Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today a great friend and colleague, Dr. Petros Grivas, who's an Associate Professor of Medicine at the University of Washington and a GU medical oncologist at the Fred Hutchinson Cancer Center in Seattle, Washington. Thank you so much for being here with us today, Petros.

Petros Grivas: Thank you so much, Alicia, for inviting me. We're very excited about ASCO GU coming up.

Alicia Morgans: Wonderful. Yes. And I understand that there are two abstracts that you and the team have put together. Can you tell us a little bit about the first one?

Petros Grivas: Sure, absolutely. I'll try to give a brief summary. So I'll talk first about the genomic landscape of CDK12 metastatic castration-resistant prostate cancer. This is a work that we did together with many colleagues in academic centers from Europe, United States, in collaboration with Foundation Medicine. This is a cohort of patients, about 5,000 patients, with metastatic CRPC, castration-resistant metastatic prostate cancer. And we try to evaluate the incidence of CDK12 mutations in those patients and do a broader, systemic, comprehensive genomic profiling of those tumors to identify concurrent alterations that happened in those mutated cancers and see whether there's a rationale or a foundation for a combinatorial strategy in terms of target therapies and clinical trials in this challenging disease.

So, overall, about 6.4% of the cases had a mutation in CDK12. Interestingly enough, those cases with the CDK12 mutation had a lower frequency in other common alterations in this disease. For example, lower incidence of the TMPRSS2 ERG fusion, as well as less incidence of p53, PTEN, ATM, PI3KCA, BRCA2, and APC alterations. At the same time, those cases with the mutations CDK12 had a higher frequency of sighting B1, BRAF, and HER2 alterations, as well as changes, alterations, in the MDM2, MDM4, and CDK4, CDK6 genes.

Overall, the cases with CDK12 mutations featured more frequent MSI-high status. Of course, MSI-high remained a relatively rare phenomenon, a low instance phenomenon in this disease. And that's relevant because in those very few patients with MSI-high status, we may use checkpoint inhibitors to treat CRPC and there was a slightly higher distribution of tumor [inaudible] scores in those cases with CDK12 mutation. However, overall, as we know, the incidence of MSI-high remains low and the role of TMB is also overall relatively low in terms of the high TMB cases. So only a few patients can be candidates for checkpoint inhibitors in this setting.

I think the practical implications for this study may include clinical trial designs that may co-target CDK12 with other genomic alterations. And I want to point out here, we have the opportunity of the upcoming ComboMATCH trial that is driven by the NCI and other corporate groups that is going to evaluate several different combinations of targeted therapies. So I think this study that we're presenting at ASCO GU is an example of how we can approach the genomic landscape of different tumor types. In this case, metastatic CRPC, to potentially inform combinatorial designs of clinical studies in this setting.

Alicia Morgans: I think that's great. And I think that we, as a field have been thinking about CDK12 for a little bit of time now, wondering whether it may be associated with DNA repair defects, whether it might be associated with this higher MSI-high status, if that was more frequent. There were definitely some case reports. I remember a few years ago where patients might have responded to things like pembrolizumab without necessarily having MSI. Though of course, you wonder maybe they missed the MSI if their assay for that was not as good. Because, in subsequent reports, and of course, just people talking, it doesn't seem to be in itself something that can sensitize these patients to things like pembrolizumab.

But I really appreciate the understanding, now, of the incidence of this particular mutation. Or, I should say, the prevalence of this mutation in our population, so that we can then, as you said, design trials. And really just to emphasize that ComboMATCH, I think might be a great direction for this particular alteration. So thank you for sharing that. And I think that there's definitely more to come on the CDK12 front, and you've certainly added.

And then the second abstract that you have at GU ASCO 2021 is this HHV8-positive mCRPC subset. And that I think is really interesting. I've not heard the HHV8 story before. Can you tell us a little bit about that?

Petros Grivas: Absolutely. You know, there has been this notion about potential additional mechanisms of prostate cancer, pathogenesis, and development, as well as a development of resistance to therapies. And there's all this notion that sometimes prostate cancer cells may have an androgen-independent growth mechanism. As we all know, at least the minority of the cases because we know that even in CRPC anti-androgen therapy and androgen deprivation therapy are still significant cornerstones of treating those cancers.

In this particular poster that we have, in this study that we did with collaboration with many colleagues in the U.S., in Europe, in collaboration with Foundation Medicine, we performed comprehensive genomic profiling in about 5,000 patients with metastatic CRPC. And we tried, number one, to assess the incidence of the HHV8 sequences present in CRPC cases. So whether there is the presence of this herpesvirus 8 in patients with prostate cancer.

And we found a small proportion, about 3% of those cases harboring HHV8 sequences. There is some data suggesting that this virus, that can be detected in also normal prostate tissue, has been linked to this potential acquisition of androgen-independent growth of prostate cancer cells in vitro, and potentially the development of anti-androgen therapy resistance. So we're interested in evaluating this incidence, as I told you, only about 3% of those cases harbored HHV8 sequences. The age distribution was similar in patients with and without these sequences. And interestingly enough, in patients, in cases, where HHV8 was sequenced, there was a slight reduction in other alterations. For example, other genomic alterations in the androgen receptor, specifically amplifications in the androgen receptor, [inaudible], were slightly reduced in the cases with HHV8 positive sequencing detection. Moreover, there was no significant difference in the genomic alteration frequency in other genes, for example, BRCA2, ATM, CDK12, PTEN, and others.

So, I think it's interesting to see this potential difference in the frequency and the incidence of those genomic alterations. And, generating a hypothesis here, whether in this very, very small proportion of patients could be opportunities for other targeting. And in terms of potential biomarkers associated with immunotherapy response, we looked at MSI status TMB and PD-L1 expression, and we did not find any major differences between those cases with and without the HHV8 sequencing detection. So overall, this is a hypothesis-generating study, trying to, again, scratch the surface and evaluate whether HHV8 might represent a rare subtype of prostate cancer, and do we need to do further studies to evaluate and validate the findings. And then we can tease out any particular opportunities for targeting, for example, PARP inhibition in those cases, especially targeting DNA repair chains. This is a work in progress, but we're very excited to present the early findings in this process.

Alicia Morgans: I also love this, and I appreciate you sharing this with us. I do think that, as you said, work to be done and lots of groups to collaborate with on this, certainly Ana Aparicio, Himisha Beltran. These are people who have been looking into these androgen-independent signatures for a long time. And like you said, just scratching the surface, but finding something new to add to the field. Is there anything you do not do, Dr. Grivas? It's always so impressive to talk to you, and I always learn from hearing what you're looking into. So as you think about this small portion of what you're going to be doing at GU ASCO 2021, what are your closing remarks or summary for those who are listening?

Petros Grivas: I think it's teamwork, obviously when you want to go far in science you work with great teams. So the kudos goes to the teams who do the work. I just want to make a quick comment for the previous subset that I mentioned, the CDK12. Obviously, there's a lot of data discussing the potential or no potential use of immunotherapy in PARP inhibition of those cases. And I also want to point out that in addition to the ComboMATCH, there is also the opportunity of the iMATCH, which is another NCI-driven trial looking at immunotherapy-based combinations. And I think the dilemma is still there regarding the role of immunotherapy CDK12 mutations in prostate cancer. But I think opportunities for clinical trials like ComboMATCH and iMATCH immunotherapy-based combinations are also great to evaluate opportunities for targeting these targets in the future, in this challenging disease. And overall, I'm very excited about ASCO GU 2021, despite being virtual, we're seeing great data. And looking forward to more discussions with you, Alicia.

Alicia Morgans: Wonderful. Thank you so much for your time today, Dr. Grivas, and I look forward to hearing more in the future. Take care.

Petros Grivas: Thank you.