Abstract CT229: Olaparib in patients (pts) with previously treated, homologous recombination repair mutation (HRRm) or homologous recombination deficiency (HRD)-positive advanced cancer: Phase II LYNK-002 study
Authors: Hyman David , Hendifar Andrew , Chung Hyun Cheol , Maio Michele , Leary Alexandra , Spanggaard Iben , Rhee Joon , Marton Matt , Chen Menghui , Krishnan Suba , Shapira Ronnie 
Published: August 2019

Abstract
Background: Human cancers are associated with defects in DNA damage repair (DDR). Evidence suggests a key role for poly(ADP-ribose) polymerases (PARPs) in repairing certain DNA damage lesions. Olaparib (a PARP inhibitor) is approved for pts with germline BRCA1 and BRCA2-mutated breast and ovarian cancers, and pts with or without BRCA mutation in recurrent ovarian cancer. Mutations in HRR genes (HRRm; beyond BRCA1 or BRCA2) and HRD may sensitize tumors to respond to PARP inhibitors. Olaparib has also shown favorable ORRs in HRRm/HRD-positive (HRD+) cancers, including prostate and ovarian. Thus, this study (NCT03742895) aims to evaluate the use of HRRm/HRD+ as biomarkers of tumor-agnostic response to olaparib monotherapy.
Methods: Eligibility for this open-label, Phase II study requires pts ≥18 years of age with a previously treated, histologically/cytologically confirmed, HRRm/HRD+ advanced solid tumor; who have failed, are intolerant to, or ineligible for all available standard of care therapies; with no disease progression during prior platinum-based treatment. At baseline, pts should also have measurable disease per RECIST v1.1 or Prostate Cancer Working Group (PCWG)-modified RECIST v1.1 (for pts with prostate cancer) without CNS metastases, ECOG PS of 0 or 1, and no persistent toxicities (CTCAE grade &gt;2) from prior cancer therapy. Pts may have received any number of prior regimens. Newly obtained or archival tumor samples will be centrally evaluated using the Lynparza HRR Assay (under development at Foundation Medicine, Inc). Pts will be grouped into 2 cohorts: cohort 1 will include pts with any solid tumor type with a BRCA1 or BRCA2 mutation (excluding breast and ovarian cancers); cohort 2 will include pts whose tumor (any type) is BRCA1 or BRCA2 wild-type and HRRm and/or HRD+ as determined by loss of heterozygosity score. Pts will receive olaparib 300 mg orally BID until documented disease progression, unacceptable toxicity, or study withdrawal. Tumor imaging will be performed at baseline, with response assessments Q8W in the first year and Q12W thereafter, per RECIST v1.1 by BICR or PCWG-modified RECIST v1.1, both modified to follow ≤5 target lesions per organ (10 total). AEs will be graded using NCI CTCAE v4.0. The primary endpoint is ORR; the point estimate and 95% CI calculated using the Clopper-Pearson method will be provided. Summary statistics for key secondary efficacy endpoints of duration of response, OS, and PFS will be provided using the Kaplan-Meier method. Safety endpoints will be summarized. Approximately 370 pts will be enrolled (~84 in cohort 1 [BRCA1 and BRCA2 mutated]; ~174 HRRm and ~112 HRD+ in cohort 2 [BRCA1 and BRCA2 wild-type]). Enrollment is ongoing in 5 countries beginning December 12, 2018.
Citation Format: David Hyman, Andrew Hendifar, Hyun Cheol Chung, Michele Maio, Alexandra Leary, Iben Spanggaard, Joon Rhee, Matt Marton, Menghui Chen, Suba Krishnan, Ronnie Shapira. Olaparib in patients (pts) with previously treated, homologous recombination repair mutation (HRRm) or homologous recombination deficiency (HRD)-positive advanced cancer: Phase II LYNK-002 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT229.