Dr. Crawford on LHRH analogues in prostate cancer

E. David Crawford, MD

Urology Times® is celebrating its 50th anniversary in 2022. To mark the occasion, we are highlighting 50 of the top innovations and developments that have transformed the field of urology over the past 50 years. In this installment, E. David Crawford, MD, discusses the development of luteinizing hormone-releasing hormone (LHRH) agonists and antagonists in prostate cancer. Crawford is a professor of urology at the University of California, San Diego.

Could you provide an overview of the development of injectable LHRH analogs?

The history of androgen deprivation therapy—what we used to call hormone therapy—really goes back to the 1940s. Out of Chicago, Charles B. Huggins, MD, and Clarence V. Hodges, MD, started working with removing men's testicles and giving estrogen as a pill. Actually, the first oral therapy for any cancer was estrogen back in the 1940s. Later, Huggins won a Nobel Prize for that. The problem with bilateral orchiectomy was that we were removing the testicles, and doing that wasn't exactly a hit with a lot of men. Plus, there were side effects—hot flashes and things like that. Estrogen was a pill, and it really worked well except for the side effects, which included cardiovascular side effects and also issues with breast enlargement.

Fast forward to the 1970s and the work of Andrew Schally, MD, from New Orleans. He won a Nobel Prize for his work in studying the messengers from the pituitary, particularly the LHRH pathways. He analyzed and described the decapeptide and began work on a way to antagonize this decapeptide. Decapeptide means 10 amino acids, so that's not a big molecule. So to play around with a couple of the amino acid sequences, and trying to do an antagonist that, when you get it, would shut down the messenger from the pituitary to the testes to produce testosterone. It's a pretty simple mechanism; the pituitary releases LHRH, that hits the testicle, that results in the rise in testosterone and some other things. And then when the testosterone gets to a certain point, it feeds back on the pituitary area and shuts it down. So it's a loop. Estrogens work at the brain level to pretend it's testosterone. Schally developed this but could never get an antagonist, something that really would shut down the axis. But he did note that if you had something that was potent, and you gave it in super physiologic doses, that you could actually just beat the pituitary down so it didn't release the LH and then also FSH, after a couple of days. These are small molecules and peptides, so they're not really taken orally very well, they're broken down; that led to the injections. The other problem was the delivery system, how would you give something into the body, intramuscular subcutaneous that would stay around and not be absorbed or broken down? That led to a lot of work, and to where we are right now, but it started out with a daily subcutaneous injection with a compound called leuprolide acetate, which is very similar to the LHRH. But what happens is that it has about 3 amino acids that are changed. We started out with daily subcutaneous injections in the 1980s. We actually did a study published in 1989 in the New England Journal of Medicine about the injections along with an anti androgen, which are very popular right now. There were 2 things that were going on back then. One is that we needed to get away from estrogens and orchiectomy, and now we had an alternative. But the challenge at that time is that these daily injectable drugs were not covered by insurance companies. It took a while for that to happen. The big breakthrough really occurred in about 1989 when a depot was released. This was a way with microcapsules to take this decapeptide, encapsulate it, and then have it in a slow release. So you would give an intramuscular injection and you would suppress testosterone. This was a game changer because now we were opening up doors to treating a lot of things. Also, PSA came along at that time. This was the start of the "industrial revolution" of LHRH compounds.

Since 1989, researchers have been able to develop not only 1 month, but 3-, 4-, and 6-month and even yearly depots to give the drug. They're very effective when they're given on time. Then, what we got into was the fact that we were using these drugs, in combination with therapies improving outcomes with radiation, improving outcomes with rising PSA, improving outcomes with metastatic disease, and then screening came along—treating patients earlier, and we were really making an impact.

LHRH compounds are the backbone of androgen deprivation therapy. Everything is built on top of these drugs. And we now have not only agonists that Schally developed, but we've been able to develop 3 antagonists over the years. One was abarelix [Plenaxis], which was developed about 20 years ago. Then we had degarelix [Firmagon], which was about a decade ago, and just in the past couple of years an oral antagonist called relugolix [Orgovyx], which is a daily pill. We've also learned that there are some risks with androgen deprivation therapy beyond what we knew about back then: hot flashes, weight gain, loss of libido, osteoporosis, osteopenia, mental changes, cardiovascular side effects, metabolic syndrome, changes in lipids, and so forth. Where we are right now is recognizing those, and one of the most significant things we can do, and we're working on this with a couple of companies right now, is to ameliorate the side effects of LHRH therapy. One of the best things to do is exercise and diet. It doesn't cost any money; it's not pills and things like that. But it's hard to motivate people. I can tell you, my patients that are on LHRH compounds that stay in shape, don't gain a lot of weight, and exercise, they get through this and do very well.

LHRH therapies are not going away. They are the standard of care. And now we're building on those with adding drugs like I mentioned. We're adding anti androgens, we're adding chemotherapy. I had the honor of presenting a study at the 2022 AUA Annual Meeting of therapy for newly diagnosed metastatic disease with a combination of ADT, chemotherapy, and darolutamide [Nubeqa]. There are other ones out there that have been done with chemotherapy alone with these new anti androgens. Apalutamide [Erleada] is one of them; enzalutamide [Xtandi] is another.

I want to see us make prostate cancer when it's in its advanced stages, a chronic disease. We don't cure chronic diseases like diabetes and heart disease; we treat them, we keep people alive so they die of something else. We're getting there now [with advanced prostate cancer].