Validation of a Prognostic Genomic Classifier in Salvage Radiotherapy Prostate Cancer from a Prospective Randomized Trial - Felix Feng

February 22, 2020

Alicia Morgans is joined by Felix Feng to discuss his recent presentation on a new analysis from the Phase III RTOG 9601 trial. They discuss the application of using Decipher, a test based on gene expression profiles in primary tumors in prostate cancer, which adds significantly to identifying the men with the most aggressive disease.  It drives the discussion to when we adopt genomic biomarkers into routine clinical use to support clinical treatment decision making.  

This video presentation is 10 minutes.

Biographies:

Felix Y. Feng MD, Professor of Radiation Oncology; Urology; and Medicine, Vice Chair for Faculty Development and Director of Translational Research, Department of Radiation Oncology,  and Director of the Benioff Institute for Prostate Cancer Research at the University of California of San Francisco

Alicia Morgans, MD, MPH, Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois



Read the Full Video Transcript

Alicia Morgans: Hi, I'm thrilled to have here with me today, Dr. Felix Feng who is a Professor of Radiation Oncology, Urology and Medicine at UCSF. Thank you so much for talking with me today.

Felix Feng: Thank you, Alicia, for having me at this interview.

Alicia Morgans: Of course. We wanted to really dig into a presentation that you made at GU ASCO this year where you were able to tell us a little bit more about the RTOG 9601 trial and really thinking about molecular classification within that study and how we might be able to choose patients based on molecular classification. Can you tell us a little bit more?

Felix Feng: Sure. The RTOG 9601 trial is a Phase III trial that we published in The New England Journal of Medicine a little bit more than two years ago. It was a trial in over 700 patients. It randomized these patients so that these were all patients who had PSA recurrences after surgery. And then they were randomized to radiation alone or radiation with two years of high dose bicalutamide, which is an anti-androgen therapy.

What the trial basically showed is that the addition of the bicalutamide improved overall survival, metastasis-free survival, pretty much all endpoints for these patients. And because of this and other similar studies, now androgen directed therapies are routinely given with radiation for patients with PSA recurrences.

However, like with any therapy, it's clear that not all patients benefit from all interventions. And so my colleagues who had run the RTOG 9601 trial had the insight to actually bank prostatectomy samples or the surgical samples from these patients to allow a biomarker analysis in the future, and the future is now.

And so what we did was we collected as many of these samples that we had and we were able to profile about 360 of these surgical samples using the Decipher® assay. And so the Decipher® assay basically measures the expression of various genes in the particular cancer. It's a tool that's been actually well validated in other settings, but never in the context of a randomized clinical trial in this setting. In which, it's actually quite interesting because this is actually the intended use population for Decipher®.

So anyway, when we ran Decipher® what we were able to see was that patients with a high Decipher® score, meaning they had a high genomic risk for metastasis, actually were the patients who derived the majority of the benefit from the addition of anti-androgen therapy.

What I mean by that is that, first of all, when you look at Decipher®, Decipher® identifies which patients are at higher risk for metastatic disease and when you account for clinical variables like PSA and Gleason score, Decipher® still adds substantially in terms of identifying the men with the most aggressive disease.

But the trial was special was because we have two populations of patients treated with two different therapies and so we can look to see who's actually benefiting from the anti-androgen therapy. Admittedly, the caveat is that it would have been great to have 700 patient samples and not 360 patient samples. But in our 360 samples, when you look at the benefit from the anti-androgen therapy, it's basically the patients with the high Decipher® scores that benefit and actually patients with low Decipher® score appear to actually have very low benefit.

Moreover, when you look at the patients whose PSAs were lower at the time of initiation of treatment, we defined lower as 0.7 or lower, what we found was that actually in those patients, it appeared that they actually may have done worse with the anti-androgen therapy than those patients who did not receive the anti-androgen therapy. And again, I have to say this somewhat cautiously because our study was not statistically powered to look at this particular difference.

Alicia Morgans: Sure.

Felix Feng: But I think it's clear that there are patients who benefit more from anti-androgen therapy than others. And I think that genomic risk stratification is one approach to identify those patients.

Alicia Morgans: So all patients in this study, just to remind everyone, received radiation, which we think was beneficial. But what the study was really assessing was whether the addition of two years of bicalutamide would actually be additive to that salvage radiation.

Felix Feng: That's correct.

Alicia Morgans: And when you broke things down by PSA in the past, and we've talked to Dan Spratt about this, I think as well, there is sort of a cutoff around this 0.7 mark were patients with a lower PSA may not have that additive benefit from bicalutamide.

Felix Feng: That's right.

Alicia Morgans: But in this situation, you actually looked at Decipher® as another way to try to identify which patients are going to benefit from that hormonal therapy that we would add to the radiation. So what are you doing in your practice in thinking about Decipher®, thinking about PSA? Are you using either or both of these? What clinical factors are you using to actually decide if you're going to add bicalutamide? I would say in some settings, people aren't adding bicalutamide, they're adding a GnRH agonist, for example.

Felix Feng: Yeah.

Alicia Morgans: Really extrapolating this data quite a bit sometimes.

Felix Feng: Right.

Alicia Morgans: But what are you doing in practice with this kind of information? Because if we can limit patients from being exposed to hormonal therapy, I think we would all be very happy to do that.

Felix Feng: Yeah. So first of all, to your, to one of your latter points, yeah, I don't give the bicalutamide as monotherapy. I give a conventional GnRH agonist with a bicalutamide.

Second point is, I think that you're asking a very good question and the question basically is, when do we start adopting genomic biomarkers into routine clinical use and how do we incorporate these into clinical practice? And that actually is a very tough question. So there is always going to be earlier adopters of technology and later adopters of technology. I tend to be an earlier adopter of technology. That's just my personal bias. And so I use a combination of both PSA levels and Decipher® to decide on which patients I believe should receive androgen-directed therapies.

And so for example, patients with high Decipher® score, high PSA, they should definitely get androgen ADT, androgen directed therapies. Patients with low Decipher® score, low PSA should, in my opinion, not. The question then becomes what happens in the middle population? Let's say patients who have high PSAs and low Decipher®, or high Decipher® and low PSAs.

Alicia Morgans: Yes.

Felix Feng: My personal practice is that given that all these trials are positive for the addition of hormone therapy to radiation, if I'm going to err on one side, I'm going to err on the side of giving the hormone therapy in the absence of any other data.

Alicia Morgans: I think that's a great way to think about it. So high PSA, high Decipher®, we know that those patients, we hope, would benefit from the addition of androgen deprivation therapy. If we have both that are low, then those are probably going to be pretty confidently patients that we can say, we're not going to give these patients additional hormonal therapy. But in the middle, if you're going to err on one side, it's probably best to err on the side of intensification of therapy until we actually know what should be driving our decision making.

Felix Feng: Absolutely.

Alicia Morgans: Great. So I wanted to talk to you a little bit more while we have the time and the opportunity, not just about 9601 because that's actually very, very exciting, but you're also the director of the Benioff Institute for Prostate Cancer Research at UCSF. I know you have a lot of really exciting things coming through that program and things in your pipeline. Do you want to just mention some of those that you're most excited about that are farthest along to really impacting patients?

Felix Feng: Absolutely. And so this is a research initiative that was recently started thanks to a very large philanthropic gift from Marc Benioff. Marc Benioff lives here in San Francisco and is a great supporter of research at UCSF.

And so we basically are starting this initiative to really delve into the biological drivers of aggressive prostate cancer. This initiative has multiple components. One component is we want to fund research that looks at what drives prostate cancer. And based on that knowledge, how do you develop better treatments for prostate cancer? And that research is directed towards androgen receptor signaling, that's a known driver, DNA repair optimality, that's a known driver of prostate cancer and also interactions between the tumor and the immune microenvironment.

And then, in addition, we're recruiting faculty to kind of build upon those areas. We're combining both studies and laboratory models with genomic studies and clinical samples. And really the goal is, we want to basically take high-risk approaches. When I say high risk it means approaches that may not be fundable by conventional grant mechanisms where you're supposed to have the exact hypothesis and follow that hypothesis. But we want to take high risk, high reward projects on, and outside the box thinking on how do we come up with better cures for prostate cancer?

Alicia Morgans: That sounds fantastic and I really look forward to hearing how those ultimately impact patient care. I love the work that you do on really helping us personalize our decision making on multiple levels. Right now, we're really talking about molecular personalization around Decipher® and I appreciate that, but I'd certainly look for more to come from the Benioff Institute.

Felix Feng: Thank you.

Alicia Morgans: Thank you so much for sharing your expertise and your time with us today.

Felix Feng: Thank you for having me here.
email news signup