European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: Phase 3, Randomised, Double-Blind Study of Rucaparib vs Placebo Following

Response to Platinum-Based Chemotherapy for Recurrent Ovarian Carcinoma (OC)

Jonathan A. Ledermann,1 Amit M. Oza,2 Domenica Lorusso,3 Carol Aghajanian,4 Ana Oaknin,5 Andrew Dean,6 Nicoletta Colombo,7

Johanne I. Weberpals,8 Andrew Clamp,9 Giovanni Scambia,10 Alexandra Leary,11 Robert W. Holloway,12 David M. O’Malley,13

Terri Cameron,14 Lara Maloney,14 Sandra Goble,14 Kevin Lin,14 James Sun,15 Heidi Giordano,14 Robert L. Coleman16

1UCL Cancer Institute and UCL Hospitals, London, UK; 2Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; 3MITO and Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 4Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 6Saint John of God Subiaco Hospital,

Subiaco, Australia; 7European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; 8Ottawa Hospital Research Institute, Ottawa, ON, Canada; 9The Christie NHS Foundation Trust and University of Manchester, Manchester, UK; 10Università Cattolica Roma,

Rome, Italy; 11Gustave Roussy Cancer Center, INSERM U981, and Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), Villejuif, France; 12Florida Hospital Cancer Institute, Orlando, FL, USA; 13The Ohio State University, James Cancer Center,

Columbus, OH, USA; 14Clovis Oncology, Inc., Boulder, CO, USA; 15Foundation Medicine, Inc., Cambridge, MA, USA; 16The University of Texas MD Anderson Cancer Center, Houston, TX, USA

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

Acknowledgements

All ARIEL3 study patients and their families and caregivers

Robert L. Coleman, The University of Texas MD Anderson Cancer Center, Houston, TX

– Co-coordinating investigator for ARIEL3Additional ARIEL3 investigators and sites: M. Amenedo Gancedo (Centro Oncológico Regional de Galicia), P. C. Fong (Auckland City Hospital), J. C. Goh (Royal Brisbane and Women's Hospital), D. K. Armstrong (The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins), S. N. Banerjee (Royal Marsden Hospital), J. Garcia-Donas (HM Centro Integral Oncológico Clara Campal), E. M. Swisher (University of Washington), A. Floquet (Institut Bergonié), I. A. McNeish (Beatson Cancer Centre Glasgow), C. L. Scott (Peter MacCallum Cancer Centre - Melbourne), Lm. Chen (University of California San Francisco), A. Lortholary (Centre Catherine de Sienne), R. T. Morris (Karmanos Cancer Institute), O. Tredan (Centre Léon Bérard), B. You (Centre Hospitalier Lyon Sud), P. Harnett (Westmead Hospital), J. Medioni (Hôpital Européen Georges-Pompidou), C. Parkinson (Addenbrooke's Hospital), D. Provencher (Centre Hospitalier de L'Université de Montréal), L. Elit (Juravinski Cancer Centre), P. Ghatage (Tom Baker Cancer Center), G. E. Konecny (University of California Los Angeles), S. Pignata (Istituto Nazionale Tumori IRCCS Fondazione Pascale), I. Vergote (Universitair Ziekenhuis Leuven), S. Welch (London Regional Cancer Centre), H. Denys (Universitair Ziekenhuis Gent), M. Leviov (The Lady Davis Carmel Medical Center), M. Plante (Centre HospitalierUniversitaire de Quebec), A. Amit (Rambam Medical Center), M. J. Birrer (Massachusetts General Hospital), A. Casado Herraez (Hospital San Carlos Madrid), S. K. Chambers (University of Arizona Cancer Center), M. L. Friedlander (Prince of Wales Hospital), E. Guerra (Hospital Ramón y Cajal), M. A. Morgan (University of Pennsylvania), R. F. Sabbatini (Azienda Ospedaliero-Universitaria di Modena - Policlinico), R. Shapira-Frommer (Chaim Sheba Medical Center at Tel Hashomer), S. Tamberi (Ospedale Civiledegli Infermi), P. Wimberger (Technische Universität Dresden), M. Buck (Sir Charles Gairdner Hospital), L. Dirix (AZ Sint Augustinus), L. Gladieff (Institut Claudius Régaud), D. Jackson (Saint James's University Hospital), G. Kichenadasse (Flinders Medical Centre), L. Ma (Rocky Mountain Cancer Centers), C. Zamagni (Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi), M. K. Buss (Beth Israel Deaconess Medical Center), H. G. S. Gabra (Imperial College Healthcare NHS Trust), S. Kovel(Assaf Harofeh Medical Centre), P. Krabisch (Klinikum Chemnitz gGmbH), J. Lotz (Hôpital Tenon), T. Neunhöffer (HELIOS Dr. Horst Schmidt Kliniken Wiesbaden - Klinik fürGynäkologie und Gyn. Onkologie), A. O'Donnell (Wellington Regional Hospital), M. Powell (Barts and The London NHS Trust), I. Romero (Instituto Valenciano de Oncología-Fundación [IVO-FINCIVO]), T. Safra (Tel Aviv Sourasky Medical Center), A. Sanchez (Hospital Regional Universitario de Málaga Hospital General), S. Stemmer (Rabin Medical Center), T. Vanderkwaak (Hope Women’s Cancer Centers), A. Bologna (Arcispedale Santa Maria Nuova), Y. Drew (Freeman Hospital - Northern Centre for Cancer Care), A. El-Balat (Universitätsklinikum Frankfurt), C. Hänle (Klinikum Ludwigsburg-Bietigheim gGmbH), F. Joly (Centre de Lutte contre le Cancer François Baclesse), D. G. Mutch(Washington University School of Medicine), I. Palacio (Hospital Universitario Central de Asturias), M. Pölcher (Rotkreuzklinikum München-Frauenklinik), B. M. Slomovitz(Sylvester Comprehensive Cancer Center), M. Vulfovich (Memorial Healthcare System)

Medical writing and editorial support funded by Clovis Oncology were provided by Nathan Yardley, PhD, and Shannon Davis of Ashfield Healthcare Communications.

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European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

No, nothing to disclose

X Yes, please specify:

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Consulting/Advisory

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Equity Position EmployeeOther

(please specify)AstraZeneca X X Speakers bureauClovis Oncology XPfizer X Speakers bureauRoche X

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

• Rucaparib is a potent inhibitor of PARP1, PARP2, and PARP31,2

• Rucaparib has shown antitumour activity in patients with recurrent OC3,4 whose tumourharbours one of the following:

– A BRCA mutation

– High percentage of genomic LOH, a phenotypic marker of HRD

• Rucaparib is approved in the United States for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced OC who have been treated with ≥2 chemotherapy regimens5,6

The ARIEL3 phase 3 trial evaluated rucaparib vs placebo following a response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent platinum-sensitive OC, including fallopian tube and primary peritoneal carcinomas7,8

Background

HRD, homologous recombination deficiency; LOH, loss of heterozygosity; PARP, poly(ADP-ribose) polymerase.1. Robillard et al. Cancer Res. 2017;77(13 suppl):abstr 2475; 2. Thomas HD et al. Mol Cancer Ther. 2007;6:945-56; 3. Kristeleit R et al. Clin Cancer Res. 2017;23:4095-106; 4. Swisher EM et al. Lancet Oncol. 2017;18:75-87; 5. Rucaparib tablets [prescribing information]. Boulder, CO: Clovis Oncology, Inc.; 2017; 6. Oza AM et al. Gynecol Oncol. 2017 [Epubahead of print]; 7. Ledermann et al. Presented at ESMO; Sep 8–12, 2017; Madrid, Spain. LBA_40; 8. Coleman et al. Lancet. 2017;390:1949-61.

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European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: Study Design

*CR (defined by RECIST) or PR (defined by RECIST and/or a GCIG CA-125 response [CA-125 within normal range]) maintained until entry to ARIEL3 (≤8 weeks of last dose of chemotherapy). †ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RPA1. BID, twice daily; CA-125, cancer antigen 125; CR, complete response; ECOG PS, Eastern Cooperative Oncology Group Performance Status; GCIG, Gynecologic Cancer InterGroup; HRR, homologous recombination repair; NGS, next-generation sequencing; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1.

• HRR status by NGS mutation analysis

BRCA1 or BRCA2

Non-BRCA HRR gene†

None of the above

• Response to recent platinum

CR

PR

• Progression-free interval after penultimate platinum

6 to ≤12 months

>12 months

Patient eligibility Stratification

• High-grade serous or endometrioid epithelial OC, primary peritoneal, or fallopian tube cancers

• Sensitive to penultimate platinum

• Responding to most recent platinum (CR or PR)*

Excludes patients without assessable disease following second surgery

• CA-125 within normal range

• No restriction on size of residual tumour

• ECOG PS ≤1

• No prior PARP inhibitors

PlaceboBID

n=189

Rucaparib 600 mg BID

n=375

Ra

nd

om

isa

tio

n 2

:1

5

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

• Primary endpoint: – Investigator-assessed PFS (per RECIST)

–

BRCA mutation and LOH in tumour samples were measured using Foundation Medicine’s T5 NGS assay

*Investigator-assessed PFS at a 2-sided 0.05 significance level

ARIEL3: Primary Endpoint and Step-Down Analysis

Visit cutoff date for all analyses: 15 April 2017.ITT, intent to treat; PFS, progression-free survival.

Germline or somatic BRCA mutation

Germline or somaticBRCA mutation

+

BRCA wild-type/LOH high(≥16% genomic LOH

prespecified)

Germline or somaticBRCA mutation

+ BRCA wild-type/LOH high

+BRCA wild-type/LOH low

+BRCA wild-type/

LOH indeterminate

If

significant*

BRCA mutant HRDITT

(all comers)

If

significant*

6

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: Diagram of Analysis Cohorts

*No more than 150 patients with a known deleterious germline BRCA mutation were to be enrolled to ensure enough patients with carcinomas associated with a somatic BRCA mutation or wild-type BRCA were enrolled to determine statistical significance between rucaparib and placebo in the HRD cohort and the ITT population. †Deleterious BRCA mutation detected by next-generation sequencing of tumour tissue but not by central germline blood test. ‡For LOH high, a cutoff of ≥16% genomic LOH was prespecified for ARIEL3.

564 enrolled/randomised196 BRCA mutant 368 BRCA wild type

7

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: Diagram of Analysis Cohorts

*No more than 150 patients with a known deleterious germline BRCA mutation were to be enrolled to ensure enough patients with carcinomas associated with a somatic BRCA mutation or wild-type BRCA were enrolled to determine statistical significance between rucaparib and placebo in the HRD cohort and the ITT population. †Deleterious BRCA mutation detected by next-generation sequencing of tumour tissue but not by central germline blood test. ‡For LOH high, a cutoff of ≥16% genomic LOH was prespecified for ARIEL3.

BRCA-mutant cohort (n=196)

130 rucaparib 66 placebo

564 enrolled/randomised196 BRCA mutant 368 BRCA wild type

130 germline BRCA mutant*

56 somatic BRCA mutant†

10 undefined BRCA mutant

8

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: Diagram of Analysis Cohorts

*No more than 150 patients with a known deleterious germline BRCA mutation were to be enrolled to ensure enough patients with carcinomas associated with a somatic BRCA mutation or wild-type BRCA were enrolled to determine statistical significance between rucaparib and placebo in the HRD cohort and the ITT population. †Deleterious BRCA mutation detected by next-generation sequencing of tumour tissue but not by central germline blood test. ‡For LOH high, a cutoff of ≥16% genomic LOH was prespecified for ARIEL3.

HRD cohort (n=354)

130 rucaparib 66 placebo + 106 rucaparib 52 placebo

BRCA-mutant cohort (n=196)

130 rucaparib 66 placebo

564 enrolled/randomised196 BRCA mutant 368 BRCA wild type

158 BRCA wild type/LOH high‡

130 germline BRCA mutant*

56 somatic BRCA mutant†

10 undefined BRCA mutant

9

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: Diagram of Analysis Cohorts

*No more than 150 patients with a known deleterious germline BRCA mutation were to be enrolled to ensure enough patients with carcinomas associated with a somatic BRCA mutation or wild-type BRCA were enrolled to determine statistical significance between rucaparib and placebo in the HRD cohort and the ITT population. †Deleterious BRCA mutation detected by next-generation sequencing of tumour tissue but not by central germline blood test. ‡For LOH high, a cutoff of ≥16% genomic LOH was prespecified for ARIEL3.

ITT population (n=564)

130 rucaparib 66 placebo + 106 rucaparib 52 placebo + 139 rucaparib 71 placebo

HRD cohort (n=354)

130 rucaparib 66 placebo + 106 rucaparib 52 placebo

BRCA-mutant cohort (n=196)

130 rucaparib 66 placebo

564 enrolled/randomised196 BRCA mutant 368 BRCA wild type

158 BRCA wild type/LOH high‡

161 BRCA wild type/LOH low

49 BRCA wild type/LOH indeterminate

130 germline BRCA mutant*

56 somatic BRCA mutant†

10 undefined BRCA mutant

10

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

• Stand-alone secondary endpoint – BICR-assessed PFS (per RECIST)

• Select exploratory endpoints – PFS by LOH status in patients with BRCA wild-type OC

– ORR in patients with measurable disease at baseline

• Other secondary endpoints (to be reported separately) – Patient-reported health outcomes

– Overall survival

11

ARIEL3: Additional Endpoints

Visit cutoff date for all analyses: 15 April 2017.BICR, blinded independent central review; ORR, objective response rate.

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria 12

ARIEL3: Baseline Demographics

Visit cutoff date: 15 April 2017. *One (0.5%) patient had a diagnosis of high-grade serous adenocarcinoma that was fallopian and/or ovarian in origin. †Tumour sample was BRCA mutant by Foundation Medicine’s T5 NGS assay, but a blood sample was not available for central germline testing. ‡Tumour sample was not evaluable for percent of genomic LOH due to low tumourcontent or low aneuploidy. Reprinted from The Lancet, vol. 390, Coleman et al, Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial, pages 1949-61, Copyright 2017, with permission from Elsevier.

Characteristic Rucaparib (n=375) Placebo (n=189)Age

Median (range), years 61.0 (39.0–84.0) 62.0 (36.0–85.0)

Diagnosis, % (n)Epithelial ovarian cancer 83.2 (312) 84.1 (159)*Fallopian tube cancer 8.5 (32) 5.3 (10)Primary peritoneal cancer 8.3 (31) 10.1 (19)

Histology, % (n)

Serous 95.2 (357) 94.7 (179)Endometrioid 4.3 (16) 3.7 (7)Mixed 0.3 (1) 1.6 (3)Transitional 0.3 (1) 0 (0)

BRCA and LOH status, % (n)

BRCA mutant 34.7 (130) 34.9 (66)BRCA1

BRCA2

Germline

Somatic

Undefined†

BRCA wild type 65.3 (245) 65.1 (123)LOH high

LOH low

LOH indeterminate‡

21.3 (80) 19.6 (37)

13.3 (50) 15.3 (29)

21.9 (82) 25.4 (48)

10.7 (40) 8.5 (16)

2.1 (8) 1.1 (2)

28.3 (106) 27.5 (52)

28.5 (107) 28.6 (54)

8.5 (32) 9.0 (17)

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria 13

ARIEL3: Baseline Demographics

Visit cutoff date: 15 April 2017. *Prior treatment with bevacizumab was permitted as part of penultimate or earlier treatment. Reprinted from The Lancet, vol. 390, Coleman et al, Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial, pages 1949-61, Copyright 2017, with permission from Elsevier.

Characteristic Rucaparib (n=375) Placebo (n=189)ECOG PS

0, % (n) 74.7 (280) 72.0 (136)

Number of prior chemotherapy regimens

Median (range) 2 (2–6) 2 (2–6)

Number of platinum-based regimens

Median (range) 2 (2–6) 2 (2–5)

2, % (n) 62.9 (236) 66.7 (126)

≥3, % (n) 37.1 (139) 33.3 (63)

Prior bevacizumab use*

Yes, % (n) 22.1 (83) 22.8 (43)

Time to progression with penultimate platinum

Median (range), months 13.8 (5.8–120.0) 14.6 (6.0–238.5)

6 to ≤12 months, % (n) 40.3 (151) 40.2 (76)

>12 months, % (n) 59.7 (224) 59.8 (113)

Response to last platinum

CR per RECIST, % (n) 33.6 (126) 33.9 (64)

Cycles of immediate prior chemotherapy, median (range) 6 (4–17) 6 (4–11)

PR per RECIST or serologic response per GCIG CA-125 criteria, % (n) 66.4 (249) 66.1 (125)

Cycles of immediate prior chemotherapy, median (range) 6 (3–15) 6 (3–15)

Measurable disease at baseline (per investigator)

Yes, % (n) 37.6 (141) 34.9 (66)

Bulky disease (any lesion >2 cm) at baseline (per independent radiological review)

Yes, % (n) 18.9 (71) 15.3 (29)

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: Investigator-Assessed Progression-Free Survival

14

Visit cutoff date: 15 April 2017. CI, confidence interval; HR, hazard ratio. Reprinted from The Lancet, vol. 390, Coleman et al, Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial, pages 1949-61, Copyright 2017, with permission from Elsevier.

BRCA mutant

At risk (events)

Rucaparib 130 (0) 93 (23) 63 (46) 35 (58) 15 (64) 3 (67) 0 (67)

Placebo 66 (0) 24 (37) 6 (53) 3 (55) 1 (56) 0 (56)

Rucaparib, 48% censored Placebo, 15% censored

Median(months) 95% CI

Rucaparib(n=130)

16.6 13.4–22.9

Placebo(n=66)

5.4 3.4–6.7

HR, 0.23; 95% CI, 0.16–0.34;

P<0.0001

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: Investigator-Assessed Progression-Free Survival

15

Visit cutoff date: 15 April 2017. CI, confidence interval; HR, hazard ratio. Reprinted from The Lancet, vol. 390, Coleman et al, Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial, pages 1949-61, Copyright 2017, with permission from Elsevier.

BRCA mutant HRDMedian

(months) 95% CIRucaparib

(n=236)13.6 10.9–16.2

Placebo(n=118)

5.4 5.1–5.6

HR, 0.32; 95% CI, 0.24–0.42;

P<0.0001

At risk (events)

Rucaparib 130 (0) 93 (23) 63 (46) 35 (58) 15 (64) 3 (67) 0 (67)

Placebo 66 (0) 24 (37) 6 (53) 3 (55) 1 (56) 0 (56)

Rucaparib, 48% censored Placebo, 15% censored

At risk (events)

Rucaparib 236 (0) 161 (55) 96 (104) 54 (122) 21 (129) 5 (134) 0 (134)

Placebo 118 (0) 40 (68) 11 (95) 6 (98) 1 (101) 0 (101)

Rucaparib, 43% censored Placebo, 14% censored

Median(months) 95% CI

Rucaparib(n=130)

16.6 13.4–22.9

Placebo(n=66)

5.4 3.4–6.7

HR, 0.23; 95% CI, 0.16–0.34;

P<0.0001

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: Investigator-Assessed Progression-Free Survival

16

Visit cutoff date: 15 April 2017. CI, confidence interval; HR, hazard ratio. Reprinted from The Lancet, vol. 390, Coleman et al, Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial, pages 1949-61, Copyright 2017, with permission from Elsevier.

BRCA mutant HRD ITTMedian

(months) 95% CIRucaparib

(n=236)13.6 10.9–16.2

Placebo(n=118)

5.4 5.1–5.6

HR, 0.32; 95% CI, 0.24–0.42;

P<0.0001

Median(months) 95% CI

Rucaparib(n=375)

10.8 8.3–11.4

Placebo(n=189)

5.4 5.3–5.5

HR, 0.36; 95% CI, 0.30–0.45;

P<0.0001

At risk (events)

Rucaparib 130 (0) 93 (23) 63 (46) 35 (58) 15 (64) 3 (67) 0 (67)

Placebo 66 (0) 24 (37) 6 (53) 3 (55) 1 (56) 0 (56)

Rucaparib, 48% censored Placebo, 15% censored

At risk (events)

Rucaparib 236 (0) 161 (55) 96 (104) 54 (122) 21 (129) 5 (134) 0 (134)

Placebo 118 (0) 40 (68) 11 (95) 6 (98) 1 (101) 0 (101)

Rucaparib, 43% censored Placebo, 14% censored

At risk (events)

Rucaparib 375 (0) 228 (111) 128 (186) 65 (217) 26 (226) 5 (234) 0 (234)

Placebo 189 (0) 63 (114) 13 (160) 7 (164) 2 (167) 1 (167) 0 (167)

Rucaparib, 38% censored Placebo, 12% censored

Median(months) 95% CI

Rucaparib(n=130)

16.6 13.4–22.9

Placebo(n=66)

5.4 3.4–6.7

HR, 0.23; 95% CI, 0.16–0.34;

P<0.0001

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: BICR-Assessed Progression-Free Survival

17

Median(months) 95% CI

Rucaparib(n=130)

26.8 19.2–NR

Placebo(n=66)

5.4 4.9–8.1

HR, 0.20; 95% CI, 0.13–0.32;

P<0.0001

Median(months) 95% CI

Rucaparib(n=236)

22.9 16.2–NR

Placebo(n=118)

5.5 5.1–7.4

HR, 0.34; 95% CI, 0.24–0.47;

P<0.0001

Median(months) 95% CI

Rucaparib(n=375)

13.7 11.0–19.1

Placebo(n=189)

5.4 5.1–5.5

HR, 0.35; 95% CI, 0.28–0.45;

P<0.0001

BRCA mutant HRD ITT

At risk (events)

Rucaparib 130 (0) 93 (19) 62 (31) 35 (36) 15 (40) 2 (42) 0 (42)

Placebo 66 (0) 18 (34) 6 (39) 2 (42) 1 (42) 0 (42)

Rucaparib, 68% censored Placebo, 36% censored

At risk (events)

Rucaparib 236 (0) 152 (49) 87 (78) 53 (84) 21 (88) 4 (90) 0 (90)

Placebo 118 (0) 34 (57) 12 (69) 5 (73) 1 (74) 0 (74)

Rucaparib, 62% censored Placebo, 37% censored

At risk (events)

Rucaparib 375 (0) 213 (95) 114 (143) 60 (157) 24 (162) 4 (165) 0 (165)

Placebo 189 (0) 50 (106) 13 (128) 6 (132) 2 (133) 1 (133) 0 (133)

Rucaparib, 56% censored Placebo, 30% censored

Visit cutoff date: 15 April 2017. NR, not reached. Reprinted from The Lancet, vol. 390, Coleman et al, Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial, pages 1949-61, Copyright 2017, with permission from Elsevier.

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: Diagram of Analysis Cohorts

*No more than 150 patients with a known deleterious germline BRCA mutation were to be enrolled to ensure enough patients with carcinomas associated with a somatic BRCA mutation or wild-type BRCA were enrolled to determine statistical significance between rucaparib and placebo in the HRD cohort and the ITT population. †Deleterious BRCA mutation detected by next-generation sequencing of tumour tissue but not by central germline blood test. ‡For LOH high, a cutoff of ≥16% genomic LOH was prespecified for ARIEL3.

ITT population (n=564)

130 rucaparib 66 placebo + 106 rucaparib 52 placebo + 139 rucaparib 71 placebo

HRD cohort (n=354)

130 rucaparib 66 placebo + 106 rucaparib 52 placebo

BRCA-mutant cohort (n=196)

130 rucaparib 66 placebo

564 enrolled/randomised

196 BRCA mutant 368 BRCA wild type

158 BRCA wild type/LOH high‡

161 BRCA wild type/LOH low

49 BRCA wild type/LOH indeterminate

130 germline BRCA mutant*

56 somatic BRCA mutant†

10 undefined BRCA mutant

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European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3 Exploratory Analysis: Investigator-Assessed Progression-Free Survival in Patients with BRCA Wild-Type OC

19

At risk (events)

Rucaparib 106 (0) 68 (32) 33 (58) 19 (64) 6 (65) 2 (67) 0 (67)

Placebo 52 (0) 16 (31) 5 (42) 3 (43) 0 (45)

Rucaparib, 37% censored Placebo, 13% censored

Median(months) 95% CI

Rucaparib(n=106)

9.7 7.9–13.1

Placebo(n=52)

5.4 4.1–5.7

HR, 0.44; 95% CI, 0.29–0.66;

P<0.0001

Median(months) 95% CI

Rucaparib(n=107)

6.7 5.4–9.1

Placebo(n=54)

5.4 5.3–7.4

HR, 0.58; 95% CI, 0.40–0.85;

P=0.0049

LOH high LOH low

At risk (events)

Rucaparib 107 (0) 49 (47) 23 (65) 8 (77) 4 (79) 0 (81)

Placebo 54 (0) 20 (32) 2 (49) 1 (50) 1 (50) 1 (50) 0 (50)

Rucaparib, 24% censored Placebo, 7% censored

Visit cutoff date: 15 April 2017. Reprinted from The Lancet, vol. 390, Coleman et al, Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial, pages 1949-61, Copyright 2017, with permission from Elsevier.

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3 Exploratory Analysis: BICR-Assessed Progression-Free Survival in Patients with BRCA Wild-Type OC

20

Visit cutoff date: 15 April 2017.Coleman et al. Lancet. 2017;390:1949-61.

At risk (events)

Rucaparib 106 (0) 59 (30) 25 (47) 18 (48) 6 (48) 2 (48) 0 (48)

Placebo 52 (0) 16 (23) 6 (30) 3 (31) 0 (32)

Rucaparib, 55% censored Placebo, 38% censored

Median(months) 95% CI

Rucaparib(n=106)

11.1 8.2–NR

Placebo(n=52)

5.6 2.9–8.2

HR, 0.55; 95% CI, 0.35–0.89;

P=0.0135

Median(months) 95% CI

Rucaparib(n=107)

8.2 5.6–10.1

Placebo(n=54)

5.3 2.8–5.5

HR, 0.47; 95% CI, 0.31–0.71;

P=0.0003

LOH high LOH low

At risk (events)

Rucaparib 107 (0) 46 (37) 20 (55) 6 (61) 3 (62) 0 (63)

Placebo 54 (0) 13 (38) 1 (46) 1 (46) 1 (46) 1 (46) 0 (46)

Rucaparib, 41% censored Placebo, 15% censored

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3 Exploratory Analysis: Investigator-Assessed ORR for Patients with Measurable Disease at Baseline

Visit cutoff date: 15 April 2017. Coleman et al. Lancet. 2017;390:1949-61.

21

BRCA Mutant HRD ITT

Rucaparib

(n=40)

Placebo

(n=23)

Rucaparib

(n=85)

Placebo

(n=41)

Rucaparib

(n=141)

Placebo

(n=66)

RECIST ORR, % (n) 37.5* (15) 8.7 (2) 27.1* (23) 7.3 (3) 18.4* (26) 7.6 (5)

Complete response 17.5 (7) 0 (0) 11.8 (10) 0 (0) 7.1 (10) 1.5 (1)

Partial response 20.0 (8) 8.7 (2) 15.3 (13) 7.3 (3) 11.3 (16) 6.1 (4)

Stable disease 47.5 (19) 34.8 (8) 50.6 (43) 41.5 (17) 50.4 (71) 43.9 (29)

Progressive disease 12.5 (5) 56.5 (13) 21.2 (18) 51.2 (21) 27.0 (38) 48.5 (32)

Not evaluable 2.5 (1) 0 (0) 1.2 (1) 0 (0) 4.3 (6) 0 (0)

*Cochran-Mantel-Haenszel P<0.05 vs placebo.

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

ARIEL3: Summary of Safety

22

Visit cutoff date: 15 April 2017. *Three patients randomised to the rucaparib arm did not receive a dose of rucaparib and are excluded from the safety population. †Excluding disease progression. AE, adverse event; AML, acute myeloid leukaemia; MDS, myelodysplastic syndrome. Coleman et al. Lancet. 2017;390:1949-61.

Rucaparib n=372, % (n)* Placebo n=189, % (n)

At least 1 AE 100 (372) 96.3 (182)

At least 1 AE grade ≥3 56.2 (209) 14.8 (28)

Treatment interruption and/or dose reduction due to AE 70.7 (263) 10.6 (20)

Treatment interruption due to AE 63.7 (237) 10.1 (19)

Dose reduction due to AE 54.6 (203) 4.2 (8)

Discontinued due to AE† 13.4 (50) 1.6 (3)

Deaths due to AE 1.6 (6) 1.1 (2)

Deaths due to disease progression 0.5 (2) 0.5 (1)

• Median (range) treatment duration was 8.3 (0.1–34.9) months in the rucaparib arm and 5.5 (0.0–35.4) months in the placebo arm

• MDS/AML were reported in 3 (0.8%) patients in the rucaparib arm and no patients in the placebo arm

ARIEL3: Treatment-Emergent Adverse Events of Any Grade Reported in ≥15% of Patients in Either Arm

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Visit cutoff date: 15 April 2017. *Combined terms. †Elevations were generally transient, self-limiting, and not associated with abnormal increases in bilirubin or other criteria for drug-induced hepatotoxicity. ALT, alanine aminotransferase; AST, aspartate aminotransferase. Coleman et al. Lancet. 2017;390:1949-61.

ARIEL3: Treatment-Emergent Adverse Events of Any Grade Reported in ≥15% of Patients in Either Arm

24

Visit cutoff date: 15 April 2017. *Combined terms. †Elevations were generally transient, self-limiting, and not associated with abnormal increases in bilirubin or other criteria for drug-induced hepatotoxicity. ALT, alanine aminotransferase; AST, aspartate aminotransferase. Coleman et al. Lancet. 2017;390:1949-61.

Chemistry Laboratory Parameters: Mean Baseline and On-Treatment Values

Alanine aminotransferaseRucaparibPlacebo

Aspartate aminotransferaseRucaparibPlacebo

Bilirubin

RucaparibPlacebo

• Alanine aminotransferase and aspartate aminotransferase concentration increases were not associated with abnormal increases in bilirubin or other criteria for drug-induced hepatotoxicity and generally resolved over time

• No cases met Hy’s law criteria for drug-induced liver injury

B, baseline; SEM, standard error of the mean. Coleman et al. Lancet. 2017;390:1949-61. 25

Rucaparib (n) 371 354 338 295 265 248 227 204 193 171 158 156 141 128 118 108 96 85 69 63 60 49 52 40 37

Placebo (n) 189 184 178 150 117 108 83 61 56 43 31 29 21 15 15 11 11 11 9 7 6 5 5 4 2

Rucaparib (n) 370 353 338 294 264 248 227 204 193 171 158 156 141 128 118 108 97 85 69 63 60 49 52 40 36

Placebo (n) 188 184 178 149 117 108 83 61 56 43 31 29 21 14 15 11 11 11 9 7 6 5 5 4 2

Rucaparib (n) 371 354 338 295 265 248 227 204 193 171 158 156 141 128 118 108 96 85 69 63 60 49 52 40 37

Placebo (n) 189 184 178 150 117 109 83 61 56 43 31 29 21 15 15 11 11 11 9 7 6 5 5 4 2

ARIEL3: Treatment-Emergent Adverse Events of Any Grade Reported in ≥15% of Patients in Either Arm

26

Visit cutoff date: 15 April 2017. *Combined terms. †Elevations were generally transient, self-limiting, and not associated with abnormal increases in bilirubin or other criteria for drug-induced hepatotoxicity. ALT, alanine aminotransferase; AST, aspartate aminotransferase. Coleman et al. Lancet. 2017;390:1949-61.

ARIEL3: Treatment-Emergent Adverse Events of Any Grade Reported in ≥15% of Patients in Either Arm

27

Visit cutoff date: 15 April 2017. *Combined terms. †Elevations were generally transient, self-limiting, and not associated with abnormal increases in bilirubin or other criteria for drug-induced hepatotoxicity. ALT, alanine aminotransferase; AST, aspartate aminotransferase. Coleman et al. Lancet. 2017;390:1949-61.

European Society of Gynaecological Oncology (ESGO)4–7 November 2017 | Vienna, Austria

Conclusions

• Rucaparib maintenance treatment significantly improved PFS vs placebo in the nested BRCA-mutant and HRD cohorts and in the overall ITT population

• PFS was improved with rucaparib maintenance treatment vs placebo in patients with BRCA wild-type OC (LOH high and LOH low)

• Several patients with measurable residual disease at baseline had further reduction in tumour burden with rucaparib maintenance treatment

• The most common side effects were gastrointestinal (nausea and vomiting), asthenia, andanaemia, consistent with prior studies of rucaparib

Rucaparib maintenance treatment could be considered a new standard of care for women with platinum-sensitive OC following a complete or partial response to second-line or later platinum-based chemotherapy

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