Alicia Morgans: Hi, I'm excited to have here with me today, Dr. Cora Sternberg, who's a professor of medicine at Weill Cornell in New York. I'm so excited to have you here.

Cora Sternberg: Alicia, it's really a pleasure to be here.

Alicia Morgans: Oh, well thank you. So Cora, you just led an entire session on castration-resistant prostate cancer (presentations by Scher, Hussain, Higano, Taplin, Halabi) here at the APCCC 2019, so can you tell us a little bit about how the session went and what were the highlights that you want us to think about as we manage patients with this disease?

Cora Sternberg: I think it was the longest session of the meeting and it was a very interesting session and it just shows you that how things are changing and moving very rapidly in this field. That's why it was such a long session with so many new things. I mean, the first part of the session focused on non-metastatic CRPC and we had a lot of discussion about what is the definition of non-metastatic CRPC and everyone seemed to agree that by definition it should be patients with a rapidly doubling PSA less than 10 months based on a lot of historic data that we heard.

Having said that, the FDA has now approved three different drugs for non-metastatic CRPC based on three Phase III randomized trials and not put in that definition of a PSA doubling time of less than 10 months. So there's a little bit of worry that out in the community, this may just be used in general for patients with non-metastatic CRPC. Remember that all of the studies that were done, the PROSPER study, the SPARTAN study, and the ARAMIS study were done using conventional imaging and we had quite a bit of discussion about the fact that using new PET scan imaging, which is not yet approved yet in the United States, which is used quite often in Europe and used in Australia a lot too. We will be seeing more metastases than we expect in those patients with non-metastatic CRPC. So the question is maybe we're not doing any harm by treating these patients earlier.

But having said that, that was not the definition. That was not what was used on the trial and the fact that the FDA has just approved it without saying anything about the PSA doubling time is perhaps a little bit worrisome. And I think that we should let the community know who are the patients that we feel should be treated at this moment because these drugs are not without some toxicities and they're not without some financial toxicity as well, as Tia Higano pointed out. So I think there was nice discussions by Howard Scher about the definition of it and by Maha Hussain about the pros and Tia Higano about the cons of those treatments.

Alicia Morgans: Really just to emphasize one thing that you said, actually two things that you said, so watching the PSA doubling time to make sure that that's probably going to be less than 10 months to really ensure that you're getting those high-risk patients limiting toxicity in other patients. Then to emphasize, the other thing you mentioned, which is that these Phase III trials were actually done with standard imaging, and so I think standard imaging is how we define non-metastatic CRPC still at least in the United States. So a positive PSMA PET or positive axumin scan does not actually negate the negative conventional bone scan and CT scan that you have. That's really what, at least I use in my clinic to make decisions about these patients.

Cora Sternberg: That's used in most clinics in the United States, but if we do find a positive PSMA scan and perhaps it's even more reason to treat these patients with these drugs. So I think-

Alicia Morgans: Absolutely. So it's something else to keep in mind. The second half of your session was really focused on the metastatic patient and some novel approaches to treatments-

Cora Sternberg: Novel approaches, yeah.

Alicia Morgans: ... and also the imaging of course. So what should we take away from that part?

Cora Sternberg: The first session was by Michael Hofman from Australia and he's done quite a lot of work with Lutetium PSMA scanning. There's been so much Lutetium PSMA scanning and treatment used in Vienna, in Austria, in Germany. When I was living in Europe, I was sending patients for this kind of treatment, but they never published it, the work really, not in the way that they have done it in Australia. They have systematically done quite a few trials on that and have accumulated quite a number of patients and have published on it. He quite nicely pointed out the fact, and I think it's very important to understand, that if PSMA is positive on the scans in that case, those are the patients who can respond to Lutetium PSMA and I think that PSMA scanning will eventually be approved in the United States.

At Weill Cornell we did a study looking at PSMA scanning versus MRI in order to be able to get the PSMA scan. Scott Tagawa has taken up the work of Neil Bander and done a lot of ... We're doing a lot of work with radio nuclear type labeled PSMA with Lutetium, with actinium participating some in the national and international trials such as the VISION trial that was mentioned looking at Lutetium-labeled PSMA as compared to standard of treatment.

I think those are the kinds of trials that are needed in the future to see what we're actually doing with these new therapies. But I think it's important to realize that those patients who have a fluoride scan, that is negative for PSMA, these are not the patients that we want to treat. Michael Hofman made it very clear that if he has a patient that's full of bone metastases and has, the liver doesn't pick up PSMA, these are not the patients that he would treat and his Phase II trial with Lutetium-labeled PSMA.

There should be other trials with combination perhaps of abiraterone and enzalutamide with PSMA-labeled therapies for those patients that have two kinds of disease because we know prostate cancer is a heterogeneous disease. We heard an interesting talk about PARP inhibitor.

Alicia Morgans: Yes.

Cora Sternberg: PARP inhibitors by Kim Chi. He gave us a beautiful overview of all of the PARP inhibitor trials that are out there. The PARP inhibitors are not all the same. I think we're still in our early phases to be able to compare one PARP inhibitor to another and there are four different ones in the Phase II and Phase III trials and they have different amounts of toxicity and they have different response rates thus far. Some responding to BRCA2, others and ATM. Others not responding to ATM at all. Anyway, he gave us a very nice overview of the TOPARP-B trial by Mateo.

Alicia Morgans: Yes.

Cora Sternberg: That was just recently published as well. So we've heard quite a little bit about the PARP inhibitors, so patients that have these DDR defects such as BRCA2, such as ATM, others, they respond to PARP inhibitors and they respond to platinum compounds as well. These are important messages to give to our physicians and our patients, if there are still other treatments. These treatments are not without side effects. I mean, I've used PARP inhibitors in trials and if you have a patient that's been heavily pretreated with radium for example or has [crosstalk 00:00:07:18] bone marrow, you're going to have some troubles with blood counts when they use these drugs, so you need to look at ... They have different toxicities and different amount of myelosuppression that I think they're really interesting new way of treating patients.

Alicia Morgans: Absolutely, and I think personalized medicine is becoming increasingly important. We're going to probably see, I'm sure we're going to see some data presented at ESMO that will move the PARP inhibitors I think into our clinical domain, at least in the United States. So that will be-

Cora Sternberg: Yes.

Alicia Morgans: ... in the PROfound study, so that I think will be really exciting.

Cora Sternberg: I think that's going to be presented as ESMO.

Alicia Morgans: Yeah, I think it will be at ESMO. So, really exciting on the PARP inhibitors. One thing to emphasize too that there can be some GI toxicity, some fatigue in addition to the cytopenias, but the TOPARP-B study did seem to demonstrate that the higher dose of olaparib, if we are using olaparib, might be more efficacious.

Cora Sternberg: More efficacious, yes.

Alicia Morgans: So something for us to consider and certainly a number of patients need to dose reduce, but it is something ... That was interesting data from TOPARP-B as well.

Cora Sternberg: I agree with you on that.

Alicia Morgans: So Chuck Drake also gave a beautiful discussion-

Cora Sternberg: A beautiful immunotherapy talk because immunotherapy ... Prostate cancer's considered to be a cold tumor and we haven't really had very much in terms of immunotherapy since the PROvenge data, the IMPACT trial. It was quite an old trial and done way before we had all our new AR targeted inhibitors and it's not even approved in Europe at all. But since then we have the checkpoint inhibitors that have been highly successful in many diseases. I think that there's certain patients who will respond to immunotherapy and he was telling us about the CDK12 patients.

Alicia Morgans: Yes.

Cora Sternberg: At least 12 ... 5% of patients will respond to checkpoint inhibitors and I don't think that's a small amount. If you have a patient you don't know what to do, that's one thing that we would want to measure or put in a trial.

Alicia Morgans: Yes, yes.

Cora Sternberg: The MSI high unstable patients have ... There's been approval in the United States for pembrolizumab based only on one patient in a big trial.

Alicia Morgans: Yes. Which I hadn't realized.

Cora Sternberg: I hadn't realized it either.

Alicia Morgans: That was interesting.

Cora Sternberg: But we're all measuring it anyway. We're measuring MSI and that's even less than the CDK12 because if we find those patients and they can respond, I think that's really interesting. Julie Graff was one of the first to present data showing that giving enzalutamide first did some ... something to prepare these patients that after the enzalutamide failure and then giving pembrolizumab, there was a higher response rate and I think we'll be hearing more from her on that as well. So I think that that data is really interesting and there's other kinds of immunotherapy that will be coming along and I'm sure that if immunotherapy is this successful on so many solid tumors that we will find a way to regulate our myelo [inaudible 00:10:18] tumor cells so that we can give you immunotherapy to our prostate cancer patients as well.

Alicia Morgans: I think you're right.

Cora Sternberg: I think there's hope there.

Alicia Morgans: I think there is hope there and I think we will find a way, but really interesting to see it sort of all put together and he really emphasized that he thinks that the hormone sensitive setting may actually even be more responsive.

Cora Sternberg: And the earlier setting and even in the neoadjuvant setting as well, and he's talked about trials such as MAGIC-8 trial, which we from ... As a consortium we're participating from Cornell with him on that trial. I think it's a very interesting trial too.

Alicia Morgans: Absolutely. So, I think there was a lot of hope and a lot of excitement in the CRPC session actually that you led. What is your ... Do you have an overarching theme or a closing thought for everyone as they're going through the materials from APCCC looking at things from your session?

Cora Sternberg: I think that we talked also about neuroendocrine-

Alicia Morgans: Yes.

Cora Sternberg: ... prostate cancer. I think not that much new was said except that there's a clinical definition and there's also more and more a molecular definition that we need for neuroendocrine prostate cancer and then up to 20% of these patients do have neuroendocrine prostate cancer and those patients probably should be treated in a different way perhaps with chemotherapy, perhaps with these ZH2 inhibitors. Perhaps we'll find out in the future. I think there's a lot of hope for our patients with castration-resistant prostate cancer. We have a number of new drugs that are working, improving overall survival, and I think that as we go further into the personalized medicine story, we are finding more and more drugs and hope for our patients with castration-resistant prostate cancer.

Alicia Morgans: Absolutely. I really appreciate your time. You did a fabulous job during the session and for summarizing, and apologies on my part for forgetting Eleni Efstathiou she did a fantastic closing session there on the neuroendocrine phenotype and all of the work that she and her colleagues at MD Anderson had been doing. So thank you for reminding me and thank you for an excellent job at APCCC.

Cora Sternberg: Thank you. Thank you very much.