ARIEL4: An International, Randomised Phase 3 Study of

Rucaparib vs Chemotherapy in BRCA1- or BRCA2-Mutated, Abstract ESGO7-0665 Relapsed Ovarian Cancer (OC) Rebecca S. Kristeleit,1 Domenica Lorusso,2 Ana Oaknin,3 Tamar Safra,4 Elizabeth M. Swisher,5 Igor M. Bondarenko,6 Tomasz Huzarski,7 Jaroslav Klat,8 Vladimir Moiseyenko,9 Róbert Póka,10 Luciana S. Viola,11 Chris Tankersley,12 Lara Maloney,12 Sandra Goble,12 Caro Unger,12 Adam Dowson,12 Heidi Giordano,12 Amit M. Oza13

1University College London Cancer Institute, London, UK; 2MITO and Unità di Ginecologia Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 3Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 4Sackler School of Medicine, Tel Aviv University and Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 5University of Washington, Seattle, WA, USA; 6Dnipropetrovsk Medical Academy, City Multiple-Discipline Clinical Hospital, Dnipropetrovsk, Ukraine; 7Private Health Care Innovative Medicine, Grzepnica, Poland; 8University Hospital Ostrava, Ostrava, Czech Republic; 9NN. Petrov Research Institute of Oncology Cancer Center, St. Petersburg, Russian Federation; 10Debrecen University Clinical Center, Debrecen, Hungary; 11Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil; 12Clovis Oncology, Inc., Boulder, CO, USA; 13Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

INTRODUCTION • In high-grade OC, including fallopian tube and primary peritoneal cancer, ≈18% and ≈7% of patients have carcinomas associated with a Figure 1. Rucaparib-Mediated Synthetic Lethality germline BRCA1 or BRCA2 mutation or a somatic BRCA1 or BRCA2 mutation, respectively1 • In cells with homologous recombination deficiency (HRD), poly(ADP- ribose) polymerase (PARP) inhibition leads to cell death2-4 (Figure 1) ‒ Rucaparib has been shown to inhibit PARP enzymatic activity and increase formation of PARP-DNA complexes (“PARP trapping”) in preclinical studies and has demonstrated efficacy in carcinomas with HRD5-9 • Based on pooled efficacy and safety data from 2 single-arm clinical trials,8-10 rucaparib received accelerated approval in the United States as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced OC who have been HRD, homologous recombination deficient; PARP, poly(ADP-ribose) polymerase. treated with ≥2 chemotherapies • Data comparing PARP inhibitors to standard of care (SOC) treatment for relapsed OC are limited11 • Randomised studies are needed to assess the benefit-risk profile of PARP inhibitors vs current SOC as treatment for patients with BRCA-mutated, relapsed, high-grade OC, particularly in the third-line or later treatment setting

ARIEL4 TRIAL OVERVIEW • ARIEL4 (CO-338-043; EudraCT 2016-000816-14; NCT02855944) is an international, multicentre, randomised, phase 3 study evaluating rucaparib 600 mg twice daily vs SOC chemotherapy as treatment for patients with germline or somatic BRCA1- or BRCA2-mutated, relapsed, high-grade OC who have received ≥2 prior chemotherapy regimens (Figure 2)

Figure 2. ARIEL4 Trial Schema

Screening Treatment 28-day cycles Follow-up Planned analysis

Rucaparib 28 days after last Primary endpoint Patients with: †† 600 mg BID Radiologically treatment dose, • Investigator-assessed PFS • Relapsed, high-grade confirmed then long-term n=230 ovarian carcinoma* disease follow-up every Secondary endpoints • ≥2 prior chemotherapy progression 8 weeks for survival, • OS subsequent regimens, with TFI per RECIST, • ORR by RECIST and by RECIST/CA-125 Randomisation 2:1 unacceptable therapies, and ≥6 months following first development of criteria toxicity, death, chemotherapy received secondary • Duration of response or termination ‡‡ • A deleterious BRCA1 or malignancies • PRO using EORTC instruments of trial BRCA2 mutation (real- If platinum-resistant‡ or partially • Safety and tolerability of rucaparib vs SOC time HRD assessment or platinum-sensitive§: paclitaxelǁ chemotherapy known mutation†) Optional ¶ crossover If platinum-sensitive : Key exploratory endpoints • Adequate organ function # Patients initially single-agent platinum or • Investigator-assessed PFS2 • No prior treatment with doublet chemotherapy** at receiving PARP inhibitors or with investigator’s discretion chemotherapy • Investigator-assessed DCR single-agent paclitaxel have option of • PRO using EQ-5D‡‡ n=115 crossing over to • Assessment of molecular changes in tumour rucaparib samples over time in matched pairs *Patients with a histology other than serous or endometrioid are also eligible if they are known to harbour a deleterious germline • Assessment of ctDNA as a molecular marker of or somatic BRCA1 or BRCA2 mutation. efficacy †Patients with a known BRCA mutation based on local test result must also submit tumour tissue; however, enrolment is not contingent on this tumour analysis. • Evaluation of the impact of gene expression ‡Progressed ≥1 to <6 months after last dose of platinum. molecular subgroups on PFS and OS §Progressed ≥6 to <12 months after last dose of platinum. ǁPaclitaxel 60 to 80 mg/m2 on days 1, 8, and 15; administered per local SOC and regulations. • Efficacy in BRCA-mutation subgroups ¶Progressed ≥12 months after last dose of platinum. • Relationship between rucaparib exposure and #Cisplatin or carboplatin; administered per local SOC and regulations. **Carboplatin/paclitaxel, carboplatin/gemcitabine, or cisplatin/gemcitabine; administered per local SOC and regulations. responses (safety and efficacy) ††Assessed per RECIST criteria.12 ‡‡PRO instruments: EORTC Quality-of-Life Questionnaire (QLQ-C30) and the ovarian cancer module (QLQ-OV28)13,14 and EQ-5D.15 BID, twice daily; CA-125, cancer antigen 125; ctDNA, circulating cell-free tumour DNA; DCR, disease control rate (proportion of patients with a complete response, partial response, or prolonged stable disease >12 weeks per RECIST); EORTC, European Organisation for Research and Treatment of Cancer; HRD, homologous recombination deficiency; ORR, objective response rate; OS, overall survival; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; PFS2, PFS on study treatment and subsequent line of treatment; PRO, patient-reported outcome; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1; SOC, standard of care; TFI, treatment-free interval.

TRIAL SUMMARY • Rucaparib has demonstrated efficacy in the treatment setting in patients with OC and a deleterious BRCA1 or BRCA2 mutation7-9 • The ARIEL4 phase 3 study aims to assess the benefit-risk profile of rucaparib vs current SOC chemotherapy as treatment for patients with BRCA1- or BRCA2- mutated, relapsed, high-grade OC • ARIEL4 is actively recruiting patients, with a goal of enrolling 345 patients from ≈100 sites worldwide (Figure 3)

Figure 3. Countries Participating in ARIEL4 REFERENCES

1. Pennington et al. Clin Cancer Res. 2014;20:764-75. 9. Swisher et al. Lancet Oncol. 2017;18:75-87. 2. Scott et al. J Clin Oncol. 2015;33:1397-406. 10. Kristeleit et al. Ann Oncol. 2016;27:abstr 856O. 3. Fong et al. N Engl J Med. 2009;361:123-34. 11. Kaye et al. J Clin Oncol. 2012;30:372-9. 1. Brazil 7. Poland 4. Farmer et al. Nature. 2005;434:917-21. 12. Eisenhauer et al. Eur J Cancer. 2009;45:228-47. 2. Canada 8. Russia 5. Murai et al. Mol Cancer Ther. 2014;13:433-43. 13. Aaronson et al. J Natl Cancer Inst. 1993;85:365-76. 6. Shen et al. J Pharmacol Exp Ther. 2015;353:446-57. 14. Greimel et al. Eur J Cancer. 2003;39:1402-8. 3. Czech Republic 9. Spain 7. Drew et al. J Natl Cancer Inst. 2011;103:334-46. 15. Shaw et al. Medical Care. 2005;43:203-20. 4. Hungary 10.Ukraine 8. Kristeleit et al. Clin Cancer Res. 2017;23:4095-106. 5. Israel 11.United Kingdom 6. Italy 12.United States ACKNOWLEDGEMENTS

This study is funded by Clovis Oncology, Inc. Medical writing and editorial support was funded by Clovis Oncology and provided by Nathan Yardley and Shannon Davis of Ashfield Healthcare Communications.

20th International Meeting of the European Society of Gynaecological Oncology | 4–7 November 2017 | Vienna, Austria