Christopher Wallis: Hello, and thank you for joining us for today's journal club discussion. Today we're talking about a recent publication entitled "MRI-guided focused ultrasound focal therapy for patients with intermediate-risk prostate cancer: a phase 2b, multicenter study".

I'm Chris Wallis, an assistant professor in the division of urology at the University of Toronto. With me today is Zach Klaassen, an assistant professor in the division of urology at the Medical College of Georgia.

You can see here, this citation led by the team at MSK and published in Lancet oncology. Prostate cancers a heterogeneous disease and this creates many therapeutic dilemmas. Well, prostate cancer is common, and a common cause of cancer. Many patients present with low-grade disease who may be safely monitored with active surveillance. In contrast, those with intermediate or higher risk localized disease typically receive whole gland treatments. However, even within intermediate-risk disease, there's substantial variation in the volume location and risk of the disease, such that uniform treatment with whole gland therapy likely ignores opportunities for nuance.

It's important to note that each of these treatment approaches, whether surgically or radiation-based, are associated with meaningful toxicity, including both urinary and sexual dysfunction.

Focal therapy is premised on the idea of selective treatment of visible and biopsy-proven cancer within the prostate. Rather than treating the whole prostate, only the abnormal region is targeted for treatment. And the idea of this is to preserve normal prostate tissue and adjacent structures with the goal of treating cancer, to reduce the risk of metastasis, also preserving quality of life. And this has really been facilitated by the use of MRI and MRI-fusion biopsies to allow for identification of specific regions of the prostate gland that may be targeted with focal therapy.

While focal therapy is a concept at its core, there are a variety of different ways that it may be achieved, and modalities include both thermal and non-thermal approaches. HIFU, or high-intensity focused ultrasound, is one such approach that's been shown to be safe and successful in the treatment of prostate cancer. However, to date, the evidentiary-based supporting HIFU focal therapy is relatively limited due to reliance on single center reports, treatment of low-risk disease, and ultrasound guidance of the focal therapy.

To address this evidentiary gap, the authors performed a multicenter phase 2b clinical trial. They enrolled men aged 50 years and older with unilateral organ confined, intermediate-risk prostate cancer, defined based on a PSA less than 20, least in grade group two or three disease, and less than an equal to clinical T2 disease.

Patients had to have a visible lesion on MRI that was conferred with both fusion targeted and systematic biopsies. They could not have received prior prostate cancer treatments. Patients were excluded if they were younger than 50 years of age, if MRI findings were consistent or suspicious for extra capsule extension if there's evidence of calcification on CT that were either greater than two millimeters in size and within five millimeters of the rectal wall, or greater than five millimeters and located between the target and the array. Further patients were excluded if the anterior margin of their tumor was more than 40 millimeters away from the rectal wall. Finally, those with hip arthroplasty-induced image distortion were excluded.

Treatment was administered using MRI-guided high-intensity focused ultrasound. This was performed under a general anesthetic in the lithotomy position. The HIFU transducer was introduced into the rectum and multi-plainer MRI was used using T2 images to plan the treatment. Real-time MRI for thermography was used to direct ultrasound energy within the prostate, focusing on the region of cancer. Treatment was titrated for tissue ablation to 60 or 70 degrees Celsius. An updated MRIs were performed between each treatment sonication. A five-millimeter margin of normal tissue is used around the lesion. Notably, only Gleason grade group two and three foci were treated, patients having concomitant grade one disease had these regions of the prostate monitored, but not treated.

Patients under an MRI targeted biopsy, both at baseline and then at six and 24 months. Patients could offer either a transperineal or transrectal according to their preference and that of their physician. For patients undergoing systematic transperineal biopsy, this was performed using a saturation biopsy template with a five-millimeter grid. For those who opted for a transrectal approach, 14 cores were taken including two anteriorly targeted cores. For all MRI-identified lesions, at least two targeted cores were taken.

Post-treatment of biopsies included at least two targeted cores highlighting the ablation zone and treatment failure was defined as Gleason grade group two or greater on either the six or 24-month post-treatment biopsy. Treatment-related toxicity measure using adverse events was assessed at one week and then one, three, six, nine, 12, 18, and 24 months post-treatment.

Patient-reported outcome measures, including the IPSS, ICIQ-UI-SF, IIEF, and FACT-P questionnaires were given at similar time intervals.

PSA monitoring was performed at six, 12, and 24 months following the treatment and patients received assessment of their sexual function according to the following grading criteria, a grade zero sexual dysfunction was defined as an IIEF of 24 or greater, or less than a four-point, a decrease in sexual function from baseline without the need for medications. Grade one, a dysfunction was defined as those with an IIEF greater than 11, but not greater than 24, who did not require medications. Grade two is defined as an IIEF greater than 11 with the use of medication. And grade three dysfunction was IIEF less than 11, whether medications were used or not.

The co-primary endpoint were oncological efficacy as assessed by the absence of Gleason gray group 2 or greater cancer in the treated region, as well as safety using adverse event monitoring through to 24 months. Secondary endpoints included GU-related functional outcomes, including urinary and erectile function, as well as the overall quality of life.

In terms of statistical analysis, the authors initially planned for a one-stage phase two design, the null hypothesis of a 60% and an alternate hypothesis of an 80% treatment failure-free rate at 24 months. This led to a need for 40 enrolled patients. This was subsequently revised on the basis of an FDA mandate, which increased the total sample size to 100 patients.

The crypto statistics were used for the assessment of biopsy outcomes and generalized estimating equations were used to estimate the mean change from baseline in functional outcomes, patient-reported quality of life, and PSA metrics. Now going to hand over to Zach to walk us through the results of this trial.

Zachary Klaassen:  Thanks so much, Chris. So for this study, there was 194 patients that were screened for eligibility and ultimately 101 patients were enrolled and treated. Among these, all of them had a six-month targeted biopsy, and subsequently, 88 patients underwent a 24-month MRI targeted biopsy.

This is the baseline patient and treatment characteristics for the study. The median age was 63 years of age, median PSA was 5.7 and the majority of these patients were white males at 86%. As expected, 83% were less than or equal to T1C, with the majority 78% being grade group two, and 22% being grade group three.

With regards to baseline patient-reported functional outcomes, 59% had excellent functional erections, and the majority 98% did not have urinary incontinence. In terms of some of the treatment parameters, the median time of duration of treatment was 110 minutes. And the median number of sonications was 15.

This table looks at the prostate cancer from the combined MRI and targeted and systematic biopsies at six and 24 months, and I've highlighted one of the co-primary endpoints as Chris laid out with regards to the oncological efficacy as highlighted by no evidence of grade group greater than or equal to two prostate cancer.

You can see that in the targeted area only at six months, 95% did not have prostate cancer greater than or equal to grade group two. And at 24 months, this number was 88%.

With regards to the biopsy outcomes, you can see these below. No evidence of cancer at six months in the targeted area, 91%, and at 24 months, 80%.

The next several slides will look like this figure, which is looking at the baseline and longitudinal mean of erectile function domain of the IIEF score. And to summarize this figure, this is 24 months versus baseline with a mean score difference of negative 3.5, which means that the baseline erectile function decreased. And this was significant with a 95% confidence interval, negative 5.4 to negative 1.6.

Again, a similar figure looking at the mean intercourse satisfaction domain of the IIEF score. Again, 24 months versus baseline with a mean score difference, decrease of negative 1.8, which again was significant at 95% confidence interval, negative 2.9 to negative 0.8.

And finally, this is the overall satisfaction domain of the IIEF score, with a 24 months versus baseline, mean score difference of negative 0.8. So a slight decrease, but statistically significant 95% confidence interval, negative 1.3 to negative 0.3.

This is a similar figure but looks at baseline and longitudinal IPSS scores. And you can see here a very flat line, and essentially as the authors highlighted, there is no change in IPSS score based on the treatment. And these are all very mild symptoms at baseline, which continue to be mild the 24 months after therapy.

This figure looks at the probability of functional erections over time without initiating erectile medication. So we can see at screening, this number set at the probability of 1.0, and over the course of 24 months of follow-up, this decreases to 0.6. So there is a deep probability decrease from 1.0 to 0.6, without initiating erectile medications.

However, the probability of functional erections over time when erectile medications are added into the process, shows that there's very little decrease if we look at screening 1.0 again, and a 24 months, 0.9. So the take-home message from the last two slides is that with the help of erectile medications after therapy, there really is no decrease in the erectile function.

This figure looks at the adverse events associated with MRI-guided focused ultrasound procedures at 24 months. And the take home from this table is that there was very few only one grade three adverse event with it, which was a urinary tract infection. And you can see the mild grade one to two adverse events here predominantly erectile dysfunction at 20%, hematospermia at 13%, hematuria at 24%, penile testicular pain at 13%, urinary incontinence at 18%, and urinary attention at 15%. So we're overall very well tolerated with only primarily grade one and two events.

So, several discussion points from this trial, there's key points that the authors highlighted with regards to functional outcomes, and then you can see them listed here. So, first of all, by 24 months, no patient reported urinary incontinence requiring pad usage.

Secondly, although the difference in mean erectile function scores was significant, the small difference should be taken in the context of two years of follow-up, in which small decreases in erectile function are likely to be common. Thus, although this was statistically significant, it probably is not clinically significant.

Thirdly, these outcomes compare very favorably with PROs that are highlighted after whole gland treatment, such as radiation or surgery.

This study versus previous studies had higher rate of success in treating cancer in the targeted regions, and there's several potential explanations for this. First previous studies were conducted using an ultrasound-guided device, which does not have MRI's ability to delineate tumor target accurately and provide precise, real-time monitoring of treatment effect with MRI thermometry.

Secondly, patients enrolled in this study under when systematic biopsy plus MRI targeted biopsy, or in gantry MRI guarded biopsy, for selection and treatment was image-guided to a region of interest on MRI confirmed by the index cancer.

And finally, treatment planning included a treatment margin around the tumor of at least five millimeters and up to 10 millimeters, to enhance the probability of treating the entire tumor during ablative therapy.

So, in conclusion, MRI-guided focused ultrasound, focal therapy targeting an MRI-visible index lesion using real-time MR thermometry has a low rate of GU adverse events, and on the basis of a 24-month biopsy outcomes, can be used to treat Gleason grade group two and three index lesions with a high degree of success.

These data support the effectiveness our MRI-guided focused ultrasound focal therapy to target prostate cancer tissue in adequately selected patients with intermediate-risk disease, seeking to avoid whole gland treatment.

Thank you very much for your attention, and we hope you enjoyed the URO Today, Journal Club Discussion.