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Neeraj Agarwal: Welcome to UroToday. My name is Dr. Neeraj Agarwal. I'm a professor of medicine and director of Genitourinary Oncology Program at the Huntsman Cancer Institute, University of Utah in Salt Lake City. I'm very happy to welcome Dr. Martino Pedrani, a medical oncology trainee at the Oncology Institute of Southern Switzerland, who just presented his data at the ASCO GU 2025 Symposium on the presence of high-risk mutations in patients with aggressive variant prostate cancer, and how this may allow us to modify therapies to customize prognostication for these patients.

So, first of all, congratulations, Dr. Pedrani, for presenting at the ASCO GU Meeting. And thank you for sharing your data with us today.

Martino Pedrani: Thank you very much for having me here for this invitation. So this is the title of my presentation. So it's Integrating Aggressive Variant Prostate Cancer–Tumor Suppressor Gene Status to Refine Prognosis and Predict ARPI Response in Metastatic Hormone-Sensitive Prostate Cancer. So we will speak about the background briefly and the objectives.

And then I will show you the results about the impact of this alteration on PFS and OS in metastatic hormone-sensitive prostate cancer patients and the impact of the status of these alterations in predicting the PFS benefit from ARPIs. So, as we know, in metastatic hormone-sensitive prostate cancer, the treatment is currently guided solely by clinical factors. So usually, we use the high or low volume definition, the presentation, the type of disease presentation, and we do not take into account the presence or absence of any of the genomic alterations.

As you can see on the left, these alterations in TP53, RB1, and PTEN change their prevalence across the prostate cancer stages, with higher prevalence of particularly RB1 and TP53 in the castration-resistant setting. They have been associated with resistance to hormonal treatments and with an aggressive disease in the castration-resistant prostate cancer settings. On the right, we have just an example of the data that we are accumulating on TP53 in the last 10 years.

In our study, we tried to see if any alteration in one of these three genes could predict the response to ARPIs and the prognosis. As you can see in the Table 1, there were no associations between the presence or absence of these alterations and any clinical relevance variable, like the tumor volume, or the Gleason score, or the other relevant clinical variables.

On the left, you can see that on both the univariate and multivariate Cox analysis for PFS, the presence of these alterations correlated with lower PFS and higher risk of progression and death. Then we tried to integrate the alteration status with the clinical variables. Here, I present just the integration with the CHAARTED volume criteria. As you can see, if you account for CHAARTED high-volume or low-volume, and for the presence or absence of any of these alterations, you can very well split both OS and PFS curves.

And we identified a group of patients with low-volume disease and TSG wild type alterations that were still alive in more than 70% of cases at seven to eight years from treatment start. Conversely, patients with at least one alteration in these genes and high-volume disease had a very poor prognosis with a very high risk of progression or death.

Then we went to see if there were some association between this alteration and the response to ARPIs. As you can see in the overall population on the left, in Figure A, ARPIs confer a benefit in the overall population. However, if you split the population with the alteration in TSG, you see that only the TSG wild type patient population could derive a real clinically relevant benefit from ARPIs.

When you then integrate this alteration with the clinical variables, you also identify a patient population who really go so well even without ARPIs that it probably does not need ARPIs. And we can identify [INAUDIBLE] certification part of these patients, and also a population with very aggressive disease that, even if they have a very high risk of progression, they do not seem to derive a benefit from addition. Conversely, the intermediate group that is very enriched from an aggressive variant TSG wild type population seem to derive an even higher benefit from ARPIs.

So our conclusions were that we need to integrate next generation sequencing analysis already in the hormone-sensitive setting because it can help us with prognostication. Also, we can predict the response to ARPI. Obviously, we have to verify this data in a prospective way, but the idea is that patients with AVPC–TSG wild type and low-volume disease might be the perfect patients for de-escalation strategy. So we can integrate this alteration to identify, also, the perfect patient population for clinical trials and the best patient population for de-escalation strategies. So I really thank you for this invitation.

Neeraj Agarwal: Thank you for sharing this data. So it looks like you had about 150 patients with metastatic hormone-sensitive prostate cancer. And about 40% of these patients had TSG alterations. And about 60% of these patients did not have tumor suppressor gene alterations on the NGS testing. And the data are intriguing as far as combining these results with the clinical findings are concerned.

So just for the sake of summarizing for our viewers today, patients who have low-volume disease and did not have any of these alterations, they do exceptionally well. They are alive for years, more than five years. They are doing very well. Patients with high-volume disease and if they have these TSG alterations, they don't seem to benefit with the ADT combination therapy with ARPI. And looks like they may need something else. Maybe upfront enrollment in clinical trials.

So it looks like the presence or absence of these tumor suppressor gene mutations may be complementing very well the preexisting clinical characteristics, which have been used to define the prognostication and partly selection of therapies in the past. Would you agree?

Martino Pedrani: Yes, absolutely. Probably the very interesting thing is also to see which—in the patients that are AVPC wild type status, we can also study which are the alterations these patients have. Probably, they could have SPOP mutations, or some other mutations that can confer a higher benefit from androgen deprivation therapy alone. So it's intriguing, and it's interesting to see what these alterations are hiding behind them.

Neeraj Agarwal: I agree. Right now, I'm obviously testing all my metastatic hormone-sensitive prostate cancer patients with NGS testing. And at this point, I agree with you. If I see these tumor suppressor gene alterations—TP53 loss, PTEN loss, RB1 loss—I definitely use them in my counseling of patients. I really hope that we saw the press release on the CAPItello trial showing that capivasertib, which is an AKT inhibitor, showed efficacy in—obviously, we don't have the full manuscript or the approval, but just based on the press release, it showed improved efficacy, met the primary endpoint, and we may have something available for our patients with PTEN-deficient prostate cancer.

And of course, NGS testing may facilitate identification of those patients who may need testing for PTEN loss by IAC testing. But this is just a start. We just had a discussion with another guest at the UroToday video that there are other underlying genomic mutations which can allow us to select for more therapies, such as PARP inhibitors, in metastatic hormone-sensitive prostate cancer.

So in your practice, do you test every patient upfront whenever you see them, or you wait to test them? That's the first question. And second, when you test them, do you obtain comprehensive genomic profiling, or you look for certain mutations?

Martino Pedrani: So in our practice, we try to test all the patients in the metastatic hormone-sensitive setting. We are not testing the localized patients. But in the patients with metastatic hormone-sensitive prostate cancer, we try to test them from the beginning. Then we are not yet very influenced by the results to choose the treatment. But what we would like to do is to understand if this data could be confirmed in another data set, or prospectively, because we really believe that this alteration could guide treatment.

Neeraj Agarwal: Yeah, I agree with you. We don't have prospective validation, but based on what you just presented and many other studies in this context, I have no doubt that these data help me in counseling my patients in how often I should do scans, how often I should be following them in my clinic because many of these aggressive variant prostate cancer may have quick disease progression, and some of these patients may not have a proportionate rise in the PSA level at the time of disease progression.

So I personally think these data are very valuable, the data you just presented, because they do help me in prognostication of my patients and how I follow them in my clinic. But beyond that, I think we may have a drug or some drugs available for these patients based on underlying genomic testing. So I agree with you. We should be testing these patients upfront in metastatic hormone-sensitive prostate cancer because these patients may not have time to get tested down the line.

Sometimes, their disease progresses so quickly. And though we may lose the tissue, the quantity or quality of tissue down the line, do you test for multiple mutations upfront, or you specifically look for these tumor suppressor gene mutations?

Martino Pedrani: No, we have a good panel with 161 genes. So we can test at least also SPOP alteration, and MET alterations. So we have the opportunity to test at least 160 different genes. And the next step will be to see which are the alterations we have found in AVPC wild type and altered population.

Neeraj Agarwal: Comprehensive genomic testing.

Martino Pedrani: Yeah, exactly.

Neeraj Agarwal: I agree with you. I think that should be the approach because studies have shown from the lung cancer literature that when patients were having point testing for a few mutations when they really needed to be tested for more mutations down the line, tissue was exhausted. The doctors could not get hold of the tissue because the tissue was already exhausted for those point tests. So I think we should be testing early. That's the message.

We should be testing comprehensively—that's the second message—as many genes as possible. And third, right now, these testing results have huge implications on how we prognosticate and follow up these patients, but we may have agents available, therapeutic agents available, based on the testing results. So thank you very much, Dr. Pedrani, for joining us today. Congratulations to you and to your mentor, Dr. Silke Gillessen, and the whole team at your institution. So thank you.

Martino Pedrani: Thank you. Thank you very much for this invitation. Thank you.