NEW YORK – On the heels of an early but encouraging data readout for its epigenomic blood-based profiling test, Precede Biosciences is optimistic that liquid biopsies will prove useful for determining patient eligibility for radiopharmaceuticals.
In the two and a half years since Novartis netted US Food and Drug Administration approval for its radiopharmaceutical Pluvicto (Lu177 vipivotide tetraxetan), a burgeoning new drug class has emerged, with a host of companies developing their own versions of both therapeutic radioligands and accompanying diagnostic PET imaging agents.
Pluvicto's approval in prostate-specific membrane antigen (PSMA)-positive metastatic prostate cancer has spurred diagnostic companies to develop radioactive isotopes that bind to PSMA and make patient's PSMA-positive lesions glow on PET scans. This has been the go-to approach to identify patients likely to respond to Pluvicto. The radiopharmaceutical's FDA-approved label states that patients are only eligible for it if their lesions express PSMA as determined by a PSMA-targeted PET imaging agent. In approving Pluvicto, the FDA also approved Novartis' gallium-based PET imaging agent, Locametz (gallium Ga 68 gozetotide).
In addition, Telix Pharmaceuticals' Illuccix (Ga-68 PSMA-11) and Blue Earth Diagnostics' Posluma (flotufolastat F 18) are other imaging agents that can be used to determine Pluvicto eligibility. However, they all require specialized equipment and expertise and involve multiple steps over several hours. After patients are injected with radioactive isotopes, they must lie in a PET scanner as it identifies how much of the agent has bound to the cancer lesions.
"Access to PET imaging is not universal," said Precede CSO Carl Barrett. "A blood draw can be done globally, and easily."
Precede's PSMA liquid biopsy test
To address this access gap, Boston-based Precede has developed a test that measures genome-wide expression of cancer surface proteins from peripheral blood draws. The platform, which Barrett says can be used as a companion diagnostic for antibody-drug conjugates and radiopharmaceuticals alike, is meant to analyze circulating chromatin structures to spot gene methylation and histone modifications, which are associated with gene enhancers and promoters.
"There are about 1 million enhancers that regulate gene expression, so the valuable thing that we have is the ability to measure these enhancers," Barrett said. "When we looked at the possible enhancers, we could see a very distinctive change in [gene] expression in healthy individuals and prostate cancer patients. We used those features to create a score, and that's what we correlated with the PET imaging score."
According to Barrett, the score developed based on this blood draw correlates with patients' progression-free survival, their time to next treatment, and their overall survival when treated with Pluvicto.
At the American Association for Cancer Research's (AACR) conference on liquid biopsies last month, Barrett and his team presented data from a retrospective analysis of their PSMA assay's performance using samples from patients treated with Pluvicto. The academic study, which was led by Emory University oncologist Jacob Berchuck, involved 45 mCRPC patients who'd been treated with Pluvicto based on their PET imaging-detected PSMA expression.
The researchers performed epigenetic analysis on samples collected when patients had their PSMA PET scans, then again at the time of their Pluvicto treatments. The profiling gauged genome-wide cell-free DNA epigenomic signals across histone modifications associated with active enhancers and promoters, as well as DNA methylation. This analysis facilitated the identification of what researchers believed to be the PSMA gene-regulatory loci at the FOLH1 locus.
Using these signals, the researchers then trained a model to predict the mean standardized uptake value (SUVmean), the measurement used with PSMA PET imaging. They found that the plasma PSMA measurements were comparable to PSMA PET imaging in stratifying patients' Pluvicto outcomes.
"The hazard ratios using the Precede PSMA assay and the PSMA PET assay were essentially indistinguishable," Barrett said.
Further validation, pharma collaboration
The results that Precede presented aren't enough to unseat PSMA PET imaging as the go-to companion diagnostic for radiopharmaceuticals. The study was retrospective, after all, and involved just 45 patients' samples.
Further validation will be required to prove that the liquid biopsy approach is non-inferior to the PSMA PET imaging approach, Barrett acknowledged. And even in that case, the blood-based biomarker would likely gain a foothold as a reflex test before it came close to becoming an alternative to PSMA PET imaging. But this is how liquid biopsy-based next-generation sequencing began too, he noted.
"The first approvals for genomic profiling liquid biopsies for [biomarkers] like EGFR were as reflex tests," he said, adding that now liquid biopsies are used much more commonly to guide frontline use of EGFR inhibitors.
Barrett does think there could be a future in which the data could warrant a label change for Pluvicto that recognizes a liquid biopsy-based companion test. He also thinks that Precede's test can be developed further in tandem with other drugmakers' radiopharmaceuticals. To both these ends, the firm is collaborating with pharmaceutical companies.
"Once we presented [these data], we suddenly got a lot of interest from Novartis along with other companies developing PSMA [radiopharmaceuticals]," he said. Even though the liquid biopsy test would enter the market alongside Novartis' PSMA PET imaging agent Locametz, Barrett's not surprised Novartis is interested in Precede's platform since it could improve patients' access to Pluvicto.
"If, in fact, we can expand their [treatable] population, that would be of interest to them," Barrett said.
Precede is also developing its test to measure expression of other targets, including several that Novartis is focusing on with its investigational radiopharmaceutical candidates, though Barrett declined to disclose additional details.
Beyond pharmaceutical companies, Barrett said that the test's early validation data also stirred interest from academic centers. "People want to send us samples," he said. "We're rapidly able to get samples, and the goal is to replicate the studies and further define the assay by adding other markers of interest to prostate cancer. That's the road that we're taking, and it's generated a lot of excitement from both the academic and biopharma communities."
Of course, there are some drawbacks to a blood-based approach that physicians have expressed to Precede, Barrett noted. For example, when an oncologist uses PSMA PET imaging to screen their patients and sees the different uptake levels of the antigen across multiple lesions, that provides a good indication of the lesions the therapeutic radiopharmaceutical will reach and to what extent. With liquid biopsy, oncologists would receive one combined value that represents the total PSMA expression across the different metastases.
Here again, for comparison, Barrett recalled how the field grew to accept DNA next-generation sequencing over time. "This was also a longstanding argument with [NGS] liquid biopsy," he said. "Is the tissue the right reference point, when the blood is the average of all the different metastases for late-stage cancers and can't give you that differential expression?"
But even though PET imaging provides visualization of the varying expression across lesions, Barrett said that it's the combined value that's predictive of overall survival. "The blood probably reflects the most aggressive lesion in the cancer, since the circulating chromatin comes from proliferating dying cells," he said.
Another advantage with liquid biopsy, he noted, is the ability to easily track patients' biomarker expressions longitudinally. "We're not just measuring PSMA," he said. "We're measuring the continuum of care, using different biomarkers within the same patient over time. That's a real advantage of the Precede assay."
As a next step, the firm is conducting further validation studies, both in the academic setting and in collaboration with drugmakers. It is also validating a version of the liquid biopsy test in other cancers, including breast and lung. In breast cancer, it is using the assay to measure estrogen receptor (ER) activation.
"In breast cancer, ER changes over the course of therapy," he said. "We can monitor that in real time and measure it quantitatively. That's really going to give us new insights into how some of the new estrogen receptor degraders are working."