(UroToday.com) Dr. Peter Albers presented the first results of the PROBASE, Prospective Randomized Evaluation of Risk-adapted Prostate-specific Antigen Screening in Young Men: The PROBASE Trial, a randomized controlled trial of risk-adapted prostate cancer screening beginning in men at age 45 vs 50 years old.
Dr. Albers began with a reminder of the results of the ERSPC trial, which showed a ~20% relative risk reduction in prostate cancer-specific mortality. However, prostate-specific antigen (PSA) screening is not currently recommended by any major governmental body in Europe due primarily to the risk of over-diagnosis and subsequent over-treatment of prostate cancer that would otherwise have been clinically insignificant. He briefly touched on the methods for avoiding this risk, including widely available methods such as age-adapted risk groups, risk calculators, and family history, as well as those that may be used more widely used in the future, including urine and serum biomarkers, MRI, and genetic screening, before introducing the PROBASE trial which attempts to reduced over-diagnosis primarily with risk-adapted screening based on baseline PSA measurement.
In this trial, which began recruitment in April 2014 and completed enrollment in December 2019, 45-year-old German men were recruited by mail general population registries.1 These men were randomized 1:1 to begin PSA-based prostate cancer screening at age 45 or 50 years of age. Screening in all men was done in a risk-adapted fashion: men with a most-recent PSA <1.5ng/ml had their next PSA drawn 5 years later; those with PSA 1.5-2.99 ng/ml had a PSA drawn 2 years later; and those with PSA >=3.0 underwent immediate mpMRI followed by systematic prostate biopsy (with software guided fusion biopsy where applicable). All screening ceases at age 60.
The primary hypothesis to be tested by the trial is a composite stating that 1) screening starting at age 50 is superior to screening at age 45 in terms of specificity of prostate cancer diagnosis and 2) screening starting at age 50 would be non-inferior to screening starting at age 45 with respect to the development of metastatic prostate cancer, with a relative increase of at most 20% considered to be within the noninferiority limit. (This would correspond to an absolute increase in the risk of developing the metastatic disease before age 60 in this population of ~0.15 to 0.18%). The recruitment goal was 50,000 men, with a minimum of 45,000 considered acceptable to achieve adequate power after attrition.
The final results of this trial are not expected until 2028. However, the preliminary results of the trial, presented for the first time by Dr. Albers at this meeting, are already yielding important findings.
First, the proportion of patients in each initial PSA-based risk group in the intervention arm was almost exactly as the study authors predicted based on prior data (predicted: 90%, 8%, 2% low, intermediate, high. Actual: 89.2%, 9.3%, 1.5% or 20,779, 2,170, and 345 patients).
Second, the trial confirmed the common understanding that prostate cancer is rare among this very young age group and added that the majority of cancers that could be diagnosed with PSA in this age group are low grade. All 345 patients with an initial PSA >=3 ng/ml were required to have a confirmatory PSA, which remained >=3.0 in 179 (51.9%). 134 patients underwent biopsy, and 45 were diagnosed with prostate cancer. Grades of these diagnosed cancers were 73% grade 1 and 2 -- 12, 28, 2, 1, and 1 cases of grades 1-5 respectively. As Dr. Albers pointed out, this contrasts sharply with breast cancer data where patients diagnosed at an early age tend to have a significantly higher proportion of high-grade disease.
Third, digital rectal examination (DRE) was shown to be a highly ineffective strategy for diagnosing prostate cancer in this age group. All 23,195 patients in the control arm were offered immediate DRE, of whom 6,548 (28.23%) accepted. 81 of these patients (1.2%) were noted to have a suspicious DRE resulting in diagnoses of two ISUP grade 1 cancers and one ISUP grade 2 cancer, though it was not stated how many of these patients actually chose to undergo biopsy. Comparing this cancer diagnosis rate to the intervention arm, the sensitivity and specificity of DRE for prostate cancer, especially clinically significant prostate cancer, can be shown to be extraordinarily low, and it is rendered all the less useful as a diagnostic tool by the extremely low rate of clinically significant prostate cancer in this population.
Dr. Albers did note some limitations of the trial at this point and during the question and answer session. First, few non-Caucasian patients are represented in the population. Second, only 12% of patients contacted agreed to participate, rendering the population somewhat selected. Third, 90% of the population was found to have a “higher education degree”, which is an impressive deviation from the overall population and is further evidence of selection bias. Finally, a 20-30% PSA screening contamination rate was noted in the control arm. It was unclear from the talk what the expected contamination rate was, but from this data, Dr. Albers felt confident in reassuring the audience that unlike the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial in the United States, which was hurt by an 89% contamination rate, PROBASE will have “a real control arm”.
The remainder of the talk was spent on an overview of other large trials going on in PSA screening and prostate cancer diagnosis.
The PRIMA trial, another German study, seeks to reduce overdiagnosis of prostate cancer in men with elevated PSA using multiparametric MRI. In this study, 1500 men with PSA >=4 and/or abnormal DRE will undergo mpMRI prior to prostate biopsy. Those with PIRADS scores 1 or 2 will undergo only a repeat MRI in 5 years and PSA based screening. Those with a PIRADS 3 MRI and a PSA density (PSAD) <0.15 will undergo MRI in 1, 3, and 5 years with regular PSAs, and those with a PIRADS 3 MRI and PSAD >0.15 or a PIRADS 4/5 MRI\ will be randomized to targeted biopsy +/- systematic biopsy.
In PROSCREEN2, the only other randomized PSA screening trial with a primary endpoint of overall survival, 67,000 men aged 50-63 will be randomized 1:3 intervention: control with those in the control arm receiving no PSA-based screening. Those in the intervention arm will have a baseline PSA level drawn followed by further screening based on this baseline PSA. Those with a PSA >3 ng/ml will undergo biopsy based on results of mpMRI and a multi-kallikrein panel.
There are 3 studies currently examining PSA screening with endpoints other than overall survival. The ProCaRis trial, published in July of 20203, found that providing general practitioners with access to germline genetic risk assessment did not reduce the number of PSA tests ordered. The STHLM 3 trial will randomize 15,000 patients to compare PSA vs the STHLM3 test and MRI on the endpoint of detection of clinically significant prostate cancer. And the MVP trial will compare dual modality MRI to PSA on the same endpoint.
Finally, Dr. Albers mentioned several large ongoing non-randomized trials in the screening space. NCT04322045 is examining the incidence of prostate cancer diagnosis in an MRI-only screened population in Nanjing, and 4 other trials (NCT02053805, BARCODE-1 [NCT03857477], PATROL [NCT04472338], and IMPACT [NCT00261456]) are examining screening in populations with various germline mutations.
Dr. Albers summarized by expressing certainty that risk-stratified screening of some type will eventually be the standard of care. Only the details of its implementation remain to be determined.
Presented by: Peter Albers, MD, Professor of Urology, Division of Personalized Prevention of Prostate Cancer, DKFZ, Heidelberg German, Düsseldorf University, Dusseldorf
Written by: Marshall Strother, MD, Society for Urologic Oncology Fellow, Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia PA, @mcstroth at the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC
References:
1. Arsov C, Becker N, Hadaschik BA, Hohenfellner M, Herkommer K, Gschwend JE, Imkamp F, Kuczyk MA, Antoch G, Kristiansen G, Siener R, Semjonow A, Hamdy FC, Lilja H, Vickers AJ, Schröder FH, Albers P. Prospective randomized evaluation of risk-adapted prostate-specific antigen screening in young men: the PROBASE trial. Eur Urol. 2013 Dec;64(6):873-5. doi: 10.1016/j.eururo.2013.05.022. Epub 2013 May 14. PMID: 23707067.