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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago in the United States. I am so excited to have here with me today a good friend and colleague, Dr. Felix Feng, who is a professor of radiation, oncology, urology, and medicine, as well as being the director of the Benioff Institute for Prostate Cancer Research at the University of California, San Francisco. Thank you so much for being here with me today, Dr. Feng.

Felix Feng: Thank you, Dr. Morgans for inviting me.

Alicia Morgans: Wonderful. Felix, I wanted to talk with you about some really interesting data that you have presented at GU ASCO 2021, our virtual meeting. And this was really looking at molecular determinants associated with response to apalutamide in patients who have nonmetastatic castration-resistant prostate cancer. We've been so impressed with some of the work that you've done in this area that helps us understand which populations may have better or worse responses to intensified therapy. I'm hoping that this work can continue to help guide us. Can you tell us a little bit about the work that you've presented?

Felix Feng: Sure. And so something that I know you and I have thought for a long time is that not all patients respond equally to all therapies and I think there is a need to molecularly characterize prostate cancer from each patient and identify predictors of either response or resistance to particular therapies. And so what we did in this particular study was we took the SPARTAN phase three study, which as you mentioned, was in non met patients with nonmetastatic castrate-resistant prostate cancer. It was a large study of over 1,200 patients and basically, half the patients got placebo added to androgen deprivation therapy, and the other half got apalutamide added to androgen deprivation therapy. And the study was positive for its primary endpoint of metastasis-free survival and also looked at a variety of other endpoints as well.

Felix Feng: And we went back, and this is in collaboration with Janssen, the sponsoring company for SPARTAN. We went back and looked at the primary prostate samples from the patients in SPARTAN and we were able to obtain 233 samples from the 1,200 patients on the trial. And then we profiled these samples with what we call a transcriptome-wide approach, meaning an approach that looks at the expression of RNA corresponding to every protein-coding gene in that particular sample. And what we started doing was trying to find specific gene signatures that were enriched in either patient who had early progression on apalutamide, meaning that they progress very, very quickly on the drug, or patients who had long term response, meaning that at the end of the treatment they either had no progression to metastatic disease or that if they did have metastatic progression, they had it very, very, very late in the course of their treatment as well. And then what we did was we asked, "Well, what are the biological concepts that are enriched in the patients who had early progression or who had a long-term response?"

Felix Feng: And one of the most interesting findings we had was that immune activation was associated in the long-term responders. And it wasn't just one immune activation signature, it was many. It was T cell activation signatures. It was IL-2 signaling, which is a known cytokine in the immune pathway. And all of these were up in long-term responders to apalutamide compared to early progressors. And I think that this is thought-provoking in the sense that the role of the immune response in prostate cancer is an area of controversy at this point in time. There have been a number of negative phases three studies of immunotherapy in the context of patients with metastatic castration-resistant prostate cancer. And now to find that these immune activation scores may play a role in identifying who responds to certain therapies or who doesn't, I think is very intriguing.

Alicia Morgans: I completely agree. And I think as you mentioned, the role of the immune system in prostate cancer, in general, is something that we are still trying to figure out and there is definitely a question as we've seen from Julie Graff's data of whether this intensive immune suppression, it may make these cancers more susceptible to immune infiltration perhaps or perhaps just to those type of checkpoint targeting therapies. This is something that definitely could ring true and may support some of the work that is ongoing in the field, where we are trying to combine checkpoint inhibitors like pembrolizumab, for example, with intensive therapies like enzalutamide. From your standpoint, looking at what you found here and what you found in other evaluations of looking at these sort of molecular characterizations or response to therapy, are there any points that seem to hang together and ring true across disease states? Or are you finding that there are really sort of different pathways coming to light in different disease states as you are putting these together?

Felix Feng: Oh, it's a great question in the sense that I think that there are some concepts that hold true across disease states and some that we still need to investigate further. And so an example of this is a while back, we demonstrated that there were different molecular subtypes of prostate cancer based on what we call luminal or basal status. And the prostate is a gland. And so prostate cancer emanates from this gland. Each gland, the inside of the gland is called the lumen and there are cells around that, which are luminal. And then there is something called the basement membrane around the outside of the gland and the cells that potentially emanate from that may be more basal-like in nature. And what we showed was that this luminal basal characterization predicts response to hormone therapy in the context of patients who have never seen hormone therapy before with localized disease, we show that it continues to predict for response to apalutamide in the SPARTAN trial as well.

Felix Feng: And then more recently we have unpublished data suggesting that it also continues to predict for response to next-generation androgen directed therapies in metastatic castrate-resistant prostate cancer. That's an example of a biological concept that kind of holds through different disease states. At the same time, there are other signatures that had failed to validate across disease states as well. In the context of kind of the immune angle, it's clear that regardless of whether you are looking at localized prostate cancer or nonmetastatic castrate-resistant disease, or metastatic disease, that there is a variety or there is heterogeneity in terms of immune signatures. And what I mean by that is that there is going to be a certain sub-portion of the population where they have higher immune activation scores in their tumors. And there is also going to be some that actually have very little immune activation as well.

Felix Feng: And this is what we saw in the SPARTAN trial and also in localized disease. Now, in the context of immune cell activation, it's less clear what that means therapeutically. We know in the context of metastatic castrate-resistant disease, that there are certain genetic changes in specific genes like mismatch repair genes that will predispose to response to immune checkpoint blockade. And that is true across all cancers, not just prostate cancer. And that's why there is an indication for immunotherapy in that subset of patients with metastatic disease, but that's a very small subset of patients. Within immunotherapy trials, I think there's the signal that there are going to be more responders than just those with that particular mutation and the mismatch repair genes. And so can we use these transcriptome signatures to better identify those patients? That's something that I'm certainly interested in exploring.

Alicia Morgans: I think that is a great question. And I always think of when I do these interviews, I always think about who might pair up to look at these things more closely. And I do wonder if you and Julie Graff at some point can pair up. She did have several of her responders actually not have an MSI high signature on their biopsy. Perhaps this is part of the story and always more questions to ask. As you think about using the information that you presented at GU ASCO in your clinical practice, I assume it's not quite ready for prime time in terms of decision making, but how is it affecting your thinking? Work that needs to done maybe or in your counseling with patients?

Felix Feng: Yes. It's a great question. I tend to start shifting or leaning towards certain recommendations based on molecular signatures earlier than most. And again, it's because I'm an early adopter of technology, I think, compared to the general population of radiation oncologists. In my personal practice nowadays, I do look at luminal basal scores because I think that's probably one of the more validated signatures across disease states. And for a patient where I am hesitant or not hesitant, but on the border of giving androgen deprivation therapy based on their clinical features, meaning that they had a little bit of aggressive disease, but not enough. And sometimes I'll use these molecular signatures to help sway my decision. For some of these other signatures, I think that they are too early, to be honest with you. And so I think that the devil's in the details of sorts.

Alicia Morgans: Yes. I agree, but I love to see this work continue to evolve. And as you said, your work around luminal basal and the PAM50 signatures, I think, as you said, it is really moving into something that we're able to use now. And this I expect will continue to move in that direction to help us understand the heterogeneity of the patients sent to us. Thank you so much for your time, for your expertise, for the work that you continue to do. We appreciate you spending some of your time with us.

Felix Feng: Thank you, again. I always love talking with UroToday and you.