Meta-analysis indicates benefit of combination treatment approach in mHSPC

Scott Morgan, MD, MSc, FRCPC

In this interview, Scott Morgan, MD, MSc, FRCPC, shares the background and notable findings from the European Urology paper, “Prostate Radiotherapy in Low-volume Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis.” Morgan is a radiation oncologist at The Ottawa Hospital Cancer Centre and an associate professor of radiation oncology at the University of Ottawa, Ontario, Canada.

Please describe the background for this research.

By way of background, I think as your audience will be aware, there's been a lot of progress in treating metastatic hormone-sensitive prostate cancer over the past decade. So for many decades, up to about 2014, standard of care initial treatment was androgen deprivation therapy alone, so it was pretty static in terms of the treatment landscape. But that's all changed, of course, in the last 10 years, when the novel therapies that started to show benefit in later stages of disease were brought forward for study in newly diagnosed metastatic prostate cancer. So first, there are 3 trials looking at the addition of docetaxel to ADT that showed us a sizable overall survival advantage. I think it's fair to say that that benefit was seen more in patients with high-volume as opposed to low-volume metastatic disease. And then beginning after those trials launched, there were trials that looked at the addition of a number of AR pathway inhibitors: abiraterone, enzalutamide, darolutamide, and apalutamide. And those trials varied somewhat in terms of their design. But generally speaking, adding an AR pathway inhibitor to either ADT alone or ADT plus docetaxel had a major improvement in overall survival, like adding 2 years to life at the median, much more than had been the case for those therapies in metastatic CRPC. So this immediately changed standard of care, and the benefits really extended to patients with both high-volume and low-volume disease. And around the same time, there was a third group of randomized trials that looked at the addition of prostate radiotherapy to ADT or to ADT plus docetaxel. And while, for the overall study populations as a whole, radiotherapy did not improve overall survival but did appear to improve time to castration resistance, in pre-specified subgroups of patients with low-volume metastatic disease and low metastatic burden, radiotherapy did improve overall survival, at least in the largest trial. And the magnitude of the benefit in low-volume disease in terms of overall survival appeared to be about the same from prostate radiotherapy as from AR pathway inhibitors in low-volume disease. For many, this was a surprising finding, and it sort of challenged the dogma that local therapy to the primary tumor had no impact on survival in patients whose cancers had spread elsewhere. So the trials looking at the addition of AR pathway inhibitors to ADT and at the addition of prostate radiotherapy to ADT were done more or less in parallel. And so it raises the question about how best to manage those patients now that present with low-volume metastatic disease. In particular, the question arises, what is the value of adding prostate radiotherapy to patients that are receiving ADT and an AR pathway inhibitor? There's only 1 randomized trial that has directly addressed that question, the PEACE-1 trial in Europe. But when one looks at the low-volume population in that trial, the numbers in each of the 4 arms are relatively small, only about 125 patients in each arm. So there's a limited sort of power in that trial for that specific question. So in our view, given the lack of direct comparisons in the RCTs, there was the potential value of doing a network meta-analysis to look at the indirect comparisons and account for all of the randomized trials that looked at the addition of prostate radiotherapy to ADT and all the trials that looked at the addition of an AR pathway inhibitor to ADT, to try to determine the relative impact on overall survival of each of the treatment approaches. So what we did was we pooled from 10 randomized trials that were eligible, and there were about 4400 patients with a low-volume metastatic disease that were included in this analysis. And we pooled these patients into 4 groups based on the treatment they received: what we callstandard of care systemic therapy, which was ADT or ADT plus docetaxel; the second group was standard of care systemic therapy plus an AR pathway inhibitor; the third group was standard of care systemic therapy plus prostate radiotherapy; and then the fourth group received all 3: standard of care systemic therapy, an AR pathway inhibitor, and prostate radiotherapy. We did a network meta-analysis, looking at these 4 treatment approaches, and the primary end point was overall survival. Before moving on, I do want to highlight that it was the first author of the paper, Dr. Soumyajit Roy, who's a very talented senior resident in radiation oncology at Rush University in Chicago, who really led the charge on this work and put in an enormous effort on it. I think he deserves the credit for it. I think that really needs to be emphasized. There were some important contributions from the statistician on this study, Dr. Yilun Sun, who's at Case Western, as well as from a radiation oncologist at Seidman Cancer Center in Cleveland, Dr. Dan Spratt.

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

The main finding from this network meta-analysis is the ranking of the 4 treatment approaches that we considered. There's something called the Surface Under the Cumulative Ranking Curve [SUCRA] score that's used for ranking the treatments. So just in terms of interpretation, a SUCRA of 1 means that the treatment is certain to the best among those that were considered, whereas a SUCRA score of 0 means that it's certain to be worst. In our analysis, the highest ranked treatment strategy was the combination of standard of care systemic therapy, an AR pathway inhibitor, and prostate radiotherapy; the SUCRA there was 0.94 compared with a SUCRA of 0.62 for standard of care systemic therapy plus an ARPI, 0.45 for standard care systemic therapy plus prostate radiotherapy, and then a very low SUCRA for those just getting as standard of care systemic therapy alone, typically ADT alone. In terms of the pairwise comparisons, the hazard ratios for overall survival similarly favored the group that received all 3 therapies, though this didn't reach statistical significance, which probably reflects a lack of power in the group that received all 3 therapies. We also did a second analysis to take account of the fact that real-world practice has changed since all these trials were completed. In particular, very few patients in 2024 presenting with low-volume metastatic prostate cancer receive docetaxel as part of their initial treatment. So we did a Bayesian network meta regression that adjusted for use of docetaxel as part of the initial treatment, and also adjusted for the mode of presentation. The trials that looked at ARPIs included a mix of patients with both de novo presentation as well as relapse after prior local treatment for localized disease. And of course, when we're thinking about prostate radiotherapy, we're really interested just in the de novo population, so we adjusted as well from mode of presentation. And in this adjusted network meta regression, the same ranking of the 4 treatment approaches held up again, with the group receiving all 3 therapies doing best overall. And in terms of the pairwise comparisons, I would point out that one that is of interested in those that received ADT plus prostate radiotherapy, there was no difference compared to ADT plus an AR pathway inhibitor in that head-to-head pairwise comparison in the population with no docetaxel use and de novo presentation. I think the hazard ratio was 1.1. I can't say we were particularly surprised by those results; I think we found them reassuring overall, and I think it validated our current practice. The message individually from most of the trials that were included in this network is that intensification of initial therapy improves outcomes over the longer term. And that also appears to be the case in terms of adding prostate radiotherapy to an initial backbone that consists of ADT and an AR pathway inhibitor.

What questions arise from this study?

I think we have to acknowledge that a network meta-analysis relies on some indirect comparisons. And of course, we would prefer to have direct comparisons to guide our practice. So there are some limitations in this analysis. Ideally, I think we would have a dedicated, large-scale randomized trial that would definitively address this question. So in other words, in patients who are presenting with low-volume, metastatic prostate cancer, it would be ideal to have a trial where patients receiving ADT and an AR pathway inhibitor are randomized to receive either prostate radiotherapy or not. I'm aware of 1 trial that's currently accruing in the US, SWOG 1802, that may shed some further light on this once it ultimately reports. It's not limited to patients with low-volume disease, and also the local therapy that can be used in that trial can be either prostatectomy or prostate radiotherapy, so it's a bit more heterogeneous in those aspects. But I think it'll still be very much of interest once it completes accrual and matures and reports. Another limitation, I think, in this analysis is that we relied on aggregate summary data from the trials. It would be preferable to do a network meta-analysis with individual patient data. You can much more cleanly account in with individual patient data on patients that received docetaxel as part of their initial treatment, and it would allow a clearer analysis in terms of patients with de novo presentation. So, I think you could arrive at a more precise effect estimates with an individual patient data network meta-analysis. We didn't have access to individual patient data, and I'm not sure really whether we will ever see an individual patient data analysis that takes account of all the data from all these trials, including industry trials. We might have an IPD meta-analysis that includes the academic trials, and that would certainly be welcomed, though. And then in terms of in this disease space, to me, that the burning question...is about the value for metastasis-directed local therapy and oligometastasis-directed local therapy; in particular, SBRT in this population. And so that's the subject of a number of ongoing randomized trials. So, in my view, at present in patients that have low-volume oligometastatic de novo metastatic prostate cancer, it's really an unknown whether comprehensive SBRT or other local therapy directed at oligomets improves survival. So, in my view, it really shouldn't be routinely used off trial, especially where trials are available.

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

From our point of view, I think the takeaway for the clinician practicing in this area, be it the urologist or the medical oncologist or the radiation oncologist, is that in patients with de novo metastatic prostate cancer and low metastatic burden—and we can debate exactly how you define low metastatic burden—but in any case, if you can reach a consensus on that, I think a combination of ADT, an AR pathway inhibitor, and prostate radiotherapy appears to confer better overall survival than a strategy in which the prostate radiotherapy is omitted. So I think that the combination of the 3 therapies, given the evidence base at present, is the approach that is best supported. There are some limitations to the existing evidence base, and ideally, a large-scale randomized trial would address this question. But while we're awaiting such a randomized trial, or while we're awaiting an individual patient data meta-analysis, I think this is the preferred treatment approach in patients presenting with low-volume metastatic disease. Another takeaway, I think, which is less important than the main takeaway, but another takeaway is that in clinical scenarios where use of an AR pathway inhibitor is not possible due to comorbidity concerns, or whether there's a lack of availability of an ARPI—which, admittedly, is not a particularly common scenario in North America—but I think in that scenario...the combination of ADT and prostate radiotherapy is a reasonable alternative in patients with low-volume metastatic disease, and I think, based on this analysis, at least, would appear to confer similar outcomes in terms of overall survival. Prostate radiotherapy is obviously widely available, inexpensive, generally [with] a mild toxicity profile. So I think it's a reasonable option in that scenario in patients who present with de novo low-volume disease.

This transcription was edited for clarity.