Synchronous Low-Volume mHSPC – in Which Patients Do You Recommend Combination Systemic Therapy plus Local Treatment of the Primary and in Which Patients Is ADT Alone plus RT Enough? "Presentation" - Robert Jones
November 15, 2024
At the 2024 Advanced Prostate Cancer Consensus Conference (APCCC), Robert Jones discusses the role of combination therapy in low-volume metastatic prostate cancer, examining evidence from PEACE-1 and meta-analyses that suggest potential benefits of triplet therapy (radiotherapy + ARPI + ADT) over doublet options despite not reaching statistical significance.
Biographies:
Robert Jones, PhD, Professor of Clinical Cancer Research, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland
Biographies:
Robert Jones, PhD, Professor of Clinical Cancer Research, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland
Read the Full Video Transcript
Robert Jones: And I'm sure you'll understand I did not set the title, but this is my exam question for this year. Specifically, note that I'm not being asked to defend or otherwise the role of radiotherapy in low volume disease. But what I'm being asked to explore is whether the androgen receptor pathway inhibitor is also indicated.
And that's probably quite a good job, because my greatest disclosure is that I'm a medical oncologist. I don't do radiotherapy, but I do work within a multidisciplinary team, and I work very closely with an enthusiastic bunch of radiation oncologists. So what is it we're frightened of here? And I guess this probably sort of summarizes our fear, because this is a patient of mine who died a few years ago.
In summary, he was diagnosed at the age of 71 with what we would now classify as low volume metastatic disease. And you can see that over the ensuing period, he had a variety of increasingly stringent androgen denying therapies. And he died at a good age, at 90 or 89. In fact, he died with negative scans of an unspecified cause, but we didn't think he died from his prostate cancer.
And of note here, his final years were really dominated by nonspecific symptoms of fatigue, sarcopenia, complications of osteopenia, which he probably correctly or at least partly correctly attributed to his systemic therapies. And so I guess what we're frightened of here is overtreatment. And this, of course, is a group of patients who will be particularly vulnerable to overtreatment.
So I was asked to speak to really explore what's changed in the last two years. So in 2022, this would have been a good news times three story. The first bit of good news: prognosis is relatively good. Of course, that's relative to patients with high volume disease. These are the STAMPEDE arm of the radiotherapy comparison. And note the median survival there in the control arm: 63.6 months.
Good news times two: radiotherapy improves survival. Not being asked to defend that. Good news times three, and of course, we know this and we've just seen these presented, is that androgen receptor pathway inhibitors also significantly improved survival in this low volume group of patients, and we've seen multiple [INAUDIBLE] of the data from STAMPEDE here. So what have we been doing in this time period in Glasgow? So I'm very grateful to Rebecca Carrozzi for helping me too, who's one of our fellows, for helping me assemble these data.
So this is our patients who received—this is 118 patients who received—they all received radiotherapy for low volume metastatic prostate cancer. And this is what we did. So you can see 86% of them got an additional systemic therapy, and the vast majority of those being either abiraterone or enzalutamide. Only 14% getting the radiotherapy alone. And there are multiple different reasons why patients didn't get anything other than main therapy alone there.
And of course, what's new since 2022? Well, I guess this is probably the most directly relevant trial to the question, which is PEACE-1. And these data were presented last year, and this was—remember, this was a factorial 2 by 2 design, both exploring the addition of abiraterone and/or radiotherapy to the primary. Specifically, it was not designed to answer my question, which is whether adding in the abiraterone to the radiotherapy is beneficial. It was two separately asked questions.
And this, of course, as we know, was negative in the low volume population, and there was no overall survival gain by adding in the radiotherapy. But if we look in a little bit more detail, you can see here that if you were to choose one of the strategies between standard of care plus radiotherapy or standard of care plus radiotherapy plus abiraterone, it certainly looks as though the triplet therapy is associated with better outcomes, although that's not a statistically valid conclusion.
And now, maybe more helpfully, we have this network meta-analysis. So this is an aggregate data network meta-analysis. I understand an individual patient network meta-analysis is planned or even underway. And this basically assembled multiple trials exploring, comparing standard of care with radiotherapy, standard of care with androgen receptor pathway inhibitor, and then, of course, this is the PEACE-1 data here—those 126 patients in PEACE-1 who received all three.
And fundamentally, from my exam question point of view, it's this analysis that we're looking at. So this is essentially comparing the triplet therapy with standard of care plus radiotherapy. And you can see that it did not reach the statistically significant benefit, although there is, I guess, probably quite a strong trend towards a benefit for the triplet therapy over the doublet therapy. And certainly, when you rank all three of the doublet and triplet options, the triplet option does appear to be the highest ranking in terms of efficacy against overall survival in this network meta-analysis.
I suppose the other factor that I think is relevant here is that, with modern radiotherapy—and in Glasgow, we use the—we're guided by the STAMPEDE protocols, the two different radiotherapy. We use both the radiotherapy protocols from STAMPEDE. Radiotherapy is well tolerated. And certainly my experience is that patients have relatively minimal short- or long-term toxicities. And most patients have no significant long-term implications from the radiotherapy.
We've only seen limited data from PEACE-1 so far, but it would look like—although they're using a slightly different radiotherapy fractionation schedule—it's giving fairly similar low incidences, at least of high-grade toxicity. And of course, we have to align this against the fact that although we congratulate ourselves on how well tolerated the androgen receptor pathway inhibitors are, a lot of these patients are going to be on that therapy for a very long period of time, because their prognosis is good. And lengthy duration of exposure to androgen receptor pathway inhibitors does have additional toxicities, as experienced by the patient I showed you at the start.
I think it is also worth pointing out that the other finding from PEACE-1 was that although it failed to show that survival gain, it did show a significant benefit for the radiotherapy in terms of local control. So this is the time to serious GU adverse events, and you can see on the right here—on the left here, the overall data. So patients who received radiotherapy had a significant improvement in time to serious GU adverse events. And just on the right here, it is broken down by the arms. And if delaying serious GU adverse events is your goal, actually it does look as though the triplet therapy is slightly better than the doublet therapy in that regard as well. So actually, if that is your goal, triplet therapy probably is the one that's still associated with the best outcomes against that—against serious GU adverse events as well.
So in conclusion, what will I do now? I think the value of triplet—radiotherapy, androgen receptor pathway inhibitor, and ADT—is still uncertain. And I think radiotherapy does appear to add value to the ADT/ARPI combination. And so I think my default still at present is that patients should be treated with the triplet therapy. But I think either doublet is a good choice. And so I think this is a situation where an individualized patient treatment decision can be made.
And if a patient—or if indeed I—am particularly keen to avoid those long-term toxicities of the androgen receptor pathway inhibitor, then I think there is a conversation to be had about giving just the doublet treatment. And we might also want to bring in considerations of life expectancy and an absolute concept of the risk of metastatic progression versus local morbidity in that patient. But what we really need is more evidence. And I think this is certainly an area which is very ripe for de-escalation.
And I'm sure we're going to hear more about this trial in due course here. It's a trial I understand underway. Bertrand is leading this, I think. And this is the DE-ESCALATE trial, which is essentially looking at this concept of randomizing between continuous doublet systemic therapy versus intermittent doublet therapy. And notice there is a stratification by prior radiotherapy. So hopefully this will give us at least some concrete way forward as to how we can de-intensify treatment for these patients. So no monsters this year. But I also live next to a spectacular lake—this is Loch Lomond, photo taken on Christmas Day. Thank you very much.
Robert Jones: And I'm sure you'll understand I did not set the title, but this is my exam question for this year. Specifically, note that I'm not being asked to defend or otherwise the role of radiotherapy in low volume disease. But what I'm being asked to explore is whether the androgen receptor pathway inhibitor is also indicated.
And that's probably quite a good job, because my greatest disclosure is that I'm a medical oncologist. I don't do radiotherapy, but I do work within a multidisciplinary team, and I work very closely with an enthusiastic bunch of radiation oncologists. So what is it we're frightened of here? And I guess this probably sort of summarizes our fear, because this is a patient of mine who died a few years ago.
In summary, he was diagnosed at the age of 71 with what we would now classify as low volume metastatic disease. And you can see that over the ensuing period, he had a variety of increasingly stringent androgen denying therapies. And he died at a good age, at 90 or 89. In fact, he died with negative scans of an unspecified cause, but we didn't think he died from his prostate cancer.
And of note here, his final years were really dominated by nonspecific symptoms of fatigue, sarcopenia, complications of osteopenia, which he probably correctly or at least partly correctly attributed to his systemic therapies. And so I guess what we're frightened of here is overtreatment. And this, of course, is a group of patients who will be particularly vulnerable to overtreatment.
So I was asked to speak to really explore what's changed in the last two years. So in 2022, this would have been a good news times three story. The first bit of good news: prognosis is relatively good. Of course, that's relative to patients with high volume disease. These are the STAMPEDE arm of the radiotherapy comparison. And note the median survival there in the control arm: 63.6 months.
Good news times two: radiotherapy improves survival. Not being asked to defend that. Good news times three, and of course, we know this and we've just seen these presented, is that androgen receptor pathway inhibitors also significantly improved survival in this low volume group of patients, and we've seen multiple [INAUDIBLE] of the data from STAMPEDE here. So what have we been doing in this time period in Glasgow? So I'm very grateful to Rebecca Carrozzi for helping me too, who's one of our fellows, for helping me assemble these data.
So this is our patients who received—this is 118 patients who received—they all received radiotherapy for low volume metastatic prostate cancer. And this is what we did. So you can see 86% of them got an additional systemic therapy, and the vast majority of those being either abiraterone or enzalutamide. Only 14% getting the radiotherapy alone. And there are multiple different reasons why patients didn't get anything other than main therapy alone there.
And of course, what's new since 2022? Well, I guess this is probably the most directly relevant trial to the question, which is PEACE-1. And these data were presented last year, and this was—remember, this was a factorial 2 by 2 design, both exploring the addition of abiraterone and/or radiotherapy to the primary. Specifically, it was not designed to answer my question, which is whether adding in the abiraterone to the radiotherapy is beneficial. It was two separately asked questions.
And this, of course, as we know, was negative in the low volume population, and there was no overall survival gain by adding in the radiotherapy. But if we look in a little bit more detail, you can see here that if you were to choose one of the strategies between standard of care plus radiotherapy or standard of care plus radiotherapy plus abiraterone, it certainly looks as though the triplet therapy is associated with better outcomes, although that's not a statistically valid conclusion.
And now, maybe more helpfully, we have this network meta-analysis. So this is an aggregate data network meta-analysis. I understand an individual patient network meta-analysis is planned or even underway. And this basically assembled multiple trials exploring, comparing standard of care with radiotherapy, standard of care with androgen receptor pathway inhibitor, and then, of course, this is the PEACE-1 data here—those 126 patients in PEACE-1 who received all three.
And fundamentally, from my exam question point of view, it's this analysis that we're looking at. So this is essentially comparing the triplet therapy with standard of care plus radiotherapy. And you can see that it did not reach the statistically significant benefit, although there is, I guess, probably quite a strong trend towards a benefit for the triplet therapy over the doublet therapy. And certainly, when you rank all three of the doublet and triplet options, the triplet option does appear to be the highest ranking in terms of efficacy against overall survival in this network meta-analysis.
I suppose the other factor that I think is relevant here is that, with modern radiotherapy—and in Glasgow, we use the—we're guided by the STAMPEDE protocols, the two different radiotherapy. We use both the radiotherapy protocols from STAMPEDE. Radiotherapy is well tolerated. And certainly my experience is that patients have relatively minimal short- or long-term toxicities. And most patients have no significant long-term implications from the radiotherapy.
We've only seen limited data from PEACE-1 so far, but it would look like—although they're using a slightly different radiotherapy fractionation schedule—it's giving fairly similar low incidences, at least of high-grade toxicity. And of course, we have to align this against the fact that although we congratulate ourselves on how well tolerated the androgen receptor pathway inhibitors are, a lot of these patients are going to be on that therapy for a very long period of time, because their prognosis is good. And lengthy duration of exposure to androgen receptor pathway inhibitors does have additional toxicities, as experienced by the patient I showed you at the start.
I think it is also worth pointing out that the other finding from PEACE-1 was that although it failed to show that survival gain, it did show a significant benefit for the radiotherapy in terms of local control. So this is the time to serious GU adverse events, and you can see on the right here—on the left here, the overall data. So patients who received radiotherapy had a significant improvement in time to serious GU adverse events. And just on the right here, it is broken down by the arms. And if delaying serious GU adverse events is your goal, actually it does look as though the triplet therapy is slightly better than the doublet therapy in that regard as well. So actually, if that is your goal, triplet therapy probably is the one that's still associated with the best outcomes against that—against serious GU adverse events as well.
So in conclusion, what will I do now? I think the value of triplet—radiotherapy, androgen receptor pathway inhibitor, and ADT—is still uncertain. And I think radiotherapy does appear to add value to the ADT/ARPI combination. And so I think my default still at present is that patients should be treated with the triplet therapy. But I think either doublet is a good choice. And so I think this is a situation where an individualized patient treatment decision can be made.
And if a patient—or if indeed I—am particularly keen to avoid those long-term toxicities of the androgen receptor pathway inhibitor, then I think there is a conversation to be had about giving just the doublet treatment. And we might also want to bring in considerations of life expectancy and an absolute concept of the risk of metastatic progression versus local morbidity in that patient. But what we really need is more evidence. And I think this is certainly an area which is very ripe for de-escalation.
And I'm sure we're going to hear more about this trial in due course here. It's a trial I understand underway. Bertrand is leading this, I think. And this is the DE-ESCALATE trial, which is essentially looking at this concept of randomizing between continuous doublet systemic therapy versus intermittent doublet therapy. And notice there is a stratification by prior radiotherapy. So hopefully this will give us at least some concrete way forward as to how we can de-intensify treatment for these patients. So no monsters this year. But I also live next to a spectacular lake—this is Loch Lomond, photo taken on Christmas Day. Thank you very much.