Rashid Sayyid: Hello everyone, and thank you for joining us today in this UroToday Journal Club recording. I'm Rashid Sayyid, a urologic oncologist and assistant professor at the University of Arizona in Tucson, and I'm joined today as always by Zach Klaassen, associate professor and program director at WellStar MCG Health in Augusta, Georgia. And today we'll be discussing the recently published RAMPP, randomized control trial that looked at the role of radical prostatectomy in the management of men with oligometastatic prostate cancer. This trial was published in September of 2025 in European Urology and was led by Dr. Markus Graefen as well as Burkhard Beyer from Europe. So when we talk about primary local therapy in the mHSPC setting, a lot of the focus has been in the low volume space and really mainly in the radiation therapy space as well. And there are two important trials in this space.

We have STAMPEDE arm H, and PEACE-1, which we'll discuss. So starting off with a STAMPEDE arm H, this important trial was published in 2018 and it was a phase three trial that randomized over 2000 men with de novo mHSPC between 2013 and 2016 to either standard of care with prostate radiotherapy or standard of care alone. The median PSA in this trial was 97, and when we talk about standard of care, all patients received ADT and about 18% received docetaxel as well. When we look at the overall cohort, there was no overall survival benefit with adding prostate radiotherapy. However, in the CHAARTED low volume group, we did see an overall survival benefit with adding prostate radiotherapy with a median overall survival benefit about four months from 45 to 49 months. More recently, we saw the PEACE-1 trial, which is a European two by two factorial trial that randomized men with de novo metastatic castration-sensitive prostate cancer into one of four arms, either standard of care alone, standard of care, plus abiraterone, standard of care plus radiotherapy or standard of care plus abiraterone plus radiotherapy.

So essentially it's the abiraterone component and the radiation are what I account for this two by two factorial design. And when we talk about standard of care in this trial, it was ADT with docetaxel, about 50% of men. And so focusing on the low volume group, just like the STAMPEDE arm H trial, we saw that adding radiotherapy to the prostate, to specifically standard of care plus abiraterone, improved radiographic progression-free survival by over three years. But when the radiotherapy was added to standard of care alone, which is ADT plus docetaxel, so kind of similar to what we saw in STAMPEDE arm H, there was no survival benefit in this setting similar to what we saw in standard care alone, when both groups were lumped together, meaning those who got abiraterone and did not get abiraterone, there was no overall survival benefit with prostate radiotherapy with 6.9 years in the group that received prostate radiotherapy and 7.5 in the group that did not.

So a weak signal towards an RPFS benefit only in patients who receive abiraterone in the PEACE-1 trial. Now, one of the things that was really emphasized and highlighted when this study was presented at ASCO was that prostate radiotherapy improved the time to serious GU events. So historically we've always thought as radiation of having a lot of GU toxicity, but the investigators in this trial really highlighted that that wasn't the case. If anything, it was the reverse. And if we look at the table here marked in red, the total number of events was twofold. Higher in the group that did not receive radiotherapy, radiotherapy was cut it by half. So 22% versus 12%. And when we look at this in more granularity and try to figure out really what are the major differences, we see that patients who did not receive radiation had a higher odds of getting double J stent as well as needing a TURP of the prostate.

But also one of the important things that was left out is that the need for prostate radiotherapy was considered a GU event. And so obviously the patients already got the radiotherapy are unlikely to get it again, but those who hadn't, 6% did. So part of this 10% difference, 6% of that was because they received radiotherapy. So it really adds a bit of skepticism towards the interpretation of these results, and it's important for the reader themselves to interpret that in the light of these minute details. Now, what about radical prostatectomy in the oligometastatic hormone sensitive setting? We do have evidence existing in this space. We had an important trial that was published in the European Urology Oncology in 2022, and this was an open-label trial that randomized 200 patients with oligometastatic prostate cancer defined as five or less bone mets or extra pelvic nodal mets of conventional imaging to either ADT alone or ADT plus radical local therapy.

And by radical local therapy, we mean either radiation or a radical prostatectomy. The median PSA here was 99, as we'll see later. This was much higher than the population of the RAMPP trial. And when we look at the intervention arm of the one hundred patients, 96 received the radical local therapy, mainly radical prostatectomy and important to note that 17 in a control arm also received radical local therapy, mainly radical prostatectomy. And we see very impressive results here with radical local therapy. The median RPFS was significantly improved with the addition of the local therapy, the hazard ratio of 0.43 and three year overall survival was 18% in the intervention arm with a hazard ratio of 0.44. So the question is really, do we need any further evaluation of radical local therapy in this setting? And the answer is clearly yes, we need to build upon this data with a trial that looks at radical prostatectomy alone as opposed to radiation as well, a study with a larger sample size, a longer follow-up, which is very important, and a study that uses more contemporary systemic agents that reflect contemporary practice.

And so to this end, the RAMPP trial was designed and recently published, and it was an international randomized trial across 39 sites in Germany, Sweden, Denmark, Australia, Finland and Spain. And eligible patients were those with newly diagnosed, meaning within six months of prostate cancer, and they had to meet the D'Amico intermediate or high risk criteria. The PSA had to be less than 200. One to five bone mets either on PET or conventional imaging. And importantly, no brain or visceral metastasis and eligible patients were randomized in a one-to-one fashion to either best systemic therapy alone, which meant here ADT plus or minus a nonsteroidal anti-androgen such as bicalutamide and ARPI, docetaxel. And in the interventional arm, they received that same systemic therapy plus a radical prostatectomy with an extended pelvic lymph node dissection. The primary outcome of this study was cancer specific mortality, and this study was designed initially to have 80% power to detect a 14% difference in five-year cancer mortality.

And so that meant it required a sample size of 500 patients, 250 in each arm, and it required 106 primary outcome events over the five-year follow-up. Secondary outcomes included clinical progression defined as new bone or soft tissue metastases on imaging or cancer specific mortality overall survival, as well as surgery specific complications that we know of, bleeding, anastomotic leak, thromboembolic, cardiac events, lymphocele, impaired wound healing. It's important to note that this study closed early for accrual and the reason being twofold, first following the publication of the STAMPEDE arm H results in 2018, showing an OS benefit with prostate radiotherapy in low volume, metastatic hormone sensitive prostate cancer patients, as well as the low recruitment rate that they saw with this trial. Based on these two reasons, the steering committee took the decision to stop the study accrual early for ethical reasons, and they shifted the available resources that they had from having a larger sample size to maintaining the smaller sample size, but extending the follow-up from five to 10 years.

When we talk about statistics in this study, this was an intent to treat analysis, meaning that patients were analyzed based on the initial intent to randomize these patients. The differences between the study arms were compared using the Wilcoxon Rank Sum and Pearson Chi score tests. And when we look at the different survival outcomes, think of them in two groups. We have cancer specific mortality and clinical progression. Other cause death is a competing event, meaning if other cause death occurs, the other two events can't occur. So with that in mind, you have to conduct a competing risk analysis with cumulative incident curves used in the setting with the comparisons performed with a Gray test. And as well, they use regression analysis additionally to evaluate the effect of RP addition on cancer specific mortality. So think of this as a sensitivity analysis to further validate the results of the primary analysis and when they looked at overall survival, because really overall survival is the binary event that cannot be affected by anything else. They looked at this with classical survival analysis, meaning Kaplan–Meier curves with comparisons performed with the log rank test. At this point, I'll turn it over to Zach. We'll go over the results, the discussion and what this means for our patients on counseling mHSPC patients in routine everyday clinical practice.

Zachary Klaassen: Thanks so much, Rashid. Excellent background for the RAMPP trial. And so this leads us into the consort flow diagram that there were 138 patients that were assessed for eligibility. Ultimately 132 are randomized 66 to radical prostatectomy plus best systemic therapy and 66 to best systemic therapy alone. Ultimately, several were lost to follow-up, but the intention to treat analysis had 66 patients in each group. So we look at the descriptive characteristics at randomization. Remember this was randomized between 2015 and 2018. The median age was 67 years. The median PSA was 20 in the RP plus BST group compared to 22 in the BST alone group. Majority of these patients, not surprisingly, over almost 90% were ECOG performance zero. The Gleason sum score of biopsy was two thirds, eight to 10 Gleason score. The majority of patients were high risk patients, clinical T3 to T4 disease, and importantly, roughly a quarter of patients were clinical N1 disease at the time of their evaluation. This was early days of PET imaging, but roughly one third of these patients did have a PSMA PET scan. Number of bone metastases, roughly 90% had one to three metastases, so a true oligometastatic prostate cancer population. When we look at the location of the bone metastases, a smattering of patients that had spine, rib and pelvis most commonly. And when we look at the initial best systemic therapy, this was ADT alone and 85% of patients undergoing RP and 64% of patients just having best standard therapy alone.

This table looks at the clinical pathological characteristics and outcomes among patients undergoing radical prostatectomy. Not surprisingly, when you have oligometastatic disease, you're also going to have locally advanced. So we see roughly two thirds of patients had Gleason eight to 10 on pathology, positive surgical margins, and roughly two thirds of patients as well. 62%, almost 80% of patients were PT3 to T4. And we see that roughly 58% of patients had PN1 disease. And the first PSA after radical prostatectomy was 0.10. This looks at the cumulative incidence of cancer specific mortality. This was the primary outcome for the RAMPP trial. The five-year rates were 13% for radical prostatectomy plus best standard therapy and 23% for BST alone. And so this was a positive trial hazard ratio of 0.39 95% confidence interval of 0.16 to 0.98. Looking at some of the secondary outcomes, cumulative incidents of clinical progression, this was not different between the two groups.

The five-year rates, 59% for radical prostatectomy plus BST versus 60% for BST alone. Hazard ratio of 1.1 overall survival, again with limited follow-up. No surprise here that there was no difference, but we do see a numerically a slightly higher increased five-year rate of overall survival in the RP plus BST group, 81% versus 74% in the BST alone group hazard ratio was 0.55, but the 95 confidence interval was not statistically significant. 0.25 to 1.22. When we look at the AEs and the surgical specific complications, this is important. So this is a patient population where they're having best standard of therapy but also undergoing surgery. And we do see 29% of the 66 that underwent RP had a Clavien-Dindo grade less than three complications, but 14% had a greater than or equal to three Clavien-Dindo complication. And so this included bowel injury 2%, bleeding 5%, anastomotic leak 5%, and lymphocele at 3%.

Not surprisingly, with any surgical trial, there is some limitations. So the first one is that the trial was stopped early, but there is three other major trials incorporating radical prostatectomy in the oligo metastatic prostate cancer setting that are ongoing. The TRoMbone trial, the SIMCAP trial, and the SWOG S1802 trial. And so pooled analysis of these trials with RAMPP may provide more robust estimates in terms of benefit from radical prostatectomy as well as it's important to mention patient enrollment was slow. And thirdly, eligibility criteria mainly relied on conventional bone scans. Again, this trial accrued between 2015 and 2018, although one third of patients did have PSMA PET scan. Fourth results for the secondary endpoint of clinical progression as we discussed, failed to validate the findings of improved cancer mortality, which was the primary endpoint. So it remains unclear if the cancer specific mortality benefit of radical prostatectomy is direct by reducing the primary cancer tumor volume or indirect by prompting earlier use of salvage therapies.

And finally, RAMPP was not powered to show a sufficient overall survival benefit. By way of discussion, this randomized trial showed a significant cancer specific mortality benefit from the additional radical prostatectomy to best standard therapy and oligometastatic prostate cancer. And so taking the literature in this trial to context, either local therapy, RP or RT should be considered for these patients. The cancer specific mortality cumulative incidence rate at five years was significantly lower in the radical prostatectomy arm, 13% versus 23%. And this is comparable to the five-year overall survival benefit of radiotherapy in the STAMPEDE arm H trial, which was 12%. The STOPCAP meta-analysis, which was published in 2019 looked at three prospective studies. HORRAD, STAMPEDE and PEACE-1 showed a consistent pattern of better cancer control with radiotherapy to best standard therapy for men with less than five bone mets. And this pooled 7% overall survival improvement was at three years.

Finally, radical prostatectomy was a safe treatment modality that resulted in excellent biochemical response and local cancer control. However, as we mentioned, 14% in the radical prostatectomy arm did have severe surgery specific complications during follow-up, and this is not just for radical prostatectomy alone in the RT arm and STAMPEDE 5% of patients receiving radiotherapy had at least one RTOG grade three or four acute toxicity, and 39% of patients experienced a CTCAE grade three plus adverse event. So we know that local therapy, either radiotherapy or radical prostatectomy, can lead to complications. So the take home message from the RAMPP trial is that although it had substantial limitations, the results support the addition of radical prostatectomy as local therapy to best systemic therapy for patients with oligometastatic prostate cancer. Thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of the recently published RAMPP trial in European Urology.