Andrea Miyahira: Hi, I'm Andrea Miyahira at the Prostate Cancer Foundation. I'm here at ASCO 2025. Joining me is Asli Munzur, a graduate student in the lab of Alex Wyatt at the Vancouver Prostate Center. Thanks for joining us today.

Asli Munzur: Thanks for having me.

Andrea Miyahira: So clonal hematopoiesis is a disorder caused by mutations in blood cells, and this is generally associated with an aging-related phenomenon. However, it is hypothesized that certain cancer treatments, particularly those that cause damage to DNA, can increase these mutations, which increases risk for secondary leukemias and lymphomas.

So you presented a study here in the oral abstract session on your study, looking at cell-free DNA and how you can use that to measure risk for clonal hematopoiesis in patients who have received lutetium PSMA versus other treatments. So tell us about the rationale for that study.

Asli Munzur: As you mentioned, clonal hematopoiesis is an aging-associated condition, which is a known risk factor for future blood disorders, but we don't really know much about its prevalence in prostate cancer and what it may mean clinically for patients and providers as well.

We know from other solid tumors and preclinical models that external radiation and DNA-damaging systemic treatment does increase the risk of clonal hematopoiesis and future blood disorders as well.

And given lutetium PSMA is a new standard of care in mCRPC, we wanted to understand what it means in terms of increased risk of developing clonal hematopoiesis, so we hypothesized that lutetium PSMA would lead to an increase in clonal hematopoiesis prevalence compared to the alternative standard of care, which would be cabazitaxel chemotherapy, and we tested this hypothesis in the TheraP clinical trial.

So TheraP is a concluded phase II clinical trial that was led by doctors Michael Hoffman and Ian Davis as part of the ANZUP Cancer Trials Group. And actually the translational Chair of the trial, Dr. Arun Azad, had the vision to embed blood collections throughout treatment.

So they collected blood first at baseline, so before exposure to either treatment agents, and later at progression, and we obtained those bloods. And we applied our ultra-deep, error-corrected DNA sequencing research assay, which can help us characterize clonal hematopoiesis at both blood collections.

And a major strength of our approach was that we required mutations to be detected in both the cell-free DNA and the white blood cell DNA as well.

And this approach was necessary because we know mutations in prostate cancer and clonal hematopoiesis could really overlap, especially in the DNA damage response genes. So without having a control, which would be the white blood cell collections, it would really be hard to delineate the source of origin of a mutation, but using this dual-source approach, we could confidently assess the clonal hematopoiesis status.

And overall, our goal was to explore how the clonal hematopoiesis landscape changed throughout treatment and compare it back to baseline and essentially ask the question, how does clonal hematopoiesis look different in lutetium compared to cabazitaxel chemotherapy?

Andrea Miyahira: And what were your most important findings? Did you see a difference in clonal hematopoiesis between lutetium and cabazitaxel?

Asli Munzur: Yes, we indeed did see a difference. So at baseline, first of all clonal hematopoiesis was prevalent. We found that 76% of the patients at baseline carried some form of clonal hematopoiesis, which would be expected given the median age of 72, and this does not necessarily mean that there's a potential risk of future blood disorder for these patients.

And importantly, there was no difference at baseline in terms of prevalence of clonal hematopoiesis between treatment groups, so we know that.

But later at progression, we saw that lutetium PSMA was associated with about three times higher risk of developing clonal hematopoiesis. And not only that, lutetium also leads to a clonal outgrowth of both new and already existing clonal hematopoiesis mutations in both established clonal hematopoiesis genes, like DNMT3A, TET2, and ASXL1, but also, importantly, in DNA damage response genes as well, including things like ATM, CHEK2, TP53, and PPM1D.

87% of these mutations expanded with lutetium PSMA compared to cabazitaxel, which was only 33%. And we know expansions in these genes from other research, we know that it's an increased future risk for blood disorders.

Andrea Miyahira: So of the clonal hematopoiesis mutations that you found, what is the increased risk that they confer for secondary malignancies?

Asli Munzur: So to understand and have an idea about the future risk of hematological malignancies, we can think of it in terms of three categories. But having said that, I think there's still a lot that we don't know about what triggers a mutation to undergo malignant transformation. So a patient could be high risk, but they could be absolutely fine.

So the first one is asking, is it a point mutation or is it a larger-scale chromosomal abnormality like large-scale insertions, deletions, or transversions? Those are usually more aggressive, and they tend to affect the lymphoid lineage more frequently than the myeloid clonal hematopoiesis.

So our research assay was designed to characterize point mutations and small-scale insertions and deletions within the myeloid sphere of clonal hematopoiesis. And secondly, the gene identity is also quite important.

We know mutations in certain genes confer a higher risk of future malignant transformation. We know mutations in DNA damage response genes have a higher risk, and here PPM1D seems to be the key player.

Case reports of secondary malignancies after lutetium PSMA point to mutations in PPM1D, and interestingly, it was also the most frequently mutated gene in lutetium-treated patients as well. We found that lutetium was associated with about 5.4 times higher risk of developing a PPM1D mutation, with some patients developing multiple variants at once. So we do know that's a risk factor.

And the last one is looking into the fraction of blood cells affected by clonal hematopoiesis. Naturally, the more cells that carry the mutation, the risk is going to be higher for future malignant transformation.

Usually, the field accepts a variant allele frequency higher than 10% to be really high risk for future malignant transformation, which would represent about 20% of the leukocytes carrying the mutation.

And we certainly had some patients that did have large-scale clonal hematopoiesis in their blood in high-risk genes, but what triggers it to undergo malignant transformation is currently unclear.

Andrea Miyahira: OK, thank you. And we've only been giving lutetium PSMA for a few years now, but what has been observed so far about the actual prevalence of secondary malignancies in patients that have received lutetium PSMA?

Asli Munzur: So yes, hematological adverse events are prevalent with lutetium PSMA. Things like thrombocytopenia or secondary malignancies have been observed. Currently, there are no studies that evaluated bone marrow changes following lutetium PSMA, but we do know that case reports of lutetium PSMA and other radioligand therapies like lutetium dotatate have noted secondary malignancies and myelodysplastic syndrome as well, but I think the question is still there.

And interestingly, these case reports do point to PPM1D mutations and high-risk clonal hematopoiesis events in a variety of DNA damage response genes, so we at least do have an idea about what is high-risk clonal hematopoiesis versus what may not be so urgent to look into immediately.

And what I think is really interesting is that these case reports that reported secondary malignancies reported that in patients that are exceptional responders to lutetium PSMA. So these patients have received more treatment compared to someone who did not derive as much benefit from PSMA, and they were also followed up longer.

I think this really speaks to the fact that the transformation of secondary malignancies is really a long-term risk that we may not be able to see immediately in our patients.

Andrea Miyahira: So right now lutetium PSMA is only approved for patients with metastatic castration-resistant prostate cancer, which is a pretty late stage, but we're testing it earlier and earlier. So as we move it forward, even as neoadjuvant therapy in trials, what risk for secondary malignancies should we be thinking about?

Asli Munzur: This is the key question, yes. I think as we're moving from using lutetium PSMA as a palliative tool to more of a long-term disease management tool, I think the quality-of-life concerns are going to be more prevalent.

Because, of course, when you're talking about localized disease or hormone-sensitive disease, of course, life expectancy is much longer, sometimes from 5 to 10 years. So maximizing survival is, of course, very important, but I think we're also going to start thinking about how to maximize quality of life in these patients as well.

And as we're constantly improving cancer-specific survival, the comorbidity of those hematological adverse events could be really considerable. And as I've mentioned, the risk of myelodysplastic syndrome or secondary malignancies is a really long-term risk, which is usually beyond the duration of follow-up in most of the lutetium PSMA trials. So I think in order to understand the true rate of blood disorders following lutetium PSMA, long-term surveillance is going to be the key.

And as we have more data to understand what is high-risk clonal hematopoiesis versus what is not, we could even start thinking about developing risk stratification strategies, or even biomarkers to understand who should be followed up closer—perhaps more frequently, perhaps in the longer term—versus who perhaps does not need as close of a follow-up?

But I think overall, to ensure safety and benefit from radioligand agents, long-term follow-up is going to be the key.

Andrea Miyahira: OK, thank you. And what are your next steps in these studies?

Asli Munzur: So we're going to continue asking, what is the clinical relevance of clonal hematopoiesis for patients and also providers? We're also running other studies looking into different agents in prostate cancer like PARP inhibitors, which are also DNA-damaging agents and are known to be a high risk for future malignant transformation as well.

And we're going to continue exploring this further to see what does it mean if you have clonal hematopoiesis and are receiving lutetium PSMA treatment?

Andrea Miyahira: Thank you, and do you have any final take-home messages for our viewers?

Asli Munzur: Yes, so this study was funded by a Prostate Cancer Foundation Challenge Award—we're of course deeply grateful for their support. And also this was a collaboration, a really great one between the ANZUP Cancer Trials Group and my institution, Vancouver Prostate Center. I'm deeply grateful to my colleagues in both institutions.

And my final message would be, as lutetium PSMA has transformed the landscape of prostate cancer, I think to ensure treatment benefit and safety, long-term follow-up and, perhaps at some point, genomic stratification of patients is going to be the key to ensure safety in the radioligand era.

Andrea Miyahira: Well, thank you so much for this study and for presenting it to us today.

Asli Munzur: Thank you for having me.