The Role of ADT in Men Being Treated with Radiation Therapy - Daniel Spratt

November 8, 2020

Contemporary Treatment Strategies For Androgen Deprivation Therapy In Prostate Cancer Presentation

The Role of ADT in Men Being Treated with Radiation Therapy Daniel Spratt (12-minutes)

Independent Medical Education Initiative Supported by Myovant Sciences 

Biographies:

Daniel Spratt, MD, Tenured Full Professor of Radiation Oncology and a leader in Prostate and Spine malignancies. Chief of the Genitourinary Radiotherapy Program, Associate Chair of Clinical Research, and the Laurie Snow Endowed Research Professor in the Department of Radiation Oncology. Co-Chair of the Genitourinary Clinical Research Team and co-Director of the Spine Oncology Program, in the Rogel Cancer Center, The University of Michigan, Ann Arbor, Michigan

Michael Cookson, MD, MMHC, Professor, and Chairman, Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

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, 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, Dr. Dan Spratt, who is a Professor of Radiation Oncology at the University of Michigan, and he will be talking to us about the role of ADT in men who are receiving radiation therapy. Thank you so much, Dr. Spratt.

Daniel Spratt: Thank you so much, Dr. Morgans. It's great to be here talking about this topic, which is, obviously close to me as a radiation oncologist and I have no relevant disclosures for this talk. And so, before I get into the role of hormone therapy with radiation, I think it's important to take a step back real quick about just the role of hormone therapy in prostate cancer.

The very first case of prostate cancer was in the mid 1800s, and it took almost a hundred years before the first effective treatment for prostate cancer really emerged, which Dr. Huggins and Hodges won a Nobel Prize for, with surgical castration showing us improved outcomes for men with metastatic prostate cancer. And then it took another 40 years for the first FDA approved agent, leuprolide, which is an LHRH agonist, which suppresses testosterone, which is still likely the most common form of hormone therapy used today, at least the United States. And then shortly thereafter, one of the first anti-androgens was approved, flutamide, which is a drug given usually three times a day.

But, there was quite a bit less progress the next 20 years. There was docetaxel, but the next big drug in the category was degarelix, which was the first GnRH antagonist approved in 2008. And then the past 12 years or so, new drugs had exploded, many of which were hormone therapy or AR signaling inhibitor drugs, including abiraterone, enzalutamide, apalutamide as well as darolutamide, and numerous other approvals shown here.

And so, while this was all ongoing, the study of radiotherapy with hormone therapy was occurring in parallel. And so, one of the very first studies was an old RTOG trial in the mid 1970s. It was a pretty big trial, 566 patients. This is how they used to stage prostate cancer back then. But these were very advanced node-positive prostate cancer, and it was a question nothing to do with hormone therapy. It was about how much radiation could you give to the lymph nodes. But they found on a very simple multi-variable analysis, that the use of hormones, which really this is hormone therapy or ADT, had a trend for improvement in what they called local control, which was just measured by a rectal exam.

And this was a promising enough signal they ran a Phase II trial shortly thereafter of 30 patients, all accrued in one year. And again, really bulky primary tumors and clinical node-positive disease. And they gave four months of an LHRH agonist and flutamide. At that time, how they assessed response was the DRE, and 28 of the 30 patients, they said had primary tumor clearance, measured by DRE, because these were stuck in bulky primaries.

Then subsequently, they followed this with a Phase III trial. And again, this was very locally advanced disease. You could have lymph nodes all the way up into the para-aortic nodes, which today we would call metastatic disease, and they randomized radiation therapy upfront, versus radiation therapy plus hormone therapy with just an LHRH agonist until progression. Those in arm one, they would add hormone therapy at time of relapse. And this is really one of the first randomized trials that showed that there was a reduction in metastatic disease in men receiving hormone therapy, as well as a improvement in survival, at least for the high Gleason score tumors, Gleason 8 to 10.

This in parallel, was done with, again, a trial where in non-metastatic patients, at least by the imaging at the time, with very bulky primaries, so this is a 25 cm2 gland. These are very big prostates. It was radiation alone +/- 4 months of combined androgen blockade, and as you see here, improvements in prostate cancer-specific mortality and a trend, but didn't lead significance for improvement in overall survival. So this was really the dawn of the era.

I won't go through, there's probably about 40 other trials, and this slide sort of is a highlight reel that over the next 30 years, there's been many trials assessing the addition of hormone therapy, assessing various durations of hormone therapy, some assessing use of neoadjuvant hormone therapy before radiation, some assessing adjuvant and prolonged adjuvant. And the summary of all of this work to oversimplify it is that in today's risk grouping, we usually use NCCN risk groups, for low-risk men, often now we don't even treat them with upfront therapy like radiation, but we definitely don't add hormone therapy. For select intermediate-risk men, we often, from these studies learn, we should be adding 4 to 6 months of a short-term hormone therapy. And for our higher risk men, to give them longer term, usually 18 to 28 months of hormone therapy.

This is hot off the press. We just presented this work last week and this paper will be published in JCO soon, and so people watching this can see the conclusions. We did a meta analysis of the two trials of intermediate-risk patients, where I just said you can give short-term hormone therapy, and we were trying to figure out that optimal timing of it, whether you should use an adjuvant or a neoadjuvant approach. And in this meta analysis of randomized trials, what we found, interestingly, was that all endpoints favored, that were significant, except for PCSM and overall survival, all favored the use of this adjuvant approach with the winning arm here. So, sequencing, in addition to duration, may be very important.

And so, all of what I've talked about so far is really oncologic outcomes, survival-type outcomes, but that's really only half the story when you're talking about hormone therapy, because quality of life is equally important, and to some patients, potentially more important to them. And it's very easy for scientists and researchers and clinicians to focus on the tumor response, but we really need to be weighing the harm, or the efficacy of our drugs to cancer, versus to the patient itself. We all too often focus when we look at things, like hormone therapy, on does it include the PSA values or various imaging results or the rectal exam findings and that early study of tumor progression. But we must remember that our treatments can harm quantity and quality of life in select patients.

And so, one of these studies, I like to always highlight is a big randomized trial done, called RTOG 96-01, which is a trial of men with recurrent prostate cancer that were randomized to receive radiation with either a placebo, or 2 years of high-dose bicalutamide and antiandrogen by itself. And what we've shown is that in men receiving early salvage radiation therapy, there's a two-fold increased risk of other cause mortality, dying of something other than prostate cancer, which was driven by a high-grade, predominantly cardiac toxicity, about a three-fold increase. This has been shown in select other studies with high-dose bicalutamide, and so again, we can't just focus on improvements in biochemical recurrence, we need to think about the overall benefit to the patient.

So hormone therapy has a variety of side effects discussed. On the right, in pink here, these are often metabolic-type side effects. On the left, these are very common things we think about. Loss of libido, erectile dysfunction, hot flushes. So some are mild, some are annoyances, but some can be serious for select patients. One that's often not probably discussed enough as this is a large meta analysis of over 150,000 patients, is hormone therapy has been shown, likely, to increase the risk of development of depression, and depression can be of various scales and severity, and so is important. And NCCN guidelines has a screening tool for this for patients.

One of the other issues with hormone therapy, especially when we're talking about with radiation where we're usually giving it for a finite period of time, it's not usually a lifelong, it's for 6 months or 18 months, is this is one of those trials that established, that compare 18 months of hormone therapy versus 36 months of hormone therapy with radiation. And although that's the duration they intended to give, it takes a long time to recover testosterone. And what you see here, is that it takes almost over double the duration that was given to recover. So for 18 months of hormone therapy, it took 3.5 years to recover back to normal testosterone, and for the 36 months, took a total of 6.6 years. And that's from initiation of hormone therapy. But what's also is important as you see that, despite this very long-term follow-up, 20% to 40% of men never even recovered back to normal testosterone levels.

This is similar and this surprises a lot of people when they actually look at this data that you've been short-term hormone therapy for 6 months is that you can see here, this is just the timing of hormone therapy, but it's 6 months in both arms, that again, starting at the initiation of that hormone therapy, keeps it low for 6 months, but it took almost an additional year for most men to get back up to normal testosterone, and still, about 20% of men have still not recovered to normal testosterone by years after treatment.

And so, it is exciting, and this is other work we presented recently, as well as this is published in the New England Journal, is the use of this novel GnRH antagonist called relugolix. Prior to the randomized trial I'll show you, they ran a Phase II randomized trial of this novel oral GnRH antagonist, relugolix, compared it to degarelix, the drug that I told you that was approved in 2008 that's an injectable given monthly, and both showed very good sustained castration levels over this 24-week period, but actually, relugolix had faster time, slightly, to achieve castration, but also a faster recovery time of testosterone after.

And what's even more impressive is their Phase III trial, which the majority of patients probably in the United States don't use degarelix, they receive leuprolide or something like leuprolide, and this was a big multi-national trial, over 900 patients. It's a registration trial, trying to get approval for relugolix. It was designed as a non-inferiority trial to achieve sustained castration of testosterone levels over a 48-week period with multiple secondary endpoints. A subset of these patients, given those talks about the use of radiation, that subset of these patients, about 150 of them, received radiation therapy with one of the two forms of hormone therapy, and it was primarily external beam radiation with the primary or curative setting or the salvage setting where we often deliver radiation therapy.

What you see here on the left, this are the overall trial results. Relugolix was not only non-inferior, it was actually superior to leuprolide, where 96.7% of patients had sustained castrate rate levels of testosterone, versus 88.8% with leuprolide. And similarly, as would be expected, those in the radiation therapy cohort had similar excellent sustained castration with the use of relugolix.

The secondary endpoints are also very interesting. They looked at, in the first column here, is testosterone suppression less than 50 nanograms per deciliter, but by day 4. And so what's amazing is, almost 60% of patients that received relugolix, and this is again, the radiation therapy subset, already had castrate testosterone and obviously none with leuprolide. And even by day 15, all the patients with relugolix were already castrate, and only 10% with leuprolide. And as even you can see with PSA responses that, of course, the testosterone goes down as expected, the PSA responds as well.

That's one of the advantages is this early, the left side of this, is comparing testosterone levels over time, as it's more rapidly you achieve castration, but it's very interesting as the tail of these curves. As I showed you with leuprolide, it can take years to recover to normal testosterone. Relugolix, you can see that within 90 days, which is just 3 months, over half of the men already had achieved normal testosterone levels. So this is something unprecedented that will allow future studies to tailor the on-and-off switch of how long you actually really want them to be under hormone therapy or castration.

And finally, a very exciting area that has been shown signals in other trials and studies, is they also showed this was not a pre-specified endpoint, but they did pre-specify they'd collect this data for safety, is they showed a significant reduction in major adverse cardiac events, which, as I showed you from that prior study of use of bicalutamide, for example, a substantial increase in risk of cardiac events. And so again, this is something, combined with prior data, that's at least promising, interesting, that requires further study.

So I think in summary, hormone therapy or ADT improves many important oncologic outcomes for men treated with radiation therapy. It's been shown in the correct patient populations to reduce recurrence of disease, reduce the development of metastasis, and even helps many men live longer. But we also must balance this with the side effects of hormone therapy, and we must personalize this risk-benefit ratio. Many of the side effects are minor annoyances, especially with short-term therapy, but some may be serious and patients need to be counseled on this. What is very exciting, as newer forms of ADT, especially a novel oral GnRH antagonist, if approved, does have, especially in combination of radiation therapy, many advantages given it's fast on-and-off mechanism, potentially, this cardiac reduction in side effects as well. So thank you so much.