Robust non-invasive biomarker assays are needed to improve patient selection and pharmacodynamic assessments for PARP inhibitors as the currently accepted biomarkers (e.g. BRCA1/2 mutations) results in variability in response and benefit. [18F] Fluorthanatrace (FTT) is a positron emission tomography (PET) tracer that has been previously demonstrated to measure in vivo PARP1 expression in breast and ovarian cancers.
We conducted a single-arm open-label, non-randomized study of [18F]FTT PET as a method to non-invasively measure regional PARP1 expression in patients with primary or metastatic solid tumors with defects in germline or somatic BRCA1/2 or other mutations along the DNA Damage Response (DDR) pathway. Patients were not previously on oncologic therapy for at least 4 weeks but who had either radiographic evidence of progressive disease or newly diagnosed solid tumors with measurable disease. Patients underwent PET imaging 90 minutes after injection of 5-10 mCi of [18F]FTT. Uptake within the primary disease and/or up-to 5 metastatic sites was quantified by measuring the maximum standardized uptake value (SUVmax). Kruskal-Wallis test was used to determine differences between groups.
A total of 44 patients consented for this study and underwent [18F]FTT PET imaging between 2/2019 and 3/2022 with the following primary sites of disease: ovarian (11), breast (19), pancreas (3), prostate (5), bladder (1), endometrial (1), primary peritoneal (1), kidney carcinoma (1) as well as leiomyosarcoma (1) and melanoma (1). All patients had measurable SUV above background. The median SUVmax in index lesions was 5.7 (range 1.76-16.52) in patients with BRCA1/2 mutations vs median 5.6 (range 2.73-5.66) in patient with other DDR pathway defects (ATM, CHEK2, PALB). No difference in SUVmax was observed between patients with or without prior PARPi (median SUVmax 5.7 [range 2.36-10.41] vs median SUVmax 5.72 [range 1.76-16.52]) respectively, p=0.64.
Measurable [18F]FTT uptake is identified across multiple solid tumors imaged. The range of SUVmax overlapped between those with and without BRCA1/2m.
Clinical trial identification
Legal entity responsible for the study
University of Texas, MD Anderson Cancer Center.
National Cancer Institute.
L.L. Lin: Financial Interests, Institutional, Research Grant: Pfizer, AstraZeneca. T.A. Yap: Financial Interests, Personal, Other, Consultant: Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Clovis, Cybrexa, EMD Serono, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Varian, Zai Labs, AbbVie, Acrivon, Adagene, Amphista, Artios, Athena, Avoro, Baptist Health Systems, Beigene, Boxer, C4 Therapeutics, Calithera, Cancer Research UK, Diffusion, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Idience, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Kyn, MEI Pharma, Mereo, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Piper-Sandler, Prolynx, resTORbio, Theragnostics, Versant, Vibliome, Xinthera, ZielBio; Financial Interests, Personal, Other, University of Texas MD Anderson Cancer Center, where I am Medical Director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios): MD Anderson Cancer Center, Institute for Applied Cancer Sciences; Financial Interests, Personal, Stocks/Shares: Seagen; Financial Interests, Institutional, Other, Grant/Research support: Bayer, Cyteir, EMD Serono, GlaxoSmithKline, Karyopharm, Pfizer, Repare, Sanofi, Artios, AstraZeneca, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Eli Lilly, Haihe, Forbius, F-Star, Genentech, ImmuneSensor, Ionis, Ipsen, Jounce, KSQ, Kyowa, Merck, Mirati, Novartis, Ribon Therapeutics, Regeneron, Rubius; Financial Interests, Institutional: Scholar Rock. All other authors have declared no conflicts of interest.