William R. Berry, MD, discusses luteinizing hormone-releasing hormone agonists versus antagonists as treatment options for patients and highlights the novel techniques for prostate cancer imaging.
William R. Berry, MD
Imaging agents for patients with prostate cancer continue to receive FDA approvals, according to William R. Berry, MD. For example, carbon-11 acetate PET/CT scans, 18F-sodium fluoride PET scans, and fluciclovine have been recently approved to add further imaging options for patients.
“All of these scans are helping us with the patients who have prostate-specific antigen (PSA)-only disease in terms of localizing disease and picking patients who have oligometastatic disease that may see minimal results to radiation or systemic therapy, giving the patient a chance for a longer-life expectancy,” states Berry.
In an interview with OncLive during the 2017 State of the Science SummitTM on Genitourinary Cancers, Berry, a medical oncologist at Duke Cancer Institute, discussed luteinizing hormone-releasing hormone (LHRH) agonists versus antagonists as treatment options for patients and highlights the novel techniques for prostate cancer imaging.Berry: My presentation was on 2 different topics related to prostate cancer. The first was the difference between the therapies of LHRH agonists versus antagonists, particularly with an emphasis on safety issues that may be related to the choice of agent.
The second part of the talk was related to new imaging techniques in prostate cancer and how they might enable us to localize disease more effectively. LHRH agonists and antagonists are similar drugs in the sense that they have the same clinical indication. They indicate for the decrease of testosterone production by the testicles. They work through the pituitary gland but they do have some differences in how they do that.
The agonists, which have been around since 1980, include leuprolide and goserelin, among others. There are 5 or 6 different FDA-approved drugs that fit that agonist category. They are called agonists because, when they bind to the LHRH receptor in the pituitary, they cause an initial stimulation of the receptor, which results in an excess release of LH and follicle-stimulating hormone (FSH). This causes testosterone to release early in the testicles within the first 10 days after therapy.
After that initial surge of testosterone is released, there is a gradual tiring of the receptor and the testosterone levels go down due to the decreased secretion of the LH and FSH from the pituitary. After a month or so after the first treatment, testosterone levels will be low despite that initial surge.
There is 1 antagonist drug approved in the United States called degarelix (Firmagon). The antagonist drug blocks the receptor and causes an immediate decrease in FSH and OH secretion, which results in an immediate decrease in testosterone production by the testicles. The levels of testosterone drop more quickly without that initial surge in testosterone. That is the basic physiologic difference in the mechanism of action. Before we had the antagonist, there was always a concern for people who presented with metastatic disease—particularly metastatic disease in the bone that they would cause a surge or exasperation of bone pain during that first or second week after starting therapy. The practice during that time was to prescribe bicalutamide or another antiandrogen drug to hit the tumor directly and prevent any flare of the testosterone that causes the increase in pain.
If you are concerned about symptoms arising during the first 2-week period, there may be an indication to use the pure antagonist during that time since you don’t have to worry about the issue, whereas with the agonist you might [have that issue]. For years, we have had primitive imaging with prostate cancer, which included technetium bone scans that have been around for more than 50 years. For example, we have CAT scans, which have been around since 1980. It is not a bad scan but it is not very sensitive at picking up metastatic disease. CAT scans can diagnose in large lymph nodes, but they can’t tell you what is in them. We do have some new scans based on molecular imaging, such as the newer PET scans. These are small molecule photon emitters of radionuclides onto a certain type of chemical product that may be specifically taken up by the tumor.
There are some that are FDA approved but are not uniformly available. Some have been around for a few years, including the carbon-11 acetate PET scans. There are 2 of those, one of which is FDA approved but at limited locations called the carbon C 11-choline scan. Choline is a molecule that is incorporated into submembranes, meaning the cells that are proliferating rapidly and making new cells need to incorporate choline to hike up the cell membrane of those new cells. Those rapidly proliferating cancers can be choline-positive and can be picked up by the carbon C 11-choline scan. You can pick up a disease in the prostate that has been radiated in the lymph nodes or bone. Since the radionuclide is specifically taken up into the tumor cell, you’re giving an image of the tumor.
The other one is a carbon C 11-acetate, which can pick up extra disease that's directly incorporating the tumor. The acetate is more of a fatty acid precursor or fatty acid synthase, which is upregulated in prostate cancer and is taken up by the prostate cancer cells in that circumstance. The results are similar to the choline acetate. However, the problem with both is that carbon C 11-acetate has a short half-life so you need a cyclotron on-site to generate the carbon-11, which creates a limited availability. The carbon C 11-acetate is not FDA approved, so patients have to pay out of pocket if they receive that scan.
Newer ones that have come out in recent years include 2 that are FDA approved. One of these is an 18F-sodium fluoride PET scan, which is the radionuclide in this circumstance. This is a scan where you can pick up bone metastases by the fluoride being incorporated in the areas of increased bone turnover which are associated with the tumor.
It will pick up the non-bone lesions and other areas where there may be some increase in bone activity. You need a good radiologist who is experienced in reading these, but it can differentiate between metastatic disease and benign disease. It is more sensitive and specific than the technetium bone scans. It's currently FDA approved, but it has not been commercially developed. Medicare has been doing a demonstration project on it for several years, so it is still available in multiple hospitals throughout the country via the Medicare demonstration project, but only for Medicare patients.
The other one that is FDA approved is becoming more available. It is fluciclovine, which is also a fluoride F18-based PET scan. Fluciclovine is a synthetic amino acid analog that is incorporated into prostate cancer cells through an amino acid transport mechanism. It is incorporated directly into the cancer cells as opposed to the F18-sodium fluoride, which is incorporated into the bone matrix. Fluciclovine can pick up lymph nodes, local disease in the prostate as a recurrence, and also in bone disease. It is a step forward in our imaging and, although it’s just becoming available, I am impressed with the results.
On the horizon are gallium-based scans with a prostate-specific membrane antigen (PSMA). This is one that would target the external domain of this transmembrane protein of PSMA. The technology is something that may be difficult to license, based on its ease of manufacture. It's not commercially available yet but hopefully we will see something like that in the future.
All these scans are helping us with the patients who have PSA-only disease—in terms of localizing disease and picking patients with oligometastatic disease that may see minimal results to radiation or systemic therapy, giving the patient a chance for a longer-life expectancy.There are some preliminary clinical data to suggest that there may be significantly less cardiovascular events with the pure LHRH antagonists versus agonists. The agonist has an FDA label associated with risk of diabetes and increased glucose intolerance, as well as the risk of cardiovascular events. There are some suggested data based on head-to-head trials that suggest that there may be a decrease in these cardiovascular events with antagonist therapy.
There is going to be a clinical trial which will be completed in 2020 that is looking at an LHRH antagonist versus leuprolide, which is one of the more commonly used LHRH agonists. This study will focus on these major adverse cardiovascular events, which includes a death by any cause or non-fatal strokes. If there is a significant difference in those events, that might change the practice of using these agents in prostate cancer.