Abstract 19P
Background
PARP (poly-ADP ribose) inhibitors have been approved for a variety of solid tumors including breast, ovarian, and prostate cancers. We evaluated a novel positron emission tomography(PET) tracer 18F-fluorthanatrace (FTT), a radiolabeled analogue of PARP inhibitors. Uptake with 18F-FTT has been shown to correlate with ex vivo tumor measures of PARP1 in prior studies.
Methods
Patients with newly diagnosed primary breast cancer enrolled on NCT03499353, a phase II trial of neoadjuvant talazoparib prior to surgery for patients with germline BRCA1/2 pathogenic variants underwent 18F-FTT PET/CT pretreatment and early (14 days) after initiation of talazoparib. Regions of interest were drawn over the primary tumor, contralateral pectoralis muscle, and lumbar vertebra body level 3 (L3); maximum uptake on PET was quantitated using standardized uptake value (SUV). Patients received up to 24 weeks of talazoparib prior to surgery.
Results
Seven patients underwent baseline 18F-FTT PET. Five of the seven patients underwent an additional 18F-FTT PET 14 days after start of talazoparib. On the baseline scan, the median SUVmax of the primary tumors was 3.7 (1.8-5.4), and the median SUVmax of L3 was 5.5 (range 2.2-7.9). On the on-talazoparib 18F-FTT PET, blocking of 18F-FTT was observed in all primary tumors. Highest grade of hematologic toxicity and baseline bone marrow-to.muscle ratio (B/M) demonstrated correlation of R=0.72, p=0.068. Apparent but non-significant correlations were found between changes in tumor volume (on ultrasound at baseline vs 1 month) and percentage change (between baseline and on-talazoparib 18F-FTT PET) in tumor-to-muscle (T/M) uptake ratio (Spearman rank correlation coefficient r=1, p=0.083); and between the highest-grade hematologic toxicity and 1) baseline bone marrow-to-muscle (B/M) uptake ratio (r=0.72, p=0.068) and 2) percentage change (beween baseline and on-talazoparib 18F-FTT PET) in B/M ratio (r=0.87, p=0.058).
Conclusions
18F-FTT can image target engagement by PARP inhibitors. Future studies are needed to determine whether 18F-FTT uptake in bone marrow may be an early predictor of hematologic toxicity and whether 18F-FTT PET can predict response to PARPi.
Clinical trial identification
NCT03604315.
Editorial acknowledgement
Legal entity responsible for the study
MD Anderson Cancer Center.
Funding
NCI.
Disclosure
L. Lin: Other, Institutional, Research Grant: Pfizer, Varian, AstraZeneca; Non-Financial Interests, Institutional, Research Grant: NCI; Non-Financial Interests, Personal, Advisory Board: Trevarx. 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, Radiopharm Theranostics, Sanofi, CUHK Committee, Ellipses. Life, LRG1, Panangium, Pliant Therapeutics, Seagen, Synthis, Tessellate Bio, TD2 Theragnostics, Tome Biosciences, Zentalis; 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: Seagan; Financial Interests, Institutional, Other, Grant/Research support: Bayer, Cyteir, EMD Serono, GSK, Karyopharm, Pfizer, Repare, Sanofi, Artios, AstraZeneca, BeiGene, BioNTech, Blueprint, BMS, Clovis, Constellation, Eli Lilly, Forbius, F-Star, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, KSQ, Kyowa, Merck, Mirati, Novartis, Ribon Therapeutics, Regeneron, Rubius, Scholar Rock, Seattle Genetics, Tesaro, Vivace, Acrivon, Zenith; Financial Interests, Institutional, Other, Grant/Research Support: Acrivon; Financial Interests, Institutional, Research Grant: Boundless Bio, Ideaya. J.K. Litton: Non-Financial Interests, Institutional, Research Grant: AstraZeneca, EMD Serono, Genentech, Medivation/Pfizer, Merck, Novartis, Pfizer, Zenith Epigenetics; Non-Financial Interests, Personal, Speaker’s Bureau: Clinical care options, Med Learning Group, Medpage, Medscape, Physicians' education resource, PrIME Oncology, UpToDate; Non-Financial Interests, Personal, Royalties: UpToDate; Non-Financial Interests, Personal, Advisory Board: AstraZeneca, Ayala Pharmaceuticals, Medivation/Pfizer; Financial Interests, Personal, Advisory Board: Pfizer. All other authors have declared no conflicts of interest.