Alicia Morgans, MD:  Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today, a friend and colleague, Dr. Felix Feng, who is a professor of radiation oncology, urology, and medicine, as well as being the George and Judy Marcus Distinguished Professor, and the Vice-Chair of the Department of Radiation Oncology, and the Director of the Benioff Initiative for Prostate Cancer where he does all of this, at UCSF. So thank you so much for being with us here today, Dr. Professor Felix Feng.

Felix Feng, MD:  Thank you, Alicia, for that overly generous introduction, and thank you for inviting me to speak about optimizing the use of androgen deprivation therapy in men with intermediate-risk prostate cancer. So here are my disclosures and I serve as a consultant or I have served as a consultant for several companies that developed therapies targeted against the androgen-signaling axis.

So let's start with a quick definition. What is intermediate-risk prostate cancer? So per the 2020 NCCN guidelines, intermediate-risk disease has one or more of the following intermediate-risk factors, including T2b - T2c disease, Gleason grade grouping two or three, or a PSA between 10 to 20, and more importantly, no high risk or very high-risk features. But it turns out that even within the spectrum of intermediate-risk prostate cancer, there is heterogeneity in terms of clinical outcomes. And so more recently, intermediate-risk disease has been broken down into what we term unfavorable intermediate-risk disease, which includes anything with a Gleason pattern 4 + 3 greater than or equal to 50% biopsy cores positive for disease or multiple of the intermediate-risk factors that I showed on the previous slide.

Favorable intermediate-risk disease is defined as all other diseases within the intermediate-risk category. And as you can tell from this study from Zack Zumsteg and others, the unfavorable intermediate-risk disease has poor PSA recurrence-free survival, or distant metastasis, and also poor prostate cancer-specific mortality compared to favorable intermediate-risk disease.

And so it turns out that we treat favorable and unfavorable intermediate-risk disease differently. So for patients with favorable intermediate-risk disease, the treatment options include active surveillance depending on patient preference and also disease parameters, surgery, or radiation. For patients with unfavorable intermediate-risk disease, the treatment options include surgery or radiation plus androgen deprivation therapy. And today I'm going to focus on the use of this androgen deprivation therapy for patients with unfavorable intermediate-risk prostate cancer.

So let's step back a bit and actually talk a little bit about why does androgen deprivation therapy improve outcomes after radiation therapy. And so for many years, it was thought that androgen deprivation therapy treats systemic disease, radiation treats local disease, and together they work better, but that's actually not the answer in the sense that if that were true, then androgen deprivation therapy would add to surgery, which it doesn't. So from a biological perspective, Karen Knudsen and I, as well as Charles Sawyers's team, actually did a number of studies trying to elucidate the mechanism by which androgen deprivation therapy improves the effect of radiation.

And so it turns out that radiation induces the activity of the androgen receptor and the androgen receptor activates the transcription of DNA protein kinase, which is a key DNA repair enzyme. Androgen receptor-mediated activation of DNAPK increases DNA repair and it results in radiation resistance. And inhibition of the androgen receptors significantly radiosensitizes androgen receptor-positive prostate cancer cell lines, and also tumor models as well in the laboratory.

And so let's go to some clinical data. RTOG 94-08 is probably the best-known trial in this space. And what it showed is that the addition of short-term androgen deprivation therapy to radiation improves patient survival. And this was a study of over 1900 patients, 54% of which had intermediate-risk disease, and they were randomized to receive either radiation alone or radiation with four months of androgen deprivation therapy. And here on the right, you can see the Kaplan-Meier curves for overall survival, but at 10 years there was an improvement of 5% in overall survival between patients who had received short-course androgen deprivation therapy and those that did not.

And when we actually look more closely at the RTOG 94-08 population, it turns out that short-term androgen deprivation therapy improves survival, particularly in patients with intermediate-risk disease. And so on the left, you can see the same Kaplan-Meier curves for patients with intermediate-risk disease within RTOG 94-08.  And on the right, you can see the same data for patients with high-risk disease, there is a significant benefit on the left in the intermediate-risk patients, not so much of a benefit on the right. And that's probably because the high-risk patients need more than just a few months of androgen deprivation therapy with their radiation.

Now recently Zack Zumsteg did a secondary analysis of RTOG 94-08, breaking down patients by whether they had unfavorable versus favorable intermediate-risk disease. And what he found was that the patients who had favorable intermediate-risk, shown on the left column, had no benefit in terms of distant metastasis and prostate cancer-specific survival from the androgen deprivation therapy but those with unfavorable intermediate-risk disease on the right, actually had a substantial benefit that was statistically significant for both these parameters.

And so there have been actually several randomized trials of radiation alone versus radiation plus short-course androgen deprivation therapy in patients with intermediate-risk prostate cancer. And here you can see some of these key studies. So the one I showed you was RTOG 94-08, which was the largest study in this space, but there was also an earlier study by Anthony D'Amico that also demonstrated a survival benefit. And I want to point out that these studies were performed with what we consider to be lower radiation doses by today's standards. But also, more recently there have been two studies run by the GETUG Group and also the EORTC Group that used more standard radiation doses by today's practice, which is what we call dose-escalated radiation. And those studies also showed that the addition of short-course androgen deprivation therapy improves clinical parameters such as biochemical control and clinical disease-free survival, but they actually were not powered to look at overall survival.

And so now the benefit of the androgen deprivation on overall survival is being assessed in patients with intermediate-risk disease on the RTOG 0815 study, and this stratifies patients by how many intermediate-risk features they have, and again, randomizes to radiation versus radiation plus six months of androgen deprivation therapy. This study has finished accruing and it is actually very large powered for survival, and hopefully will read out in the next few years.

Now, one question we can ask is, is a few months of androgen deprivation therapy enough for patients with intermediate-risk disease? And so RTOG 99-10 was a Phase 3 study that showed that a longer duration of androgen deprivation therapy does not improve outcomes in patients with intermediate-risk disease. It was a study of over 1400 patients, 84% of which had intermediate-risk disease, and they were randomized to radiation with four months of androgen deprivation therapy versus radiation with nine months of androgen deprivation therapy. And what they showed was actually that there's just no difference in overall survival or disease-specific survival as you can see on the right between these two groups, meaning that longer androgen deprivation therapy was not better for this patient population.

Now we've talked a lot about the impact on tumor outcomes in terms of short-term androgen deprivation therapy added to radiation. Let's talk about the impact on the quality of life for these patients as well. And so this is data from the EORTC study that I referenced earlier, where patients were randomized to radiation alone or radiation and six months of androgen deprivation therapy. And here are some quality of life measures that were collected from patients in this study. And what you can see, is that there is actually a significant change in hormonal symptoms, in sexual activity, and in sexual functioning as reported by these patients. And also, what I want to emphasize is that this was only half a year of androgen deprivation therapy that was given, but that included a GnRH agonist. And you can see that the impact on the symptoms extends far beyond six months actually like it doesn't really resolve until close to the one to two-year mark for all of these quality of life metrics.

And so one question we can ask is, can alternative forms of androgen suppression such as GnRH antagonists shorten the duration of testosterone suppression in intermediate-risk patients? And so this is a study that was just published in European Urology, which was a randomized study of the oral GnRH antagonist relugolix versus degarelix, which is the conventional GnRH antagonist that involves an injection. And this was in 103 patients, mostly intermediate-risk and the primary endpoint was the rate of effective castration.

And here you can see the time course of testosterone levels as a function of treatment. And what you can see, I think, is that both treatments achieved highly effective levels of castration in terms of testosterone levels. But at three months after discontinuing treatment, 52% of patients on the oral GnRH antagonist relugolix experienced testosterone recovery. The trial wasn't powered to statistically compare the two groups and so I think we can just look at the broad numbers, but that is a pretty good number in terms of testosterone recovery.

Now, what does the future holds for us in terms of potential approaches for personalizing androgen deprivation therapy for patients with intermediate-risk disease? And I would say that at least part of that future includes genomic classifiers. And so this is a paper published by Alejandro Berlin, which looked at a retrospective cohort of 121 patients with intermediate-risk prostate cancer treated with radiation alone. And 72% of them had unfavorable intermediate-risk disease, and all under one testing with the genomic classifier, decipher. And so in the plot on the left, you can see the Kaplan-Meier curves for freedom from metastasis by NCCN sub-groups, unfavorable versus favorable intermediate-risk disease.  So there was no big difference in this particular cohort. And again, it was a small cohort, but if you look on the right, we have the same plot based on genomic classifier decipher scores. There it is lower in blue versus intermediate to high in red. And what you can see is decipher scores were more strongly associated with outcome compared to the NCCN sub-groups.

And so this has led us to start an international phase 3 study NRG GU010, also called the Guidance study. And it is a genomic risk-stratified trial for patients with unfavorable intermediate-risk prostate cancer. And in this study, patients with previously untreated unfavorable intermediate-risk prostate cancer, will all undergo testing with a genomic classifier, decipher. Those with low decipher scores will be randomized to either the standard of care, which is radiation and short term androgen deprivation therapy versus a de-escalated treatment arm of radiation alone. And so this is a phase three treatment de-intensification study for patients with low decipher scores.

Now, on the other hand, patients with intermediate or high decipher scores will be enrolled in a phase three study that randomizes patients again to the standard of care, radiation, and short term androgen deprivation therapy versus an escalated therapy arm of radiation and short term androgen deprivation therapy plus the next-generation anti-androgen darolutamide. And the primary endpoint is metastasis-free survival, it's a 2,400 patient study.

And so this leads us to our conclusions. And conclusion number one is that patients with unfavorable intermediate-risk prostate cancer benefit from the addition of short-term androgen deprivation therapy to radiation. Number two, given the impact of short-term androgen deprivation on quality of life, there is a need for further individualized treatment for patients. Number three, newer androgen deprivation therapy approaches may shorten the duration of testosterone suppression for these patients. And number four, clinical trials are evaluating the impact of using genomic classifiers to select patients for treatment intensification or de-intensification.

And with that, I would like to thank you for your time and your attention.