Treatment of Metastatic Prostate Cancer. At the end of this lecture, students will be able to, number one, understand how and when hormonal therapy is used to treat advanced prostate cancer. Number two, understand how and when supra-castration therapy is used to treat advanced prostate cancer. Number three, understand how and when chemotherapy is used to treat metastatic prostate cancer. Number four, understand how and when immunotherapy is used to treat metastatic prostate cancer. And number five, understand how and when systemic radiotherapy is used to treat metastatic prostate cancer. It is an unfortunate fact that nearly a 100% of men with prostate cancer have involvement of their bones at the time of their death. These metastases are osteoblastic, consisting of poorly woven bone. They represent a challenge for treatment. The main treatment types for advanced and metastatic prostate cancer are hormonal therapy, chemotherapy, targeted therapy, immunotherapy, systemic radiotherapy and stereotactic body radiation therapy, or SBRT. Let's take a look at how and when these are used. When patients develop clinical metastases, they are first treated with androgen deprivation therapy and then move on to other therapies when they become castrate resistant. We are going to go through each of these therapies in some detail. First-Line Hormone Therapy for Metastatic Prostate Cancer. As we have talked about previously, hormones are chemicals that your body makes to tell various organs what to do. The female hormone estrogen controls the development of female secondary sexual characteristics, such as breast growth and regulation of menstrual cycles. The male hormone testosterone tells male reproductive tissue, such as the testicles and prostate to grow as well as promote increased muscle bone mass and body hair. First line therapy for prostate cancer has traditionally been called hormone therapy. Why? Well, hormones can contribute to the growth of cancer. The female hormone estrogen stimulates breast cancer growth and anti-estrogen agents are used to help treat breast cancer. The male hormone testosterone stimulates prostate cancer growth. And anti-testosterone agents are used to treat prostate cancer. Let's look at where circulating testosterone comes from. Inside the brain, the hypothalamus secretes luteinizing hormone releasing hormone, or LHRH, to the pituitary, which then secretes liutinising hormone or LH. LH travels through the bloodstream to the testicles. And the testicles then produce 90% of the testosterone in a patient's bloodstream. About 10% of circulating testosterone also comes from the metabolism of steroids that are produced by the adrenal gland. Regardless of where that testosterone is produced, it circulates through the blood and can enter a prostate cancer cell. There, it is broken down by the enzyme to dihydrotestosterone, its active metabolite. Both testosterone and dihydrotestosterone can then bind to androgen receptor. When the androgen receptor binds dihydrotestosterone, it moves to the nucleus and causes proliferation of the cancer cells. Blocking the action of testosterone can essentially be done in two ways. One, you can block the secretion of LHRH from the hypothalamus and this is done with LHRH blockers. A second way is to bind the androgen receptor directly with inhibitory blockers. That's why we call them androgen receptor blockers. So the first line therapy for treating Metastatic Prostrate Cancer is hormonal therapy to decrease circulating testosterone. This castrates the patient. Since we do not like to use the word castration in referring to treatment, we have often called it hormonal therapy. Make no mistake what is happening is that we are castrating the man. In fact, the first therapy for prostate cancer really was to surgically remove the testicles. These medicines do it for us. The most common hormonal therapy is with drugs that tell the brain not to stimulate testosterone production. These are the LHRH analogs and include Eligard, Zoladex, Trelstar, Vantas and Firmagon. Another common drug is Lupron. These drugs can also be used in combination with agents that block testosterone binding to the androgen receptor in the cancer cell. These medicines include Eulexin, Casodex and Nilandron. The most commonly utilized medicine for this in the United States is bicalutamide, which goes by the trade name Casodex. Patients often ask, how effective is first-line hormone therapy, or as we now know, first-line castration therapy? Well, this can be measured in a couple of different ways. One is progression-free survival, how long before a patient has their disease progress to the the next phase of their cancer? In this case, we refer to that as how long before a patient becomes castration resistant. Another way that physicians measure is overall survival, how long before a patient dies? Currently, the approximate average survival from the start of first line hormone therapy is five to six years for men with metastatic disease. This depends on age of patient at the diagnosis, depends on the amount of disease at diagnosis. And it's important to note that this is a broad range that will change as other therapies are developed. Let's look at some specific examples of where these numbers come from. In this study from the Southwest oncology group, approximately 1000 men were followed for survival after starting hormonal therapy for their metastatic disease. The median survival was five to six years. What this means is that, at six years, half the men had passed away and half were still alive. You can see along the tail of the curve on the right, that some men were still alive as far out as 15 years after starting therapy. A recent study, called CHAARTED, looked at the overall survival of men with metastatic prostate cancer, who were started on hormonal therapy or hormonal therapy plus six doses of chemotherapy with docetaxel. You can see from this graph, when all patients were examined, the median survival in the hormonal therapy treatment alone ADT, which stands for androgen deprivation therapy, was 44 months. In the patients who received chemotherapy plus androgen deprivation therapy or hormone therapy, the median survival was almost 58 months. The data reported here was for all patients. But we can also break it down by how much disease the patients had at the time of diagnoses. For patients with what was called high-volume disease, meaning that they had quite a bit of cancer at the time of diagnosis. You can see that the hormone therapy alone group, the medium survival was only 32 months. But the chemotherapy plus hormone therapy group was 50 months. For patients with low-volume disease, meaning they only had a few spots of metastatic cancer, all of the patients are still alive at 60 months. The median survival or the average survival has not been reached yet. The data from the CHAARTED study suggests that how much disease a patient has at the time of diagnosis matters to overall survival. It also suggests that patients with a lot of cancer at the time of diagnosis may benefit from adding chemotherapy to hormonal therapy at the start of treatment. Many physicians are starting to treat patients in this manner. The CHAARTED study has changed the way we think about how to treat men with newly diagnosed metastatic disease. As I mentioned to you at the start of this lecture, first line therapy for men with newly diagnosed metastatic disease is hormone therapy. What the CHAARTED study revealed was that, for men with newly diagnosed metastatic disease, especially those men with high disease burden, it may be beneficial for them to receive not only hormonal therapy, but six doses of chemotherapy at the start of their treatment. Many practitioners around the United States and indeed around the world, are adapting this as practice. Therefore, the new standard of care for men with high volume metastatic prostate cancer is either androgen deprivation therapy alone or androgen deprivation therapy plus docetaxel. What are the side effects of hormone therapy? The side effects of hormone therapy are really the result of low testosterone. These include reduced or absent sexual desire, erectile dysfunction, shrinkage of the testicles and penis, hot flashes, which may get better or go away with time. Breast tenderness and growth of breast tissue, osteoporosis or bone thinning, loss of muscle mass, weight gain, fatigue, decreased mental sharpness, depression, and increased cholesterol levels. We will address how to mitigate some of these side effects in lecture five. Eventually, hormone therapy almost always fails. Although there are many mechanisms, a major mechanism is the amplification, which means the increase in the numbers of the androgen receptor. As the prostate cancer cells are starved, they make more androgen receptors to try to use the little bit of testosterone that is left. This is referred to as Amplification of AR, meaning amplification of the androgen receptor. This allows the prostate cancer cells to use testosterone to keep growing, despite being castration resistant. Therefore, the official definition of castrate-resistant prostate cancer, or CRPC, is cancer that is still growing, despite the fact that hormone therapy given through an orchiectomy or an LHRH agonist or antagonist, is keeping the testosterone level in the body as low as what it would be expected if the testicles were removed. This is called castrate levels of testosterone. Let's look at this in picture form. Here you see a bright circle with AR in it and that's referring to the androgen receptor. The androgen receptor, as testosterone is taken away, starts to amplify, many more receptors are there. And that is the main way that cancer cells escape castration therapy. So AR amplification is the number one way this happens. The androgen receptor can also mutate. And this is referred to as a gain of function mutation, meaning it can activate itself. There are other ways that a cancer cell can outsmart not having enough testosterone. It can actually use other signalling pathways that either turn on the androgen receptor independently of androgen, or, can go around the androgen receptor completely, in what are called AR independent pathways. These AR independent pathways simply turn on the androgen responsive genes in the nucleus without androgen receptor even being present. On the right hand side of the slides, you also see this idea of intracrine androgen synthesis. This means that the prostate cancer cells can actually start making their own testosterone or androgen to turn itself on in a very independent way of any circulating testosterone. In the middle of the slide, you can see this box called Constitutively active AR splice variants. This refers to the fact that androgen receptors can actually change their formation, lose the part where they have to bind testosterone completely, and turn themselves on. This is called ligand-independent splice variation. These variants are present in some men with castrate-resistant prostate cancer and may account for why their androgen receptor is still working.
