Alicia Morgans: Hi. I am delighted to have here with me today Dr. Ana Aparicio, who is a GU Medical Oncologist in the Department of Genitourinary Medical Oncology at MD Anderson Cancer Center. Thank you so much for being here.

Ana Aparicio: Thank you for having me. It's always a pleasure.

Alicia Morgans: Wonderful. Well, you are really, in my mind at least, the guru of this AR indifferent subtype of prostate cancer and helping us understand who are these patients and then think through after we identify them how do we best treat them because standard therapies, particularly AR-directed therapies may not be as effective. I'd love to hear you sort of just let us know as a field, remind us what are AR indifferent tumors and then we can talk about how do we think about approaches that you've been defining and continue to do with your work.

Ana Aparicio: Yeah, so I actually think that this is one of the most critical questions in the field. We really need to be able to divide or classify the disease into different biologies. I keep thinking we're trying to develop treatments and combinations for prostate cancer, putting them all into the same basket. It's a little bit, if you think about it, as if we were trying to develop therapies for acute myelogenous leukemias and we had chronic myelogenous leukemias in the same group of patients in a clinical trial. The effect gets diluted. So that's why my efforts have been to try to identify this one subset of the acute prostate cancers if you will, the ones that respond poorly to the available AR inhibitors and for which we really have very limited therapies. I think there's a lot of effort in that direction.

We saw at the meeting the effort to classify it with a luminal A, B, and the basal subtypes. So I think we sort of all sense the need and we're trying to do the same thing and I think various molecular signatures have been proposed to identify the subsets and eventually it'll come together and we will then be able to separate these prostate cancers for the rest. Then I think that will expose their unique therapeutic vulnerabilities and we'll be able to really build combination therapies that are effective. So I think it's exciting times and I think the field will change shortly in the next couple of years.

Alicia Morgans: As I think we're all excited to see, but if you're a clinician now and you're just trying to use the data that you have in your clinic, what are some of the features that you think about, the pathologic features, maybe some molecular features that you would use to identify this AR indifferent subtype just for clinicians who are trying to do it today?

Ana Aparicio: So when we started asking this question, the obvious subset to go look at were the small cell prostate cancers because those were classically, at least, AR negative and poorly responsive to AR inhibitors. So we started there and what we did is we were running a Phase II clinical trial and in order to put patients on that Phase II clinical trial, we had to have documentation of small cell morphology. So everybody that walked in the door and they would have the clinical features that we typically associate with small cell prostate cancers would get a biopsy. It turned out that nine out of 10 times, instead of having small cell morphology at the end of that needle, what we found was a variety of morphologies. It went from adenocarcinoma to poorly differentiated carcinoma without neuroendocrine differentiation to all sorts of different morphologies.

And yet, they still behaved as if they had small cell. They did just as poorly. You have to realize this was at a time, and you may be too young, but this was at a time when giving chemotherapy to prostate cancer patients was considered almost a sin. So to give them a platinum doublet was really not a good thing. So that's why we did a clinical trial and we said, "Look, if you have these aggressive features that are associated with the small cell morphology, we think you're going to do poorly and we think that you're going to benefit from platinum-based chemotherapy." That's what really started this concept of aggressive variant clinical prostate cancers. It was a clinical, a group of cancers that had heterogeneous morphologies and they had clinical features associated with small cell.

Then we went on to describe a molecular signature that identifies that we think characterizes these tumors and that in this latest paper of the randomized Phase II trial of cabazitaxel plus/minus carboplatin, we saw it seemed to predict for the benefit from carboplatin. So it's a work in progress. The clinical definition is not perfect. If it were perfect then we would be done and we wouldn't need to do anything else. But it does serve to enrich a population that has more virulent disease and what we think are more androgen indifferent features.

So the molecular signature also needs to be further refined and very much like the triple-negative breast cancers for example, they are set aside and apart from all the other breast cancers, but there's heterogeneity within them and I think we'll find that heterogeneity too. So there's a lot of work to be done, but I think we're making advances.

Alicia Morgans: Absolutely. Can you tell us a little bit about your clinical trial? It was the cabazitaxel plus or minus carboplatin and really saw some nice results.

Ana Aparicio: Yes. There have been many studies suggesting a benefit from platinum-based chemotherapies and prostate cancer and yet as has often happened in prostate cancer when we took it to a Phase III trial, the [inaudible 00:06:02] trial, it was a negative trial. And again, we felt that that was because we hadn't selected for the population that was going to benefit. So we embarked on this Phase II clinical trial with the idea that we may not find much of a difference in the overall population, but that we would find a difference in a certain subset of the disease that we sort of predefined. And sure enough, there was a small benefit and median progression-free survival, but it became really remarkable when you selected patients for these aggressive variant features. So that's sort of been our building block, the platinum combination with the platinum taxane is the backbone for this aggressive variant phenotype. We're doing a number of clinical trials.

One of them is the DYNAMO clinical trial that we presented in a poster at this meeting and there what we're trying to do is we're trying to show in a prospective clinical trial that these aggressive variant features are indeed associated with androgen indifference because we extrapolate from the small cells, but we haven't actually shown that in the aggressive. We've shown the platinum sensitivity but we haven't shown clinically the androgen indifference. So that's the work that's ongoing there. Then even though they benefit from platinum, the fact of the matter is the progression-free survival is still fairly short and the overall survival is far from being satisfactory. So to build on this therapy, we now have a trial where men with aggressive variant features, clinical and molecular features, will undergo treatment with chemotherapy and then they're randomized to observation versus olaparib.

Alicia Morgans: Oh, great.

Ana Aparicio: We're about 10 patients away from finalizing accrual. I think it's looking pretty promising, so I'm hoping that we'll be able to present those data either at ASCO this year or maybe next year. Then, of course, there's how do we add to the I-O therapies to that whole combo? That's the other piece that we'll follow up and that's our next trial.

Alicia Morgans: That's wonderful. So just to touch back to the study where it sounds like it's maintenance elaborate, that's really fascinating. You're selecting these patients based on ... What are the features for these patients to get enrolled in that trial?

Ana Aparicio: So the aggressive variant clinical-pathological features are, well, if you have small cell on a biopsy, then that counts obviously. That's what we're after. There's exclusive visceral metastasis, predominantly lytic bone metastasis is supposed to the blastic ones that are typical of prostate cancer. Relatively low PSA levels with respect to the tumor burden. So if you are someone that walks in at diagnosis or at symptomatic progression, that's symptomatic castrate-resistant progression and your PSA is less than 10 when you have more than 20 bone metastases, that's a sign of bad disease. Bulky primary tumors, bulky tumor masses actually are not typical of your garden variety prostate cancer if you will, but they present an aggressive variant disease.

As a side note, we think this is where the impact of the definitive treatment of the primary tumor in the site-directed therapies will be greatest. That's our hypothesis. Then there is a short response to upfront hormonal therapy. We have one that's high levels of LDH and CEA. So I think I went through all of the clinical-pathological features. Then, of course, there's the molecular features which we identify either by immunohistochemistry. We've used just labeling index, just counting cells because intensity is always difficult, and a genomic by DNA sequencing, copy number loss or mutation.

Alicia Morgans: Wonderful. So it's always nice to hear about the use of a PARP inhibitor approach in patients who do not necessarily have identifiable DNA repair defects. I think that your combinations and your patient selection are going to make this a really, really interesting trial for us because we know that there is this undefined BRCA-ness and so it'll be really interesting to see you help work on defining that concept.

Ana Aparicio: Yeah. One of the exciting things is that all of these trials have biopsies embedded in them and so we're looking at those to identify these markers and the biology associated with them.

Alicia Morgans: Wonderful. So as we wrap up, if you see a patient, and imagine you don't have a clinical trial, and I know you have many, but if you did not have a clinical trial, is there any patient in the mCRPC setting that you would say based on these features, and you've named them, based on these features, because you have so many, I actually think that I'm going to try not just cabazitaxel as your next line therapy, but cabazitaxel/carboplatin. Is there any patient that you would say that?

Ana Aparicio: Pretty much when anybody presents with one of those features, that's what I treat them with. I think certainly if there's an exclusive visceral disease, there's no question. I think if there is early progression to upfront hormonal therapy, I think that's another one that's a no brainer. Then symptomatic primary tumors, those people that walk in your door and have T-4 disease and metastatic disease, those people I think need upfront platinum chemotherapy.

Alicia Morgans: Great. Well, thank you so much for sharing your insights and really giving some clinically relevant guidance to people who are trying to sort through what is really, like you said, a hodgepodge, a heterogeneous population of patients that we all classify the same way, but I sincerely appreciate how you and your team are actually making sure that we sort through that heterogeneity to find discreet buckets so that we can personalize our treatment decisions for these patients. So thank you.

Ana Aparicio: Thank you.