Alicia Morgans: Hi, I'm so excited to have here with me today Dr. Ana Aparicio, who is an Associate Professor of Medicine in the Department of Genito-Urinary Oncology at MD Anderson in Texas. Thank you so much for being here with me today.

Ana Aparicio: Thank you for having me.

Alicia Morgans: So Ana, you have really defined the world of aggressive variant prostate cancer transitioning it all the way from anaplastic through AR in different phases and aggressive variant I think really so well defines this phenotype that we see. Today, the PCF Annual Retreat, you gave just a really engaging and lovely talk about the journey that you've been on with this disease. I'd love to hear you review where we've been, where we're going and where we're going to go in the future. So where have we been?

Ana Aparicio: We all started with trying to understand the small cell prostate carcinomas, morphological variants of the disease that is known to not respond well to the AR targeted therapies and we were looking for small cell cancers. So everybody that walked in the door that had the atypical sort of virulent clinical features that are often associated with small cell carcinoma morphology, we would biopsy, expecting to find small cell morphology. And yet, what we found nine out of 10 times, was that there were heterogeneous morphologies that went anywhere from adenocarcinoma to poorly differentiated carcinoma without neuroendocrine features. So we then went back and said, "Well, what if we just defined the phenotype based on clinical features and clinical-pathological features?"

So that's what we did. We defined seven clinical-pathological criterias and if you met one of those, then we would treat you with platinum-based chemotherapy, which was the standard for a small cell carcinoma. Then we went back and we looked at those patient's tumor tissues and we defined a molecular signature. We went through a sort of copy number analysis and a lot of them immunohistochemistry. We actually paralleled that with studies in patient drive xenografts and we arrived at this signature of combined tumor suppressor defects. Actually, we sort of gained confidence in that signature by the fact that animal models show that any one of those tumor suppressors alone do not result in invasive or aggressive disease. But when you put two of them together, then you get the androgen indifferent disease.

So we got to the molecular signature and most recently, we just published the results of a trial that was led by Paul Corn in our group. We saw that this molecular signature really appears to identify the people that benefit from the addition of carboplatin to cabazitaxel chemotherapy. So people that have the signature have a significant improvement in progression-free and overall survival, and people that do not have the signature really don't have that benefit at all. So we're sort of taking it from there.

Alicia Morgans: So the signature, when I think about it in my clinic, I think about RB, p10, p53 and I think about using these when I'm doing sequencing on patients' tumor tissue to help me identify those patients who might be in this boat. Are you using the same features? Are you using other methods of identifying these patients?

Ana Aparicio: So we define the signature based on immunohistochemistry results and also genomic analysis. In that particular clinical trial, we use circulating tumor DNA. As I mentioned in my talk today, for now, this seems to be a signature that can discriminate a phenotype of prostate cancer. However, a lot of recent papers and we've known obviously, the biology's very complicated. I actually really enjoyed reading the FOXA1 papers by the [inaudible 00:04:23] group and you see how different genomic alterations in one gene can have such different phenotypic outputs. So clearly, we need to dig in deeper to really understand the diversity within the signature. But like I said in my talk, for now, this is a starting point. I think that with that we have enough to integrate this into our clinical and our basic research, which I think is critical. We have to stop thinking of prostate cancer like it's all one, same disease.

Alicia Morgans: Definitely agree with that. What steps is your group taking to take these findings to the next level?

Ana Aparicio: Well, as I was sort of discussing in my talk, I think we, obviously you have this point in time where you have the aggressive variant clinical features and like I said, it really feels like you're stopping this train that's coming down the tracks at very high speed. So what we're trying to do is we're trying to go a little bit earlier to early castration-resistant disease. I showed some data, that RNA sequencing of tumor biopsies from patients with early castration-resistant disease that had not been exposed to secondary hormonal therapies already distinguish different biologies and we expect one of them to be marked by this aggressive variant molecular signature. But even in the hormone-sensitive or castration-sensitive hormone naïve population, both in metastatic and in localized, we can find this signature.

So we're excited about trying to not just develop therapies for when you already have this full-blown aggressive phenotype, but if that program is already present early on in the disease and we can identify it, then we can implement these secondary prevention measures and stop it from actually occurring altogether.

Alicia Morgans: That would be phenomenal because it may be that there's... Earlier like we see with so many therapies, the earlier we intervene, the more we can prevent and the longer the therapeutic benefit. So I'm sure your team has clinical trials that you are rolling out perhaps in hormone-sensitive disease, perhaps in more advanced disease. What are these trials and where are you going?

Ana Aparicio: So I think we went from the chemotherapy, the PARP inhibitors, and clearly the piece that we have to integrate right now are the immunotherapies. Part of the data that I showed today is that what we expect are going to be the androgen in different disease are highly enriched in immune response genes. Our clinical experience tells us that these are patients or tumors that have a very immunosuppressive microenvironment. For starters, we know that chemotherapy is immunomodulatory and we want to see whether adding a checkpoint inhibitor, immune checkpoint inhibitor to the chemotherapy will enhance the immunomodulatory effects of the chemotherapy. Of course, as with all of our trials, we will be asking patients to donate their tumor biopsies so that we can really look carefully at what are the immune profiles that emerge and help us narrow down the targets and understand what combinations we should be putting together.

Alicia Morgans: Great. Well I really look forward to that and I know your center has done quite a lot of work on immunotherapies. You're just a hotbed of actually that activity. So I really look forward to the synergy that I'm sure will come from these approaches and the basic science that will help us understand which patients may benefit most. Your group is also very, very good at doing that as well. So if you had to give an overarching message or just take-home message to the clinicians who are trying to understand aggressive variant prostate cancer in their clinics and do the right thing for the patient, what would that message be?

Ana Aparicio: So I think you have to anticipate. There comes a point where you actually can... You can tell, they walk in the door and you can tell, not perfect accuracy perhaps, but you can tell. It's important to... There are some people that you can treat and see every three months and there are other people that you just have to be watching every month because you have to anticipate which way they're going to go. In the clinic, I think we have to be very vigilant and also be bold about using early combination chemotherapy. I think if you're worried, in my mind at least, it's better to err on the side of caution and treat that disease aggressively when you have evidence that there are some aggressive features. It's a delicate balance because we all have the other patients who do so well and you don't really want to burden them with all the toxicity of very aggressive therapy. So just to remain vigilant, I think that's an important thing.

Alicia Morgans: I think that's a great message and I think that we all look forward to your work for the characterizing, both the patients who may respond to these more aggressive approaches and your work really defining what these approaches might be, whether they involve combination chemotherapies and PARP inhibitors and immunotherapies at some point remains to be seen. But I have a feeling your group is going to be the group that shows us the way to go. So thank you for sharing your insights today. I really appreciate your time.

Ana Aparicio: Thank you.