with residual disease <1 cm (yes or no) Stratification factors Newly diagnosed stage III/IV advanced ovarian cancer Cycle 1: Carboplatin + paclitaxel ± bevacizumab Randomisation Estimated enrolment: =~720 to 960 Treatment 21days cycle x 5 cycles Carboplatin + Paclitaxel + Placebo (TSR-042) Carboplatin + Paclitaxel + Placebo (TSR-042) Carboplatin + Paclitaxel + TSR-042 +/- Bevacizumab Maintenance Up to 3 years Placebo (TSR-042) + Placebo (Niraparib) Placebo (TSR-042) + Niraparib TSR-042 + Niraparib Gonzalez-Martin et al. ESMO Poster Figure 1 and Study Assessments PROs +/- Bevacizumab (i.e., maintenance doublets and triplets) Adaptive design anticipates evolving first-line standard of care: double-placebo maintenance arm may be transitioned to niraparib maintenance for BRCAmut (pending SOLO-1 success) and BRCAwt (pending PRIMA success) patients over time Primary Endpoint PFS by investigator-assessment per RECIST v1.1 criteria Key Secondary Endpoints Overall Survival PFS by BICR HRQoL Safety & Tolerability PFS by irRECIST BRCA, breast cancer gene; HRD, homologous recombination deficiency; PFS, progression-free survival; RECIST, response evaluation criteria in solid tumours; BICR, blinded independent central review; irRECIST, immune-related response criteria in solid tumours; HRQoL, health-related quality of life; OS, overall survival 1. https://www.clinicaltrials.gov/ct2/show/NCT03602859; Accessed 30.7.18; 2. TESARO, Inc. Data on File.

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