Clonal Hematopoiesis Expansion Following 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer

Key Clinical Summary: 

• Design/Population: Randomized phase 2 TheraP trial in metastatic castration-resistant prostate cancer comparing lutetium-PSMA radioligand therapy with cabazitaxel; paired blood samples were analyzed for clonal hematopoiesis.
• Key Outcomes: Baseline clonal hematopoiesis rates were similar; post-treatment, lutetium PSMA was associated with higher clonal hematopoiesis mutation rates, larger clone sizes, emergence of new mutations, and dose-dependent clonal expansion.
• Clinical Relevance: ¹⁷⁷Lu-PSMA-617 promotes clonal hematopoiesis, including expansion of high-risk genotypes, supporting further study and consideration of longitudinal monitoring as radioligand therapy moves earlier in prostate cancer care.

Alexander Wyatt, PhD, University of British Columbia, Vancouver, Canada, discusses results from a post hoc correlative analysis of the phase 2 TheraP trial comparing ¹⁷⁷Lu-PSMA-617 with standard cabazitaxel chemotherapy in patients with metastatic castration-resistant prostate cancer.

Results demonstrated that patients who received ¹⁷⁷Lu-PSMA-617 experienced increased clonal hematopoiesis, supporting the earlier integration of longitudinal monitoring for potential long-term hematologic sequelae.

Transcript: 

Hi, I'm Alex Wyatt, I'm an associate professor at the University of British Columbia and the Vancouver Prostate Centre and cross-appointed at BC Cancer in Vancouver, Canada. I'm here to talk about a recent study that we published in Clinical Cancer Research where we looked at clonal hematopoiesis after patients received either lutetium PSMA or cabazitaxel in a randomized phase 2 trial. 

As you may be aware, clonal hematopoiesis is a state that's generally associated with aging of the hematological system but it is a risk factor for future hematological neoplasms, leukemias, MDS, and so forth. It's marked by mutations that you can detect in the blood, typically in the white blood cell populations, or even the cell-free DNA that's coming from the white blood cell populations, and these mutations can be at low levels in the blood or, particularly when there's high risk of future leukemias, can be at higher and higher levels. And you see them in genes that are associated with leukemias. Particularly, clonal hematopoiesis can fall in epigenetic regulators: DNMT3A, TET2, ASXL1, and others but, increasingly, you can see them in genes like TP53, PPM1D, ATM and there are some genotypes, particularly TP53, for example, that are particularly associated with progression from clonal hematopoiesis of indeterminate potential to myeloid or other blood-based cancers.

In prostate cancer, we haven't typically seen clonal hematopoiesis as a particularly big factor, or interacting factor, with oncological outcomes historically. We don't use DNA-damaging systemic therapies historically in prostate cancer, so our chemotherapies are taxane-based or we use hormone therapies so we haven't really seen that clonal hematopoiesis or leukemias have been a big sort of side effect of therapy. But in recent years, we've had a new class of therapies, which is now approved in late-stage prostate cancer and increasingly tested earlier in disease, and that's radioligand treatment. The flagship of that is lutetium PSMA and this works by delivering radiation, ideally just to the prostate cancer cells, but of course deals with some off-target radiation and there's concern about off-target effect on the bone marrow.

We asked a pretty simple question, is lutetium PSMA associated with an increase in clonal hematopoiesis, [are we] seeing more of those mutations that are associated with clonal hematopoiesis after treatment, or expansion of those existing ones that were present before treatment. And the way that we addressed this question was by going to a randomized phase 2 trial, and my group has been very lucky over the years to collaborate with the ANZUP team in Australia and they run a really great trial, sort of pivotal trial, called the TheraP trial where they tested lutetium PSMA against cabazitaxel in the third-line castration-resistant prostate cancer setting. Michael Hofman was the trial chair, and they've had countless publications on this over the years so I encourage you to look them up if you haven't already. One of the strengths of this trial is they collected blood samples before and after treatment so we were able to perform deep targeted sequencing on blood samples collected before treatment and after treatment and look at the clonal hematopoiesis that was present in both of those samples. 

What we saw was really quite dramatic, actually, it was that although we get similar levels of clonal hematopoiesis before you start treatment, after progression on lutetium PSMA we see far more of those clonal hematopoiesis mutations than we do after taxane-based cabazitaxel. We saw this whether you look at the number of mutations, or the number of patients affected by mutations, or the clone size of those mutations– all of these different metrics were greater after lutetium PSMA and there were even some very large clones that emerged out. It was also true that we saw brand new mutations that we hadn't detected before that may have been selected out by treatment and we also saw expansion of those ones that were present before. Interestingly, there was even a dose relationship where the more cycles of lutetium PSMA that an individual received, the larger the increase in those clone sizes over time.

What we weren't able to do with this study is look at potential clinical correlatives of these findings so we weren't able to say in these individuals that had large changes in clonal hematopoiesis, they went on to have either side effects from that or MDS or leukemias– that was not something that the trial was powered to assess and it's also quite a late line of therapy. We also weren't really able to look at any interaction with oncological outcomes, or at least we didn't see any difference there but I think, again, this wasn't a study that was designed for that.

What it does show is that this phenomenon is very pervasive after exposure to radioligand therapy and we think this matters because increasingly we're moving these treatments earlier in disease. We're testing actually even in a castrate-sensitive setting where many individuals will have life expectancies beyond 5 or even 10 years so in that setting, perhaps there is the possibility that we will see increased MDS, leukemias, or other adverse effects from this increased clonal hematopoiesis. And I think it really underscores that we need to learn more about this phenomenon that's arising in prostate cancer, really for the first time, and we also need to understand is there going to be any value in monitoring for clonal hematopoiesis. What constitutes a bad genotype or a big clonal hematopoiesis clone to detect, what's really a clinically meaningful clonal hematopoiesis finding. We don't know the answer to those questions yet, but I think our study hopefully underscores the urgency that we should go forward and start studying that earlier in disease.

Source: 

Munzur AD, Herberts C, Kwan EM, et al. Clonal hematopoiesis after ¹⁷⁷Lu-PSMA-617 radioligand therapy in prostate cancer. Clin Cancer Res. Published online: February 6, 2026. doi:10.1158/1078-0432.CCR-25-4001