Androgen Receptor-Targeted Treatments for Prostate Cancer: 35 Years' Progress with Antiandrogens - E. David Crawford

(Length of Presentation: 20 min)

Neal Shore, MD, FACS interviews E. David Crawford on a forthcoming paper he authored titled, Androgen Receptor–Targeted Treatments for Prostate Cancer: 35 Years’ Progress with Anti-androgens. This paper takes the historical approach in reviewing the treatment of prostate cancer, where we started in the 60's, where we are today and where we hope to be in the future.   

Biographies:

E. David Crawford, MD

Neal Shore, MD, FACS
Read the full video transcript:

Dr. Neal Shore: Hi everyone, this is Neal Shore, and it's my pleasure to interview my good friend and colleague, David Crawford. David has now accepted a publication that is now online in the Journal of Urology, or will be shortly, and will be published later on this year. I wanted to talk to him about it because in so many ways I think it just summarizes an exceptional career that David has brought to urology, and he's the first author of this paper, and I want to ask him about the other coauthors on the paper. It's really an exceptional group of folks who've penned the following article called: Androgen Receptor Targeted Treatments for Prostate Cancer: 35 Years of Progress with Antiandrogens

I'm really honored to have this opportunity to talk to David, who has been clearly at the absolute top of research and publications in the field of urologic cancer. One of the things, David, you've always done better than anybody I know, is getting together our colleagues internationally, nationally, to do really cutting edge, highly educational and informative papers on research, but also meta-analyses, guidelines, new recommendations and reviews. So what I wanted to ask you in the first question is, what was your inspiration for organizing this particular paper? And tell me a bit about this remarkably august group of folks, with the exception of me on this. But how did you come up with this list and the topic for this review paper?

Dr. E. David Crawford: Neal, thanks, and thanks for those nice comments. It's an honor to be involved with this. This is sort of a passion I've had for a long time, going back into the '80s, hormone therapy for prostate cancer. You know, I kind of grew up when I first started, when we had this orchiectomy and estrogens, and the two big arguments, you know, for a long time, was about dose of estrogens and treating patients with metastatic prostate cancer that did not have symptoms, maybe watching them and not treating them because you didn't want to have them experience side effects and become refractory.

My interest in this also paralleled a number of people in their work with the androgen receptor back in those days and in the early '60s when it first was discovered and characterized. We learned a lot about that receptor, and I always thought the best way to treat a prostate cancer would be to just inactivate the androgen receptor, and that sort of led to work with the antiandrogens, which are the subject of this paper. Why I was interested in doing that is that over the years there was a lot of interesting history that was developed and made regarding antiandrogens in prostate cancer, and a lot of controversy existed about this concept of using antiandrogens and combined androgen blockade.

So what I wanted to do was actually, and this has been going on probably for 10 years, thinking about doing a review paper on antiandrogens. So finally got in first place on my list of things to do, and you know what I did, how I got the people involved, these were the people that, they're the real leaders in this whole arena of antiandrogens. Paul Schellhammer, who worked a lot with this; David McLeod, who was with the National Prostatic Cancer Group; Judd Moul at that time also; Celestia Higano, who was involved in hormone therapy and intermittent therapy; Dr. Louis Denis from Europe, who was a leader there; Peter Iversen; Mario Eisenberger from Hopkins, who was my co-chair of the GU Committee at SWOG ; Fernand Labrie, who we can credit for starting this whole concept of antiandrogens with LHRH agonists; and of course, you, Neal. We appreciate everybody.

So I sent around the letter to people, and I said, "I want to write this article, you want to get involved?" It was amazing, everyone said yes right away. The group, that many of us haven't been together for a long time, sort of gelled and really in a short period of time put together an outstanding review, I think, of the 35-year history of antiandrogens, coming from this simple concept to where we are right now with the excitement with the new, we call, third generation antiandrogens that are out there.

Dr. Neal Shore: Well, that's a great overview, and I would echo exactly what you said. What an honor to be involved in this paper spearheaded by you and your innovation and your leadership, none of this gets done without you. But one of the things I've heard you say, I've heard you say it so many times is, "What we really need is an antiandrogen or an androgen receptor that really works and really works well." I've heard you say this for over a decade, and it's always been interesting to me that so many papers begin with, "Androgen deprivation therapy is the mainstay of prostate cancer care." There's a certain truth obviously to that, but you've been the one out there saying, "Let's think about it in a different term, let's think about it just an androgen receptor blocker, antiandrogen, whatever the parlance, that really works."

Dr. E. David Crawford: Well, you know, testosterone is king here, and we've learned over the years that as you block it, and now even down to lower levels with third generation antiandrogens and androgen biosynthesis inhibitors, and so forth, that you can eke out responses. You know, it makes sense. I don't think there's anything brilliant about, what I've been saying actually for several decades is that the best drug to treat prostate cancer or any one that alters testosterone is an antiandrogen that really knocks out the androgen receptor. The androgen receptor is really our key to understanding this.

You know, we have learned a lot even since the 1960s about the ligand binding area, the DNA binding area, that antiandrogens now do more than one thing, block the receptor, but also can be involved in blocking the translocation into the nucleus, as well as DNA binding. As we progress from the early antiandrogens, flutamide and nilutamide, and even the steroidal antiandrogens that we discuss in this paper, a lot of people forget about, those were the first ones out there, Megace, megestrol acetate, and cyproterone acetate, but they were steroid moieties that had antiandrogen properties. So they sort of acted like estrogens, and unfortunately had some of the side effects of estrogens, but they were weak antiandrogens.

So we started out with a concept that, hey, you know what, even if you do a bilateral orchiectomy, you still have testosterone around, and where does it come from? It comes from the adrenal gland, which was the main target with antiandrogens early on in some of our early work and Labrie's work, and others, and also, the concept of the tumor itself making androgens. So there are really three sources of androgens, there's the testicular source, there's the adrenal source, and there's the tumor. We only really deal with one, basically, when we use orchiectomy or LHRH agonists and antagonists, and we sort of let the others slide by. That really led to that first big trial that we did and published in 1989, showing that the combination of flutamide with daily subcutaneous leuprolide improved survival rate from 28 to 36 months, and that was significant, that's like a six-month survival benefit or more.

So what we said is that this is sort of the new therapy, six to eight-month survival benefit is huge. But it really sparked a lot of controversy back in the '80s, and things like, "LHRH compounds aren't very good drugs, and flutamide just made it look better, and you only needed it for the flare," and things like this, so controversy ... There were a lot of trials that were done both in the US and Europe, and that's how I got some of my coauthors, Dr. Denis and Iversen, from Europe, and people from the United States, Schellhammer, Mcleod, Eisenberger; and Canada, Labrie, and you, and others that have contributed here. That sort of stopped for a while, but people still use combined androgen blockade, and I think they really should.

So that really led up to, you know, the first antiandrogens were not very good. Flutamide, interestingly, was developed by Rudy Neri at Schering. He was working to find a bacteriostatic agent, thought it was, and then found out it was an antiandrogen, and that really opened up a lot of doors. Then we had nilutamide. Then the next big jump was the second generation, which was bicalutamide. That really put antiandrogens back on the radar screen. Lots of studies were done with bicalutamide.

So the concept was, wow, if antiandrogens are really good, why do you need LHRH agonist or other ways? And so if you can bind the receptor. Bicalutamide did better than flutamide, but in every study that was done, an antiandrogen monotherapy was never quite better or equivalent to LHRH therapy or bilateral orchiectomy. But again, there were less side effects when you did that, because you're not lowering testosterone, it actually goes up a little bit, and that's why you get some breast enlargement, because of aromatization of testosterone to estrogens.

So the ground was set, and the combined androgen blockade continued. Monotherapy with Casodex, bicalutamide was studied, even up to 150 milligrams. But what pretty much shut that down was the cardiovascular side effects in some of these trials even with an antiandrogen, and people backed away from it. You know, it's back right now, and that's something you can discuss in length at another time, is this whole cardiovascular step. So we went forward, and now we have what we call third generation antiandrogens, Neal.

Dr. Neal Shore: That's an amazingly succinct summary of really so many of the great points in this paper. I think folks will really enjoy reading the paper, not only just residents and fellows, but any of our colleagues, medical oncologists, urologists, radiation oncologists who treat patients with advanced prostate cancer. Before we end though, David, I'd love to hear your thoughts about the third generation now of antiandrogens and where it's moving with enzalutamide, apalutamide, and even potentially drugs in the pipeline like darolutamide.

Dr. E. David Crawford: Yeah, and I think that's where the fun part of this paper has been the evolution, and you know, like first, second and third generation cephalosporins, we have first, second and third generations of lots of things in drugs. We've come a long way from that two flutamide tablets three times a day, with the side effects, the diarrhea and liver enzyme elevation, hepatitis, anemia, things like that. Then we've learned a lot about antiandrogens and the way to make better molecules. So we were sort of stagnated from, I would say, the '90s to 2010, maybe 2009, when enzalutamide was announced in a metastatic paper, a castrate-resistant paper, to have an effect on advanced prostate cancer. 

So enzalutamide, and as you mentioned, most recently apalutamide, and darolutamide, then they're all lutamides as you can tell, flutamide and so forth. Right now, basically, enzalutamide, having that in this space as a third-generation drug, and what was found out was that taking patients in the worst-case scenario post-chemotherapy in a trial called AFFIRM, showed that you could eke out a response with an antiandrogen, and then failing chemotherapy and on hormonal therapy. The companion thing with that was the androgen biosynthesis inhibitor, abiraterone, Zytiga. That suddenly opened up a whole new interest in antiandrogens.

Then, as you and I know, and have talked many times in meetings, that the way forward is earlier and not just in a severe state of post-chemo. What we saw enzalutamide move up to was a PREVAIL trial, and pre-chemo, and then TERRAIN trial, and one you've been involved in, most recently the PROSPER trial in the M0 space. Concomitantly we had just recently a lot of excitement with apalutamide and the M0 space in 2018.  Smith published this in New England Journal of Medicine, and FDA approval. This is an unmet need, so now we have antiandrogens in this space, and the PROSPER trial was also positive with enzalutamide.

Then we have even maybe a different approach, darolutamide, which is another third generation antiandrogen. So the excitement to me here and with this paper, Neal, was the fact that a foundation was started some 35 years ago, it was a little rough getting it off the starting line, and then some very positive studies, but a lot of controversy about combined androgen blockade. We're starting to see people say, "Hey, you know what, that's real, and controlling testosterone as best you can is important, and we do that variably with some of the LHRH agonists, and so forth, and antiandrogens do help."

Now we've evolved into, hey, in patients failing everything, they can respond to antiandrogens. You know, we kind of knew a little bit about that in the past, because when patients who were failing monotherapy with LHRH agonists, adding antiandrogens got a 30% response, and also withdrawing antiandrogens did early on, and because some of the early antiandrogens after a while had a reverse effect, they were agonists.

So just sort of finishing up here, it's an exciting time with all the new drugs in prostate cancer, not just only antiandrogens, but other drugs, and combinations as we go forward. We're starting to see the major impact that moving these drugs early, early, earlier in the disease. Trials are ongoing right now with men with localized disease actually hormonal therapy versus active surveillance, and things like that. So it's really a great time and we've come a long way in the history of the antiandrogens to where we are right now.

Dr. Neal Shore: Well, David, I know on behalf of all of the coauthors, everyone was so happy to be involved in this paper, because you invited them. The paper doesn't get done without you and your leadership and your perspective. Your experience and your historical perspective, as you articulated today, is priceless, frankly, for the urologic community. I know we're all really excited to see the paper in print, and I think it'll be coming out sometime in the fall in Journal of Urology; it's EPUB now. I can't thank you enough. I know all the coauthors feel the same way. Enormous contribution, it's a great article thanks to you, and thanks for your overview.

Dr. E. David Crawford: Well, thanks, Neal. I do want to recognize you and all the coauthors. Without the input, and believe me there was a lot of input, and arguments back and forth, but we had a consensus, you know, and it's nice to get this in print for historical reasons, that they'll be able to go back and get the leaders that were involved in this, and get this laid out and all their different points of view and how we got to where we are now. So, thanks.

Dr. Neal Shore: All right, thank you very much.
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