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Andrea Miyahira: Hi, everyone. I'm Andrea Miyahira at the Prostate Cancer Foundation. Joining me today is Dr. Alexandra Sokolova, an assistant professor at Oregon Health and Science University. Dr. Sokolova's team just presented an ASCO poster that is looking at genomic alterations associated with response to lutetium PSMA. Dr. Sokolova, thank you for joining me today.

Alexandra Sokolova: Thank you for having me today.

Andrea Miyahira: Lutetium-177, also known as Pluvicto, was recently approved for patients with metastatic castration-resistant prostate cancer based on overall survival benefits in the VISION trial. Patients had to be selected for Pluvicto based on PSMA PET levels, but not all patients respond, and this suggests that we need better biomarkers to identify patients for this treatment and also to identify mechanisms of treatment response and resistance. So what was your team looking at in this study?

Alexandra Sokolova: In this study, we looked into a retrospective database that included some clinical genomic data to see if we could identify genomic alterations associated with primary resistance, secondary resistance, or a better response to Pluvicto. As you said, not all the patients respond, so we do need to look for better biomarkers to understand which patients do respond, which patients don't. So that was the main goal of this study.

Andrea Miyahira: Tell us about the patient cohort and also the timing of what tissues were collected relative to Pluvicto treatment that were evaluated for genomic alterations.

Alexandra Sokolova: For this study, we used a retrospective PROMISE clinical genomic database, which is a collaborative effort of multiple institutions led by Michigan University that included over 2000 patients in the database. Data in this dataset is abstracted by each site and includes any germline or somatic testing that was done, as well as the clinical and treatment information of the patients.

So we've extracted patients that had Pluvicto treatment done within this database. The timing of the tissue was before the Pluvicto, but because it was clinical testing, the timing varied. Some patients had it at the time of diagnosis of metastatic disease, some patients had it later in the disease state, so there was not a unified time point, but they all had it before their Pluvicto treatment.

Out of more than 2000 patients in the dataset, we identified 201 patients with metastatic CRPC that received Pluvicto treatment. The median age was 53, 21% of patients were non-white. As far as prior lines of treatments, over 50% of patients had at least two lines of ARSI treatment, a little less than 50% of patients had at least two lines of taxanes, and 11% of patients also had an ARSI treatment along with their Pluvicto treatment in our dataset.

Andrea Miyahira: Tell me about your most important findings and were there any genomic alterations that were predictive for outcomes or response to Pluvicto?

Alexandra Sokolova: As far as our overall survival, PFS, and PSA50 endpoints, they were very consistent with the VISION data. So our real-world data kind of confirmed the study-reported data. What we found is that patients with FGFR, MYC, and CDK12 alterations had less PSA50 response compared to patients without those alterations. We also looked at patients with tumor suppressor genes and found that they had worse overall survival and PFS compared to patients who did not have a tumor suppressor gene such as TP53, RB1, and PTEN.

Andrea Miyahira: Okay, thank you. And did you evaluate any associations between genomic alterations and PSMA levels?

Alexandra Sokolova: Unfortunately, in this dataset, we didn't have the tissue to look at PC/IHC and the data on PSMA PETs was limited. As you know, there is not a uniform way to record yet the PSMA uptake and SUVs, but this is something that our team is looking at as the next steps.

Andrea Miyahira: Do you have any hypotheses for why CDK12, MYC, or FGFR receptor were associated with responses to Pluvicto?

Alexandra Sokolova: All those three alterations have been reported to be associated with the worst outcomes in prostate cancer, worse overall survival, and resistance to existing treatments. So my hypothesis is that this is just reflective of a kind of poor phenotype of prostate cancer and poor response, but something we'll have to investigate further and as we'll get more patients in our dataset to see if the signal holds through.

Andrea Miyahira: Thank you. So alterations in the tumor suppressor genes PTEN, RB1, and TP53 are associated with aggressive variant prostate cancer and NEPC, which are also associated with loss of PSMA levels and poor response to Pluvicto. So did your team look at NEPC or AVPC markers in this cohort?

Alexandra Sokolova: Unfortunately, those markers were not available in this cohort, but I absolutely agree with you. The data does suggest that NEPC might have a lower response to Pluvicto and that would kind of be aligned with what we saw in our dataset, but something that we need to investigate further.

Andrea Miyahira: Thank you. So what are the next steps in your study and what do you think is needed for genomics to be used to select patients for Pluvicto?

Alexandra Sokolova: As far as our next steps, our teams are working on inputting more patient data into our dataset. We only have 200 patients at this point, but I think as a collaborative effort, we can significantly increase this number. We're hoping to have a large cohort of patients with Pluvicto and genomic data to validate some of the signals we saw and investigate others. For example, early data by Tagawa et al. reported that patients with HRD mutations have a better response to Pluvicto because it is a DNA-damaging agent. We did not see that signal in our database, and we would love to continue investigating with a larger sample size if that would change or not. Another hypothesis, data presented by Schweizer et al. showed that patients with ATM mutations had a higher response compared to all the HRD. Again, we would like to investigate when we have a larger sample.

As far as next steps for the field overall, I think we do need to look in a more prospective manner where we take the tissue and we take the tumor sequencing at the time of Pluvicto initiation and at the time of Pluvicto progression so we can understand the mechanisms of primary resistance, the mechanisms of secondary resistance, and see what's driving that so we can select patients better for this treatment. It is a life-prolonging treatment, it is FDA approved, but yet only about half of patients respond. And so it would be great to know which ones are more likely to respond and which ones are less likely to respond.

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

Alexandra Sokolova: Pluvicto is an FDA-approved treatment that prolongs life, but we do need to understand better which patients respond and which patients do not respond. Tumor testing is really important for patients. Both the tumor testing and germline genetic testing are important and should be offered to patients with metastatic prostate cancer. In our dataset, we show that patients with tumor suppressor genes had shorter PFS and shorter overall survival, likely reflective of just being a worse phenotype of prostate cancer with a poor response to treatments. We also saw the signal that MYC, FGFR, and CDK12 had less of a PSA response from the dataset. Something we're going to keep investigating and looking further.

Andrea Miyahira: Okay. Well, thank you so much, Dr. Sokolova. I really appreciate you sharing this with us today.

Alexandra Sokolova: Thank you.