Safety and feasibility of PARP1/2 imaging with 18F-PARPi in patients with head and neck cancer

Abstract

Purpose.

We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with ¹⁸F-PARPi in patients with head and neck cancer.

Patients and Methods.

Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with ¹⁸F-PARPi (331 ± 42 MBq) and dynamic PET/CT imaging was performed between 0 min and 25 min post-injection. Static PET/CT scans were obtained at 30 min, 60 min and 120 min post injection. Blood samples for tracer concentration and metabolite analysis were collected. Blood pressure, ECG, oxygen levels, clinical chemistry and CBC were obtained before and after tracer administration.

Results.

¹⁸F-PARPi was well-tolerated by all patients without any safety concerns. Of the 11 patients included in the analysis, ¹⁸F-PARPi had focal uptake in all primary lesions (n = 10, SUV_max = 2.8 ± 1.2) and all ¹⁸F-FDG positive lymph nodes (n = 34). ¹⁸F-PARPi uptake was seen in ¹⁸F-FDG negative lymph nodes of three patients (n = 6). Focal uptake of tracer in primary and metastatic lesions was corroborated by CT alone or in combination with ¹⁸F-FDG. The overall equivalent dose with ¹⁸F-PARPi PET was 3.9 mSv – 5.2 mSv, contrast was high (SUV_max(lesion)/SUV_max(trapezius muscle) = 4.5) and less variable than ¹⁸F-FDG when compared to the genioglossus muscle (1.3 versus 6.0, p = 0.001).

Conclusions.

Imaging of head and neck cancer with ¹⁸F-PARPi is feasible and safe. ¹⁸F-PARPi detects primary and metastatic lesions, and retention in tumors is longer than in healthy tissues.

Introduction

Diagnosis and treatment of many malignant tumors have dramatically improved in recent decades, and oral and oropharyngeal squamous cell carcinoma are no exception to this trend. However, most patients with oral and oropharyngeal squamous cell carcinoma still present with advanced disease and regional or distant metastases at the time of diagnosis.

Presence of pathological regional lymph nodes is the most powerful and consistent predictor of outcome for oral cancers (1), and the ability to accurately assign the exact extent of metastatic spread within the neck lymphatic system is therefore of great significance (1,2). Complete surgical removal of metastatic disease in the neck has a clear impact on prognosis, but it often remains unclear until histopathological analysis is complete, if a lymph node was metastatic or not (3,4).

Clinical palpation of the neck is inadequate, as are the available radiological investigative tools. This is because many patients present with enlarged lymph nodes due to inflammation around the tumor site. These inflamed lymph nodes may mimic neck metastases on CT scans and are often ¹⁸F-FDG PET avid (5). On the other hand, some metastatic neck nodes may not be enlarged and show no abnormal ¹⁸F-FDG uptake. For these reasons, elective neck dissection or irradiation are often recommended in patients with head and neck cancer for prophylactic treatment of occult metastases. Ideally, however, these procedures, which can lead to increased co-morbidities and reduced quality of life due to overtreatment (6,7), would be avoided if the presence of occult metastases could be definitively ruled out.

PARP PET imaging could potentially provide a solution for this unmet clinical need. Because of its importance for cell survival, PARP is overexpressed in many malignancies, including oral and oropharyngeal squamous cell carcinoma (8,9). Several radiolabeled PARP inhibitors were tested in preclinical studies, showing correlation of uptake with PARP1 expression, and suggesting that imaging is possible with little unspecific uptake in healthy head and neck tissue (10,11).

The purpose of this study was to clinically translate ¹⁸F-PARPi, a PARP inhibitor derived from the core scaffold of olaparib (12), and to provide a first step toward validating the tracer as a clinical tool. Other PARP inhibitor-based imaging agents, based on different core scaffolds, were translated earlier (13,14). In this first-in-human phase I clinical trial in patients with oral and oropharyngeal cancer, we determined the safety and feasibility of ¹⁸F-PARPi imaging. We also correlated ¹⁸F-PARPi uptake in tumors and normal tissue to standard of care ¹⁸F-FDG imaging.

Patients and Methods

Further description of the experimental procedures and methods, including radiopharmaceutical preparation, tracer formulation and quality control can be found in the supplementary materials.

Study design.

This exploratory, phase I, single-center, open-label, prospective Health Insurance Portability and Accountability Act (HIPAA) compliant study was approved by the Memorial Sloan Kettering (MSK) Institutional Review Board and conducted in accordance with the Declaration of Helsinki (Clinicaltrials.gov, NCT03631017). Written informed consent was obtained from all patients. The primary objectives of this phase I trial were to evaluate the safety and feasibility of ¹⁸F-PARPi. We report the biodistribution and radiation dosimetry, and describe the tumor uptake of ¹⁸F-PARPi compared to ¹⁸F-FDG. Patients were accrued between January 2019 and September 2019 and referred to the MSK Molecular Imaging and Therapy Service for their newly diagnosed or recurrent oral or oropharyngeal cancer. Twelve patients were enrolled on this study protocol. Of these, eleven patients completed the study (8 patients with oropharyngeal squamous cell carcinoma and 3 patients with oral cavity squamous cell carcinoma). One patient withdrew consent before administration of ¹⁸F-PARPi. No patients were excluded from the analysis. Inclusion and exclusion criteria are summarized in Supplementary Table S1.

Procedures.

All patients underwent clinical examination, baseline vital signs, pulse oximetry, ECG and blood tests (< 2 weeks prior to imaging). No fasting was required prior to ¹⁸F-PARPi imaging. On the day of imaging, two IV catheters were placed in each forearm, one for injection of ¹⁸F-PARPi and one for drawing of IV blood samples. ¹⁸F-PARPi was administered to patients at an average activity of 333 ± 44 MBq (9.0 ± 1.2 mCi) by intravenous bolus injection. For the first six patients, a dynamic PET scan (with the field of view including the heart, lungs, liver, and kidneys) was acquired to study the biodistribution and clearance of the tracer. For the subsequent five patients, the dynamic PET scan was centered on the head and neck region. In all instances, the CT component of the dynamic PET/CT was acquired with a tube current of 40 mA. Immediately after the dynamic study, a static PET/CT scan (extending from skull vertex to upper thighs in 6 patients, and over the head and neck region in 5 patients) was obtained (30 mins post injection; CT tube current: 80 mA). Two further static PET/CT scans were taken at approximately 60 min and 120 min post-injection (CT tube current: 10 mA).

A total of 5 blood samples (at approximately 1 min, 5 min, 30 min, 90 min and 150 min post injection) were drawn to quantify blood pool activity and to study ¹⁸F-PARPi metabolites. After imaging, vital signs were obtained and an ECG performed, and blood samples were collected for hematology and blood chemistry analysis). A follow-up phone interview (1–3 days after the imaging study) was conducted to document any side effects occurring after completion of the imaging study.

Immunohistochemistry.

Paraffin embedded slides from surgical specimen or core biopsies of the primary tumor were obtained from consented patients and processed at the molecular cytology core facility at MSK. PARP1 immunohistochemistry was performed using the Discovery XT processor (Ventana Medical Systems, Tucson, AZ). The anti-PARP1 rabbit monoclonal antibody (46D11, Cell Signaling Technology, Danvers, MA) specifically bound both human PARP1 (0.4 μg/mL). Paraffin-embedded formalin fixed 3 μm sections were deparaffinized with EZPrep buffer, antigen retrieval was performed with CC1 buffer (both Ventana Medical Systems, Tucson, AZ), and sections were blocked for 30 minutes with Background Buster solution (Innovex, Richmond, CA). Anti-PARP1 antibody was incubated for 5 hours, followed by 1 hour of incubation with biotinylated goat anti-rabbit IgG (PK6106, Vector Labs, Burlingame, CA) at a 1:200 dilution. For immunohistochemical (IHC) detection, a DAB detection kit (Ventana Medical Systems, Tucson, AZ) was used according to the manufacturer’s instructions, sections were counterstained with hematoxylin and cover-slipped with Permount (Fisher Scientific, Pittsburgh, PA). Incubating with a rabbit IgG instead of the primary antibody controlled for non-specific binding of the secondary antibody. Slides were scanned (Mirax, 3DHISTECH, Budapest, Hungary) to allow for digital histological correlation. H&E stained slides were used to determine areas of tumor and areas of normal muscle. Those exact same areas were used for PARP1 quantification using a consecutive slide.

Blood clearance and metabolite analysis.

Blood clearance measurements were performed as previously reported. Briefly, multiple venous blood samples were obtained between 1 min and 150 min after intravenous injection of ¹⁸F-PARPi. Activity in whole blood and plasma was measured in duplicate using a calibrated NaI (Tl) Wallac Wizard 2480 automatic γ-counter (Perkin Elmer, Inc.). The measured activity concentrations were converted to percentage injected activity per kilogram (%ID/kg). Metabolite analysis of activity in plasma was performed by reversed-phase HPLC with in-line radiation (Posi-RAM model 4, LabLogic) detection using a Kinetex Biphenyl column (Phenomenex, 150 × 4.6 mm; 5 μm particle size) and a mobile phase gradient of 10–75% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes. Intact ¹⁸F-PARPi elutes at 16 minutes and a number of metabolites elute from 7–8 minutes.

Dosimetry.

Absorbed radiation doses to normal tissues were estimated for the first 6 patients of the study, based on dynamic and static PET/CT images. Activity concentration-time curves were generated by analysis of VOIs generated for liver, kidney, spleen, cardiac blood pool, bone, lung, gallbladder and urinary bladder. Red marrow activity concentration was assumed equal to that of blood. Whole body time-activity-time curves, generated using the 4 points defined by the administered activity (time zero) and the total activities in the three whole-body PET scans, were used to calculate mono-exponential clearance half-times. The areas under activity concentration-time curves (AUC) were estimated by trapezoidal integration with a terminal contribution calculated by extrapolation from the last measured value using the shorter of apparent terminal clearance rate or physical decay. Whole-organ AUCs were obtained by multiplying the activity concentration AUC by organ mass. Baseline values of organ mass were taken from the Oak Ridge National Laboratory (ORNL) phantoms of OLINDA/EXM® 2.0 (Hermes Medical Solutions, Sweden) representing standard human. Organ masses were rescaled if body mass differed by more than 15% from the standard value (73.7 kg for males; 56.9 kg for females). Organ residence times were derived by dividing organ AUC values by administered activity. For urinary bladder contents, residence times were estimated by the OLINDA/EXM 2.0 voiding bladder model based on the fraction of activity clearing via urinary bladder, the mono-exponential whole-body biological half-time, and an assumed voiding interval of 1 hour. Residence times for the remainder of body were derived by subtracting all the individually estimated residence times from the whole-body residence time. Absorbed radiation doses to the whole body and various organs were calculated using OLINDA/EXM 2.0 with effective doses based on the tissue weighting factors of ICRP Report 103.

PET/CT imaging and analysis.

All PET/CT images were obtained on a Discovery 710 PET/CT scanner (GE Healthcare), using low dose CT settings (10–80 mA, 120 kV) for CT images that were used for attenuation correction and anatomic correlation. All studies were reviewed using the Hybrid Viewer display and analysis application (Hermes Medical Solutions, Sweden). ¹⁸F-PARPi PET/CT and ¹⁸F-FDG PET/CT studies were interpreted by two nuclear medicine physicians with at least 10 years of PET/CT experience. Three-dimensional threshold-based volumetric regions of interest (VOI) were placed in reference regions (bilateral submandibular gland, parotid gland, blood pool of neck, contralateral posterior neck muscles (trapezius and semispinalis), genioglossus muscle, bone marrow, mediastinal blood pool, myocardium, normal liver, renal cortex, and spleen) and over all sites of abnormal uptake in lymph nodes, or soft-tissue lesions with reference to the PET/CT images. Abnormal ¹⁸F-PARPi and ¹⁸F-FDG uptake was defined as outside physiologic sites (such as palatine tonsils or skeletal muscle) and of intensity greater than regional background. Uptake of ¹⁸F-PARPi in the soft-tissue lesions and lymph nodes was assessed by measuring the maximum standardized uptake values (SUV_max).

Statistics.

Uptake values are presented as mean ± standard-error, unless otherwise specified. Distribution of uptake with ¹⁸F-PARPi and ¹⁸F-FDG (on lesions where both were available) were compared using a Mann-Whitney-Wilcoxon test for paired data, while their variances were compared using a Levene’s test. R version 3.6.0 was used for analysis.

Results

Patient population.

A total of 11 patients with cytologically or histologically confirmed squamous cell carcinoma of the oral cavity or oropharynx completed the study protocol. Supplementary Table S2 lists the patient demographics and key diagnostic parameters, including stage and lymph node status, and Figure 1 shows a schematic overview of the study workflow. There were 10 males and one female, with a mean age of 64 years. At the time of imaging, 8 patients had newly diagnosed disease (all with the primary lesion in the oropharynx). The 3 patients that had recurrent disease at the time of imaging had previously been diagnosed with oral cavity squamous cell carcinoma. One patient had their primary lesion surgically removed before imaging. Nodal involvement (anatomically abnormal lymph nodes) was present in 9 out of the 11 patients, and disease stage ranged from I to IVb (8^th edition AJCC). Lymph nodes were considered to be abnormal when at least one of following criteria was met: central necrosis or inhomogeneous enhancement (contrast-enhanced CT and /or MRI), shortest axial diameter greater than 11 mm in cervical regions and change in shape and/or ill-defined irregular margins in a lymph node. 27% of patients (n = 3) were HPV-negative (all oral cavity squamous cell carcinoma) and 73% were HPV-positive (all oropharyngeal cases).

Figure 1.

Schematic overview and flow chart of the ¹⁸F-PARPi Phase I clinical trial.

Radiotracer characteristics.

The radiochemical synthesis of ¹⁸F-PARPi was performed using a synthetic route similar to what we have reported before (Supplementary Fig. S1, (12)). We first synthesized para-[¹⁸F]fluoro-benzoic acid as a radiolabeled synthon before conjugation with the 1(2H)phthalazinone targeting group. On average, patients were therefore injected with 290 pmol of ¹⁸F-PARPi, 6.7 orders of magnitude lower than the bi-daily administered dose of olaparib (2 × 300 mg) and therefore unlikely to elicit a pharmacodynamic response.

Adverse events and metabolism.

All patients tolerated the injection of ¹⁸F-PARPi well, and no adverse events were recorded related to the ¹⁸F-PARPi injection. One patient died within a 2-week window after completing the study, and one patient experienced grade 1 mucositis over the tumor site, which resolved the following day. The death was considered unrelated to the administered drug. The mucositis was considered possible related to the administered drug. For all patients, clinical chemistry and hematology were determined and an electrocardiogram was performed before and after the administration of ¹⁸F-PARPi (Supplementary Table S3). While some patients presented with abnormal findings before imaging, no clinically relevant changes were observed after radiotracer injection or at follow-up.

Biodistribution and dosimetry.

Maximum intensity projection PET images of a representative patient injected with ¹⁸F-PARPi (images obtained at 30 min, 60 min and 120 min post injection) are shown in Figure 2A. At 120 min, uptake in the primary tumor had an SUV_max of 4.1, whereas the metastatic lymph node had an SUV_max of 3.6 (radiologic lymph node level 2). Across the entire patient population, the average primary tumor SUV_max was 2.8 ± 1.1 at 120 min. The primary routes of excretion were renal and hepatobiliary with most of the tracer excreted renally. Activity in the renal cortex diminished over time (SUV_max = 16 ± 8 at 30 min, 9 ± 4 at 60 min and 7 ± 5 at 120 min) with commensurate accumulation in the urinary bladder. The maximal observed activity in the urinary bladder corresponded to 20–38% of the total administered, typically at the 30–60 min scan times.

Figure 2.

Biodistribution, histology and dosimetry of ¹⁸F-PARPi. (A) Maximum intensity projections at 30 min, 60 min and 120 min post ¹⁸F-PARPi injection in a 67 year old male with oropharyngeal squamous cell carcinoma. Green arrow: primary tumor; Red arrow: metastatic lymph node. (B) Dosimetry of select organs, whole body and effective dose in patients (n = 6) injected with ¹⁸F-PARP (see Supplementary Table S4 for the comprehensive dataset). (C) PARP1 IHC and corresponding H&E images of the primary lesion of a 49 year old male with carcinoma in the right palatine tonsil and corresponding H&E images. (D) PARP1 IHC and corresponding H&E images of the primary lesion of a 51 year old male with oral tongue carcinoma.

Absorbed radiation doses to normal tissues from ¹⁸F-PARPi were estimated based on the tracer biodistribution of the first six patients. Key dosimetry data are plotted in Figure 2B, and the entire dataset can be found in Supplementary Table S4. The effective dose of ¹⁸F-PARPi was 0.014 ± 0.002 mSv/MBq, calculated with ICRP103. In a typical diagnostic setting, the effective radiation dose is projected to be 3.9 mSv – 5.2 mSv.

PARP1 was highly expressed in both oral and oropharyngeal squamous cell carcinoma in our patient population (Fig. 2C and D and Supplementary Fig. S2)), corroborating earlier work (8,9).

Metabolism.

Research blood draws were obtained for 10 patients at five timepoints after tracer injection, activity counted and metabolites analyzed (Supplementary Fig. S3A). Using a 2-phase decay curve, we determined the weighted blood half-life to be 4.2 min (whole blood, Supplementary Fig. S3B). Only small quantities of metabolites were detected at 1 min and 5 min (99.2 ± 1.5% and 89.9 ± 11.4% ¹⁸F-PARPi, respectively, Supplementary Fig. S3C). At 30 min, and with decreasing blood pool concentration of the injected tracer, we detected a radiometabolite with a retention time of 7–8 min (50.9 ± 11.5%; Supplementary Fig. S4).

Organ residence time.

Investigating the specificity of ¹⁸F-PARPi, we looked at the residence times of the tracer in tumors, metastatic nodes and healthy tissues (Fig. 3). In spleen and liver, which both express large physiological amounts of PARP1 and PARP2 (15), initial uptake was high, followed by rapid clearance over the 2-hour imaging period (SUV_max(spleen, 30 min) = 6.1 ± 1.3 and SUV_max(spleen, 120 min) = 2.2 ± 0.6, representing a 64% drop). Similarly, the SUV_max in bone marrow was high in the 30 min PET/CT scan, but values declined by 53% between 30 mins and 120 mins. Comparably fast clearance was found for physiologic structures within the head and neck region. Uptake in the submandibular and parotid glands decreased by 57% and 56%, respectively. In contrast, tracer retention in tumor and metastatic nodes was significantly longer, with SUV_max values declining by just 13% for both primary and PET-avid lymph nodes (SUV_max(tumor, 30 min) = 3.4 ± 0.8 and SUV_max(tumor, 120 min) = 3.0 ± 1.1; SUV_max(lymph node, 30 min) = 3.3 ± 1.3 and SUV_max(lymph node, 120 min) = 2.9 ± 1.1).

Figure 3.

¹⁸F-PARPi pharmacokinetics in physiologic tissue, ¹⁸F-PARPi avid lymph nodes and primary tumor. (A) ¹⁸F-PARPi tracer accumulation in a 67-year-old-male with oropharyngeal squamous cell carcinoma is initially high in the submandibular gland (white triangles) and subsequently decreasing. In comparison, the primary tumor in the base of the tongue (black arrow) and metastatic lymph node (black triangles) exhibit more sustained retention of the radiotracer. Top row: PET image only; Bottom row: PET/CT. (B) Time-activity curves of a 67-year old male patient, derived from the area with highest ¹⁸F-PARPi uptake (SUV_max, primary tumor and metastatic lymph node) or from the whole structure (SUV_mean, parotid gland, submandibular gland and suboccipital muscle). (C) SUV_max uptake values for normal structures (left), and primary tumor/metastatic lesions (right, each n = 6 patients with whole-body PET scans).

¹⁸F-FDG and ¹⁸F-PARPi in primary tumor and normal neck tissues.

To determine if ¹⁸F-PARPi could be a relevant imaging tracer for the head and neck region, we compared its retention with that of standard of care ¹⁸F-FDG (Fig. 4). For both imaging agents, uptake was corroborated with tumor outlines defined by standard of care T1-weighted Gd-MRI imaging (Fig. 4C). Across the patient population, ¹⁸F-FDG had higher average tumor SUV_max values than ¹⁸F-PARPi, but SUV_max values for ¹⁸F-FDG decreased for level 2 and level 3 lymph nodes. A smaller decrease in SUV_max values was found for ¹⁸F-PARPi (66% and 15% for ¹⁸F-PARPi and ¹⁸F-FDG, respectively, when grouping primary/level 1 lymph nodes and level 2/level 3 lymph nodes; Fig. 4D). Uptake ratios (SUV_max(lesion)/SUV_max(trapezius muscle)) for ¹⁸F-FDG were higher than for ¹⁸F-PARPi (median = 10.4 versus 4.5, p < 0.0001, Fig. 4E). Interestingly, when comparing uptake ratios (SUV_max(lesion)/SUV_max(genioglossus muscle)), we found similar median values for ¹⁸F-FDG and ¹⁸F-PARPi (median = 3.0 versus 3.3, p = 0.23), although the variance was less for ¹⁸F-PARPi than for ¹⁸F-FDG (1.3 versus 6.0, p = 0.001, Fig. 4F). This could be of potential relevance in patients with recurrent oral cancers or in the post treatment setting, leading to asymmetric uptake in the oral cavity or higher uptake in the genioglossus muscle secondary to partial glossectomy, tongue movement or hypoglossal palsy (16–18).

Figure 4.

Comparison of standard of care ¹⁸F-FDG and ¹⁸F-PARPi in a 52 year-old-male with cancer in the base of the tongue. (A) ¹⁸F-PARPi PET at the level of the epiglottis (black triangles) showed an ¹⁸F-PARPi avid primary lesion in the base of tongue (white arrows) and metastatic lymph node (right level 2, black arrow) at 120 min after ¹⁸F-PARPi administration. (B) ¹⁸F-FDG PET at the same level showed ¹⁸F-FDG avid lesion in the base of tongue (white arrows) and metastatic lymph nodes (black arrow). (C) Post contrast T1 weighted axial MRI image (epiglottis level) showed a large expansile multicompartmental heterogeneously, ill-defined enhancing lesion centered in the base of tongue with effacement of the bilateral valleculae and extension along the median and lateral glossoepiglottic folds into the epiglottis. (D) Comparison of SUV_max values obtained for ¹⁸F-PARPi versus ¹⁸F-FDG in tumors and lymph nodes across the patient population. (E) SUV_max-based uptake ratios (lesion and trapezius muscle) for ¹⁸F-PARPi and ¹⁸F-FDG without separation of primary lesion and lymph nodes. (F) SUV_max-based uptake ratios (lesion and genioglossus muscle) for ¹⁸F-PARPi and ¹⁸F-FDG without separation of primary lesion and lymph nodes.

¹⁸F-FDG and ¹⁸F-PARPi uptake matched with respect to the presence and location of the primary lesion. However, the two tracers had divergent uptake patterns in the lymphatic system (Supplementary Fig. S5). For ¹⁸F-FDG, 34 lymph nodes were PET-avid. For ¹⁸F-PARPi, we observed 40 ¹⁸F-PARPi avid lymph nodes. These 40 lymph nodes included all of the lymph nodes that were detected using ¹⁸F-FDG. No evidence of additional FDG-avid and PARPi-avid adenopathy or distant metastatic disease was seen. Due to protocol regulations, no biopsy material was available for the additional 6 lymph nodes, however, a subset of them resolved after chemoradiation (which, however, does not prove malignancy, Supplementary Fig. S5A and S5B).

Discussion

Recently, PARP-targeted agents have received considerable attention as imaging agents (10,19) based on the ubiquitous expression of PARP in many types of cancers, with the promise to serve as an accurate sensor of malignancy where standard of care methods currently fail.

Radiation doses associated with ¹⁸F-PARPi PET imaging were relatively low. The overall equivalent dose was 3.9 mSv – 5.2 mSv, lower than that reported for ¹⁸F-FDG (8.1 ± 1.2 mSv, (20)). This was in part due to the selective uptake of the tracer, paired with a short blood half-life and fast clearance. ¹⁸F-PARPi rapidly cleared from the circulatory system and accumulated in the urinary bladder and gallbladder following respective transit through the kidneys and liver.

PARP1 is located in the nuclei of cells. Consequently, the cell membrane and nuclear membrane permeability of ¹⁸F-PARPi has to be high, allowing both fast uptake of radiotracer and clearance of unbound material for image contrast generation. This was seen in the submandibular glands, where the SUV_max at 20–30 min was higher than in the primary tumor for 80% (n = 10 evaluable patients) of all patients (Fig. 3). Subsequently, the delivered activity in these healthy tissues cleared quickly, whereas the activity persisted longer in tumor and metastatic nodes (Fig. 3B). At 120 minutes post-injection the situation had inverted, and none of the submandibular glands showed activity higher than the primary tumor. Similar rapid clearance of radiotracer was noted in other healthy organs, including the spleen, genioglossus muscles, parotid glands and bone marrow. For future studies, imaging with PARP inhibitors after longer time intervals post-injection might yield further improved contrast ratios.

Since this is a phase I study, we were unable to collect unstained histological slides (for primary and metastatic lesions) from a statistically meaningful number of patients. Consequently, the focus of an upcoming phase II study will be to determine the sensitivity and specificity of ¹⁸F-PARPi in head and neck cancer.

In conclusion, we performed the first-in-human translation of ¹⁸F-PARPi, a PARP-targeted 1(2H)phthalazinone, and the first imaging of PARP in head and neck cancer. Administration of ¹⁸F-PARPi was safe, and aside from a grade 1 mucositis, which was possibly related, no adverse events were attributed to the tracer injection. ¹⁸F-PARPi is a promising new agent for the imaging of head and neck squamous cell carcinoma.

Translational Relevance.

Preclinically, labeled PARP1-targeted olaparib derivatives have been used to visualize several malignancies with high contrast, including head and neck cancer. These results suggest that PARP1-targeted imaging agents could potentially be used as a quantitative whole body imaging test for primary and metastatic lesions, improving diagnostic sensitivity and specificity compared to the standard of care. This first-in-human study of ¹⁸F-PARP1 in patients with head and neck cancer established that imaging with the olaparib-based PARP1 imaging agent ¹⁸F-PARPi is feasible and safe, and that contrast ratios in the head and neck region are comparable to ¹⁸F-FDG. Retention in tumors and metastatic nodes is longer than in physiological tissues, including the salivary glands. The number of PET avid lymph nodes is higher for ¹⁸F-PARPi than for ¹⁸F-FDG, and a subset of ¹⁸F-PARPi positive and ¹⁸F-FDG negative lymph nodes resolved after chemoradiation. Further study of ¹⁸F-PARPi in head and neck cancer is being pursued.