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Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we are discussing a recent publication entitled MRI-Targeted or Standard Biopsy in Prostate Cancer Screening. I'm Chris Wallis, Assistant Professor in the Division of Urology at the University of Toronto, and with me today is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia.

And this is the citation for this recent publication out of the STHLM3 consortium, recently published in the New England Journal of Medicine. PSA screening, as most will know, is relatively controversial. And we have here the most recent recommendations from the US Preventative Services Task Force. And the reason why prostate cancer screening is controversial is that there is a trade-off of benefits and harms. And so we know from randomized data that prostate cancer screening is associated with reducing cancer-related morbidity and mortality.

However, there are substantial harms of over-diagnosis, as well as over-treatment, each of which comes with associated morbidity. And so in most jurisdictions, worldwide population-based screening using PSA testing is not currently recommended. However, other screening approaches, including imaging rather than simply biomarkers are used for other cancer types. And so the integration of imaging into prostate cancer screening may optimize the benefit of prostate cancer screening.

And so, most will know that prostate cancer diagnosis for more than 30 years now has been made through a TRUS-guided prostate biopsy. And while this provides anatomic guidance, most would agree that it lacks the ability to accurately distinguish between benign and cancerous tissues. Whereas a multiparametric MRI does have increased diagnostic accuracy. And so we see from one example here from the literature, looking at MRI targeted or standard biopsy, that among these men who are randomized, when the use of MRI-targeted biopsy is employed, we see an increase in the diagnosis of clinically significant cancers and a decrease in the diagnosis of clinically insignificant cancers. And so this may actually optimize the utility of screening.

Furthermore, we see that a significant proportion of men in the MRI targeted arm in this study could avoid prostate biopsy entirely, thus reducing the morbidity of screening. And so the overall objective of the STHLM3-MRI trial is to compare several different screening strategies using a variety of combinations of risk prediction models, MRI-targeted biopsy, and standard biopsy in a population-based, organized screening by invitation design.

And the current study we are discussing today focuses on comparing MRI-targeted and standard biopsy in men who had positive results when having an MRI. And this is all predicated among a subset of men who had an initial elevated screening PSA.

And so, as we alluded to before, this trial is a prospective, randomized, population-based trial among men aged 50 to 74 years to evaluate a variety of strategies for prostate cancer detection. And this study is an initial paired-screening positive design, employing two different screening tests for all participants.

And so you can see here that patients undergo the PSA testing with a threshold of three defined for abnormal, and also undergo Stockholm3 testing within a threshold of 11% defined as abnormal. And those who screen positive on either of those are then randomized to either undergo a systematic biopsy or MRI.

And so just to reiterate, the Stockholm3 test has previously been both derived and validated, and this comprises a variety of clinical variables, blood-based biomarkers, and a polygenic risk score.

So again, in this report, they are focusing on men with an elevated PSA or Stockholm3 scores who then underwent randomization in a two to three ratio to either a standard biopsy or the experimental approach, including MRI first. And stratification was further performed according to six cancer-based risk strata. However, in this analysis, we are only considering the PSA as a trigger for biopsy, not Stockholm3 scores, that is all men included in this report had a PSA greater than three.

So key exclusion criteria for this population-based screening study were prior prostate cancer diagnosis, previous prostate biopsy within 60 days of invitation, any contraindication to MRI, or severe illness. And following passing these exclusion criteria, patients underwent a blood sampling with a study nurse, a PSA screening was performed and for those who had low PSA's, a repeat in six years was recommended. For those who had a PSA greater than or equal to 1.5, they underwent testing with a Stockholm3 test.

And so in the context of this study, all biopsies are performed by experienced urologists. And those who are randomized to the standard arm received a 10 to 12 core TRUS-guided biopsy. In the experimental arm, patients underwent a biparametric MRI with T2 weighting and diffusion-weighted imaging. This was reviewed by three uroradiologists with a consensus of at least two required for calling all abnormalities.

These were interpreted according to PIRADS version two and v2.1, with up to three lesions allowed to be identified. A biopsy was performed for all identified lesions on MRI using MRI fusion and a standard template biopsy was also performed for these patients.

So the primary endpoint was the probability of clinically significant cancer. And the authors define this as a Gleason score of three plus four or greater, and an ISUP grade group two or greater. The secondary endpoints included clinically insignificant diseases. That is grade group one, high-grade disease, grade group three or greater, as well as serious adverse events.

So they planned to invite 50,000 men, assuming one quarter would participate. And 13% of those who participated would have an elevated PSA. Thus they expected 1,625 participants with an elevated PSA. Using the non-inferiority margin of 4% and an alpha of 0.025, 80% adherence, and 18% detection probability in the standard group, and at 1.3 times relative detection probability in the MRI group, the authors would have greater than 90% power for this non-inferiority margin.

They examined the absolute differences in detection probabilities between the standard and MRI-guided biopsy arms. And where the lower limit of the 95% confidence interval was greater than negative 4%, the experimental arm would be deemed non-inferior. If however, the lower limit of the 95% confidence interval was greater than 0%, the experimental arm would be deemed superior.

The authors planned subgroup analyses according to strata of age and PSA, as well as whether patients had undergone a prior biopsy. It further used a number of sensitivity analyses using imputation to assess the effect of missing outcome information due to the failure of patients to undergo recommended testing procedures. They further performed pre-specified analysis, examining the effect of only performing a targeted biopsy in men with MRI-visible lesions and omitting the systematic biopsy.

At this point in time, I am now going to hand it over to Zach to take us through the results of this trial.

Zachary Klaassen: Thanks Chris. So this figure looks at the enrollment randomization and follow-up of the trial population. And we'll walk through this.

It's a dense figure so the font is a little bit small, but you can see here that 49,118 men were invited to participate of which 12,750 provided blood samples and were included in the study. There were 2,300 that had a PSA greater than three or a Stockholm3 score greater than 11%. Ultimately there were 1,532 patients that were randomized, including 929 that were assigned to the experimental biopsy group and 603 that were assigned to the standard biopsy group. Of this, 790 in the experimental arm were included in the per-protocol analysis, and 436 were included in the per-protocol analysis for the standard biopsy group.

This is table one looking at characteristics of the participants at baseline. You can see on the left is the characteristics, in the middle are all of the enrolled patients and then broken down by experimental versus standard biopsy group. The median age in the two biopsy groups was 66. 17% and 16% of patients in the experimental and standard groups respectively had a previous biopsy. The median PSA you can see was just over four for both groups. And the median prostate volume was roughly 45 for both groups. In the MRI group, you can see that 7% of patients had PIRADS five lesions, 9% had PIRADS four and 19% had PIRADS three.

So this table looks at the comparison of cancer detection in the trial groups. And we'll focus on several of these important outcomes here. In terms of the number of procedures that were performed in terms of biopsies, 36% of patients were in the experimental group, and 73% were in the standard biopsy group. And if you look at the biopsy outcome, this is quite interesting. In terms of benign findings, 11% were in the experimental group and up to 43% were in the standard biopsy group. Gleason score six for prostate cancer, 12% in the standard biopsy group, and only 4% in the experimental group. Gleason three plus four, 13% in the experimental group, 10% in the standard group. And in terms of four plus three and greater than or equal to four plus four, equivalent between the two groups of 3% and 4%.  In terms of the detection of clinically significant prostate cancer, which is defined as a Gleason score greater than or equal to seven, 21% in the experimental group and 18% in the standard biopsy group.

This figure looks at the intention-to-treat, the imputation, and the inverse probability weighted analyses of the primary outcome for the detection of clinically significant prostate cancer. And you can see here that because the lower bound of the 95% confidence interval for all three of these analyses is above the non-inferiority margin of negative four, the experimental compared to the standard biopsy was non-inferior. Because the lower bound was not above zero, we cannot say that the experimental strategy was better. However, it was non-inferior to the standard biopsy group.

This figure looks at the elevated PSA levels, the procedures performed, and detected cancers. And so we will walk through several highlights of this figure. On the left, looking at the experimental strategy in red and the standard strategy in blue, for PSA levels greater than or equal to three, the relative differences are essentially the same at 1.04. When we look at the biopsy procedures in the middle of the figure, the relative difference is 0.52 in terms of the experimental strategy with a 95% confidence interval of 0.45 to 0.60.

Moving to the right of that in terms of benign biopsies favoring the experimental strategy, a relative difference was 0.27 with a 95% confidence interval of 0.22 to 0 34. And similarly, in the Gleason six prostate cancer, 0.38 relative difference, the 95% confidence interval of 0.26 to 0.55. And essentially similar detections of Gleason three plus four and four-plus three on the far right.

This figure looks at the percentage of men by Gleason score according to PIRADS. And you can see here on the far right, no biopsy is in gray, benign is in light yellow, Gleason score six is in orange, and Gleason score greater than or equal to three plus fours is in red. And if we take a global look at this figure, focusing particularly on PIRADS four and five, we can see that the majority of these Gleason scores are greater than or equal to three plus four. Whereas when we get down to PIRADS three, there are essentially similar findings between the number of benign biopsies, as well as clinically non-significant and clinically significant prostate cancer. So really the money is, as we know in clinical practices, on the PIRADS four and five lesions.

So several discussion points from this trial. In this population-based screening by invitation trial, a detection of clinically insignificant tumors and benign findings were lower by 64% and 74% respectively among men with elevated PSA when the biopsy was performed only in men with a positive MRI versus a standard biopsy.

As we know, most studies of MRI-targeted biopsies have shown greater sensitivity to detect clinically significant cancer compared to standard biopsies. However, these study populations were restricted to men referred for a biopsy on the basis of clinical suspicion of prostate cancer. So as we saw in this trial, median PSA was just over four versus some of the other trials for clinical suspicion of prostate cancer, the median PSA was in the range of six. And this is challenging to interpret in the context of population-based screening as there is a lower risk of clinically significant prostate cancer.

So the question is, should men with positive MRI results undergo standard biopsy in addition to targeted biopsy? In this study, 30 fewer clinically significant cancers would have been detected in the experimental group if standard biopsy had not been performed and 18 fewer clinically insignificant cancers would have been detected. That's the detection of 1.7 clinically significant cancers would be delayed for each clinically insignificant cancer avoided. So the answer to this question is yes, we should still be performing the standard biopsy in these patients.

And then finally, in the discussion section, overall adherence to trial recommendations was 85% in the experimental biopsy group and 72% in the standard biopsy group, which the authors interpreted as patients being willing to undergo biopsy after identification of lesions visible on MRI.

So in conclusion, among men with elevated PSA levels, combined biopsy performed only in men who had positive results in MRI was non-inferior to standard biopsy for detecting clinically significant prostate cancer. Reduced unnecessary biopsy and diagnosis of insignificant prostate cancer addresses key barriers impeding the implementation of population-based screening for prostate cancer. And finally the reduced biopsy rate and potential downstream savings resulting from less over-treatment offer potential cost savings that may offset the additional cost of an MRI.

Thank you very much, and we hope you enjoyed this UroToday Journal Club discussion.