He is the chairman and senior member of the Department of Radiation Oncology at the H. Lee Moffitt Cancer Center. He gave a talk on which patients with prostate cancer we should be giving metastasis-directed therapy without systemic therapy, and I am so excited to welcome him.
Thank you for doing this, Dr. Yamoah. Welcome to UroToday.
Kosj Yamoah: Thank you so much for having me. It's really been a wonderful conference and consensus panel with amazing speakers. And this topic is really a topic that comes up a lot when we are treating patients with oligometastatic disease and which patients can we only do metastasis-directed therapy without including systemic treatments.
And mostly where we want to focus on at first, maybe do a few key definitions because we wanted to really understand what that state is.
Because in oligometastatic prostate cancer, we have patients that are known to be de novo synchronous oligometastasis where they are hormone-sensitive. They've been recently diagnosed. And in those patients usually want to, by definition, which is not exactly clear, you want lesions to be less than five lesions.
And then you have, what we call the metachronous oligorecurrent hormone-sensitive prostate cancer patients. And they are those that might have been already treated in first line and have a recurrence coming at a different timeframe or a different time point. And still these recurrences are metastatic, but they are low burden, somewhere less than a quarter to five lesions.
And then you have the oligoprogressive castrate-resistant patients that have been heavily treated that are basically progressing through treatment, so hence, castrate resistance and having lesions that are appearing, but still small in numbers overall.
Those three categories are three distinct type of patients that we need to be aware of when we are trying to answer this type of question.
And so we went through a few definitions of what NCCN would say to the metastatic-directed therapy that is preferred for metachronous oligorecurrent hormone-sensitive prostate cancer, and that MDT is acceptable based on clinical and medical need for synchronous patients and oligoprogressive.
But MDT alone is not suitable if you have a synchronous oligometastatic hormone-sensitive, and that rather, we should go into doing a combination of ADT with ARPI, which is androgen receptor inhibitors, and that the primary tumor could be treated with radiotherapy in some patients, and then we can add MDT in selected cases.
And the reason why these definitions are important is because we're able to just quickly walk through what led to those type of recommendations by the NCCN.
So patients with oligometastatic prostate cancer may be treated with MDT alone or concurrently with ADT, usually about short-term ADT. And the evidence supporting this is strongest for metachronous oligorecurrent hormone-sensitive prostate cancer in a setting as compared to the synchronous patients.
And the two main studies that we went over was the STOMP and ORIOLE trials that demonstrated for the first time that MDT safely delays the onset of systemic therapy initiation and also prolongs progression-free survival.
And just in a real quick high-level overview, we went over STOMP Trial, which was the first phase-two randomized study that provided evidence that it can actually delay initiating systemic treatment for oligometastatic prostate cancer patients. And then also in this cohort of about 68 patients that had up to about three extracranial sites, randomized one-to-one to either surveillance or MDT to all sites, the primary endpoint being ADT-free survival. And indeed, the five-year ADT-free survival was 8% in the surveillance group, and up to 34% in the MDT group.
Now, ORIOLE did something slightly different, but similar way. It was also a phase-two trial that looked at SBRT and showed that stereotactic body radiotherapy improved progression-free survival compared to observation in men with oligometastatic prostate cancer. Again, 54 patients who had about one to three sites detected on conventional imaging, randomized two is to one to SBRT versus observation. And at six months, progression was 19% of patients who received SBRT, but up to 61% in observation arm.
Now, there were other studies that came after that supporting this notion of using MDT, which is in this case SBRT for metachronous that was in the SABR-COMET Study, something similar here. They observed an increase in improvement in overall survival in that patient cohort, even though there were several diseases. Prostate cancer constitute about 16% of patients. So that was further evidence to support that.
Other studies that came through was the EXTEND Study, which looked at about 87 patients in the randomized manner to MDT versus intermittent ADT. And here again, they showed that it was a progression-free survival was significantly improved with the use of combination MDT and hormones versus when you did hormones alone.
RADIOSA also came along. RADIOSA was a phase-two single-center study that looked at SBRT with or without ADT for six months. SBRT was done in 30 gray in about three fractions every other day with a BED over 100. And here what we recognized, what came out of that study was the median progression-free survival was only 15 months and with the ADT and then... With the arm that had SBRT alone. And when we added ADT was 32 months, median survivor not reached supporting that even the combination could be better.
Now, we put all this together. This is a take-home slide, the most important slide that we can look at, that the bulk of MDT in oligometastatic prostate cancer was really centered around metachronous oligometastatic prostate cancer with all the studies that I've run over very quickly. And so this gives you a flavor of where the field is going, and this was a study put out in Seminars of Radiation Oncology last year. And as you can see, a bulk of the data supporting MDT in oligometastatic prostate cancer has been in the metachronous environment.
The largest meta-analysis we've had is a WOLVERINE meta-analysis that looked among all these patients at a patient-level data, looking at all the endpoints we cared about when you had added MDT to standard of care in patients with oligometastatic prostate cancer. And you can see, whether you looked at progression-free survival, on the left side, you have in all the studies that they looked at here, there was an overall benefit, also overall benefiting radiographic progression-free survival on the bottom here of all the studies included, and overall survivor was just barely meeting significance so just touching the one line here in Overall. And then in castrate-resistant, free survival as well, suggesting that indeed MDT adds a lot of benefits to standard of care for a lot of patients who have oligometastatic prostate cancer.
There are some ongoing studies also that we quickly talked about, the DART Study, the SPARKLE and Promethean. I'm not going to go through all this, but these are studies that will shed more light on the path towards MDT and how we can integrate that into patients that are being treated with oligometastatic prostate cancer.
So back to the topic at hand, now which patients would we use MDT alone without systemic treatment? And these are a few things that were up for discussion, which is first of all, the disease characteristics is very, very important. Of course, the definition has always been somewhere in the neighborhood of less than, or equal to, five metastatic sites on conventional imaging.
When we use more advanced imaging like PSMA-PET, sometimes the number can be a little bit higher because of the sensitivity of PSMA, and these metastases sites should typically be limited to lymph nodes and the bony sites. Visceral organs are often excluded. And as I mentioned earlier on, it should be a metachronous oligorecurrent hormone-sensitive prostate cancer is a group that you can safely omit systemic treatment for.
But there are some limitations. We talked about you do not want to use that for patients that are really synchronous oligometastatics. In that case, you want to really include systemic treatments and as well as even radiotherapy to the local organ.
And so other things that we want to consider when thinking about MDT, along with our systemic treatment, is really looking at biochemical recurrence, the PSA. The PSA density, the PSA velocity is very, very important. The PSMA-PET signals that we've talked about, if there is any genomics that has been done on the patients, if they have high risk of mutations, these are things that might sway you away from using MDT alone for oligometastatic prostate cancer patients.
I talked about PSA doubling time being something to be aware of as well. If you have a shorter doubling time, you may not want to use MDT alone, especially if it's less than three months. And now obviously patients with any TP53, ATM mutation, BRCA mutations, RB1. These are patients that you may want to require systemic therapies for.
And so with this, I know we can have a discussion. I can answer any questions that might come up in this conversation.
Leslie Ballas: Thank you so much for reviewing this with us. Great presentation.
Something that comes up a lot in my own clinic, either from patients or referring physicians, is the RADIOSA trial, which you briefly discussed. It's the most recent trial that asks basically the exact question, radiation alone and metastasis-directed therapy alone versus metastasis-directed therapy with ADT, and they found a progression-free survival benefit of metastasis-directed therapy and ADT.
How do you discuss this with your colleagues or patients in terms of maybe it's not for everyone?
Kosj Yamoah: Exactly, exactly. So this is a very important concept where RADIOSA, I think, puts everything in picture.
Now, have I treated a few patients without systemic therapy? Yes.
What were those patients? These were patients that either had a intolerable reaction to ADT, they have a lot of cardiac comorbidities, they have other competing risk factors that makes the benefit of ADT in that scenario not as high as the competing risk factors. So in those patients, I'll just treat with MDT alone and we'll watch the PSAs, right?
So that's an easy one where the clinical picture just tells you that ADT is not adding much more benefit to them, and the lesions are basically something you can take care of with MDT alone.
In other scenarios as well that I've seen that being useful is where maybe the lesion is small enough that you want to make sure that that's the area that is actually causing the PSA recurrence. And by introducing ADT, it makes MDT a lot more difficult, right? And so you want to treat that lesion and watch the PSA to make sure that you've got the area that is of most concern.
And so there are scenarios like that that MDT alone makes sense, especially knowing that you can always go back to introducing ADT if needed, right?
But I think that this, in looking at studies that are looking at all-comers and having a SBRT, PSMAs, ADT, the details matter. What type of patients were they? Did they have high-risk features? Or were they patients that would actually not even want to recommend MDT alone in them?
And so these things, I think, with more studies and more long-term follow-up, be able to fine-tune that a lot better.
Leslie Ballas: Yeah. I often also just mentioned that progression-free survival in terms of months is very clearly linked to also the time that they're on the ADT. I mean, you have to make sure that patients and providers are really understanding that it's not eugonadal progression-free survival.
Kosj Yamoah: Exactly. Exactly.
Leslie Ballas: It's progression-free survival in patients who have testosterone suppressed.
Kosj Yamoah: Exactly. And that's a very, very important point, that's very, very because the goalpost is different, right? You have a patient that is eugonadal, and then you're measuring it for a patient that has to have a low testosterone, which eventually recovers, and then they're able to get those cancer cells reintroduced to testosterone. So where is that goalpost and position? So that's a very important point as well. And it's always important to look at the data carefully when analyzing these things.
And I'm not even sure if the... Quality of life is also very, very important in patients like that in terms of not just progression-free survival, but at what costs? And that's a very, very important component when introducing some of these treatment modalities for our patients.
Leslie Ballas: The other question I have for you, which I think you also touched on, is sometimes when we do feel the need to add ADT with MDT, the question becomes ADT alone, or ADT and ARPI?
How do you make that decision when you've got clearly oligometastatic disease?
Kosj Yamoah: So with the addition of ARSIs, I think a lot of it has to do with the concept of the factors that are discussed towards the end of the talk. What is doubling time of the PSA? Are there any high-risk genetic features? I think those things are very, very important. And what's the time from the appearance of the oligometastatic lesions? If I have a patient who, say, is oligorecurrent and within a year after treatment, they're having oligometastatic disease and I want to start treatments, I'm not comfortable not adding an ARSI because the clinical picture shows that this is somewhat more aggressive.
If the patient is 10 years out of treatment and has a node pop up or a little lesion that has taken so long to appear, maybe not, right? And so I think the clinical picture and also the emergence of the oligometastatic disease is very, very important when deciding that.
But I think all these patients who have genomic sequencing, I'm of the school where I think all these patients need to be sequenced, they need to see their somatic mutations or general mutations that really guide us better in how we add targeted agents.
Leslie Ballas: Well, thank you so much for taking the time to educate us on this and review this data with us. We really appreciate it, Dr. Yamoah.
Kosj Yamoah: Thank you so much, and it's been a pleasure being at this meeting, and just looking forward to having more conversations around this topic.