Phase 2b data point to safety, efficacy of focal therapy in intermediate-risk prostate cancer

Behfar Ehdaie, MD, MPH

Patients with intermediate-risk prostate cancer often have the dilemma of choosing a treatment: Radical whole-gland therapy can produce detrimental adverse events for these patients and active surveillance (AS) is an option they are typically ineligible for.

In a study presented at the 2021 American Urological Association annual meeting, Behfar Ehdaie, MD, MPH, and colleagues assessed the efficacy of focal therapy in treating patients with grade group 2 or 3 prostate cancers. Ehdaie is an assistant member of the urology service department of surgery at Memorial Sloan Kettering Cancer Center, New York City, New York.

Could you discuss the background for this study?

The background of this study deals with improving patient outcomes for treatment for prostate cancer. We know from research over the past 2 decades that radical prostatectomy and radiation therapy, which are both whole-gland treatments, are associated with significant impact on patient quality of life with regard specifically to urinary continence or urinary control, sexual function, and bowel function. Although these treatments are very successful, from the oncologic perspective, our goal was to develop and test a new treatment modality in which we treat only the area with the significant cancer using focused ultrasound in the MRI gantry. This study was designed to be multicenter, including both academic centers and a private practice center. We tested the hypothesis that this treatment is both safe and effective, eliminating the area targeted with Gleason grade group 2 or grade group 3 prostate cancer, and assessed whether we properly select patients to undergo this treatment by looking at cancer throughout the prostate gland based on both MRI-targeted and systematic biopsy.

What were some of the notable findings? Were any of them surprising to you and your co-authors?

What's most important to talk about are the primary outcomes. 1 was safety. We show that there are no adverse events reported that are a grade 3 or higher in these patients. One patient had a urethral stricture, or tightening of the urethra after treatment, but after 1 dilation and within 90 days of treatment, it resolved. So, the first takeaway is that this treatment is safe, despite our goal to eliminate the cancer using wide margins, and that should be reported as well—that we tried to achieve at least 5 mm but planned for greater than almost 1 cm of a margin of benign tissue based on imaging.

The second primary outcome was cancer effectiveness. This study is unique because all patients underwent 6-month, and in patients [who were] eligible, 24-month biopsies. This was not based on reasons to go biopsy, including imaging or laboratory values. It was protocol mandated. We biopsied not only the area of treatment, but throughout the prostate gland. And it's notable that only 12% of patients by 24 months had grade group 2 or higher prostate cancer detected in the treatment area. When we looked at the entire prostate gland, a secondary outcome, we learned that 40% of patients by 24 months had grade group 2 or higher prostate cancer, suggesting that although we're very good in selecting patients with a dominant lesion or single lesion that we think we can confer prostate cancer risk based on the highest Gleason grade or volume of tumor, we still need to do a better job selecting patients. Or, what this means is that we can extend this treatment for a second treatment in areas that were not detected outside the treatment area after the initial assessment.

How does MRI-guided focused ultrasound compare with other forms of focal therapy for prostate cancer?

It is very important to really make a distinction in both the technique and outcomes, specifically with focused ultrasound. This device is unique in that because it's done during real-time MRI imaging while the patient is in the MRI machine, we can monitor the temperatures achieved by our treatment in real time and make adjustments in real time. What that means is that we're able to determine areas that will be sensitive to the treatment, both cancer and areas from a quality-of-life perspective.

Another outcome that we'd like to highlight is sexual function. Over 75% of patients in the study returned back to functional erections without the need for additional erectile dysfunction medications. That's a high bar we used to define sexual function, but those numbers were very encouraging. Of those, we had over 65% of patients by 2 years achieve functional erections with the additional medications, so what we can tell patients is that having this treatment, from a quality-of-life perspective, can achieve superior outcomes compared to whole-gland treatments.

Also, no patient in this study had urinary incontinence requiring pad use. So, when we compare this modality to other focal treatments, it's important to compare outcomes. We're unique in that we're showing mandated prostate biopsies at 6 and 24 months. By achieving numbers above close to 88% success in the targeted area, we look at a series of other studies. The numbers achieved for cancer detected in treatment area were closer in the 70 percentile. Mind you, the other focused ultrasound device is a urethral device. Ours is through the rectum, which is the way we perform MRIs traditionally and treatments for prostate cancer traditionally. Those treatments through the urethra were previously reported as whole gland. Other older or historic treatments, which are ultrasound guided, achieved 70% to 75% success in the treatment area. I think this is an important fact; however, I would also say that the limitation is that we did not compare these treatments head-to-head. Patient selection is different. We did a more high-risk group, including not only grade group 2, but grade group 3 patients, and the modalities for subsequent assessment, including biopsies, MRI imaging, and biomarkers may have been different between the studies. But at least we know these studies are encouraging and important from our perspective and how we define the end points and primary outcomes.

What is the learning curve like for this procedure?

As with everything, it requires a period of understanding the technology with didactic lectures. Having said that, patients and physicians have experience with MRI imaging, MRI, targeted biopsies, and localizing areas that are of suspicion. So, that learning curve can be improved with experience on how patients or physicians undergo biopsy. As far as in the treatment, many of the treatment steps are automatic or automized and can be guided with experience and a team to mentor the practitioner. Although we have no data on how many treatments before a patient or before a physician is considered a master or proficient, from my experience and the investigators', we included a period of 3 to 5 treatments with the engineers associated with those who designed this device to be able to mentor and guide us through those treatments. Subsequent treatments were monitored either remotely or in person with greater confidence of the physician and leadership in doing the procedure.

What is the take-home message for the practicing urologist?

It's important to realize this is a phase 2 study. I think these results are very encouraging in that we may be able to bridge the gap in prostate cancer treatment, in which we're selective and prostate gland-sparing. These results do suggest that doing that will improve quality of life in patients as compared to whole-gland treatments. However, I think we need to ask the critical question: if these patients did not undergo treatment and were monitored on active surveillance, did this treatment delay their need for subsequent therapies based on either eliminating or delaying disease progression? So, my first take-home message is I think this is an encouraging and important step, but will lead into a second step, which is to compare patients being monitored and patients undergoing this treatment.

The second take-home message is that we continue to improve our ability to select patients who have a dominant lesion or an area with the prostate that we would consider higher risk. Imaging has improved our ability to enhance our biopsies, but we continue to improve so we can eliminate the detection of significant cancer outside of the targeted area based on the initial assessment.

Is there anything else you feel our audience should know about the findings?

It's important to realize that these results are generalizable given that this is an important multicenter study, including both academic centers in a private clinic setting. Number 2, these are patients with significant cancers. The only patients treated in this study were grade group 2 and grade group 3 cancers. Number 3, patients subsequently had good quality of life outcomes and the procedure was safe. And number 4, focal therapy is encouraging for the future management of patients with localized prostate cancer. We're marching forward, looking at further studies and determining the safety of this approach and the effectiveness and the clinical benefit for patients as compared to monitoring them with active surveillance. So, I would say that focal therapy should remain something that's studied in the clinical trial setting.

Reference

1. Ehdaie B, Tempany C, Holland F, et al. MRI-guided focused ultrasound (MRgFUS) focal therapy for intermediate-risk prostate cancer: final results of a phase IIb multicenter study. Paper presented during the 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-12