Abstract 2575
Background
Loss-of-function mutations in genes encoding components of the homologous recombination (HR) machinery are associated with tumor sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. In ABRAZO, the PARP inhibitor talazoparib demonstrated encouraging efficacy in gBRCA-mutated ABC, both in pts whose cancer responded to prior platinum therapy (cohort 1) and in pts who had received ≥3 prior nonplatinum chemotherapy regimens for ABC (cohort 2).
Methods
Baseline tumor tissue (primary or metastatic sites) from enrolled pts was sequenced using the FoundationOne CDx NGS panel. 60/84 pts (71%) in the intent-to-treat population had available tumor tissue, which could be sequenced. Mutations summarized below were known or likely pathogenic single-nucleotide variants, insertions, deletions, or rearrangements. Additional exploratory computational analyses pertinent to HR deficiency were performed, including genomic loss of heterozygosity (gLOH) and somatic-germline-zygosity assessments.
Results
Tumor mutations in BRCA1 and BRCA2 were detected in 29 (48%) and 28 (47%) of 60 evaluable pts (no pts exhibited mutations in both BRCA1 and BRCA2). These mutations were most commonly single-nucleotide variants (BRCA1: 12 [20%] and BRCA2: 10 [17%]) or deletions (BRCA1: 11 [18%] and BRCA2: 12 [20%]). Mutations in other genes implicated in HR were comparatively rare, with mutations in CHEK2 (2 pts), ARID1A, ATR, BARD1, BRD4, BRIP1, FANCC, and STAG2 (each in single pts) detected. In addition to BRCA1/2, genes where mutations were detected in ≥ 10% of evaluable pts included TP53 (45%) and PIK3CA (12%). TP53 mutations were more commonly observed in BRCA1-mutated than in BRCA2-mutated tumors (22/29 [76%] compared with 4/28 [14%]). Associations of genetic/genomic events with progression-free survival will be presented.
Conclusions
NGS of tumors from the ABRAZO study of talazoparib in patients with gBRCA-mutated ABC revealed a complex mutational landscape. Exploratory correlative analyses are ongoing and will be reported.
Clinical trial identification
NCT02034916.
Editorial acknowledgement
Legal entity responsible for the study
Pfizer Inc.
Funding
Pfizer Inc.
Disclosure
N.C. Turner: Advisory / Consultancy, Research grant / Funding (institution): Pfizer Inc.; Advisory / Consultancy, Research grant / Funding (institution): BioMarin. A..D. Laird: Full / Part-time employment: Pfizer Inc. M.L. Telli: Advisory / Consultancy, Research grant / Funding (institution): Pfizer Inc.; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Advisory / Consultancy, Research grant / Funding (institution): PharmaMar; Advisory / Consultancy, Research grant / Funding (institution): Vertex; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoSec; Research grant / Funding (institution): Sanofi. H.S. Rugo: Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GSK; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OBI Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Plexxikon; Travel / Accommodation / Expenses: Mylan; Travel / Accommodation / Expenses: Puma; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OBI Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Plexxikon; Travel / Accommodation / Expenses: Mylan; Travel / Accommodation / Expenses: Puma. A. Mailliez: Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Research grant / Funding (institution): PharmaMar; Advisory / Consultancy: Vertex; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoSec; Research grant / Funding (institution): Pfizer Inc. J. Ettl: Honoraria (institution), Advisory / Consultancy: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Eisai; Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self): TEVA; Honoraria (self): AstraZeneca. J. Balmaña: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZenca; Advisory / Consultancy: Clovis; Advisory / Consultancy: Tesaro; Advisory / Consultancy: BMS; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharMar. P.A. Fasching: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Puma; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Teva; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (institution), Speaker Bureau / Expert testimony: Myelo; Research grant / Funding (institution): BioNTech. S.A. Hurvitz: Research grant / Funding (institution): Ambryx; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BI Pharma; Research grant / Funding (institution): Biomarin; Research grant / Funding (institution): Cascadian; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Dignitana; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GSK; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: OBI Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pieris; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): Roche. L.A. Albacker: Full / Part-time employment: Foundation Medicine Inc. G.M. Frampton: Full / Part-time employment: Foundation Medicine Inc. J. Chelliserry: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. P. Bycott: Research grant / Funding (self), Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. U. Conte: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. A.M. Wardley: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche. M.E. Robson: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: McKesson; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): BioMarin; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Myriad Genetics; Research grant / Funding (institution): Tesaro. All other authors have declared no conflicts of interest.
Resources from the same session
3907 - Exploration of efficacious alternative regorafenib regimens to manage hand-foot-skin-reaction (HFSR)
Presenter: Axel Grothey
Session: Poster Display session 2
Resources:
Abstract
3958 - Quality of Life (QoL) in Metastatic Colorectal Cancer (mCRC) in the Real World: Final Results of a European Survey
Presenter: Zorana Maravic
Session: Poster Display session 2
Resources:
Abstract
3563 - BISQUIT: A Randomized Phase II Study of the Administration of Prebiotics and Probiotics During Definitive Treatment With Chemotherapy-radiotherapy for Patients With Squamous Cell Carcinoma of the Anal Canal
Presenter: Rachel Riechelmann
Session: Poster Display session 2
Resources:
Abstract
1184 - iSCORE: Immunotherapy Sequencing in COlon and REctal Cancer
Presenter: Fiona Turkes
Session: Poster Display session 2
Resources:
Abstract
3346 - Phase II study of preoperative (PREOP) chemoradiotherapy (CTRT) plus avelumab (AVE) in patients (PTS) with locally advanced rectal cancer (LARC): The AVANA Study
Presenter: Lisa Salvatore
Session: Poster Display session 2
Resources:
Abstract
3895 - A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study.
Presenter: Maria Aurelia Barbera
Session: Poster Display session 2
Resources:
Abstract
2012 - Open Label Phase III Study of Arfolitixorin vs. Leucovorin in mFOLFOX-6 for First Line Treatment of Metastatic Colorectal Cancer: AGENT
Presenter: Josep Tabernero
Session: Poster Display session 2
Resources:
Abstract
2198 - SOLSTICE, a phase 3, randomized, open label study of trifluridine/tipiracil+bevacizumab (bev) versus capecitabine+bev for the 1L treatment of patients with unresectable metastatic colorectal cancer (mCRC) who are not candidates for intensive therapy
Presenter: Thierry Andre
Session: Poster Display session 2
Resources:
Abstract
2921 - A Phase Ib/ II Trial to Assess the Safety and Efficacy of CXD101 in Combination with the PD-1 Inhibitor Nivolumab in Patients with Metastatic, Previously-Treated, Microsatellite-Stable (MSS) Colorectal Carcinoma (short title CAROSELL)
Presenter: Mark Saunders
Session: Poster Display session 2
Resources:
Abstract
3695 - A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination with FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer in Patients with a KRAS Mutation
Presenter: Heinz Josef Lenz
Session: Poster Display session 2
Resources:
Abstract