Dr. Leonard Gomella spoke at the 24th International Prostate Cancer Update on Saturday, February 22, 2014 on “New Oral Androgen Receptor Pathway Agents are Changing the Way Prostate Cancer is Treated.” In his presentation, Dr. Gomella discusses new oral therapies for treating prostate cancer.
Presentation:
Keywords: abiraterone, androgen, castrate-resistant prostate cancer, enzalutamide, testosterone, docetaxel
How to cite: Gomella, Leonard G. “New Oral Androgen Receptor Pathway Agents Are Changing the Way Prostate Cancer Is Treated.” Grand Rounds in Urology. January 22, 2015. Accessed Dec 2024. https://dev.grandroundsinurology.com/prostate-cancer-leonard-gomella-new-oral-androgen-receptor/.
Transcript
New Oral Androgen Receptor Pathway Agents Are Changing the Way Prostate Cancer Is Treated
So I think you’ve seen at this meeting and progressively as we’ve gone over the last couple of years that we’re really doing well with men with advanced prostate cancer. This has sort of been an unprecedented time in the history of men with advanced prostate cancer.
This is a great graph. You’ve probably seen it before, where you can probably spend an hour just talking about this graphic. But we know early on, prostate cancer is hormonally sensitive. We do pretty well with surgery and radiation, but once we fail surgery and radiation, the cancer becomes metastatic. Androgen deprivation is our major approach.
However, eventually what happens is cancer cells figure out how to live, survive, and grow in the absence of normal level of testosterone. And along this pathway, what happens is patients gradually have a rise in PSA M0 pre-metastatic, asymptomatic, and as time goes on, they develop radiographic disease and then become symptomatic. This is the zone that we’ve had all the progress in. The patients who develop metastatic castrate-resistant prostate cancer and the amazing number of new agents that are available to us.
So the critical issues in castrate-resistant prostate cancer are making sure we understand the definition. It’s two consecutive rises in PSA while on androgen deprivation therapy, with a serum testosterone of less than 50. We’ve reviewed the fact that we’ve got to be a little bit better about checking testosterone levels as urologists and particular in men on androgen-deprivation therapy.
There is some data that suggests lower testosterone, the better you will do with advanced prostate cancer. We also know that the LHRH agonists, antagonists, or surgical castration actually don’t ablate testosterone to the lowest level as possible. And this has really become apparent to us as we have new agents such as abiraterone that get us down to testosterone levels to previously unseen that we’ll talk about in a couple of minutes.
And again, the key concept here is that prostate cancer and castrate-resistant prostate cancer remains responsive to the hormonal axis and this is a very critical key point. Most men with new castrate-resistant prostate cancer do not have radiographic metastasis. This is when the PSA starts to go up, with a low testosterone. But if you follow these men serially and Dave spoke about our radar project, where we’re trying to actually define what’s the best way to catch these men at the earliest possible stage of developing metastatic castrate-resistant prostate cancer.
In the literature, the median time to radiographic metastasis is around two to three years. As we go forward, the metastatic castrate-resistant prostate cancer domain is where the majority of our new advanced prostate cancer therapies have been approved the last three or four years.
So what does this all come from? Well, I think one of the big things we’ve seen is translational discoveries. Taking things that have been found in the laboratory and bringing them to the bedside as quickly as possible. And a lot of these new management strategies of castrate-resistant prostate cancer are based on what has been done in the laboratory and in the pre-clinical setting.
So what we’ve seen in castrate-resistant prostate cancer on the translational end is that prostate cancer responds to castration by increasing the synthesis of androgens from weaker androgens and cholesterol. The other thing is we’ve seen changes in the androgen receptor and that the androgen receptor may respond to castration with molecular and biochemical changes that cause it to have increased sensitivity or hypersensitivity to extremely low levels of circulating androgens. And basically, progressing prostate cancer with low levels or castrate levels of testosterone is still sensitive to androgen.
While this was theoretical, it’s actually now been shown and here’s really just a quick snapshot of a lot of basic science studies. But essentially, castrate-resistant prostate cancer samples have increased expression of the androgen receptor. At autopsies, very high amplification of the androgen receptor in patients with castrate-resistant prostate cancer. So clearly, this has been a big understanding for us. How in this low testosterone state, does prostate cancer continue to progress? And again, this is the new world of castrate-resistant prostate cancer.
Other key discoveries that were made was that prostate cancer can make its own androgens. This is a huge discovery that was only really found out about around 2006 or 2007, that when the patient has a low testosterone state and the prostate cancer progresses, one of the ways it progresses is by making its own androgens. So things also happen.
The androgen receptor also becomes hypersensitive to low levels and this can either happen through over expression of the androgen receptor, mutations in the androgen receptor, or androgen receptor cofactor imbalance. In other words, things that don’t normally activate the androgen receptor as the cell gets more and more malignant, new mechanisms turn on that can stimulate the androgen receptor.
So basically, we’ve known about this for a while, except we haven’t been able to put our arms around it. In fact, Dr. Huggins in a lecture, when he got the Nobel Prize in 1996, actually talked about the fact that despite regressions of great magnitude, it was obvious that there were many failures of endocrine therapy to control the disease.
In fact, it was in the 1990s that a bunch of investigators, such as Eric Small and Nick Vogelzang, defined the term “secondary hormonal therapy,” recognizing the fact that maybe there was still something going on in the hormonal axis that could be manipulated.
So the secondary hormonal therapies, once prostate cancer traditionally progressed, are things that we used for the last 20 years. The problem with all of these secondary hormonal therapies, they really were not durable and they didn’t really help us that much. They might help us for a few months, but rarely can they give you any type of prolonged response.
So fast forward to what’s happened over the last 10 years based on these basic science discoveries. We have developed some newer androgen receptor pathway agents. Dr. Mulders talked about a little bit of this yesterday. We’ll kind of go through some of the basics behind these new agents. But you all know that abiraterone was originally approved in 2011 in the post docetaxel space and in 2012 in the pre-docetaxel space.
But there’s also a couple of other oral agents that are in development that are very interesting. TAX 700 is another androgen biosynthesis inhibitor that is in late stage clinical trial. The — product, known as “TOK-001” or “Galeterone” is actually one of the more interesting new oral agents that’s out there, because it seems to do everything.
And if the promise of what this looks like in the preclinical settings is what it looks like on paper, this could be a very interesting drug and why is that? It seems to sort of smatter across the whole androgen axis. So it’s not only an androgen biosynthesis inhibitor. It’s an androgen receptor blocker, but also does something very interesting. It speeds up the degradation of the androgen receptor.
And ARN 509 is a new androgen receptor blocker that’s recently been picked up by Janssen that will be getting more and more play over the coming years. But we’re going to focus our discussion on the FDA approved agents right now.
We mentioned the abiraterone. Enzalutamide was originally approved in 2011, also in the post docetaxel space and again it’s anticipated that some time in the next year or so, based on the Prevail trial, it may be approved in the pre-docetaxel space.
So abiraterone has actually been around for a long time. It’s a — derivative, but it has irreversible and it’s a high infinity inhibitor of the SIP 17 axis, which is involved in steroidal adrenogenesis.
What’s interesting about the abiraterone is that unlike our old androgen blockade or combined androgen blockade where we just focused on the testicles and the adrenal gland, what abiraterone does, which is unprecedented across the spectrum of drugs for prostate cancer, it inhibits all sites of androgen production. And as we mentioned, what we now know is that the tumors themselves in the castrate-resistant phase, actually make their own androgen.
So not only will abiraterone eliminate the traditional testicular and androgen production, but much more importantly, it will go directly to the site of the tumor and interfere with the cells’ local ability, the tumor cells’ intracrine and autocrine production of androgens.
One of the tricks with using abiraterone is because of the decreased cortisol production, you get an increase in ACTH that can cause some of the side effects which is hypertension and hypokalemia. But again, we all know that’s why you give a low dose of the prednisone to try to block that.
This is the thing that has never been seen before. The dramatic changes in androgens with abiraterone. In fact, the assays, the standard assays that we have that stop basically at 1 ng/dL. Remember standard androgen ablation sometimes gets you down to less than 20, but virtually, these numbers have never been seen and this is because every site of androgen production, be it androstenedione, DHT, or testosterone is impacted by abiraterone. So abiraterone inhibits the SIP 17 enzyme complex and again it hits anything including the tumor in the body that could be producing androgens.
So we all know that this is the thing that we all remember from biochemistry. The androgen biosynthesis pathway taking from cholesterol, going down to either mineralocorticoids, glucocorticoids or androgens and estrogens. And again, this cholesterol precursor now we’ve been able to show can be taken up by tumor cells themselves and going through these same pathways, turning on these different enzyme pathways, the cell can actually begin to make its own androgens.
So abiraterone is known as an androgen biosynthesis inhibitor and it just turns out that abi is a short term that people use for abiraterone, but it’s also the ABI, the androgen biosynthesis inhibitor. So when you go down the pathway, abiraterone hits two places in the testosterone synthesis pathway. It hits the SIP 17, known as 17-alpha-hydroxylase, and also the SIP 17 pathway known as the C17C lyase pathway. So you end up blocking several points in the production before DHEA and the conversion to testosterone and dihydrotestosterone.
However, what happens is in some patients, and this is not all patients, but it was in enough patients that the FDA felt that prednisone should be added to the regimen of abiraterone. In fact, there’s data out there that suggests from very early work that the majority of patients don’t need prednisone. In fact, we’re hearing now that there’s a lot of practitioners around the United States who give abiraterone without the prednisone. However, having said that, the labeled indication for it is the use of prednisone, along with the abiraterone.
Basically what happens is because of your blockade of the pathway and the fact that you’re blocking the production of cortisol as well, you end up with a feedback to increase ACTH and, because of the relatively low cortisol levels, you end up increasing your mineralocorticoids. By replacing a little bit of prednisone down here to compensate the decreased cortisol levels, you block the hypokalemia, the hypertension, and the fluid retention in most patients that can occur with abiraterone.
Again, this was the registration trial that we’ve gone over several times that led to the approval of abiraterone in the post docetaxel space. Again, this is the 14.8 versus 10.9-month survival advantage after abiraterone. This was the trial that had abiraterone approved in the pre docetaxel space.
And again, the interesting thing about this trial. It was approved based on a dual primary endpoint of progression-free survival and overall survival. So it did meet the progression-free survival standpoint, but did not meet the endpoint of overall survival.
This is something that’s very interesting because if you look at this, this looks like a statistically significant P value. However, the way the trial was designed, the bar was so high, it had to reach a P value of 0.0008 to be statistically significant.
So although we saw a statistically significant overall survival in this pre docetaxel trial with abiraterone, because of this known as the “O’Brien Fleming Boundary, the way clinical trials work, it really had to be a much higher P value. And that’s whey when you see it, the quote “overall survival” was not necessarily met for the pre docetaxel trial.
So abiraterone is now approved pre and post chemotherapy. If you look at the followup analysis. The overall survival in the pre chemotherapy space was actually 5.2 months, which again by standard statistics is good, but by the strict trial criteria, the company actually cannot say it was statistically significant. But it’s clinically significant that you get this good survival.
It’s administered with four 250 mg taken once with 5 mg of prednisone b.i.d. Important to take it on an empty stomach and that’s a very critical thing that needs to be stressed. Patients need to be monitored for increased LFTs, hypertension, and hypokalemia.
Next, briefly we’ll talk about enzalutamide, which is a high affinity anti-androgen receptor blocker. What’s different, if you go back to the old androgen receptor blockers that we’re familiar with, bicalutamide and flutamide, this has absolutely no agonistic activity, which makes it a very promising drug.
The Affirm Trial was the post docetaxel trial which was the registration trial. The Prevail trial, was the most recent pre docetaxel trial and a very interesting ongoing study is known as the “Strive trial” in castrate-resistant prostate cancer, comparing enzalutamide early in the development of castrate-resistant prostate cancer to bicalutamide and that trial is currently ongoing.
So this was the Affirm study, the registration study that led to the approval of enzalutamide and post docetaxel. Again, I’ll go through these fairly quickly since Dr. Mulders already did a nice job of reviewing this. But the Affirm trial prolonged the survival in men by 4.8 months versus the placebo. And as David Crawford mentioned, the placebo was not a true placebo. These patients were on low dose of steroids because of the fact most of them were post docetaxel.
This was the very hot topic the last month or so presented at GU ASCO by Dr. Beers, the Prevail trial. This was the enzalutamide pre docetaxel trial where it randomized men to enzalutamide 160 mg a day, four 40-mg capsules versus placebo. Again, remember the placebo had to also include steroid and there was a dramatic improvement in radiographic progression-free survival.
There was a reduction of death by about 29%. The absolute reduction in death was about 2.2 months. So depending how you look at it, you can either say it was reduction in deaths of 29% or reduction in death by about 2.2 months.
Dr. Mulders went over some of the common side effects. Again, the seizure issue always comes up. In this particular study, there was only one patient in the placebo arm who had a seizure. But it should be noted these patients were excluded if they had any prior seizure history.
So enzalutamide right now is approved with a 4.8-month survival benefit in the post docetaxel space. Pre docetaxel, the improvement is only about 2.2 months, but the important thing is that there was a dramatic improvement in progression and it delayed chemotherapy by about a year and a half.
If you’re going to use enzalutamide, it’s four 40-mg capsules once a day. This particular drug is with or without food. Remember abiraterone has to be given on an empty stomach because of the absorption problems that can happen if it’s taken with food.
And an important point is there was a very, very low overall incidence of seizures, but remember there’s no absolute contraindication for seizures. It’s just a relative caution in the label.
When you compare our two hot oral agents that we have right now in this space, abiraterone or enzalutamide, you can see they line up fairly well. Each of them have some unique side effect profiles, but the bottom line, the most critical difference I think is the fact that abiraterone requires the use of prednisone according to the label and enzalutamide does not.
Well, where are we going with this? Much like Dave Crawford and others did the pioneering work on combined androgen blockade in the early 1990s, we’re now looking at a new wave of combined androgen blockade actually combining abiraterone with enzalutamide.
A preliminary trial is underway right now that will be out hopefully later this year, but Alliance, which is the new merged NCI cooperative group, Old –- CLGB and the North Central Cancer Treatment Group is opening a trial that will be combining about 1300 patients nationally. I think will be at the 29th Avail Symposium, Dave, by the time the data comes out for this study. But nonetheless, this is the direction we’re going in, combining these therapies together. So it will be very interesting to see where this comes out.
We have a whole bunch of agents out there with benefits in metastatic castrate-resistant prostate cancer. Certainly we focused on the oral agents, the abiraterone, the enzalutamide. Again, right now, enzalutamide is not FDA approved in the pre chemotherapy space, but it’s anticipated that it will be.
The reason I show you this. If you look at the survival, we’re all kind of stuck in this somewhere between three and five months survival advantage. So we’re going to have to hopefully combine agents in the future through sequencing. And how to administer and when to administer and combine these drugs, it’s going to be something that we’ll be seeing a lot of data on in the next few years. But which drugs to use first and what sequence to use them, we don’t know.
Lastly, Dan talked about a few of these drugs. There are just literally hundreds of medications out there in this space. Many of them are systemic. Many of them are orally administered and it’s a really hot area.
So if you go back to another look at our original diagram, if you look at the pre 2010, that was only a little more than three years ago, all we really had out here in this symptomatic metastatic castrate-resistant space was docetaxel and palliative chemotherapy with agents such as mitoxantrone.
Now in 2014, you have sipuleucel-T. You’ve got enzalutamide and abiraterone. In the post chemo, you’ve got cabazitaxel. In the post chemo, you’ve got radium 223, which could be used across the spectrum of castrate-resistant prostate cancer. And you now have abiraterone in the pre chemo and the post chemotherapy spaces.
So a lot going on. We have a lot of new oral therapies that have shown benefits in prostate cancer and these therapies are generally very well tolerated. They do require monitoring whether you’re using enzalutamide or abiraterone, you need to monitor liver function tests. You need to keep an eye on the blood pressure and the cardiac status. And basically, the sequencing of these is going to take really several years to establish.
And you all have seen these floating around the meeting. This will be a very useful supplement particularly for urologists. This supplement, which will be coming out in March, will be a CME supplement. And essentially, it’s going to be a mini textbook of all the new advanced agents that are available for prostate cancer, going from early metastatic disease through late metastatic disease.
And I think it’s going to be a very useful, practical resource that will take all this information and put it into individual — that could be used as a reference. This will be widely available. It’s going to be CME. It’s going to be in a flipbook format. So keep your eyes open for it. It should be out in late March of 2014. Thank you.
References
Ang JE, Olmos D, de Bono JS. CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer. Br J Cancer. 2009 Mar 10;100(5):671-5. http://www.ncbi.nlm.nih.gov/pubmed/19223900
Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008 Oct 1;26(28):4563-71. http://www.ncbi.nlm.nih.gov/pubmed/18645193
Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004 Jan;10(1):33-9. http://www.ncbi.nlm.nih.gov/pubmed/14702632
Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol. 2009 Oct;10(10):981-91. http://www.ncbi.nlm.nih.gov/pubmed/19796750
de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. http://www.ncbi.nlm.nih.gov/pubmed/21612468
El-Amm J, Aragon-Ching JB. The changing landscape in the treatment of metastatic castration-resistant prostate cancer. Ther Adv Med Oncol. 2013 Jan;5(1):25-40. http://www.ncbi.nlm.nih.gov/pubmed/23323145
Friedlander TW, Roy R, Tomlins SA, et al. Common structural and epigenetic changes in the genome of castration-resistant prostate cancer. Cancer Res. 2012 Feb 1;72(3):616-25. http://www.ncbi.nlm.nih.gov/pubmed/22158653
Hoffman-Censits J, Kelly WK. Enzalutamide: a novel antiandrogen for patients with castrate-resistant prostate cancer. Clin Cancer Res. 2013 Mar 15;19(6):1335-9. http://www.ncbi.nlm.nih.gov/pubmed/23300275
Hofland J, van Weerden WM, Dits NF, et al. Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer. Cancer Res. 2010 Feb 1;70(3):1256-64. http://www.ncbi.nlm.nih.gov/pubmed/20086173
Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004 Jan;164(1):217-27. http://www.ncbi.nlm.nih.gov/pubmed/16510604
Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006 Mar 15;12(6):1665-71. http://www.ncbi.nlm.nih.gov/pubmed/16551847
Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008 Jun 1;68(11):4447-54. http://www.ncbi.nlm.nih.gov/pubmed/18519708
Mostaghel EA, Nelson PS. Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. Best Pract Res Clin Endocrinol Metab. 2008 Apr;22(2):243-58. http://www.ncbi.nlm.nih.gov/pubmed/18471783
Nakabayashi M, Werner L, Oh WK, et al. Secondary hormonal therapy in men with castration-resistant prostate cancer. Clin Genitourin Cancer. 2011 Dec;9(2):95-103. http://www.ncbi.nlm.nih.gov/pubmed/21958520
Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. http://www.ncbi.nlm.nih.gov/pubmed/23228172
Scher HI, Fizazi K, Saad F, Taplin ME, et al.Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012 Sep 27;367(13):1187-97. http://www.ncbi.nlm.nih.gov/pubmed/22894553
Scher HI, Heller G. Clinical states in prostate cancer: toward a dynamic model of disease progression. Urology. 2000 Mar;55(3):323-7. No abstract available. http://www.ncbi.nlm.nih.gov/pubmed/10699601
Small EJ, Vogelzang NJ. Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol. 1997 Jan;15(1):382-8. http://www.ncbi.nlm.nih.gov/pubmed/8996165
Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006 Mar 1;66(5):2815-25. http://www.ncbi.nlm.nih.gov/pubmed/14695335
Taplin ME, Rajeshkumar B, Halabi S, et al. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J Clin Oncol. 2003 Jul 15;21(14):2673-8. http://www.ncbi.nlm.nih.gov/pubmed/12860943
Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009 May 8;324(5928):787-90. http://www.ncbi.nlm.nih.gov/pubmed/19359544
ABOUT THE AUTHOR
Leonard Gomella, MD, FACS, is the Bernard W. Godwin, Jr., Professor of Prostate Cancer and Chairman of the Department of Urology at the Sidney Kimmel Medical College of Thomas Jefferson University. He joined the Jefferson faculty in 1988 and was appointed Chair in 2002. He serves as Senior Director for Clinical Affairs for the NCI-designated Sidney Kimmel Cancer Center, Clinical Director of the SKCC Network, and Urology Chair for NRG (RTOG). Dr. Gomella is involved in translational basic science and clinical research in the development of new diagnostic techniques and treatments for prostate and bladder cancer through the Sidney Kimmel Cancer Center as Co-Leader of the Biology of Prostate Cancer Program. In 1992, he led the team that first used molecular techniques to detect circulating tumor cells in prostate cancer. He has given over 500 presentations, written over 400 papers, and edited dozens of chapters and monographs in the field of urology. Dr. Gomella has authored and edited many editions of a number of books for medical students, residents, and practicing physicians, including the “Clinician’s Pocket Reference” (aka “The Scut Monkey Book”) and “Five Minute Urology Consult.” He is also Editor-in-Chief of the Canadian Journal of Urology. “Recovering from Prostate Cancer,” which Dr. Gomella wrote in 1993, was the first book released for the general public specifically on the topic of prostate cancer.
“Best Doctors in America,” “Top Doctors for Cancer,” and Philadelphia Magazine’s “Top Doctors” have recognized him for many years for his contributions to urologic oncology and prostate cancer care. He also received national recognition in Newsweek in 2015. In 2007, Men’s Health listed Dr. Gomella as one of the 20 top urologists in the US. He has received numerous awards, including the American Cancer Society’s “Volunteer Achievement Award” and an “NCI Achievement Award.” He has been President of the Mid-Atlantic Section of the AUA and has been elected to the American Association of Genitourinary Surgeons and the prestigious Clinical Society of Genitourinary Surgeons. The University of Kentucky College of Medicine awarded him a “Distinguished Alumnus Award” in 2009. From 2015-2017, he was President of the Society of Urologic Oncology. In 2015, he received a “Distinguished Contribution Award” from the AUA and Jefferson honored him with the “Jefferson Achievement Award in Medicine.”