But I want to stress that most of these concepts, I think, are applicable for other radioligand therapies, but also beyond prostate cancer. So starting with the ctDNA quantity, and maybe most of you know this, but the ctDNA quantity is actually related to all sorts of factors that associate with disease aggression. One of them is disease stage, which you can see here, but also for example, the extent of the metastases and where are these metastases? Are they in the liver, which often results in a lot of ctDNA, or are they only in the lymph nodes? But also markers of prostate cancer aggression such as PSA or LDH are associated with higher levels of ctDNA. And this is relevant because ctDNA is actually highly prognostic. So it's highly prognostic for overall survival, regardless actually, of what therapy you can give. And this systematic review actually highlighted that across all these studies in metastatic prostate cancer, you see this continuous prognostic impact of ctDNA on survival with higher levels of ctDNA associating with a poorer prognosis. And this is actually independent of these clinical factors where it associates with. But interestingly, ctDNA fraction may also be predictive in certain contexts. And an interesting context is actually in the context of radioligand therapy.
So this is the TheraP trial where we looked in circulating tumor DNA and patients were treated with either cabazitaxel or lutetium PSMA. And this is the primary results for the TheraP trial. But when we looked into the ctDNA quantity in this trial, what we observed was actually something that we may not have expected in the beginning. And that was that especially patients with a low quantity of circulating tumor DNA did very well on the lutetium PSMA arm compared to the cabazitaxel arm. Well, for the patients with a lot of ctDNA, so higher than 30%, for example, they did equally well on both therapies. And this resulted actually in a significant interaction, treatment interaction with ctDNA, and this was additive to PSMA expression by SUV mean measurements. But ctDNA is dynamic. We can measure it over time, and because it's minimally invasive, it actually allows us to measure it over time. And what we can see is that upon effective treatments, ctDNA can rapidly decrease. And good examples of this are in the hormone-sensitive setting for prostate cancer. When we initiate ADT, or we see already after days or a couple of weeks, we see this very steep drop in ctDNA quantities, but we can also see this upon ARPI initiation and castration-resistant settings. And many patients that benefit from therapy, we see that they convert to actually undetected levels of ctDNA within a few weeks. And this again is relevant also in the radioligand therapy space because what we observe, what we and others have observed also in other clinical trials is that with the treatments of radioligand therapy, after six weeks or after 12 weeks, we see that some of these patients convert to undetected levels of ctDNA and often they associate with a long progression-free survival.
While the patients that have detected ctDNA, even early on still in the treatment setting, they seem to have a very poor progression-free survival with a median of around three to four months, really indicating that this is a group of patients that might have limited benefits or even primary resistance to therapy. What I find very important, and I'm very enthusiastic about this, is that there's now multiple international efforts trying to see how ctDNA can be established as a monitoring response biomarker, not only for routine clinical practice, but also as an intermediate endpoint for clinical trials. And we really need to know how do we test and also when do we test and what is the added value to all these novel imaging strategies that we have for PSMA, PET imaging, for example. And then finally, I want to touch upon the characterization of ctDNA because we can measure this over time. We can take multiple blood samples so we can get this real snapshot of what does your tumor look like now? And we can look at the epigenetics, and I think many in the fields are now studying epigenetics more and more.
You can look at neuroendocrine differentiation, for example, but some clinically relevant genomic alterations, especially for prostate cancer, were also highlighted today. So of course we have the DNA damage repair genes, and I want to also stress that it's actually recommended to test both the germline and the somatic alterations in DNA damage repair, not only for radioligand context, but also for hereditary cancer patient prognosis and treatment selection. But then there is multiple actually genomic markers that we can look at that might be associated with poor disease, such as TP53 mutations or RB1 mutations, but these are also very relevant in the context when we start combining therapies. So we heard today from Dr. Shahneen Sandhu that we're now combining radioligand therapies with other agents, and these agents might be more or less sensitive to these genomic characteristics of the tumor as well. So we really have to take this into account. For radioligand therapy specifically, what we observed again in the TheraP trial is that actually PTEN alterations appear to derive a greater benefit for patients with PTEN alterations from lutetium PSMA compared to cabazitaxel.
While, for example, TP53 mutations were poorly prognostic regardless of treatments. And what was highlighted before as well is that ATM mutations, we saw some very promising responses on lutetium PSMA for ATM mutant individuals. And then finally, I want to highlight one more thing, and that is that we can look at all these tumor characteristics from liquid biopsies, but we can also look beyond the tumor, actually in the same blood tube. So there's also normal cell-free DNA in there, and a lot of that cell-free DNA is actually from our white blood cells. And clonal hematopoiesis, so that is the somatic mutations in our hematopoietic stem cell lineage that is common and it happens with age that you acquire some of these mutations in your hematopoietic lineage, but clonal hematopoiesis is actually also a risk of developing hematopoietic malignancies. And what we saw in the TheraP trial is that when patients started this trial, the amounts of clonal hematopoiesis was actually the same, whether they started on cabazitaxel or lutetium, but after they finished treatment, we saw much more clonal hematopoiesis events in the lutetium PSMA trial lutetium arm compared to the cabazitaxel arm. So considering this, not only liquid biopsies can help us inform on the tumor biology, tumor response, but actually might also give us some indication on what are the side effects of the treatment and which patients should we really keep an eye on or might be prone to develop a secondary malignancy.
And with that, I want to state my key takeaway, and that is that liquid biopsies, in my opinion, enable investigation into radioligand therapy response and resistance. And this field is rapidly expanding, I would like to say, and I think that liquid biopsies can really help answer some key questions. So thank you so much for your attention.