majority of the patients. And taking an aggregate of all trials, very possibly has a modest effect on improved survival.

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1 Hello. I am Farshid Dayyani. I am Assistant Professor in Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center. We will be talking today about prostate cancer for survivorship and the role of chemotherapy, and specifically, androgen-deprivation therapy in prostate cancer. This will be a two part lecture. The objectives --- the objectives for today s talk are the following: upon completion of these lectures, the participant will be able to discuss the role of chemotherapy in localized and advanced prostate cancer. They should be able to state the indications for androgen-deprivation therapy, or ADT, in prostate cancer, and also recognize and manage short-term and long-term adverse events of androgen-deprivation therapy in men with prostate cancer. Chemotherapy has been tested for decades in the neoadjuvant and adjuvant trials of prostate cancer in the localized settings. Unfortunately, so far, we do not have convincing evidence that in localized prostate cancer there is any role in improving overall survival in men with prostate cancer. Therefore, chemotherapy is currently not recommended as a standard of care for early stage prostate cancer outside of clinical trials. We have many clinical trials ongoing that are re-addressing the issues currently, but, at this point, there is no recommendation for giving chemotherapy. In terms of more advanced disease, just as a sum --- an overall review, there are three cytotoxic agents approved for advanced castrate-resistant prostate cancer. Mitoxantrone is an anthracycline that was approved not based on survival benefit, but based on improvement of pain and other quality of life measures and basically relieves palliation. Docetaxel was tested in two large Phase 3 trials that were published in 2004 and compared to mitoxantrone. And both trials showed in men with advanced castrateresistant prostate cancer, a survival advantage of about two to three months. And based on these two trials, docetaxel was approved as an agent in metastatic prostate cancer. More recently, the TROPIC trial tested the role of cabazitaxel, a synthetic taxane, that was designed to overcome resistance to docetaxel in patients with metastatic castrate-resistant prostate cancer who had progressed or did not tolerate a prior docetaxel. And, again, there was a 2.4 months survival benefit when compared to mitoxantrone in this group. And, therefore, a cabazitaxel was approved as a secondline agent after docetaxel in men for castrate-resistant prostate cancer. Since the median survival for castrate-resistant metastatic prostate cancer unfortunately to date is around two years with very few long-term survivors and the objective of this talk is prostate cancer survivorship, I will, in the remaining slides, focus my talk on the long-term effects and management -andr --- of androgen-deprivation, rather than chemotherapy. ADT is the most important therapy in men with metastatic prostate cancer. It has been shown to improve bone pain in more than 80% of all patients. It does induce tumor shrinkage in lymph nodes and other soft tissue --- tissue metastatic disease in the

2 majority of the patients. And taking an aggregate of all trials, very possibly has a modest effect on improved survival. It s clinically used in several settings. As mentioned, it is used as a palliative treatment in advanced prostate cancer and builds the baseline on which we build other therapies. But it s also an early stage disease combined with definitive external beam radiation therapy for localized high-risk or intermediate-risk prostate cancer. Studies randomized have shown overall survival benefit with six months of ADT in patients with med --- intermediate-risk disease and overall survival benefit when ADT is combined for three years with external beam radiation in patients with high-risk disease. Selection of men with high-risk features who undergo salvage radiotherapy after initial prostatectomy might also benefit from addition of ADT to their salvage radiation. And possibly, men with localized disease who are not --- are not willing to undergo surgery or radiation and still want some sort of treatment might be selected to undergo androgen-deprivation if they don t want to the surveillance option. Very briefly, the pathophysiology of steroid synthesis and release: Gonadotropinreleasing hormones are released from the hypothalamus that activate receptors in the pituitary gland. And their LH is released through the systemic pathway that goes to the end organ, such as the testicles, but also the adrenal glands. There, testosterone is produced and acts on the end organ, here in our case the prostate, where testosterone is converted through the fal --- 5α-reductase into the dihydrotestosterone, binds the androgen receptor and translocates to the nucleus to induce survival advantage proliferation and other biologic phenotypes that are associated with cancer. The way we achieve castration is through surgical bilateral orchiectomy. This is still the standard of care in many other countries. It s cost effective. But here in this country, the majority of the patients undergo castration with LHRH agonists, such as leuprolide or LHRH antagonists such as degarelix. The way the LHRH agonists work is by overstimulating the hypothalamus. And after initial surge, the production of LHRH hormone is decreased and, therefore, down-streamed testosterone is suppressed. That means that there will be initial flare of the disease because there will be initial increase in testosterone. Therefore, these agents are combined with antiandrogens initially. On the other hand, degarelix as an antagonist inhibits the release of LH from the pituitary gland and, therefore, does not need to be combined with antiandrogens. Suppression of testosterone is achieved faster with degarelix, but in the long-term survival there is no clear benefit between these two agents. As already mentioned, in the United States, 90% of the patient s choose to undergo tes --- testosterone suppression with medical castration. Other options to castrate patients, especially for those who do not want to have medical castration is a single-agent antiandrogens, such as bicalutamide. The advantages are fewer hot flashes, less sexual dysfunction, less bone and muscle loss. And we will talk about this later in more detail. However, there is more gynecomastia. There is more pain in the breast. And which is probably more important, compared to LHRH agonists or antagonists, as well as bilateral orchiectomy, these antiandrogens as single agents

3 seem to be less effective clinically. And based on the negative feedback loops that I showed you before, antiandrogen therapy alone actually increases serum testosterone levels rather than decreasing them. The major adverse events with androgen-depris --- androgen-deprivation therapy to consider include: loss of libido, erectile dysfunction, decreased quality of life due to hot flashes, gynecomastia, fatigue, loss of muscle and bone mass, possibly cardiovascular disease, insulin-resistance and diabetes, psycholog --- psychological changes, and other. The question is if ADT is so effective in palliating pain and possibly also improving survival, why do we have to pay such special attention to long-term side --- adverse events? This is because of the paradox in prostate cancer where many men will be diagnosed with the disease, but only few will die of it. Given the PSA era and the controversies with screening, we have increasing numbers of patients who have been treated with localized disease --- diagnosed with localized disease, treated, and now have PSA-only recurrence without any additional signs of symptoms or disease burden. From published large trials and the series we know that only about 15% of patients who un --- who have a PSA-only relapse will go on to have metastatic disease. And maybe only a third of those will eventually die of the disease. This means that many of them will never progress to metastatic disease. A lot of them are otherwise relatively healthy and have a good quality of life. Therefore, we have to be very, very considerate and make efforts to focus on the different schedules and modes of ADT to minimize the decrease in quality of life that is associated with this treatment modality. One --- one of the ways where we try to minimize the adverse events of androgendeprivation is by giving it intermittently. The principle of intermittent ADT is one starts with induction, either giving a LHRH agonist for a set amount of time such as six or eight months or until a maximum PSA response is achieved. Typically since the response is thought to be achieved pretty rapidly, we combine it with antiandrogens. Once we have our maximum response, Lupron, for example, or leuprolide acetate, is stopped and the PSA is monitored regularly such as every four weeks. Then, at a certain pre-specified threshold, for example 10 ng/ml of PSA, the androgen-deprivation is restarted. The studies that I will show you have this cutoff for restarting ADT. But as we know in clinical practice, patients are much more anxious and urge the physician most of the time to start ADT sooner such as PSA levels of 1 or 2. The purpose of intermittent androgen-deprivation is to reduce the adverse effect of ADT during the off periods, such as: sexual dysfunction, vasomotor, hot flashes, loss of energy and fatigue, an --- and such. Based on the trials and the published data, we estimate that about 35-50% of the time that the patient is treated with this modality, he spends off androgen-deprivation and during those times it has been shown that libido and potency are regained and increase. Unfortunately, with each treatment break, the time to the next treatment becomes shorter and shorter, corre --- corresponding to biology that adjusts to the environment and becomes more resistant.

4 The largest trial published, Phase 3, supporting the use of -in --- intermittent androgendeprivation was a Canadian PR.7 trial where men with PSA-recurrent disease but no signs of metastatic disease were randomized to undergo either standard continuous androgen-deprivation therapy or intermittent ADT for eight months as mentioned before. Only those who actually achieved a PSA of less than 4 were enrolled further to undergo intermittent -adap ---- deprivation. People --- men who did not achieve maximum response, they were switched to the continuous arm. Once ADT was stopped, PSA was checked every two months and at the prespecified level of 10 was restarted. The control arm received the continuous androgen-deprivation therapy. The primary endpoint was to show that there is non-inferiority of intermittent ADT compared to continuous ADT in terms of overall survival. Almost 1,400 patients were enrolled with a median follow-up of 6.9 years. The median cycle of intermittent ADT given was only 2. But the range was up to 9. As shown here, overall survival was 8.8 years in the intermittent arm and 9.1 years in the continuous arm. Based on prespecified statistical requirements, it was concluded that intermittent ADT is non-inferior to continuous ADT in the setting of PSA-only relapse. If you look a little bit more in detail, we see that there were more prostate cancer-related deaths in the intermittent arm, but less unrelated death --- causes of death in the intermittent arm. As expected by some people, the time to castrate-resistant disease was actually prolonged in the intermittent arm in a statistically significant fashion; again, supporting the use of this modality. There were fewer hot flashes with intermittent treatment. There were other side effects, such as libido and potency that were also improved continu --- compared to the continuous arm. Therefore, in patients with PSA-only disease and no metastatic disease, one can use intermittent androgen-deprivation therapy to improve the quality of life of the patient without sacrificing the survival. Other modalities to improve quality of life as mentioned include monotherapy with antiandrogens, for example, with bicalutamide. Unfortunately, as I told you before, this treatment modality is inferior to castration in several clinical parameters including survival, time to PSA relapse, time to metastatic disease, and such. But the men will experience fewer hot flashes. But because of other effects of the antiandrogens, there is a higher incidence of gynecomastia, breast tenderness which might require even breast reduction surgery or radiation to the breasts. I will show you, as an example, two trials that randomized or compared high-dose bicalutamide of --- at 150 mg daily with more standard castration. In the first trial, the modality was compared to surgical castration. And it was shown the sus --- survival is inferior compared to castration if we only give bicalutamide. As expected, we had few -- - fewer hot flashes, better libido, less fatigue compared to the castration arm. Similar results when bicalutamide was compared to chemical castration with leuprolide, and as already expected, more gynecomastia and breast tenderness, fewer hot flashes, less fatigue, less bone loss, and better libido. Still, given the inferior clinical outcomes in terms of survival androgen monotherapy is not standard of care in metastatic patients because of these concerns.

5 Another modality that sometimes is used, although based on smaller trials, is the socalled sequential androgen blockade, also known as peripheral androgen blockade. The principle is to combine an antiandrogen that blocks the androgen receptor with a 5α-reductase inhibitor, such as flutamide, that inhibits the conversion of testosterone to the more potent dihydrotestosterone. We only have small reports from single centers, so there is no large randomized data. But based on the mechanism of action, which is in the peripheral tissue rather than centrally, zerum --- serum testosterone levels are not affected which may contribute to preserving potency. But similar to the antiandrogens alone, there has been reports of painful gynecomastia and men had to undergo breast reduction surgery for that. A major decrease in quality of life for the men that occurs with androgen-deprivation is sexual dysfunction. It develops in men on continuous ADT and starts with loss of libido within a few months followed by erectile dysfunction. Therefore, every physician starting ADT should be discussing with their patients sexual dysfunction prior to initiating the ADT. And some studies show consulting sex therapist might actually be of benefit for these patients. Sometimes, for example in the radiation combined setting, after short-term ADT, the erectile dysfunction can intru --- improve. But this might be incomplete or delayed and the patient should be aware of that. Alternative strategies to reduce erectile dysfunction, as mentioned, are intermittent ADT as shown in the P.R7 trial or antiandrogens alone. But more importantly, we have been getting more and more data on various other side effects and metabolic effects of androgen-deprivation therapy. Of the greatest concern so far was the effect of ADT on cardiovascular disease and mortality. Review of the literature shows there is no perspective randomized trial that compares the role of ADT to placebo with the primary end point of diabetes or cardiovascular risk or mortality. And given the clinical benefits of androgen-deprivation in prostate cancer, we will always have to weigh the potential harm of this modality with the possible risk of cardiovascular disease. What we can say to date is based on data based on large observational studies, retrospective studies of large randomized trials with other end points. And although conflicting, some of them indicated there might be a possible ---- increased risk of diabetes and cardiovascular disease with ADT. The mo --- the largest piece of data we have today is based on meta-analysis that was published last year in JAMA. And this study did not show an increased risk of cardiovascular death with a fairly long follow-up of 13 years. But it did show that prostate-specific and overall mortality was improved with ADT. So based on what we know today, the benefits of ADT do outweigh, in the majority of the patients, the cardiovascular risk that is potentially associated with this modality. Several trials have shown and examined the side effects of androgen-deprivation to be shown time dependent. Here, for example, the effects on bone marrow density on men and we see a correlation with time being on the treatment.

6 But more recently, we have had emerging evidence that hormonal changes and risk factors that contribute to metabolic syndrome might be modified and worsened by androgen-deprivation therapy. The pathophysiology is multifactorial. It is thought that increase in adipose tissue, fat mass, by ADT and the decrease of lean muscle mass results in a decreased glucose uptake in the muscle tissue. And there is increased release of hormones that are inflammatory in nature such as IL-6 [and] TNF-alpha from the adipose tissues and these two pathways taken together contribute to insulin resistance and metabolic dysregulation that is associated with ADT. It is thought that castration affects in the following ways: Metabolism and body composition. As I mentioned before, the lean body mass decreases, the adipose tissue increases, mainly in the subcutaneous adipose tissue. And these changes lead to decrease insulin sensitivity, hyperlipidemia. And they --- they occur fairly within the first one to two years of androgen-deprivation. It is thought that decreased serum testosterone levels affect muscle mass and increase adipose tissue. But also the fatigue that s associated with ADT leads to less exercise for the patients, which in turn also increases fat. Therefore, we do recommend regular exercise both endurance and resistance for our patients on ADT to help avoid or even sometimes reverse the body composition changes that we see to increase their fitness and energy levels. Encourage regular exercise regimens four to five times a week and consider monitoring with labs regularly for metabolic changes. The next few slides will just show you data from specific articles that examined the role of ADT to several parameters that contribute to the metabolic syndrome. Here, men who were undergoing androgen-deprivation shown in green in several bars were compared to controlled men with prostate cancer that did not receive ADT and normal controls. And we see abdominal obesity is significantly higher. Hypertriglyceridemia is more prevalent. And fasting glucose is higher compared to men with prostate cancer who do not undergo ADT. And these three parameters result in the metabolic syndrome. On the other hand, other factors that in the general population are thought to be associated with metabolic syndrome, such as hypertension and low HDL, do not seem to be affected by the androgen-deprivation. This other paper confirms that we have a significant increase in fasting glucose levels, hyperinsulinemia as a sign of insulin-resistance, as well as increase in the HOMA insulin resistance score, which is a multivariable score, in patients undergoing ADT shown here in the gray bars. Here represented in fasting glucose levels greater than 126 occurring in 40% of men with ADT compared to controls with prostate cancer or healthy men.

7 And as a resulting factor hyperinsulinemia in men who receive at least three months of ADT. Abdominal obesity, hypertriglyceridemia, and hyperglycemia. But not LDL [speaker intended to say HDL ] or hypertension, are the factors that contribute to metabolic syndrome in men with prostate cancer. Thank you very much. This concludes the first part of this talk, and I welcome all of your feedback.

Metastatic prostate carcinoma. Lee Say Bob July 2017

Metastatic prostate carcinoma. Lee Say Bob July 2017 Metastatic prostate carcinoma Lee Say Bob July 2017 Scenario A 58 year old gentleman presents with PSA 200 ng/ml with hard prostate and bone mets. LUTS but upper tracts are normal with normal RP. history