Abarelix: The First Long-Acting Antagonist

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Dr. Hugo Verhoeven: "My name is Hugo Verhoeven and I'm from the Center for Reproductive Medicine in Dusseldorf, Germany. I'm on the Editorial Board of the OBGYN.net, I'm reporting from the 6th International Symposium on GnRH Analogues in Cancer and Human Reproduction in Geneva, Switzerland. It is an exceptional honor for me to introduce Professor Claude Schulman from the Erasmus Hospital, University of Brussels in Belgium. Professor Schulman, thank you very much for giving me the pleasure of doing this interview with you. I just attended your lecture on Abarelix which long-acting antagonist. Before we talk about Abarelix, tell our listeners what is an antagonist and what is the difference with an agonist?"

Professor Claude Schulman: "Of course, the main interest is for the first time we have a new approach to the treatment of prostate cancer regarding the hormonal pathway. Usually we are using pharmacological castration with agonists of GnRH that act indirectly. Castration is obtained indirectly by two steps - through the pituitary as an analogue so it's administered with normal GnRH and then it interferes with the usual pathway from the pituitary to the testes but there is also a different feedback mechanism to obtain this castration. With an antagonist, you have a direct blockade at the pituitary level of the GnRH access and stimulation, a pathway that goes directly and acts at the level of the prostate. This is a nice theory but what does that mean clinically and where is the difference? Well, the difference is many folds and graphs could help to explain this but when you use an agonist you have an initial stimulation at the pituitary level of the main hormones like FSH and LH. You immediately see the implication of a surge of testosterone, which is called the flare reaction so you have a rise in testosterone and then you have a progressive decrease and you obtain castration after several weeks. With the antagonist you have absolutely no problem with flare and you have a very rapid castration within days. Usually at one week more than two-thirds of the patients are castrated so it's much more rapid, it's faster, and you don't have a flare and a surge. There are further differences…"

Dr. Hugo Verhoeven: "Why don't you like the flare up? What are the disadvantages of the flare up?"

Professor Claude Schulman: "It's not a question if I like it, it may kill patients. You have a flare, and what does a flare mean - in advanced disease you in fact stimulate cancer because you have a rise in testosterone. It's like you would give estrogen to somebody who has breast cancer, it's the same, I would say, nonsense. So you have a rise in testosterone that stimulates the cells so this can be observed clinically in advanced disease where patients have more pain if they have metastases. If they have bone pain and you give them an agonist alone, it will increase the pain. It can paralyze some patients who are at risk of medullary compression because you increase the cancerous cell and you can increase urinary symptoms, and renal insufficiency by urethral obstruction - this is in advanced disease. In local disease, nobody knows exactly what the implication of this surge is but it certainly can be potentially very harmful because it stimulates a cancer, and then you first simulate it before you kill it. That's why usually or as a rule the usual agonists of LHRH have to be combined with an anti-androgen precisely to avoid this surge. So when you use an agonist you have to combine two drugs, the agonist and an anti-androgen so it increases the cost and it increases the side effects even if the use of an anti-androgen is limited in time. Important is also when you use an agonist or even when you use the combined maximal androgen blockade after castration you have a progressive rise in FSH. The significance of this rise is not yet very clear but it might play a very important role in the development of hormone resistant prostate cancer. We know that in the beginning all patients with prostate cancer are sensitive but at the end of the story they all die from their hormone resistant prostate cancer and in a way probably find some new pathways that were presented at this Congress like FSH receptors, probably the traditional way does not suppress and control the FSH receptors, and at the end of the day patients die from becoming hormonally androgen resistant. Eventually with the new antagonist you don't see this rise in FSH, the FSH remains very low and eventually this can be a potential significance in avoiding or decreasing the development of hormone resistant prostate cancer."

Dr. Hugo Verhoeven: "Why should the patient develop a resistance to an agonist and not to an antagonist?"

Professor Claude Schulman: "He does not develop a resistance to the analogue, he develops a resistance to hormones because the androgen receptors are not the only receptors you block. When patients die they still have androgen receptors but they are hormone insensitive so it's either through a mutation as it was also shown recently in some prostate cancer cells and cell lines. You have mutations that become hormone resistant or you induce a progressive adaptation of the cells that are not sensitive to hormones anymore. So the mechanism is not yet clearly and entirely understood but we know that there are problems, and we hope that we will decrease these problems but this is not yet clear."

Dr. Hugo Verhoeven: "The first antagonist we had was Cetrorelix, then we had Ganarelix, and now we'd like to concentrate on Abarelix. What is new about Abarelix?"

Professor Claude Schulman: "The first two drugs that you mentioned are essentially used in gynecology and obstetrics. In the field of prostate cancer, which of course is the one for urologists and oncologists, the two initial antagonists have not been used so far or at very early pilot study level. Abarelix is the first one that is now clinically available in studies so far but will become important in the near future because it has the advantage of being given in a depot formulation - a one month depot and eventually two weeks depot if you want to increase the dose but the formulation is a one month depot formulation."

Dr. Hugo Verhoeven: "So the way of administration of Abarelix is a depot."

Professor Claude Schulman: "Yes, it's a intramuscular injection once a month which is very convenient."

Dr. Hugo Verhoeven: "The product is not on the market?"

Professor Claude Schulman: "No."

Dr. Hugo Verhoeven: "But research is going on."

Professor Claude Schulman: "And it's under FDA approval."

Dr. Hugo Verhoeven: "How far are the studies now?"

Professor Claude Schulman: "There are three Phase III studies, two in the U.S, and one in Europe covering about 700 patients so far. These studies are already quite advanced; we already have early data on three months and for some studies we already have one-year data that will be presented later in April in Geneva during the European Association of Urology Congress. The long term data on Abarelix also looks promising."

Dr. Hugo Verhoeven: "You're final remark during your presentation was : are we still going to be talking about agonists two years from now. I have the impression you are very fascinated about antagonists. What are the indications for Abarelix and especially what are the results? What will be the change or the difference for the patients?"

Professor Claude Schulman: "At the present time with the present observation and data at short term but, hopefully, confirmed at the long term we see many advantages as I outlined initially on the use of an antagonist versus an agonist. So far we don't see any disadvantage so what place will be left for an agonist is leading to a question - why should we use a drug that will be outdated that needs to be combined, which probably raises significantly more side effects and costs especially if you have to combine two drugs? If a new approach is available and confirmed on the long term, I would be tempted to think that the place of agonists will disappear."

Dr. Hugo Verhoeven: "Where do you see the main differences? Is indeed the death rate really different between agonists and antagonists ?"

Professor Claude Schulman: "We cannot speak yet about a change in the death rate, if the treatment is similar it will not have a significant impact on survival mortality except, as we hope from this preliminary data on FSH receptor, it may improve the results by decreasing the hormone resistance. But not speaking about survival and just on clinical data on background, there are several different clinical situations where we see an advantage. If you take a patient with advanced disease - metastasis, you avoid the flare, there are less risks of bone pain, medullary compression, you have a much more rapid decline of PSA, and a more rapid castration so the more rapid you are, the more effective you hope to be. In locally advanced disease there are different settings, which are attractive, you have patients that undergo radiation therapy or brachytherapy with implantation of seeds. Nowadays it is considered that neoadjuvant hormonal treatment is of interest because you reduce the tumor volume and you target and potentiate the radiation effect by hormones, so with a drug like Abarelix you will act much quicker and you have a much more profound decrease in the volume of the glands. You also have a transient effect, that means that once you stop giving Abarelix, you see very rapidly and quite immediately testosterone rises again, so if you wish to have neoadjuvant treatment or intermittent treatment, as we call it, it's an ideal drug because once you stop it you really stop the effect. When you use an agonist, you maintain castration for a long time and then you don't really improve the quality of life and the sexual possibilities. With an agonist for those patients used as a neoadjuvant treatment for radiation and as intermittent treatment, it has many advantages also."

Dr. Hugo Verhoeven: "I heard today that every five seconds in the United States a prostatic cancer is discovered so the demand for this treatment must be enormous."

Professor Claude Schulman: "Yes, because in addition every thirty seconds somebody is dying from prostate cancer so with the increase in the aging of the population the incidence and the mortality of prostate cancer will increase significantly. It is already the most frequent cancer in men and it is the second killer after lung cancer. This incidence is on the increase with the increasing life expectancy and for patients that were considered old a few years ago, who were seventy-five, in five or ten years being seventy-five gives you a life expectancy of more than ten years so one could not ignore prostate cancer in an elderly patient anymore. We need to treat them if you want to maintain people in a good clinical and quality of life situation."

Dr. Hugo Verhoeven: "My final question is : is there also an indication for Abarelix or other antagonists in the treatment of benign prostatic hypertrophy? "

Professor Claude Schulman: "That's a very good question and a very difficult one to answer because at present we don't really have strong data on this but we think at some level we focused too much previously on the androgen receptor especially in BPH. If we focus more on new receptors like the FSH receptor that are directly present in the human prostate, we might find a new pathway to treat BPH with antagonists if this receptor plays a role in BPH, which at the present time we do not know."

Dr. Hugo Verhoeven: "So Abarelix is important for the future?"

Professor Claude Schulman: "Certainly."

Dr. Hugo Verhoeven: "Professor Schulman, thank you very much. It was a real pleasure talking to you."

Professor Claude Schulman: "Thank you very much."