3140 - Phase 2 study of olaparib in previously treated advanced solid tumors with homologous recombination repair mutation (HRRm) or homologous recombination repair deficiency (HRD): LYNK-002

Background

Poly(ADP-ribose) polymerases (PARPs) play a key role in DNA damage repair (DDR). DDR defects due to HRRm (eg BRCA mutation [BRCAm]) or resulting in HRD (eg global loss of heterozygosity) may sensitize tumors to PARP inhibitors, eg olaparib. Olaparib monotherapy has activity in BRCAm ovarian, breast, pancreatic, and prostate cancer, and in prostate cancer with DDR defects beyond BRCAm (TOPARP). Olaparib improved efficacy outcomes vs placebo/chemotherapy as treatment in ≤ 3rd-line (3L) HER2-negative BRCAm breast cancer (OlympiAD) and ≥2L BRCAm ovarian cancer (SOLO3), and maintenance therapy in ≥ 1L ovarian cancer irrespective of BRCAm (SOLO1, Study 19). LYNK-002 (NCT03742895) evaluates HRRm/HRD positivity (HRD+; per Lynparza HRR-HRD assay, Foundation Medicine, Inc., Cambridge, MA) as biomarkers of tumor-agnostic response to olaparib.

Trial design

This open-label, phase 2 study will enroll ∼370 patients (pts) ≥18 y with previously treated, histologically/cytologically confirmed HRRm/HRD + (per Lynparza HRR-HRD assay) advanced solid tumors who failed/are intolerant to/ineligible for available SOC and have no PD during prior platinum-based treatment (any number of prior regimens), measurable disease per RECIST v1.1/Prostate Cancer Working Group (PCWG)-modified RECIST v1.1, no CNS metastases, ECOG PS 0–1, and no persistent toxicity from prior therapy. Newly obtained/archival tumor samples will be centrally evaluated using the Lynparza HRR-HRD assay to confirm eligibility. Pts will be grouped into 2 cohorts: 1) solid tumors with BRCAm (n∼84; excluding breast and ovarian), 2) solid tumors with HRRm (BRCA non-mutated; n∼174)/HRD (n∼112) per Lynparza HRR-HRD assay. Pts will receive olaparib 300 mg BID until documented PD/unacceptable toxicity/study withdrawal. Tumor imaging will occur at baseline, Q8W for 1 y, and then Q12W per RECIST v1.1 by BICR/PCWG-modified RECIST v1.1 (modified for ≤5 target lesions/organ; 10 total). Primary endpoint is ORR. Key secondary endpoints are DOR, PFS, and OS. AEs will be graded using NCI CTCAE v4.0. Enrollment is ongoing at 51 sites in 15 countries. As of Apr 18, 2019, 23 patients have been enrolled.

Clinical trial identification

NCT03742895.

Editorial acknowledgement

Cindy Taylor, PhD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and AstraZeneca.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and AstraZeneca.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and AstraZeneca.

Disclosure

D. Hyman: Travel / Accommodation / Expenses, Personal fees: Atara Biotherapeutics; Travel / Accommodation / Expenses, Personal fees: Chugai Pharma; Travel / Accommodation / Expenses, Personal fees: CytomX Therapeutics; Travel / Accommodation / Expenses, Personal fees: Boehringer Ingelheim; Travel / Accommodation / Expenses, Personal fees: AstraZeneca; Research grant / Funding (institution), Research funding: Puma Biotechnology; Research grant / Funding (institution), Research funding: AstraZeneca; Research grant / Funding (institution), Research funding: Loxo Oncology. A. Hendifar: Advisory / Consultancy: Novartis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Perthera. H. Cheol Chung: Research grant / Funding (institution): Lilly; Research grant / Funding (institution): GSK; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Merck-Serono; Research grant / Funding (institution): BMS/Ono; Research grant / Funding (institution): Taiho; Honoraria (institution): Merck-Sorono; Honoraria (institution): Lilly/Foundation Medicine; Advisory / Consultancy: Taiho; Advisory / Consultancy: Celltrion; Advisory / Consultancy: MSD; Advisory / Consultancy: Lilly; Advisory / Consultancy: Quintiles; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck-Serono. M. Maio: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Incyte; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Glaxo SmithKline; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Roche. A. Leary: Advisory / Consultancy, Advisory board: Tesaro; Advisory / Consultancy, Advisory board: AstraZeneca; Advisory / Consultancy, Advisory board: Clovis; Advisory / Consultancy, Advisory board: GamaMabs; Advisory / Consultancy, Advisory board: Gridstone; Advisory / Consultancy, Advisory board: Seattle Genetics; Research grant / Funding (institution), Research funding from the lab: Merus; Research grant / Funding (institution), Research funding from the lab: Inivata; Research grant / Funding (institution), Research funding from the lab: GamaMabs. J. Rhee: Full / Part-time employment: AstraZeneca Pharmaceuticals LP. M. Marton: Full / Part-time employment: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. M. Chen: Full / Part-time employment: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. S. Krishnan: Full / Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. R. Shapira: Speaker Bureau / Expert testimony, Speaker honoraria: MSD; Speaker Bureau / Expert testimony, Speaker honoraria: BMS; Speaker Bureau / Expert testimony, Speaker honoraria: Roche; Speaker Bureau / Expert testimony, Speaker honoraria: Novartis; Speaker Bureau / Expert testimony, Speaker honoraria: AstraZeneca. All other authors have declared no conflicts of interest.