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Ruchika Talwar: Hi, everyone. Welcome back to UroToday's Health Policy Center of Excellence. As always, I'm Ruchika Talwar and today I'm really excited to be joined by Dr. Danny Triner from the University of Michigan. He's going to be discussing his recent work in the management of lymph node positive prostate cancer after radical prostatectomy. Thank you, Dr. Triner. We appreciate your time.

Daniel Triner: Great. Thank you so much for having me. I'm really excited to present our work looking at how patients with lymph node positive prostate cancer are being managed in the state of Michigan. Now, the main idea for this project really came out of a run of patients that we were seeing in our own clinics who had positive nodes at the time of radical prostatectomy. And as most people know, decision-making for post-prostatectomy management of these patients is complex. And this is largely because this is a heterogeneous group of patients. We know that these patients are at a high risk for disease recurrence and progression. However, upwards of 30% of these patients will never have a post-prostatectomy recurrence and could potentially be spared the morbidity of additional treatments. Now, in this space there's only been one prior randomized clinical trial, ECOG 3886, which most people would know as the Messing trial, in which patients with pathological lymph node positive disease at the time of radical prostatectomy were randomized either to immediate lifelong androgen deprivation therapy or observation.

And this group found that there was a significant overall and cancer-specific survival benefit. And since that time, there have been a few additional studies that suggest the addition of radiation therapy may also improve long-term oncologic outcomes for these patients. Currently, the AUA guidelines suggest that for patients with node-positive disease and an undetectable post-prostatectomy PSA, that initial observation is also appropriate to avoid the morbidity of ADT and radiation. And so at the time we were thinking about this, there really was not a lot of data on how these patients are being managed, so we wanted to address this. And so for this study, we turned to the Michigan Neurological Surgery Improvement Collaborative, or MUSIC, prostate cancer database. MUSIC is a statewide quality improvement consortium that comprises over 90% of all urological practices in the state of Michigan and prospectively maintains a prostate cancer database.

And in this dataset, we were able to identify a total of 666 patients who had node-positive prostate cancer at the time of prostatectomy between 2012 and 2023. And a couple of things to highlight from this cohort are that the majority of patients had grade group three or higher disease and T3 or greater disease and 60% had positive surgical margins. So I think this really just highlights the high-risk nature of this cohort. The objective of our study was really threefold. We wanted to determine the rates of secondary treatment utilization in this population. We wanted to identify patient and practice-level factors associated with secondary treatment as well as look at practice level throughout the state of Michigan.

And so the first thing that we looked at was the rate of receipt of secondary treatment after prostatectomy. And we found that by 12 months the vast majority of these patients, approximately two out of three with node-positive disease, would go on to some form of secondary treatment. Now, interestingly, there was some heterogeneity in the treatment modality that patients received. There was a large subset of patients receiving immediate ADT alone within 60 days after prostatectomy and we think this is likely providers strictly adhering to the data from the Messing trial. If we look greater than 60 days after prostatectomy, there's a split where approximately a third of patients receive ADT alone, a third of patients receive radiation alone and a third of patients received a combination of both ADT and RT. So after 60 days, two out of three patients received radiation in some form, either alone or in combination, which we think is reflective of the increasing role for radiation in this space for these patients.

We also looked at patient and practice-level factors that were associated with the receipt of secondary treatment in multi-variable models. And interestingly, if we looked at the practice type, academic practice type specifically was associated with higher secondary treatment rates compared to community or private practices. And for us, this really highlighted the heterogeneity and lack of consensus on this question. And perhaps unsurprisingly we also found that a persistently detectable PSA as well as other high-risk pathologic disease features, such as higher Gleason grade group and positive surgical margins were also associated with receiving some form of secondary treatment within 12 months.

Now, one concerning finding was that of patients with a persistently detectable PSA after prostatectomy, approximately 20% of these patients did not receive any form of secondary treatment at 12 months in MUSIC. And if we look further out to 24 months, there remains still a subset of these patients with an initially persistently detectable PSA who have not received any additional treatment. Now, we know from several prior studies that this group is at a particularly high risk for disease recurrence and progression and the five-year metastasis-free survival is only around 50%.

And lastly, we found that even within the state of Michigan there's wide variability in rates of secondary treatment among practices managing these patients. And it ranged from 28% of patients within a practice receiving some form of secondary treatment at 12 months to as high as 80%, so there really is a wide degree of variability even at the practice level within the state of Michigan. And so why is this important? Well, these data really highlight the variability in care for patients with lymph node metastases at the time of prostatectomy, which really underscores the lack of data we have to guide management in this particular field. So really, we need more trials to best understand which patients will benefit from early secondary treatment and which modality, which we think will cut down on some of this variability and likely improve patient care. Okay.

Ruchika Talwar: Thank you so much. I think you are exactly right. A lot of this stems from the lack of a really good consensus and high-level evidence since the initial Messing trial, but I think the MUSIC collaborative has really been at the forefront of standardization of care and identifying areas for improvement based on practice variability. So I commend you all in your work and I'm curious, let's dive a little deeper into that heterogeneity that you witnessed specifically over different time periods. Did y'all look at the effect of higher grade disease perhaps on patients who underwent radiation versus those who received ADT alone?

Daniel Triner: Yeah, we didn't actually break down those groups into which specific subsets of patients are receiving what specific modality. It's a great question and something that we've talked about also looking into because certainly that could be important, looking closer at the actual site of recurrence based off patients who may or may not have molecular imaging. It may help guide who's getting RT versus combination with ADT. So yeah, all of those are things that we've been considering looking at across MUSIC.

Ruchika Talwar: And now that you've identified this variability, particularly in academic versus community settings, what are you all thinking in terms of the way forward? How do we address some of these variations in care?

Daniel Triner: Yeah, so I think I can relate this back to our data on patients who had a persistently positive PSA after prostatectomy and that subset of patients who still had not received any form of secondary treatment even two years out. So again, that is a very, very high-risk group of patients. And so across the MUSIC collaborative that is one quality improvement area that we have discussed partaking in, is making sure that we reach out to centers to understand why some of these particular patients are not receiving secondary treatment so we can understand why there's such a high degree of variability out there, even within the same state.

Ruchika Talwar: Yeah, absolutely. I think one strategy to improve healthcare access is bringing the level of evidence that we see at large academic centers to centers that are closer to patients because it obviously addresses some of those transportation-related issues or distance-related issues, so certainly agree with you there. And again, this study is just one of many that are very needed in terms of auditing our practice patterns. But tell me as we wrap up here, what are your big takeaways for the urologic community?

Daniel Triner: Yeah, I think that this space, our data really highlight just how heterogeneous this group is and, again, as we've kind of been talking about, just the lack of consensus for how to manage these patients. And so I think it really just underscores two issues, that we don't fundamentally understand the biology of this disease. How do we identify which patients can be cured for all intents and purposes with a prostatectomy and lymph node dissection alone? How do we identify with what biomarkers for those particular patients? So again, I think it just highlights the heterogeneity in this cohort. And again, to your point about the practice level data, a lot of that, too, is just disseminating some of this information from the larger academic medical centers outwards to the community so that way we can decrease some of the variability and care that our patients are receiving.

Ruchika Talwar: Yeah. And as we get better at identifying patients who are at risk and risk stratifying them after surgery, I think a lot of this will become clear because I don't want to forget the fact that some of these patients you probably can observe and it would be better for their quality of life, whether it's various comorbidities, et cetera. I do want to acknowledge that, but I think we need to better delineate who would be most appropriate for what treatment algorithm. So congratulations on this work. Really interesting conversation and we appreciate your time.

Daniel Triner: Awesome. Thank you so much for having me. Really appreciate it.

Ruchika Talwar: And to our audience, thank you so much for joining us. We'll see you next time.