NEW YORK (GenomeWeb) – Anticipating a commercial launch in the second quarter of this year, Exosome Diagnostics and its academic collaborators have published a new paper describing the prospective validation of the company's first diagnostic in the prostate cancer space, ExoDx Prostate.
ExoDx Prostate is an RT-PCR test that measures three exosomal RNA biomarkers. Using a proprietary algorithm that combines the relative weighted expression of the three-gene expression signature, the test assigns an individual risk score for patients ranging from 0 to 100. A score greater than 15.6 is associated with an increased likelihood of high-grade prostate cancer on a subsequent biopsy.
Michael Donovan, one of the lead authors of the new study, told GenomeWeb this week that the results — which appeared online ahead of print in JAMA Oncology — show that ExoDx Prostate adds significant predictive power over the standard clinical assessments used by urologists today to determine whether a man should or shouldn't have a biopsy. The test has the potential to more specifically pick out men who are at high risk and truly need a diagnostic tissue sample, while helping to encourage more men with low-risk results to avoid the procedure.
What the study didn't yet show is whether Exosome's RNA-based assay (or other non invasive tests in development by other groups) can significantly change physicians' choices for their patients from what they would recommend based on prostate specific antigen testing and other clinical variables.
"That's the subsequent study we are putting together now," Donovan said, " to get at the decision impact, how this can change decisions, in conjunction with the patient, as to whether to go on to a biopsy."
According to Exosome, current screening methodologies for prostate cancer — which rely mainly on measurement of PSA and physical exams — lack sufficient specificity. As a result, they can kick off a cascade of unnecessary interventions starting with biopsies, then overdiagnosis, and down the line, potential unnecessary treatment with surgery or anticancer drugs.
The company estimates that clinicians perform more than 2 million prostate biopsies in the United States and Europe each year, 75 percent of which appear to have been unnecessary in retrospect because the results indicate non-aggressive, low-risk disease.
This has created a well-recognized need for better pre-biopsy tools that can accurately identify high-grade cases that require more immediate intervention without unnecessarily implicating indolent or low-risk cases.
In the JAMA Oncology study, researchers from Exosome and several collaborating academic centers first trained ExoDx Prostate in 499 patients with PSA levels between 2 and 20 ng/ml who were referred for an initial or repeat biopsy based on PSA or physical examinations.
After patients that didn't meet criteria were removed, 255 men were left in this training cohort, and among them, the researchers found that ExoDx Prostate combined with standard of care clinical factors showed a better ability to discriminate between high-grade (Gleason score-7 or greater) versus low-grade disease. The AUC in the training cohort was 0.77 versus on 0.66 when using clinical factors alone.
The team then validated the derived prognostic score in a separate cohort of 1,064 patients, narrowing to 519 patients after removing those that didn't meet the right criteria. In this group, the test plus clinical factors yielded an AUC of 0.73 versus 0.63 for standard-of-care assessments.
According to the authors, the results suggest that if clinicians altered their decision making to correspond to patients' risk as assessed by ExoDx Prostate, almost 30 percent of biopsies could have been avoided in this group.
Even though 12 patients with Gleason scores above the cutoff point would have gone un-biopsied if the assay were used to guide care, the authors wrote, the clinical records for nine of them indicated that their tumors were of a type that is often indolent, leaving only three patients, or 5 percent of the cohort, for whom use of ExoDx Prostate may have led to under treatment.
The actual clinical impact of the test on physician and patient decision making will have to be determined by future studies, which Donnovan and Exosome said are now in the works.
In the meantime, Exosome plans to launch ExoDx Prostate for interested customers some time during the second quarter of this year, Exosome President and CEO John Boyce, COO Thomas McLain, and Chief Scientific Officer Johan Skog told GenomeWeb this week.
ExoDx Prostate is not the only non-invasive assay being advanced as a potential adjuvant or alternative to PSA in guiding clinicians as to when and when not to order a prostate biopsy. Two other urine tests on the market include Hologic's FDA-approved Progensa PCA3 assay, which detects PSA3 transcript levels, and another test developed at the University of Michigan, which combines blood-based PSA testing with urine analysis of both PCA3 and expression of the TMPRSS2:ERG fusion gene.
One major way that Exosome's test differs from a potential alternative like the Michigan assay or Progensa, is that it doesn't require an enhanced digital rectal examination prior to collecting a urine sample.
Exosome's test instead is performed directly on what is called "first-catch urine" from a patient. According to McLain, this means the test is truly non-invasive in a way that tests that require digital rectal exams are not, making it more flexible and less disruptive for doctors and more attractive to patients.
With appropriate future research and development, there is also the possibility of a version of the test that allows patients to collect their own sample at home and send it in to their doctor. "It could be run even before the patient has their appointment, so the data is available when the patient sees their urologist," McLain said.
Another important distinguisher, according to Skog, is that ExoDx is a molecular test, and more specifically, an exosomal RNA-based test. An ability to assay exosomal RNA is something Exosome Dx cites as a major achievement for its overall business, because exosomes are relatively stable and resilient compared to freely floating RNA molecules that rapidly degrade in circulation, and thus are much more difficult to assay.
Moreover, Skog said, being able to test RNA makes the ExoDx prostate test potentially relevant not just in predicting risk, but also in further stratifying or informing the molecular or biological features of prostate cancers.
For example, he said, in the current study, while 12 men with Gleason score-7 results on biopsy were deemed low risk by ExoDx, three quarters of these turned out to be among a known low-risk subgroup of GS7 called GS3 + 4. The view that all GS7 tumors are the same is losing acceptance in the prostate cancer field, the study investigators wrote, meaning the potential ability of ExoDx to more precisely subdivide GS7 patients could be a further advantage.
According to the JAMA authors, one other test — the University of Michigan prostate score assay, which includes PSA and urine-based gene fusion testing — has reached an AUC of 0.77 — the same as ExoDx Prostate — when combined with other clinical algorithmic tools in a separate study. Other urine and blood-based tests have come close, hovering around the 0.7 mark in separate research studies.
Skog cautioned, however, that test performances from separate cohorts can't reliably be compared to one another. Exosome's test has not been put head to head against other available assays for assessing prostate cancer risk, so its predictive value directly compared to other assays is unknown.
Other commercial plans
Reflecting on the company's commercial plans as a whole, McLain and Boyce said that near-term expansion of Exosome's test menu will focus on areas where there is a relatively reasonable expectation of insurance reimbursement.
In addition to ExoDx Prostate, Exosome currently offers a test for ALK fusions for lung cancer patients and plans to expand with EGFR testing to predict patient's sensitivity to kinase inhibitors, as well as emerging therapeutic resistance via the T790M mutation.
While the company has said in the past that it intended to develop and make commercially available a broader pan-cancer oncology panel, Boyce and McLain said that the revenue proposition for such a test isn't as reasonable under current reimbursement trends. However, as the field changes, launching a larger panel may make sense in the future.
In the meantime, Boyce said Exosome is bolstering its focus on partnerships with pharmaceutical companies and is developing new regulatory and companion diagnostics-focused departments within the company.
As relevant companion diagnostic biomarkers emerge in these collaborations, that could shift or guide the direction of how future Exosome panels evolve, Boyce said.