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Clinical Trial Underway for New-and-Improved Prostate Cancer Test

By Deborah Borfitz

May 14, 2024 | Researchers at the University of Michigan (U-M) have developed a urine test for prostate cancer known as MyProstateScore 2.0 (MPS2), now a property of spinoff LynxDx, which they expect to significantly improve upon the performance of existing assays by focusing on clinically significant cancers and capturing more biomarkers in a single test. The latest reasons for optimism are findings of a recent study showing the 18-gene panel meaningfully reduces unnecessary prostate biopsies while providing highly accurate detection of worrisome prostate cancers, according to Jeffrey Tosoian, M.D., assistant professor of urology and director of Translational Cancer Research at Vanderbilt University Medical Center. 

Tosoian, co-first author of the study and a cofounder of LynxDx, was at the time doing his urologic oncology fellowship at U-M. A prospective clinical trial, led by U-M urologist John Wei, M.D., is now underway to determine how to use validated biomarker tests, including MPS2, in combination with prostate MRI for optimal detection of clinically significant prostate cancer in patients considering a prostate biopsy.  

In the latest published study (JAMA OncologyDOI: 10.1001/jamaoncol.2024.0455), the multiplex urinary panel for high-grade prostate cancers was externally validated relative to current guideline-endorsed biomarkers—among them, the traditional serum prostate-specific antigen (PSA) alone, the Prostate Cancer Prevention Trial risk calculator, the Prostate Health Index, and  the original two-gene MPS test developed by the U-M team. In patients who had not previously had a biopsy, MPS2 was found to reduce unnecessary biopsies by 35% to 42% versus 15% to 30% with the other biomarkers, and the new test performed even better (46% to 51% versus 9% to 21%) in men with a history of a previous negative biopsy. 

The cost effectiveness of the test, a critical real-world consideration, will be the topic of a talk Tosoian is soon to give to the Cancer Intervention and Surveillance Modeling Network of the National Institutes of Health. A cost effectiveness study published on the original MPS test a few years ago found that use of the urine-based test was more cost-effective than MRI, he says, and that same question will be important to answer regarding the new-and-improved MPS2. 

As he would like patients and families everywhere to know, “screening for prostate cancer is drastically improved from even a few years back… and offers great benefit in terms of identifying harmful cancers at an early stage where they can be treated and, in many cases, cured.”  In the past, patients with an elevated PSA routinely underwent a prostate biopsy, most of which were negative. 

“Nobody wants to undergo an unnecessary biopsy,” says Tosoian, “and these newer tools allow us to more accurately determine which patients truly do need a biopsy.” Given the more favorable benefit-to-risk ratio, he urges men to “consider strongly” prostate cancer screening.  

The once-controversial PSA test can now be recognized for its strengths as a first-line screening test, in addition to its limitations. Long-term follow-up from early PSA-screening trials show a more than 40% reduction in cancer mortality, which compares favorably to screening for breast and colon cancers, he notes. Because prostate cancer tends to progress slowly, it took several years to see the positive impact of early detection with PSA screening. 

“The benefit of PSA screening is significant, but when used alone to prompt a biopsy, the potential harms were not trivial,” says Tosoian. The use of second-line tests, such as MRI and biomarkers, has really shifted the balance by reducing the likelihood that a patient without significant prostate cancer will have to undergo an invasive biopsy.”  

Then and Now

Current biomarker-based tests for prostate cancer were developed before it was known that low-grade prostate cancer poses minimal harm because it grows very slowly if at all, Tosoian says. “The clinical focus has truly shifted to diagnosing the higher-grade cancers, and so we went looking for new biomarkers that were specifically associated with the clinically significant ones.” 

Moreover, the prior generation of prostate cancer biomarker tests measured no more than three or four genes associated with cancer. “There are several genes that can potentially serve as markers of cancer, but most prostate cancers will only express a limited number of them,” says Tosoian. Including several-fold more biomarkers in a single test, like the 18 genes measured in MPS2, “gives you more lines in the water” for picking them up, he explains with a fishing analogy. 

In 2012, the U.S. Preventive Services Task Force (USPSTF) recommended against PSA-based screening in the absence of evidence that it had clear benefits relative to the risks caused by false-positive results, including unnecessary biopsies and unnecessary diagnosis and treatment of low-grade cancers, says Tosoian. That further prompted efforts to develop non-invasive tests that might reduce those harms. 

The emergence of biomarker tests and imaging, combined with more widespread use of active surveillance for low-grade cancers, contributed to the USPSTF in 2018 revising its stance to make PSA testing a matter of individual choice for men aged 55 to 69 years.  

Other currently available urine-based options include the EPI test, which helps predict clinically significant prostate cancer in men who have not yet had a biopsy; the Select MDx test, which measures messenger RNA levels of two biomarkers commonly expressed in prostate cancer; and the U-M-developed MPS test that combines PSA with two biomarkers for prostate cancer. 

MPS2, in contrast, was specifically developed to identify prostate cancers classified as Grade Group 2 or higher, meaning cancers that are more likely to grow and spread compared to Grade Group 1—the low-grade form that does not seem to metastasize, Tosoian says. For years, cancer aggressiveness was assessed using the Gleason score system which, while still used and legitimate, is “very confusing for patients… it starts at 6 and ends at 10, and there are two different types of 7s that mean different things and have a different prognosis associated with them.”  

Grade Group 2, for example, is equivalent to Gleason 3+4=7. Given the interpretation difficulty, the newer Grade Groups system was developed that is “essentially a direct translation of the Gleason scores, except it more intuitively ranges from 1 to 5,” says Tosoian. 

Patients with the Grade Group 1 prostate cancers are appropriate for active surveillance, and select patients with Grade Group 2 are candidates, whereas “the higher-grade cancers are the ones that benefit from early detection and treatment to prevent harm,” he says. In the days when everyone with an elevated PSA got a biopsy, about half of those diagnosed had Grade Group 1 cancer but today the low-grade form describes about one-third of prostate cancer diagnoses. 

Validation Work

MPS2 builds on the original, two-gene MPS test, developed in the lab of Arul Chinnaiyan, M.D., Ph.D., who was Tosoian’s research mentor and a senior author on the latest study. Their team started by identifying new markers of cancer and high-grade cancer in publicly available data from The Cancer Genome Atlas and other shared databases. This allowed them to identify 54 candidate markers in the first phase of the project.   

In the second phase, they tested the association of the candidate markers with prostate biopsy results in a development cohort of U-M patients from over several years who had provided a urine specimen prior to prostate biopsy. This allowed them to narrow the testing panel down to an optimal combination of 18 genes to predict the presence of significant cancers to include in the final test. Each of the markers is weighted by a certain factor based on its relative influence on test results. 

That model was then externally validated in a separate population of nearly 800 men that participated in a clinical study through the National Cancer Institute – Early Detection Research Network. To that end, urine samples were sent, blinded, to the U-M lab where measurements were performed and returned to collaborators at the Fred Hutchinson Cancer Center to carry out the analysis. 

The collaborative nature of the study group allowed MPS2 to be directly compared to other existing tests, and the results were highly encouraging for the new test, Tosoian points out. For example, compared to the original MPS test, MPS2 increased the number of unnecessary biopsies that could be avoided by 8% to 15% in initial biopsy patients and 31% to 46% in repeat biopsy patients.   

The original MPS test was previously available as a laboratory developed test (LDT), although there was little commercial effort put into promoting it, Tosoian says. Whether MPS2 will remain an LDT or seek formal approval by the U.S. Food and Drug Administration remains an open question. 

The ongoing, multicenter clinical trial could be a step in that direction. The study launched in 2019 and paused for an interim analysis before picking back up recently, says Tosoian. It is open to patients with a moderately elevated PSA who agree to undergo an MRI and biopsy as well as give blood and urine samples. The idea here is to determine the most accurate and efficient approach to sequentially using the various tests to diagnose clinically significant prostate cancer, he adds.  

Separately, the research team has moved on to the second part of MPS2 validation testing in a more diverse cohort. Since the molecular pathways to the development of prostate cancer differ by race, it stands to reason that the model’s performance could vary in individuals who weren’t represented in the initial optimization exercise, Tosoian says.