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Imaging Agent May Have Potential as Noninvasive Test to Predict PARP Inhibitor Response

Imaging machine

PARIS – During the European Society for Molecular Oncology Congress on Sunday, researchers shared preliminary data on a radiolabeled imaging agent that they eventually hope to advance as a novel, noninvasive test to guide treatment with PARP inhibitors.

PARP inhibitors can be highly effective treatment options for patients with certain cancers, but genetic tests for germline and somatic mutations typically used to identify patients likely to benefit from these therapies have been difficult to integrate into clinical practice. Many of the gene mutations associated with PARP inhibitor response tend to be inherited and associated with familial cancer syndromes, though mutations can also occur in the tumor only.

Even though these biomarkers can manifest as germline or somatic mutations, it isn't standard practice to do both types of tests. Germline testing on patients' blood or saliva can identify a lot of patients likely to benefit from PARP inhibitors as well as those at risk for inherited cancer syndromes, but such tests aren't always offered.

Oncologists are increasingly performing large somatic next-generation sequencing panels on tumor DNA to personalize treatments for their patients, but these tests have their limitations, too. Invasive tumor tissue biopsies are often difficult to perform on patients with advanced cancers and because tumor samples used in next-generation sequencing usually only come from one tumor site, they don't necessarily reflect molecular heterogeneity across metastatic lesions.

A new radiolabeled tracer designed to light up the tumor cells to which PARP inhibitors will ultimately bind may provide a less invasive and more direct measure of these drugs' therapeutic benefit while avoiding the challenges of germline and somatic testing, some researchers are betting. Lilie Lin, a radiation oncologist at MD Anderson Cancer Center, presented data on the novel radiotracer, [18F] FluorThanatrace ([18F]FTT). The tracer involves the radioisotope fluorine-18 bound to FTT, what Lin called an analog to Clovis Oncology's PARP inhibitor Rubraca (rucaparib).

"FTT, when radiolabeled with fluorine-18, can then be used as a PET imaging agent [which] theoretically also joins with the same binding site as PARP inhibitors," Lin said. That binding site is the NAD pocket, which is exposed when the PARP1 enzyme binds to DNA in its active state. For this reason, she said, "[18F]FTT could also be used as a pharmacodynamic biomarker of PARP inhibitor target engagement."

In other words, if tumor lesions glow on a PET imaging scan after a patient is injected with [18F]FTT, it is reasonable to expect that those same lesions would be targeted by PARP inhibitors. The idea is similar to that of diagnostic imaging agents for radiopharmaceuticals, such as the gallium-based PET tracer Locametz (68Gallium-PSMA-11) used to flag prostate-specific membrane antigen (PSMA) in prostate cancer lesions that would be targeted by Novartis' radiopharmaceutical Pluvicto (177Lu-PSMA-617).

In a Phase I study, Lin and colleagues evaluated [18F]FTT as a way to measure PARP1 expression among patients with primary or metastatic solid tumors harboring germline or somatic BRCA1/2 mutations or other DNA damage response (DDR) mutations. Lin presented data from 44 patients with ovarian, breast, pancreatic, prostate, bladder, endometrial, primary peritoneal, and kidney cancers as well as leiomyosarcoma and melanoma. The patients underwent PET imaging after injection with [18F]FTT, and the investigators used the standardized uptake value (SUVmax) to measure the radiotracer's ability to reach cancer cells in the primary tumor and up to five metastatic sites. This imaging was done about one week before patients started therapy, which most often involved either PARP inhibitor monotherapy or combination therapy on a clinical trial.

All patients had measurable SUV, and the overall median SUVmax was 5.7. There was no significant difference in SUVmax among patients with BRCA1/2 mutations versus other mutations.

In her presentation, Lin explained how in preclinical studies, ex vivo analysis of the tumors showed that the uptake of [18F]FTT correlated well with measures of PARP1 expression detected by methods such as immunofluorescence. The uptake was significantly higher in patients who hadn't received prior PARP inhibitors, Lin added.

"Although the study that I reported today is largely observational, this is very hypothesis-generating," she said, adding that she looks forward to sharing the results from a second [18F]FTT PET imaging test that patients on the trial received once they began their PARP inhibitor treatment. The data from those studies could help shed light on the PET tracer's value as a predictive biomarker of response to PARP inhibitors.

In a discussion of the MD Anderson study data, Sandra Demaria, a radiation oncologist at Weill Cornell Medical College, commended Lin and colleagues for their work on the PET tracer, pointing out that other attempts to develop such a radiotracer for PARP1 have not made it to clinical trials due to issues such as uptake by non-tumor tissue, instability in vivo, and inability to cross the blood-brain barrier.

In terms of whether the [18F]FTT tracer could potentially outperform germline or somatic mutation-based biomarkers in predicting PARP inhibitor response, Lin said she and her team are actively investigating that question. "The upside of using a noninvasive imaging biomarker is that you can image the entire patient at one time, and you could do it multiple times over the course of therapy," she said, adding that the approach could also address the tumor heterogeneity challenge that somatic testing faces when it assesses a single tumor sample taken at one time point.