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Andrea Miyahira: Hi everyone. I'm Andrea Miyahira with the Prostate Cancer Foundation. Joining me today is Dr. Edmond Kwan, a postdoctoral fellow and medical oncologist at Vancouver Prostate Center. He just presented a poster at ASCO on circulating tumor DNA as a predictor for response to Lutetium PSMA versus cabazitaxel from the phase II TheraP study. Thank you so much, Ed, for joining me today.

Edmond Kwan: Thank you, Dr. Miyahira. It's an absolute pleasure to be joining you today. I really am thankful for the opportunity to present our study findings on behalf of my esteemed co-investigators.

Andrea Miyahira: So, TheraP was a phase II trial that compared Lutetium PSMA versus cabazitaxel. And so in this particular study, what were you looking at?

Edmond Kwan: Yeah, that's right, Dr. Miyahira. So, Lutetium PSMA-617 is now an established standard of care option in treatment-refractory metastatic castration-resistant prostate cancer. And we know this as part of the vision trial, as well as what we'll discuss today, the phase II ANZUP-led TheraP trial. But what we also know is that Lutetium PSMA is a very scarce resource. It's often given in specialized centers and with a number of different treatment options now in this disease space, I really think that we need more better prognostic and predictive biomarkers to improve and prioritize patient selection.

So in this particular study that we presented at ASCO this year, we wanted to understand in our research laboratory group led by Dr. Alex White, we're very interested in leveraging the wealth of information in circulating tumor DNA to identify predictive and prognostic biomarkers, not just to new therapies like Lutetium PSMA, but also existing therapies. So in this particular study, we were interested in a particular ctDNA variable known as ctDNA fraction, which you can think of as analogous to tumor fraction in tissue samples. So ctDNA fraction is the proportion of cell-free DNA that is tumor-derived. We were interested in understanding how ctDNA fraction relates to clinical outcomes as well as imaging variables.

Andrea Miyahira: Okay, thank you. So tell us about the patients in this trial. What were the samples collected and what were the correlatives tested?

Edmond Kwan: So the TheraP trial, as you pointed out before, was a phase II ANZUP-led randomized control trial in docetaxel progressive castrate-resistant prostate cancer testing Lutetium PSMA-617, versus the active control of cabazitaxel chemotherapy. One thing that's important to remember about this study on top of the active control arm is the use of dual imaging preselection using molecular imaging, not just PSMA PET but also FDG PET. In 2021, led by Professor Michael Hoffman, we presented the preliminary results and analysis from TheraP, which showed that Lutetium improved progression-free survival, biochemical response rates, objective response rates, and all under better tolerability and quality of life compared to cabazitaxel. So at ASCO this year, we looked at the baseline samples from 180 patients on the TheraP trial and quantified the amount of ctDNA fraction in these patient samples, and then stratified them into three different ctDNA categories, less than 2%, which we call undetected ctDNA, 2 to 30%, and greater than 30%. We then looked at the association between these ctDNA categories and clinical outcomes as well as imaging variables.

Andrea Miyahira: Okay, so tell us about your findings. Did ctDNA fraction correlate with patient outcomes or FDG or PSMA PET levels or treatment responses?

Edmond Kwan: I think the first key finding was the ctDNA fraction, which was 24% in the cohort and balanced across treatment arms. This is several fold higher than other historical metastatic castrate-resistant prostate cancer trials, especially in the treatment-naive setting. And then when you take a step back, this isn't completely unexpected. We know that these patients are heavily pretreated. All patients have had docetaxel, and 91% had prior novel androgen receptor targeting with the novel agents. But the primary finding that was most intriguing is that there seemed to be a strong link between ctDNA fraction and Lutetium activity and efficacy. In the high ctDNA fraction group, so the greater than 30% group, we saw no difference between outcomes, both biochemically or progression-free survival across the treatment arms. However, when we looked at the ctDNA undetected group, there was a disproportionate benefit to patients that received Lutetium PSMA-617 compared to cabazitaxel.

They had exceptional biochemical response rates, so it was 100% PSA-50 response in the Lutetium group versus just 58% in the cabazitaxel group. When we looked at PSA-90, it was even more striking. It was 87% in the Lutetium group and only 17% in the cabazitaxel group. This biochemical response, this deep durable biochemical response, really carried over to progression-free survival, which was 6.0 months in the cabazitaxel group, and 14.7 months in the Lutetium group. And that's an absolute difference of 8.7 months. When we looked at the hazard ratio, that equated to a hazard ratio of 0.12, which is a very compelling result. And importantly, these associations held up in a multivariable analysis when we incorporated PSMA SUV mean at baseline, which is arguably the strongest predictor of PSMA Radio-Ligand response. So all in all, I think what we have here is that ctDNA fraction is not only a prognostic biomarker, but may in fact also be predictive of disproportionate benefit from Lutetium PSMA Radio-Ligand therapy in imaging-selected metastatic castration prostate cancer.

Andrea Miyahira: Okay, thank you. That's so compelling. So what do you think ctDNA is actually measuring? Is it tumor burden or tumor growth rate, and can it indicate tumor heterogeneity?

Edmond Kwan: So I think ctDNA fraction is both a proxy for metastatic disease burden as well as intrinsic disease aggression. We know that patients with visceral metastases as well as a high number of bone metastases have a higher overall ctDNA fraction. What we were capable of doing within the TheraP study was to correlate ctDNA fraction with baseline imaging variables such as PSMA SUV mean, and importantly, FDG metabolic tumor volume. We were unsurprised to see that ctDNA fraction strongly correlated with metabolic tumor volume as assessed by FDG PET.

However, what was quite intriguing was the inverse relationship was seen with PSMA SUV mean. So at low ctDNA fraction, a high proportion of patients had high PSMA SUV mean. And in contrary as well, on the other side, we see that patients with high ctDNA fraction have low PSMA SUV mean. And this comes back to your point, Dr. Miyahira, about tumor heterogeneity. I wonder whether or not ctDNA fraction is telling us a little bit about tumor heterogeneity with regards to PSMA expression. Maybe the framework is that patients with low ctDNA fraction have more higher and more homogenous PSMA avid disease, and in high ctDNA fraction, we may be dealing with patients who are more genomically unstable, and are more likely to have discordance with regard to the PSMA and FDG imaging.

Andrea Miyahira: Thank you. So we've seen in other studies that ctDNA fraction can indicate treatment response to therapies such as ER-targeted therapies. So why do you think ctDNA fraction matters for some treatments such as Lutetium PSMA and maybe ER-targeted therapy, but not others like cabazitaxel?

Edmond Kwan: Dr. Miyahira, I think that's the million-dollar question. I think that one possibility is that the tumor proliferative rate may have an influence on whether or not patients respond to specific types of therapy. I'm reminded of a study led by Professor Kim Chi at the BC Cancer Vancouver, looking at abiraterone-enzalutamide crossover, and the sequential use of these agents in metastatic castration-resistant prostate cancer. What Dr. Wyatt and Professor Kim Chi found was that its in patients with low ctDNA fraction after progressing on abiraterone. Those are the patients that are most likely to respond to sequential enzalutamide, and perhaps that's what we're seeing here. Patients with low ctDNA fraction are going to be much more responsive to Lutetium PSMA Radio-Ligand therapy. The other possibility of a course is that these results that we showed at ASCO annual scientific meeting this year are completely context dependent. We may find that these results may not translate when we transpose these into earlier disease settings, as well as looking at studies that don't use the dual imaging tracer, including FDG PET.

Andrea Miyahira: Okay. Thank you. And are you evaluating any genomics from these patients?

Edmond Kwan: Absolutely. So to determine ctDNA fraction, we use a number of genomic alterations, including mutations, copy number alterations, as well as structural rearrangements. And we are definitely looking at clinical outcomes and a correlation and association with the tumor genotype. And there are some high candidates there that others have shown, such as DNA damage repair genes, alterations, as well as alterations in the PI-III kinase pathway.

Andrea Miyahira: Okay, thank you. And what are the next steps in your study?

Edmond Kwan: So, our lab has been mainly focused on genomics, but the next step, as others have shown, is that epigenomics may be really important as well. Through the support of a Prostate Cancer Foundation Challenge Award last year, we're bringing together a group of international investigators across Australia, the United States, as well as Canada, looking at two randomized trials, not just TheraP, but also the Canadian Cancer Trials Group PR21 study, looking at Lutetium PSMA-617 versus docetaxel. And we'll also bring together the large Peter MacCallum Cancer Centre ProsTIC registry to look at clinical outcomes in this context.

Andrea Miyahira: Okay. Well, I look forward to those studies. I think they'll be very informative. Do you have any final thoughts or take-home messages for our viewers?

Edmond Kwan: I think this is a very exciting time to be involved in biomarker research, especially with new therapies such as PSMA Radio-Ligand now coming to our patients. I'd like to thank several groups in particular that have been instrumental in making this study possible. The first, of course, is the TheraP trial management committee, as well as the ANZUP investigators, and of course, the patients and families that without them this trial and the study results would not be possible. The second group that I'd like to thank is the Prostate Cancer Foundation that have really been instrumental, especially with the PCF Challenge Award, in helping us move this work forward. And finally, from a personal standpoint, in terms of career development, I'm extremely thankful for the support of the ANZUP Synchrony Fellowship, as well as the ASCO Conquer Cancer Foundation Merit Award that I received to attend ASCO this year.

Andrea Miyahira: Okay. Well, thank you so much Dr. Kwan, for sharing this with us today.

Edmond Kwan: Thank you so much, Dr. Miyahira.