TRITON2: An International, Multicenter, Open-Label, Phase 2 Study of the PARP Inhibitor Rucaparib in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Associated with Homologous Recombination Deficiency (HRD) Wassim Abida, 1 Alan Bryce, 2 Arjun Balar, 3 Gurkmal Chatta, 4 Nancy Dawson, 5 Elizabeth A. Guancial, 6 Arif Hussain, 7 Gautam Jha, 8 David U. Lipsitz, 9 Akash Patnaik, 10 Daniel Petrylak, 11 Charles J. Ryan, 12 Thomas Stanton, 13 Nicholas Vogelzang, 14 Jingsong Zhang, 15 Andy Simmons, 16 Jowell Go, 16 Tony Golsorkhi, 16 Simon Chowdhury, 17 Howard I. Scher 1 1 Memorial Sloan Kettering Cancer Center, New York, NY; 2 Mayo Clinic Arizona, Phoenix, AZ; 3 New York University Perlmutter Cancer Center, New York, NY; 4 Roswell Park Cancer Institute, Buffalo, NY; 5 Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC; 6 University of Rochester, Wilmot Cancer Institute, Rochester, NY; 7 University of Maryland Greenebaum Cancer Center, Baltimore, MD; 8 Fairview Hospital, Burnsville, MN; 9 Carolina Clinical Trials, Concord, NC; 10 University of Chicago Comprehensive Cancer Center, Chicago, IL; 11 Yale University - Yale Cancer Center, New Haven, CT; 12 University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 13 St. Joseph Heritage Healthcare, Santa Rosa, CA; 14 Comprehensive Cancer Centers of Nevada, Las Vegas, NV; 15 H Lee Moffitt Cancer Center, Tampa, FL; 16 Clovis Oncology, Inc., Boulder, CO; 17 Guy's Hospital & Sarah Cannon Research Institute, London, UK INTRODUCTION • There are limited treatment options available for patients with mCRPC following androgen deprivation and taxane treatment • A deleterious germline and/or somatic mutation in BRCA1, BRCA2, ATM, or other homologous recombination (HR) DNA-repair gene is present in up to 25% of patients with advanced prostate cancer, including mCRPC 1-3 • Poly(ADP-ribose) polymerase (PARP) inhibitors, such as rucaparib, have shown activity in tumors with HRD through synthetic lethality (Figure 1) 4-6 • PARP inhibitors have demonstrated preliminary evidence of antitumor activity in patients with sporadic mCRPC with an alteration in an HR gene 7 ACKNOWLEDGMENTS This study is funded by Clovis Oncology, Inc. Medical writing and editorial assistance were provided by Nathan Yardley and Shannon Davis of Ashfield Healthcare Communications and were funded by Clovis Oncology. REFERENCES 1. Robinson et al. Cell. 2015;161:1215-28. 2. Pritchard et al. N Engl J Med. 2016;375:443-53. 3. Abida et al. JCO Precis Oncol. 2017 [Epub ahead of print]. 4. O'Connor. Mol Cell. 2015;60:547-60. 5. Lee et al. Ann Oncol. 2014;25:32-40. 6. Scott et al. J Clin Oncol. 2015;33:1397-406. 7. Mateo et al. N Engl J Med. 2015;373:1697-708. 8. Eisenhauer et al. Eur J Cancer. 2009;45:228-47. 9. Scher et al. J Clin Oncol. 2016;34:1402-18. TRIAL SUMMARY • Up to 25% of patients with mCRPC may harbor a deleterious mutation in BRCA1, BRCA2, ATM, 1-3 or other HR gene and potentially benefit from targeted treatment with the PARP inhibitor rucaparib • TRITON2 is actively recruiting patients, with a goal of enrolling approximately 160 patients from >100 sites worldwide (Figure 3) PLASMA-BASED COMPANION DIAGNOSTIC • There are significant challenges in collecting and analyzing tumor tissue specimens from patients with mCRPC • TRITON2 will explore the use of circulating tumor DNA (ctDNA) purified from blood as a companion diagnostic • Pretreatment blood samples will be collected from all patients and analyzed for BRCA1, BRCA2, ATM, and other HR gene mutations in ctDNA (Figure 2) • A central retrospective analysis is planned to evaluate the agreement between HR gene alterations identified in tumor tissue samples and ctDNA obtained from plasma Genitourinary Cancers Symposium | February 8–10, 2018 | San Francisco, CA Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO ® and the author of this poster. Corresponding author: Wassim Abida; email: abidam@mskcc.org Figure 3. Countries Participating in TRITON2 1. Australia 2. Belgium 3. Canada 4. Denmark 5. France 6. Germany 7. Israel 8. Italy 9. Republic of Ireland 10. Spain 11. United Kingdom 12. United States TRITON2 TRIAL OVERVIEW • TRITON2 (CO-338-052; NCT02952534) is an international, multicenter, open-label, phase 2 study evaluating rucaparib 600 mg twice daily in patients with mCRPC associated with HRD (Figure 2) • Patients are being allocated into cohort A, B, or C based on HR gene mutation and measurable disease status (Figure 2) • Mutation in HR genes can be determined in various ways (Figure 2) HRD, homologous recombination deficient; PARP, poly(ADP-ribose) polymerase. Figure 1. Rucaparib-Mediated Synthetic Lethality Figure 2. TRITON2 Trial Schema *Patients with a known deleterious BRCA1, BRCA2, or ATM mutation (documented in the patient’s medical record) should also submit archival tumor tissue, if available; tumor tissue samples of visceral/nodal metastasis preferred. † BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, or RAD54L. ‡ Patients without measurable disease must have PSA >2 ng/mL on the most recent measurement. § Modified RECIST 8 criteria will be used to document radiographic response in soft-tissue (visceral and nodal) disease, and Prostate Cancer Clinical Trials Working Group guidelines version 3 9 criteria will be used to document radiographic progression of bone lesions. AR, androgen receptor; BID, twice daily; ctDNA, circulating tumor DNA; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, homologous recombination; IRR, independent radiology review; mCRPC, metastatic castration-resistant prostate cancer; ORR, objective response rate; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1. Treatment 28-day cycles Post-treatment Key eligibility criteria • 28-day follow-up visit • Long-term follow-up • Tumor assessments every 8–12 weeks for patients who discontinue for a reason other than progression • All patients to be followed every 12 weeks for survival and subsequent therapies • Patients receiving clinical benefit may be considered for continued treatment beyond progression Primary endpoints • Cohort A: centrally assessed ORR using modified RECIST • Cohort B: locally assessed PSA response (≥50% decrease) • Cohort C: centrally assessed ORR using modified RECIST in patients with measurable disease or locally assessed PSA response in patients with nonmeasurable disease Planned analysis • mCRPC • HR gene mutation • Disease progression on AR-signaling directed therapy (eg, abiraterone or enzalutamide) and 1 prior line of taxane- based chemotherapy for mCRPC • ECOG PS of 1 or 0 • No prior PARP inhibitor treatment, mitoxantrone, cyclophosphamide, or platinum-based chemotherapy Rucaparib 600 mg BID Cohort C (≈20 patients) • Deleterious mutation in another HR gene associated with sensitivity to PARP inhibition † • With or without measurable disease Cohort B (≈54 patients) • Deleterious BRCA1, BRCA2, or ATM mutation • Without measurable visceral or nodal disease ‡ Cohort A (≈83 patients) • Deleterious BRCA1, BRCA2, or ATM mutation • With measurable visceral and/or nodal disease Radiographic progression or treatment discontinuation for other reason Screening Secondary endpoints • Radiographic PFS by IRR § • Overall survival • Clinical benefit rate • PSA response of ≥50% and ≥90% • Time to PSA progression • Steady-state pharmacokinetics • Safety and tolerability Local genomic testing* Central genomic testing Identification of a deleterious somatic or germline mutation in BRCA1, BRCA2, ATM, or other HR gene † or Screening tumor tissue Archival tumor tissue Blood or or Key exploratory endpoint • Analysis of pretreatment blood samples collected from all patients for BRCA1, BRCA2, ATM, and other HR gene † mutations in ctDNA