David Albala, MD

Prostate cancer is the second leading cause of cancer in men globally, with more than 1 million new cases and 300,000 deaths attributed to this disease each year.

 In 2021, an estimated 248,530 new cases of prostate cancer and approximately 34,130 prostate cancer deaths are expected in the United States.

The COVID-19 pandemic resulted in unique clinical and real-world challenges in the screening, detection, and management of prostate cancer. Reductions in cancer screening in the United States led to delayed identification of men who may be at high risk of prostate cancer, leaving the population underdiagnosed and potentially undertreated.

 For example, estimates of new prostate cancer cases from the American Cancer Society (ACS) increased from 2020 to 2021 (191,930 and 248,530, respectively), suggesting lower detection, diagnoses, and treatment corresponding with COVID-19–related cancer screening deficits during the peak of the pandemic in 2020.

 Clinical care teams, from the primary care to urology settings, need to adopt and implement telehealth/telemedicine practices to address the cancer screening deficit associated with the COVID-19 pandemic.

There is an opportunity to implement prostate cancer biomarker testing to stratify patients into groups having high risk (combined Gleason Score ≥7 [3+4] or grade group 2+ [GG2+]) versus low risk of clinically significant prostate cancer. This risk stratification can help to overcome the lack of specificity of current prostate cancer screening tools (eg, prostate specific–antigen [PSA] testing, digital rectal examination [DRE]). This article highlights the ExoDx Prostate test, a urine liquid biomarker test that helps urologists identify patients who have a low versus high risk of clinically significant disease, independent of PSA testing and other standard of care parameters.

PSA and DRE are primary tools used to screen men for prostate cancer; however, both have limitations.

 Whereas PSA screening may reduce prostate cancer mortality risk, it is associated with potential harm, including false-positive results, overdiagnosis, and biopsy complications.

 Active surveillance has reduced rates of overtreatment, but serial biopsy follow-up can be burdensome, and contemporary screening strategies have focused on detecting clinically significant (GG2+) prostate cancers rather than indolent disease.

The ACS recommends that PSA screening be considered; however, its benefits are debatable.

 The United States Preventive Services Task Force (USPSTF) and other organizations have expressed concern that use of PSA screening can lead to increased prostate cancer detection and overtreatment.

In 2018, revised guidelines from the USPSTF recommended against PSA-based screening for prostate cancer in men aged 70 years and older and those who do not express a preference for screening. The guidelines also advised men aged 55 to 69 years to make an informed choice with their physicians by discussing whether PSA screening was right for them.

 The USPSTF and other organizations recommended against performing DRE in the primary care setting.

PSA screening is not a standardized test that can be used in all circumstances to reliably indicate the presence of an aggressive prostate cancer (defined as GG2+).

 Often, other risk factors (eg, age, family history, ethnicity, DRE results) are considered when a physician discusses prostatic biopsy with a patient to make a shared decision.

Notably, PSA screening has several other limitations. It does not distinguish between high- and low-grade prostate cancer.

 It is not prostate cancer–specific; in fact, it offers low sensitivity and specificity for prostate cancer.

 Additionally, PSA levels can be elevated by noncancerous conditions, such as benign prostatic hyperplasia (enlargement), prostatic inflammation, and lower urinary tract infection and instrumentation.

COVID-19–related cancer screening deficits

Two recent peer-reviewed studies demonstrated a marked reduction in prostate cancer screening during the COVID-19 pandemic.

 These findings highlighted the unmet clinical need for improved identification of men at risk for a prostate cancer diagnosis. The investigators recommended that tools be adopted to help discriminate those at high risk from those at low risk of prostate cancer and prioritize them for diagnostic biopsy and treatment. In addition, they noted that screening biomarkers that do not require an in-person office visit are needed.

A retrospective cohort study of single-payer United States administrative claims data from approximately 60 million people within Medicare Advantage and commercial health plans identified a reduction in prostate, breast, and colorectal cancer screening rates during the COVID-19 pandemic.

 When compared with screening rates in 2019, screening for all 3 cancers declined sharply from March 2020 to May 2020. A 63.4% reduction in prostate cancer screening was observed in April 2020 among the cohort of men aged 50 to 69 years identified to evaluate monthly prostate screening rates. Despite near-complete recoveries in monthly screening rates by July 2020 across these cancer types, an estimated screening deficit remained that affected 9.4 million Americans in 2020, including 1.6 million men for prostate screening.

 A multivariable analysis of this data showed that telehealth use was associated with more cancer screening.

A separate study reinforced the challenges noted during the COVID-19 pandemic that resulted in cancer screening deficits.

 During a 3-month primary pandemic study period from March 2020 to June 2020, there was a 63.4% reduction in prostate cancer screening when compared with 3 control periods.

 In addition, there was a 20% to 30% reduction in cancer diagnoses during the 3-month primary pandemic study period. A total of 1438 diagnoses of cancerous and precancerous lesions were “missed” when the primary pandemic period was compared with the control periods (1985 vs 3423 diagnoses, respectively).

 The percentage of positive PSA screening tests was 13.2% lower during the primary pandemic period (9.9%) than during the 3 control periods (22.7%).

Overall, the results from this study highlighted the gap in the identification of men who may be at high risk of prostate cancer and remain underdiagnosed and potentially undertreated because of the COVID-19–driven screening deficit.

 These cancer screening deficits in the United States suggest that urologists should consider adopting telehealth/telemedicine practices, especially with progression of and/or status changes that may arise during the course of the continued COVID-19 pandemic, such as the emerging delta variant and its care complications.

The ExoDx Prostate test is a simple, non-DRE, urine-based, liquid biomarker test indicated for men aged 50 years and older with PSA levels between 2 and 10 ng/mL who are considering an initial biopsy or for men who received prior negative biopsy results and are considering a repeat biopsy.

The ExoDx Prostate test provides a personalized risk score to assess whether or not clinically significant prostate cancer will be found on biopsy. This risk assessment tool affords greater confidence for identifying high-grade prostate cancer than supplied by PSA screening alone. The ExoDx Prostate test is designed to alleviate clinical uncertainty by providing a standardized approach for assessing the risk of aggressive prostate cancer.



The ExoDx Prostate test helps clinicians and patients to make a more informed prostate biopsy decision. It can be used in the primary-care setting to prioritize highest risk patients for early urologic referral for prostate biopsy. Moreover, the results can be used to support urologists and their patients to feel confident about decisions to proceed with a biopsy, to help reassure a patient about avoiding a prostate biopsy, and to improve patient compliance with physician recommendation for biopsy.

The ExoDx Prostate test provides unique, actionable information about risk stratification that is independent of PSA and other standard-of-care clinical features. This risk stratification liquid biomarkeris emerging as an important component of clinical practice and utility in the shared decision-making discussion about biopsy.

 The ExoDx Prostate test analyzes 3 exosome-located genomic biomarkers that become elevated in high-grade prostate cancer.

 The ExoDx Prostate IntelliScore (EPI) gene signature measures exosome RNA levels of 3 genes—PCA3, ERG, and SPDEF—linked to high-grade, aggressive prostate cancer.

 The RNA expression levels of these 3 genes are incorporated into an equally weighted proprietary algorithm and a personalized risk score.

The workflow for this test is provided in

Advanced purification techniques are used to isolate RNA from exosomes in the “first-catch” urine specimen (15 mL) without the need for a prior DRE. Exosomes are small, double lipid–membrane vesicles (typically, 30-200 nm in diameter) that are a rich source of cellular protein, DNA, and RNA.

 RNA is extracted from urine exosomes to analyze the expression of PCA3, ERG, and SPDEF.



The ExoDx Prostate test returns a personalized risk score ranging from 0 to 100 to help assess a man’s risk for high-grade, clinically significant prostate cancer.

 An EPI result below the cut-off point of 15.6 is associated with a lower likelihood of high-grade prostate cancer; on the other hand, an EPI result above the validated cut-off point of 15.6 is associated with an increased likelihood of high-grade prostate cancer.

, pooled data collected from more than 1000 patients showed the likelihood of finding high-grade prostate cancer on biopsy in the intended-use population of males aged 50 years and older with a PSA level of 2-10 ng/mL who are presenting with initial biopsy. The EPI score correlates with the incidence of clinically significant prostate cancer (defined as a combined Gleason Score ≥7 [3+4] on prostate biopsy) and can be thought of as a percentage risk of high-grade clinically significant prostate cancer up to a maximum of ExoDx scores.

The EPI gene signature was validated in 2 prospective, large-scale, clinical validation studies. First-catch urine samples were collected from more than 1000 biopsy-naive patients (men aged ≥50 years with a PSA of 2-10 ng/mL) who presented for initial biopsy across 28 clinical sites.

The results from the ExoDx Prostate test were compared with those of PSA screening and 2 clinical risk calculators (ie, Prostate Cancer Prevention Trial Risk Calculator and European Randomized Study for Screening Prostate Cancer Risk Calculator). The ExoDx Prostate test outperformed PSA and both risk calculators for clinically significant prostate cancer and was shown to be an independent, stand-alone risk assessment tool.

 The ExoDx Prostate test score demonstrated improved accuracy in the test population; PSA level alone had an area under the curve (AUC) of 0.55 (95% confidence interval [CI], 0.49-0.60) compared with ExoDx Prostate test without standard of care, which had an AUC of 0.71 (95% CI, 0.66-0.75) in the same population. Standard of care with ExoDx genomic testing had an AUC of 0.73 (95% CI, 0.68-0.77). The Prostate Cancer Prevention Trial Risk Calculator had an AUC of 0.62 (95% CI, 0.57-0.67), and the European Randomized Study for Screening Prostate Cancer Risk Calculator had an AUC of 0.58 (95% CI, 0.52- 0.63).

Results of the first validation study demonstrated that use of the ExoDx Prostate test was associated with improved identification of higher-grade prostate cancer among men with elevated PSA levels and could reduce the total number of unnecessary biopsies. It discriminated men with high-grade (Gleason Score ≥ 7 [3 + 4] prostate cancer on a biopsy) cancer from men with low-grade cancer and biopsy benign disease (Gleason Score = 6).

 An EPI score above the 15.6 cut-off point in the intended-use population identified clinically significant prostate cancer when compared with an EPI score below that cut-off point. With an EPI score cut-off point of greater than 15.6, the urine exosome gene expression assay demonstrated good clinical performance in predicting a prostate cancer of Gleason Score of 7 or more and showed that 27% of unnecessary biopsies would have been avoided with use of this diagnostic in patients with PSA levels of 2 to 10 ng/mL.

In the second validation study, the ExoDx Prostate test helped to stratify risk among men given a diagnosis of prostate cancer of grade 2 or greater or grade 1 or benign disease.

 The ExoDx Prostate test was significantly more accurate than any individual clinical feature or combination of features. It was superior to optimized standard-of-care clinical models, results of 2 risk calculators, and PSA determination alone for predicting grade 2 prostate cancer.

 The test had a negative predictive value of 97% for ruling out disease having a combined Gleason Score of 7 or more (4 + 3) based on the findings of validation studies.

The ExoDx Prostate test was evaluated in a unique prospective, blinded, randomized, controlled, multicenter prostate cancer utility and decision impact study performed in partnership with CareFirst BlueCross/BlueShield (NCT03235687). This is the first prospective prostate biomarker trial to have a blinded control arm.

This real-world study involved 72 urologists across 24 clinical sites (ie, the Large Urology Group Practice Association Group) and more than 1000 subjects to evaluate the impact of the ExoDx Prostate test on shared clinical decision-making between patients and physicians.

A total of 1094 men aged 50 years and older with a PSA level of 2 to 10 ng/mL scheduled for initial prostate biopsy were enrolled. Patients were randomized to either the ExoDx Prostate test arm (n=458) or the real-time, blinded, standard-of-care control arm (n=484).

 ExoDx Prostate test results were collected for the population of both arms. Urologists in the control arm were blinded to the ExoDx Prostate test results and used standard of care to make shared biopsy decisions. In the ExoDx Prostate test arm, results from the diagnostic were shared with both urologists and patients and used for shared decision-making about the need for biopsy. ExoDx Prostate test and biopsy results were collected, and patients were followed for up to 5 years to monitor decision-making and the impact of the diagnostic.

The results demonstrated that use of the ExoDx Prostate test improved compliance with the urologist’s biopsy recommendations. Patients demonstrated improved compliance with the physician’s recommendation to defer prostate biopsy when the EPI score was below the cut-off point of 15.6 and to proceed with biopsy when the EPI score was above 15.6.

 In fact, 92% of patients in the group that had a test score below 15.6 complied with the urologist’s recommendation to defer biopsy based on the EPI test result and physician-patient shared decision-making.

 In the group that had a test score above 15.6, 72% of patients complied with the physician’s recommendation to proceed with biopsy based on both the EPI test results and physician-patient shared decision-making, resulting in a higher biopsy rate in the EPI arm vs the standard of care control arm (72% vs 39%, respectively).

In the ExoDx Prostate test study arm, 30% more clinically significant cancer cases were detected among patients with higher EPI scores.

 Men with an ExoDx Prostate test score above the cut-off point of 15.6 were more likely to have clinically significant cancer when compared with those having a score below 15.6.

 In all, 72% of patients in the EPI arm and 39% of those in the control arm underwent biopsy; further, 30% more cases of clinically significant or high-grade prostate cancer were identified among patients in the EPI arm than among those evaluated with standard of care.

Overall, the results from this real-world clinical utility study showed that use of the ExoDx Prostate test was associated with improved identification of clinically significant cancer among men with elevated PSA levels.

ExoDx Prostate test performance in prior negative biopsy settings

Results using the 15.6 cut-off point of the ExoDx Prostate test also have helped to rule out high-grade prostate cancer in men with a PSA level of 2 to 10 ng/mL and a prior negative prostate biopsy.

Whereas PSA testing is routine and a standard part of screening for prostate cancer, the 2018 USPSTF guidance against PSA testing and the conflicting outcomes of 2 clinical trials for PSA screening have created uncertainty about its usefulness in helping patients and their physicians decide to proceed with a prostate biopsy.

 The ExoDx Prostate test is a noninvasive urine assay that does not require a DRE and that can be used to assess the risk of high-grade prostate cancer in men aged 50 years and older who have a PSA level of 2 to 10 ng/mL and are considering initial or repeat prostate biopsy. Clinical validation and utility studies support the effectiveness and value of the ExoDx Prostate test in assessing the risk of high-grade prostate cancer.

In the urology setting, the ExoDx Prostate test enhances the specificity of PSA in identifying high-grade prostate cancer. The ExoDx Prostate test can help urologists decide whether biopsy is necessary independent of PSA results and other standard-of-care features. Results of the test can help urologists and their patients feel confident in their decision to proceed with a biopsy. In a clinical utility study, use of the ExoDx Prostate test improved compliance with physician recommendations, including the decision to undergo a biopsy.

 It may also be used in the primary setting to triage high-risk patients for referral to a urologist for help with the biopsy decision.

In response to COVID-19 pandemic–related cancer screening deficits, it is important for urologists to consider telehealth strategies such as the ExoDx Prostate Test: At-Home Collection Kit to increase cancer detection and aid decision-making.

 Urine for this test can be collected at any time of the day without the need to visit an office or lab.

 Adoption of a telehealth solution may also help to reduce administrative burdens on urology office staff as well as various practical in-office health care staffing challenges (eg, workload, responsibilities) that were introduced as a result of the COVID-19 pandemic.

As part of the shared decision-making process, urologists can provide patients with downloadable resources and educational materials available at 

 to support patient discussions and shared decision-making. These materials, which include a clinician brochure and 2 patient brochures that provide a high-level overview of the diagnostic, can help support patients in deciding whether use of the ExoDx Prostate test is the right choice for them.

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Articles

The Role of the ExoDx Prostate Test in Early Detection  of Prostate Cancer

Screening helps to determine whether a full histopathological examination of prostate biopsy should be performed to diagnose prostate cancer. Although blood-based prostate-specific antigen (PSA) tests help clinicians to determine the need for this invasive tissue testing, PSA tests can give false-positive results that can result in unnecessary testing, treatment, and treatment complications.

 New liquid biomarker–based tests can provide additional information and help circumvent these unnecessary outcomes.

 program, 2 specialists discussed the need for risk assessment tools and the role of new liquid tests in early detection of prostate cancer: David Albala, MD, chief of urology at Crouse Hospital and medical director for Associated Medical Professionals in Syracuse, New York; and Judd W. Moul, MD, urological oncologist at the Duke Cancer Center in Durham, North Carolina. This article summarizes the key takeaways from that conversation.

US PREVALENCE OF PROSTATE CANCER AND PSA-TEST SCREENING

According to Moul, the US incidence of prostate cancer has dropped to about 200,000 cases per year compared with 330,000 cases annually over the past 15 to 20 years. Previously the US Preventive Services Task Force gave PSA-test screening a low rating, but Moul said that more primary care physicians are reembracing PSA-test screening.

Albala added that when PSA testing was first introduced, the US incidence of prostate cancer was about 1 in 6 or 7 men. “But we saw a drop in the [number of] patients [with metastatic disease] who we were seeing,” noted Albala. “I remember when I was at the [Veterans Health Administration], we’d see many of these [patients with meta-static disease] come in, and the PSA era really changed that.”

Although PSA-test screening does need to be refined, it should continue because it is an effective basic screening, Moul said, with secondary tests often used to “fine-tune” decisions before completing a biopsy. Albala added that urologists do recognize that the PSA test has limitations, as it is not cancer specific. The wide criticism of PSA-test screening may have been derived from how the medical field used the information generated by the test, Moul said. Indeed, PSA testing does not match the accuracy of tissue-based biopsy testing and is not recommended for diagnosis.

 However, as high PSA levels may indicate meta-static disease, PSA screening can help catch metastatic prostate cancer. Albala echoed Moul’s advocacy of PSA testing as a significant contributor to detecting prostate cancer; it has been used in various ways, he said, in testing free-to-total PSA ratios, PSA velocity, and PSA density in patients.

“Back when I [was] in training, 1 in 5 men [who presented with prostate cancer] typically presented with metastatic disease. And then in the PSA era, that dropped to 2% or 3%, meaning that only 2% to 3% of guys presenting with pros-tate cancer had [metastases],” Moul explained.

USE OF NOVEL LIQUID BIOMARKER TESTS IN PROSTATE CANCER SCREENING

Numerous next-generation tests to screen for pros-tate cancer have become commercially available, said Albala, including blood-based (eg, Prostate Health Index [PHI], 4Kscore) and urine-based tests (eg, Exosome, SelectMDx, PCA3).

When doing an Exosome test, practitioners do not need to complete a rectal exam, Moul explained, whereas with a PCA3 test, an attentive digital rectal exam must be done before the urine test. In completing the Exosome test, patients void urine through a special device; previously, this would be done in house, but as tests by mail have become available, patients are now able to collect the urine sample at home, return it through the mail, and receive results within a week. Regarding blood testing, Moul said that he has more experience with the PHI than other tests; the PHI predicts the likelihood of cancer in 4 risk groups: low, low-intermediate, intermediate, and high. Crucially, however, the Exosome test does not predict cancer or no cancer but rather the probability of Gleason 7 or higher. Moul believes that PHI and Exosome are somewhat complementary to one another.

Albala said that when most patients arrive at his clinic, they need to leave a urine sample, and it is often difficult to produce a second sample during the same visit. He has been using the Exosome test because patients can complete their second sample at home, but the Exosome and SelectMDx urine tests are comparable, Albala believes. With the SelectMDx test, a rectal massage is not necessary. Because urine tests predict prostate cancer slightly more accurately than do blood tests, Albala’s institution has pivoted more toward urine testing. “When a new test comes out, I look at the efficacy, cost, [adverse] effect profile, the ease of doing the test, and then the durability. I always think of those 5 things—whether it’s a new drug, a new procedure, or whatever—in the back of my head to try to put these tests in perspective because when new tests come out, there’s a lot of hype, a lot of excitement…You want to [come] back down to earth” and use tests when they are truly appropriate, Albala said.

With the COVID-19 pandemic, the use of tele-health skyrocketed, allowing patients who did not want to come into the office to still meet with their physicians. A benefit of this trend, said Moul, is that it has helped him to develop a good therapeutic relationship with new patients, especially those with an elevated PSA level who would otherwise have been physically visiting the cancer center and been very uncomfortable and nervous. With telehealth, some first-time visits have been more relaxed and open. Exosome testing by mail has been especially convenient during this time, Moul stated.

SELECTING SECONDARY TESTS IN PROSTATE CANCER SCREENING

After a standard PSA test indicates that PSA level is elevated, borderline, or in the “gray zone,” many patients request more data before they undergo an invasive tissue biopsy, Moul explained. Those data can be generated by various secondary tests. A blood test (such as PHI) can be used to measure a patient’s risk of pros-tate cancer. Benefits of a PHI include fewer potential biopsies and more accurate detetion of prostate cancer, helping doctors not only see whether a more aggressive type of cancer is detected but also better target any necessary treatment. Urine tests can detect the overexpression of PCA3 and assess risk of prostate cancer.

 The PHI test is the first choice of secondary blood tests at Duke, said Moul, because it is done in house and can be performed right away. They have even begun to train primary care physicians to do this test.

When Moul first came to Duke, they were using the PCA3 urine test as a secondary test to standard PSA blood testing, but because it was a first-generation test, the data were not robust enough. Now, said Moul, they tend to use Exosome as their secondary urine test, and they have been satisfied with it. The Exosome diagnostics and SelectMDx tests are both widely used, said Moul, and his advice to new urologists is to become comfortable with at least 1 secondary blood test and 1 urine test to best be able to work with their patients.

Moul completes a rectal exam during a patient work-up to contextualize the PSA level based on prostate size, he explained. “Rectal exams are not perfect, and it’s hard to teach a primary care physician to do them—[plus] many of them are not that interested. But as urologists and as urology educators, we need to make sure that all residents who we train know how to do a good rectal exam, [including assessing the] size of the prostate,” Moul said.

If a patient is borderline on a rectal exam and has a borderline PSA level family history, a PHI is usually the next test Moul will order. Albala said that his institution uses PSA as its primary test, and for secondary tests, they previously used a blood test with 4K score but have started pivoting more toward urine tests.

Among the challenges presented by the use of MRI to screen for prostate cancer is that MRI quality can vary, depending on the institution.

“Sometimes patients will come in with an MRI [they’ve had done elsewhere], and they want a fusion biopsy based on that outside MRI. That’s problematic…because…we tell them, ‘Well, you have to repeat the MRI at our institution before we do a fusion,’” Moul said.

Also, said both Albala and Moul, insurance coverage presents another challenge. Moul said that in North Carolina, for instance, many insurance plans will not cover MRI in the setting of no previous biopsy, and the expensive out-of-pocket costs can run from $800 to $2500 at their institutions, Albala and Moul stated.

Several areas of unmet need exist in the prostate cancer screening space. Underserved populations is one, said Moul; many under-served patients who are at high risk for prostate cancer present with disease too late in the clinic. Also, patient adherence in following through with tests is less than ideal. Finally, both Moul and Albala emphasized the need for standardization in assessing the size of the prostate through rectal exam. Moul noted that if they could quickly capture the estimated size of the prostate, they could then more effectively contextualize the PSA level.

Albala echoed the need for a standardized way of assessing the size of the prostate. “I remember the days when Merck would give us the little models of the prostate. There was 30 g, 40 g, 50 g, and I remember trying to feel those. There was a disconnect with what you felt on the rectal exam and in the models, but that was the best that we had 20, 30 years ago. We are [getting] better, I think.”

In the urology community, Moul opined, more education is needed to better under-stand the use of secondary tests, including how to determine whether to use PHI or 4K, how to use a urine test, and when to order an MRI. Algorithms have been put in place at Duke, but much individual variation still exists.

“We’ve become more sophisticated. We’ve used these tools [and] put them together,” Albala concluded. “That’s the beauty of what we deal with [in] practice, that we’re assimilating different tests to try to decide. Because biopsy is a big commitment and complications [can happen—although] they’re relatively minor, they do exist for patients—and if we can be better clinicians, make diagnoses with [a higher] comfort level, I think that’s what our goal is. 

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Prostate cancer: advancements in screenings. Accessed June 11, 2021. https://www.hopkinsmedicine. org/health/conditions-and-diseases/prostate-cancer/prostate-cancer-advancements-in-screenings

This article features insights from David Albala, MD, and Judd W. Moul, MD, on using liquid biomarker-based testing for the early detection of prostate cancer.

UroView: The Role of Liquid Biomarkers for Early Detection of Prostate Cancer

 do you see any unmet needs in early detection for prostate cancer? We have what we have now, do you think we can be better and what do you see in your crystal ball as you look forward? Your contributions in this area have been significant. You are a prolific writer, you've seen the changes much like I have, we saw the PLACO and the European studies for screening, we saw the task force recommendations. There has been a lot of changes that have happened over the years. First is, what do you see the unmet needs and what are your predictions for the future?

 Just unmet needs. I can speak locally, I'm not sure if this would apply to everyone, but we still have unmet needs in our underserved population. We have a lot of underserved patients who are at high risk for prostate cancer and sadly, we still see those patients presenting too late. I do not have all the answers for that but that is clearly an unmet need. We have an unmet need in having patients be more compliant to following through on some of these tests. We have an unmet need in assessing the rectal exam. I know that sounds weird, but I wish there were a simple, very easy way, almost like a bladder scanner where one could measure prostate size a little more accurately but make it so easy where even it could be done in a primary care office. And I think that even in urology offices, if you could quickly get a prostate size estimate you could contextualize the PSA more effectively. PSA [prostate cancer antigen] density is a great task. We as urologists do these ultrasounds and do a pretty good job – we are not perfect; PSA density is powerful but it is not practical. What we talked about earlier, the prostate health index, the secondary blood test or the urine test, a lot easier to deploy than other things, but PSA density is useful if you can get it. Finally, I would say that we as a urologic community and our physician extenders, just to get more education in having a better understanding of how to use these secondary tests. How to decide when to use a pHi or 4K, how to use the urine test, and then when to apply MRI. We have tried to put algorithms in place at Duke and they work to some extent but there's still a lot of individual variation.

 I agree. If we could standardize how to assess the size of the prostate. I remember the days when Merck would give us the little models of the prostate, there was 30 grams, 40 grams, 50 grams, and I remember trying to feel those. There was a disconnect with what you felt on the rectal exam and in the models but that was the best that we had back 20, 30 years ago. We are better, I think. We have become more sophisticated, we have used these tools, put them together. That is the beauty of what we deal with practice, that we are assimilating different tasks to try to decide. Because biopsy is a big commitment and there are complications, thank God they are relatively minor, but they do exist for patients and if we can be better clinicians, make diagnosis with a much more comfort level, I think that is what our goal is. Well, listen, this has been terrific. Judd, thank you. It is always great to work with you and I enjoyed my years with you. I just want to thank our viewing audience. We hope that you found these Uroview videos discussion today to be rich and informative. I look forward to working with you again and thank you for listening.

 Thanks, David. It was a sincere pleasure. Really enjoyed it.

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Expert urologists remark on unmet needs in prostate cancer by emphasizing the importance of reaching under-served communities, addressing patient discomfort, increasing education about liquid biopsy testing, and standardizing prostate size assessment.

Unmet Needs in the Early Detection of Prostate Cancer

 I am trying to get a practical little algorithm developed for the audience. Obviously, almost everybody around the country does PSA [prostate cancer antigen] testing in some form, maybe regular to total PSA or free to total PSA or looks at PSA velocity. Then would you go to the blood test, or would you go to the urine-based test? I am curious on how you put that together and then I will tell you what my algorithm is, and we'll see if we're similar.

 Sure. There may be patients who only get a PSA and a rectal exam. For example, a patient with a PSA more than 20 and an abnormal digital rectal exam.

 We need a biopsy. We have been seeing quite a number of those guys seem more as we have gone through COVID. I do not know if it is just more or the fact that this primary care initiative that we have has just been bringing these guys out of the woodworks.

 Or maybe the after-effects as well of the task force were stuck. Several papers have shown that when prostate screening and PSA testing got a de-rating, we started to see an uptake in metastatic disease then they reduced it to a C rating a couple of years later. I do not think we have caught up completely. You are exactly right. I think that patient that has a PSA of 20 or you find an abnormality on the rectal exam, that is a no-brainer. We are going to biopsy those guys and that's the standard of care. Let us take a guy that comes in, his PSA is abnormal, maybe it's between 4 and 10, you don't feel anything which is many of the patients that we examine. How do you work that patient up and what do you do? Do you do the urine-based test first or do you do the blood test?

 First, as a urologist, I do the rectal exam. That is my first step when I'm seeing a patient because I really want to contextualize the PSA based on the size of the prostate. Rectal exams, we all know, are not perfect, and it is hard to teach a primary care physician to do a rectal exam and many of them are not that interested. But we as urologists and as urology educators, we need to make sure all our residents who we train know how to do a good rectal exam and size of prostate. If I have a gentleman who has a very robust prostate, significant BPH on DRE, and it's a smooth DRE with no nodules, sometimes I may just only do the PSA test and reassure that gentleman and schedule him back in a year. Just important to point out that the basics of what we do as urology is still there. However, if it is a borderline on rectal exam, if the patient has a borderline PSA family history, our next test usually is going to be a prostate health index and those are going to be binned in four groups. Generally, if the patient is low risk on pHi then they're going to be reassured and maybe come back in six to 12 months. If it is a high-risk pHi with a 50% greater probability of prostate cancer most of the time, we will recommend a biopsy without necessarily going to the exosome. However, as you said, sophisticated patients, many patients are reluctant, and they want more data. In those patients who want more data we will get the exosome and then if they have a combination of high-risk pHi and exosome greater than 15.6, we are going to really push for a biopsy. If the patient still does not want a biopsy and insists on an MRI, we will order the MRI counseling the patient that he might have to pay out of pocket. Where the exosome has helped me, the most is in patients who have that intermediate prostate health index – the gray zone. There is a gray zone there too. Then I like to get the exosome. Or the patient who is just reluctant and just has a no show and I am the third urologist telling him he needs a biopsy. Sometimes I am using the exosome test to try to convince him that he has a condition that needs to be taken seriously. I use it to try to increase compliance as much as anything. Also, finally I will say, our practice is employing more physician extenders, APPs. We train them the best we can, but they are not urologists, they have not been in practice 30 years like I have. Sometimes our younger APPs are using these tests because they are not quite as confident with a rectal exam. Is that right or wrong? It is a reality of needing some of those tests in our current workforce.

 I think that is terrific. We up here have adopted obviously using PSA as our primary test, much like what I did when I was at Duke. We did go to a blood test with the 4K score and then we pivoted a little bit to the urine studies. It started with SelectMDx and now, I think, with exosome, having the home kit – a couple of things. One is, for exosomes they must be over the age of 50 to do the test. Most of our patients, when they come into the urology clinic leave a urine specimen so it is hard to get them to urinate again. Then I just say, "We're going to mail this to you," and it works out well. That has been my test. When they get the exosome test, as you say, if they are hesitant about a biopsy, that is where the MRI, to me, fits in place. If the patients are concerned, then we go directly to a biopsy. I think the algorithms can be massaged depending on the area where you are and the tests that are readily available. We don't have pHi up here, so we relied on the K, which is commercially available, and it was a good starter test.

 Dave, I do not have a lot of experience or any experience with the Select urine test. What is the difference or what has been your experience when you look at those two?

 They're very comparable tests. With the Select test, you do need to do a rectal massage, so it is almost like a PCA 3 test. Maybe it is a PCA 3 on steroids, so to speak, because you do have to do a rectal exam in these patients. But when you looked at the areas under the curve and the accuracy of the test it appeared to be a little bit better than some of the blood tests and so that's why we initially pivoted a little bit to the urine test and then when exosome came out, just the ease for the physician made it a little bit easier to do. When a new test comes out, I look at the efficacy, I look at the cost, I look at the side effect profile, I look at the ease of doing the test and then the durability. Those five things, whether it's a new drug, a new procedure, or whatever, I always think of those five things in the back of my head to try to put these tests in perspective. Because when they come out, there is a lot of hype, there's a lot of excitement about these new tests, you want to bring them back down to earth and put them in their place on where they really have a place. That is how I've used things and it's served me pretty well.

Key opinion leaders in urology review factors to consider when selecting screening and risk-assessment tests for the diagnosis of prostate cancer including insurance coverage, commercial availability, and patient preference.  

David Albala, MD

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