Castrate Resistant Prostate Cancer

>> we'll get started. today is a beautiful fall day, the week of the nih research festival. our first speaker today is kieron dunleavy, and he obtained his medical degree at the university of college of dublin, the medical school, consequently

came to nih doing a medical, oncology fellowship. precision treatment of diffuse large b-cell lymphoma. is the title. at the end if you have any questions i'm happy to answer

them. just to put nonhodgkins lymphoma into epidemiological into perspective, you can see from the slide, the incidence of nonhodgkin lymphoma has been -- has been studied 20 years in male but not in females.

there are reasons, one being hiv is associated with increased risk of nonhodgkin lymphoma. hiv is much more common in males than females in the u.s. the good news is that the death rate from nonhodgkin lymphoma has been decreasing in males and females.

if you look at the brain stem of nonhodgkin lymphoma, 40 to 45%, the second most common type, with a number of different ones, t-cell lymphoma. we're particularly interested in the most common type, curable in a high proportion of cases. so over the past 30 years, the

most significant advance in this feet has been the addition of a drug, the chop therapy. the standard treatment since the 1970's has been chemotherapy regimen called chop. p is prednisone. people have been using this since the 1970's.

sixteen years ago the french did a study where they added a monochromal antibody, they did a study in people over the age of 60, and they showed, as you can see, there was a significance at the chop, these are the results of that study, approximately ten years on.

this is the standard treatment for patients with this disease. they get the monoclonal antibody. if you look at patients at all ages with t-cell and b-cell lymphoma, we invite our patients into the different risk groups, based on clinical

characteristics when they present, but as you can see here for patients with intermediate or high risk disease, cure rates are low. there's a lot of room for improvement. this is really what the focus of the program is on, trying to

better understand why this is so -- i'll explain this over the next 14 minutes or so. this reiterates what i said already, go back to the 1970's, chop was the standard treatment. this is a summary of the major studies done over the last 30 years, but there were lots of

good ideas but they didn't improve upon results using chop and chemotherapy. in our field we have tried to improve upon the developments, one thing people have done is giving more cycles of treatment, they used to give six segments, gave eight instead of six, but

it didn't help. people have tried giving more frequently than every 21 days, so two big trials, one in the u.k. and one in france looked at the giving the r-chop every 14 days and compared that in randomized studies to giving it every 21 days, both of those

were negative, giving that over a shorter period of time was not a better survival and associated -- most investigators have abandoned studying this for that reason. something that can be useful, in patients who have a very good response at treatment, that has

been tried in the up-front setting but not shown to have any advantage. what about superior chemotherapy platforms to the r-chop? well, the french same group who showed that adding was associated with the survival advantage, developed another

regimen called acvbp, and they did a study in younger patients under 60 with good risk factors and they showed this treatment was better than r-chop. but most people in their 60s and 70s would not be able to tolerate this treatment. although it's an advance, it

showed better in a select group of younger patients, the majority of people with this disease it's not really a good option. we've been studying the regimen, and we recently compared it to r-chop, randomized study around the u.s. where we had 550

patients and obtained biopsies, the pharmagenic expression, i'll explain why this is important coming up. so one of the most important advances in our field over the last 20 years has been the breakdown of t-cell and b-cell

lymphoma into different diseases. this is work led by nih and lymphoma and leukemia molecular profiling project. they looked at the differential expression of tens of thousands of genes and when they did this, they were able to divide into

three different subtype. con is the activated b-cell, or abc. one was gcb, and one primary b-cell, pmbl, originating from different stages of t-cell differentiation. abc comes from an activated b-cell, the gcb from the

germinal, and it's important -- this is important on a lot of levels, there's certain pathways that are important in the abc and gcb and pmbl side. this allowed us to think about what targets we want to go after and what makes sense in terms of developing new treatment for

each of these three types. and the distinction into the three different types is important clinically because it's not clear from several studies that patients who develop the abc subtype are a worse outcome. this is the comparison of the

outcome, patients who received r-chop and this is their probability of survival. you can see in orange patients with gcb have better than abc subtype. a lot of focus of my work at nci has been trying to understand the abc subtype better and

developing new treatments for it, with my colleague, wyndham wilson. so with this talk, i'm just going to focus on work that we've been doing in the abc subtype, and then i'll talk about targeting the dlbcl 2, overexpressing large cell

lymphoma and finally finally a type of diffuse that occurs in young women in their 20s and 30s, closely related to another type of lymphoma, modular hodgkins lymphoma, we've done a lot of work in that i'll finish this talk by talking about that again.

so when you see the abc, gcb subtype, it's almost always children and young people with the gcb, it's rare to see it in those people but as they get older they have a higher risk of developing the abc subtype. you're familiar with nf-kappab.

one thing is that there's activation of the nfkappab path way, shown here are a number of nf-kappab, lowly stressed from the gcb subtype. approximately ten years ago, we did a study at the nci, we set out to specifically target the abc subtype, and work in the

lab, looking at the gcb cell lines and abc cell lines the show that abc cell lines were very sensitive to an nf-kappab inhibitor, this was not commercially available, so there was a drug, a broad proteozome

which was available. we accrued patients with relapse or refractory large cell lymphoma of both the abc and gcb subtype into the study, did gene expression profile to develop which subtype they had. they were treated, targeting nf kappab and chemotherapy.

patients with the abc subtype did much better than patients with the gcb subtypes in terms of response and overall survival after the treatment. the survival curves don't look very good but keep in mind most of the patients were heavily pre-treated, with median number

of regiments of four, a lot had a bone marrow transplant before they came with us. they were very refractory people. this was an interesting signal that adding this was more effective in the abc subtype than the gcb subtype.

about the same time we did our study another group at cornell added this to chemotherapy and rituximab and didn't do gene expressing profile but used the algorithm, and they also found interestingly that the gcb and abc patients had a similar outcome.

you would expect the abc patients would do much worse, as i showed you in the curve before. both of these studies just as you could preferentially target the abc subtype, since the time we did our study we understand and mechanisms of nf-kappab

activation better, and one thing that has been shown to be important is b-cell receptor signaling, with different mechanisms in the cells. there's active, that's shown here, and that is felt to be antigen driven, compared to conic.

the abc subtype, studies here at nci have shown chronic b-cell receptor signaling an important driver of nf-kappab. we've known for a long time that abc tumors, about 10% of them have a card 11 mutation, but only the last few years have we understood this pathway of

experience and a few years ago work at nci identified that about 21% of patients with this abc subtype have a mutation in the b-cell receptor. and that's important because, when you think of ways that we can target nf-kappab and interfere with this pathway,

there's an enzyme, bta, bruton's tyrosine kinase. this binds to the side, an irreverse able inhibitor of btk. and cell line studies showing it's not toxic at the gcb cell line or abc cell lines that have a card 11 mutation.

we were involved in doing a study of ibrutinib, and the hypothesis was ibrutinib study would be restricted to the abc subtype, and activity would be dependentent on the bcr pathway, a multi-center study in 70 patients, and they all had relapse or refractory t c and

bc lymphoma, received ibrutinib 560 milligrams orally, at the end of the study their outcome was analyzed by molecular these are the patient characteristics in the study, these are the abc patients, these are the gcb patients.

in all studies we always want to make sure that both are matched in terms of clinical characteristics and treatment in case there is -- there is one arm with better prognostic features and for that reason they might do better. when

we look at ecog status, they were equally matched between abc and gcb patients. 23% of patients had a response, 14% of the patients had a cr, what was interesting when we looked at response according to whether a patient had abc or gcb almost all the responses were in

the abc subtype, one patient with gcb large cell had a response. this really has a hypothesis giving ibrutinib has selective activity in the abc subtype and these are the survival curves, blue is abc, orange is gpc. the median survival in the abc

subtype was 9.7 months compared to 3.3 months in the gcb looking at mutational status, we looked at b-cell and myd88. this is one patient on the treatment, on the study who had had three prior treatments, and had been unresponsive to the

most recent one and received oral ibrutinib and after three weeks had a significant reduction in the disease. so other results of the study that we were involved with, there is now an ongoing international study looking at patients with large cell

lymphoma, abc subtype, and the question is does adding ibrutinib improve the cure rate of these patients? patients are randomized to receive the standard treatment r chop with placebo, or r-chop with ibrutinib, and this is restricted to patients who have

the nongcb subtype, we don't do gene-expression profiling to determine this. but we use an immunohitto algorithm. this will answer a very important question, is adding ibrutinib helpful if you have

the abc subtype. so there are other mechanisms of we have a lot of interest in myd88. the lymphoma and leukemia molecular profiling project surveyed a pathway and discovered in abc lymphoma 30% of them had mutant myd88.

this is important in and a drug has interesting activity in a broad range of histological diseases but may be particularly helpful where it works through irf to increase interferon, we're starting to study where we combine ibrutinib in patients with relapsed

refractory. and as i said, there's a lot of interest in rx4 and now there are rx-4 inhibitors in development. there's the toxic abc cell line, in the lab this is where -- the rx4 inhibitors with ibrutinib is synergistic.

in talking about abc lymphoma, i'm going to talk about a study we've started doing, and there's a type of primary cns lymphoma, large-cell lymphomas in the central nervous system, 95% of time are confined to the cns. and that's intrigues, they are not very well understood, but

it's the question of whether or not there is an antigen in the brain that maintains them there, and is responsible for them not going outside the brain in 95% is a possibility. this type of lymphoma is increased in incidence in patients who have

primary and acquired immunodeficiency. and it's been challenging to understand primary cns lymphoma for a lot of reasons. it's hard to do biopsies on the brain. the tissue in the train can be challenging to interpret because

of architecture. you know, it's different from other tissues. there's lots of normal brain cells that can make the diagnosis of cns lymphoma challenging. there's not been a huge number of studies done as the case in

systemic large cell lymphoma but in the few that have been done almost all are of the abc actually the limited studies that have been done show that there are even a higher incidence of these various mutations in primary cns lymphomas.

so we're doing a study that incorporates ibrutinib with a regimen called teddi-r. i won't go into the details. we recently a few weeks ago put our first patient on this study. this was a patient who had had several lines of treatment

before and radiation to the as you can see, this is the tumor in her brain before she started the ibrutinib, and after three weeks of single agent ibrutinib the area has almost completely resolved. so this type of lymphoma is not lymphoma that does well with the

standard treatment. one of the challenges is it's very difficult to get certain drugs into the brain, they have to go through the blood-brain barrier, and a drugs we use are not the best but get into the cms. this is a significant response

for ibrutinib. we put our second patient on the study and she had a good we have three or for more patients coming for this study. so i'd like to switch to myc-rearranged in dlbcl. i don't know how familiar with

you are myc. this is something that was pretty recently recognized, and in large cell lymphoma, after standard treatment, the presence is associated with the worst so these people have a much worse outcome after -- or if they have a myc arrangement.

these are four studies, a number of patients here. the treatment most patients receive chop or chop-like treatment, and in these various studies up to 10% of patients -- up to 14% had a myc rearrangement. the outcome was worse than those

without a myc-rearrangement. this is from the u.k., 303 patients, 14% had a myc-rearrangement, those with the myc-rearrangement had a much worse survival. there's been a lot of interest in our field recently, looking at something called double hit

lymphomas, and double hit large cell lymphomas have got two genetic abnormalities, typical a myc, and now various studies, two large studies looked at 250 patients with double hit lymphomas, they have a bad with various different types of treatment.

some people in our field have suggested they should have a bone marrow transplant, up front, in the initial setting, but really this has not been shown to be beneficial in retrospective studies published earlier this year. so as i said, we've had a lot of

interest in developing an alternative regimen to chop, da-epoch. one thing about epoch compared to chop, it's as effective in tumors with a high or proliferation, not the case with chop with tumors with a high proliferation.

because of that we decided to test the regimen, a number of years ago we started doing a study, and the hypothesis was because this treatment works very well in large cell lymphomas, with a high proliferation versus with very high proliferation, it goes to a

hundred percent in almost all situations we hypothesized this would be effective in patients with the disease and published results last year and found that it was very effective. the times of progression was 97%, the overall survival in hivness patients were 100%.

this works well in burkitt lymphoma. we looked back over all of our large cell lymphoma patients that we treated in two studies and retroively assayed them for a myc-rearranged, we performed fish and found 8% had a myc

rearrangement, equally distributed between different prognostic groups, low ipi and high ipi groups. and when we looked at the outcome of patients, we found patients with a myc rearrangement are equivalent survival, similar to standard

treatments like r-chop. we were doing a multi-center study of this regimen in burkitt we recently looked at the results of this study and so far we treated 52 patients, median age 61, 71% males, most of them have a high ipi score.

86% of them had diffuse r and b-cell lymphoma. this is under 80%, the progression-free survival, overall survival shown here, and interestingly when we look at the patient of double-hit lymphoma, they so far -- this is

a very early analysis with limited follow-up, but our initial results show that this group of patients do well, and that's in contrast to the other groups who have published that they do not do well, follow-up is short, median follow-up is 14 months, we have to wait for

longer and continue with the analysis to confirm these results. there's a lot of interest in our field. large cell lymphoma with high expression of myc do not have these are called double-expresser lymphomas,

these make up up to 44%, and have a poor outcome in various studies after r-chop or r-chop-like treatment. there's a lot of debate about how these patients should be treated, several studies show they have a poor outcome. one important point is that

these cases usually track with the abc subtype, and there have been many retrospective studies with potential pitfalls, chemistry defines these. there are different cutoffs. there's a lot of controversial about how bcl 2 staining should be down and different groups

have done bcl2 staining differently. findings are interesting, double-expression has a worse outcome, these results need to be up validated in a prospective study that's carefully controlled with one or two pathology labs doing the

analysis. there's inhibitors, which may be interesting. next i'm going to talk about targeting primary myc. this is very different. if you look at gene-expression profiling, it actually much more

closely resembles classical hodgkin lymphoma, and primary mediastinal shared about a third of genes, they appear to be cousins, and we're now understanding that there exists a spectrum of b-cell lymphomas that present in the mediastinal,

or the chest, certain markers on the tumor cell help us distinguish these from each other but pmbl has staining of pb-20 and low staining of pb-30. plus we now know that there are lymphomas in between nf hodgkin and pmbl that do not fit in the

boxes, mediastinal gray zones, with hissologyic and immunohistochemical features in between nf hodgkins and pmbl. they are rare. clinically these is similar, typically affected females in their 20s and 30s, they both

have a similar presentation, 80% of people with classical hodgkin lymphoma present with disease in their chest, and in primary mediastinal, you almost see it in the chest, both clinically and biologically they are very similar diseases. and this is an old study, the

outcome has been favorable compared to the other subtypes. this was quite an old study that shows these people in the past have done well with the standard the treatment for mediastinal lymphoma is very controversial. it is a lack of prospective studies and no randomized

studies. for the most part, primary mediastinal b-cell lymphoma has been approached like other b-cell or t-cell lymphomas, r-chop is standard. mediastinal radiation is typically given to patients, and the cure rate with this lymphoma

is low. it's really critical to optimize the up-front treatment approach, if this disease comes back most of the time it's incurable. early studies are done by italian groups 13 years ago, suggesting that mediastinal radiation was a necessary

component of treatment and use a regimen with gallium scan, if they got mediastinal, it went down. oncologists gave mediastinal to the patients, there's always been a suggestion from past studies that dose intensity is

important in pmbl, hodgkin lymphoma, they are closely related, that's not surprising it would be important in pmbl as well. in terms of advancing therapeutics of this disease, it's something i think needs to be challenged, and we really

need to find ways of removing the need for radiation because it has long-term problems, a very high percentage of people get secondary cancers, females especially get breast cancer, and this group of p a

tients live for a long period of time so it's very important to focus on that. this is something called a min trial, they treated 824 patients, most received r-chop and did a subset analysis of patients with primary lymphoma, identifying 87 patients.

shown here are the outcome of the patients, eventual and overall survival. 70% received ratation treatment, eventual survive was 65 per cent, overall was 85%. when we interpret this study, they only included scores of 0 to 1, which does not represent

the entire spectrum of this disease, these are the patients who have less outcomes. if you look at all patients with the disease, this is a very interesting study that was published this year, at mass general. they looked back over their

experience and patients with r-chop, 63 patients, 77% of them received radiation treatment. their progression free survival was same floor what the other group saw, plus if you look at the outcome of patients who have a high ipi score, you can see these patients did really

terribly and patients advance disease did terribly following r-chop. we study dosage, it's a disease of young people with a female predominance, there are good outcomes in low risk patients following r-chop. are r-chop there are poor

outcomes in advance disease, and patients with a high ipi score. there's a need to develop treatments that are as effective or more effective, that remove the need for radiation we studied with this in mind, this is a regimen shown here, three of the drugs are

continuously infused. over four days, and then one given as a bonus. this is the treatment paradigm. at the end of treatment they had a ct and pet scan. if the pet was negative they went to follow-up, if it was negative they had a biopsy to

confirm residual disease and reached radiation. we had patients with suspicious test scans and we typically follow those with another pet scan, four to six weeks after the suspicious pet scan, in most cases the pet scan became negative, or became less

negative, and they went into standard follow-up. these are the characteristics of our patients. we treated 51 patients, most of them were females, and there are other characteristics shown here, similar to other studies of patients, so we did not use

radiational treatment, and a median follow-up time of five years, 93%, two patients out of 52 required mediastinal radiation treatment, one patient has surgical removal of a residual mass that contained some disease but all the other patients did fine, as shown here

as the overall survival. i'm not going to talk much about this. one thing we learned from our study was that at the end of treatment, a pet scan is very helpful if it's negative. but if it's positive, half the cases were positive or mildly

positive, it doesn't tell you an awful lot. what we did typically was follow these patients and repeat their pet in four to six weeks, almost all the time the pet became negative. this was one patient on the study, at the end of treatment

she had an end of therapy test which showed residal abnormality and we observed her, six weeks later it's almost completely resolved, the subsequent pet was completely negative. and as a result of our study there are other studies ongoing in pmbl.

the regimen is being tested in children, there's a german study that has so far treated 15 patients, and found the same results as us. there are pediatric studies in the children's oncology group and baylor group ongoing, so we're looking forward to the

results and hopefully they will reproduce the same results we had in our study. briefly, we did a study of patients with gray zone lymphoma, they had a significantly inferior outcome. we're currently doing gene-expression profiling of

gray zone lymphoma, this has not been done before. it looks like this type has a unique molecular signature with as aspectses of hodgkin and particularly dendritic cells which are important in hodgkin lymphoma appear to be important in gray zone.

in conclusion, is there a better regimen than r-chop? this question is still unanswered, and we await the results of our randomized study where it's been compared but it appears in subsets of large cell lymphoma, there are better approaches than r-chop, and i

think in our field we have to think of this as constituting many distinct molecular diseases, and as we move forward we need to keep this in mind and build strategies from new molecular insights. there's an increasing recognition the subtypes needs

to be approached differently therapeutically, and we're starting to think of treating large cell lymphoma in terms of precision therapy. for subtypes with high curibility, we need to focus on reducing toxicity.

i'd like to thank my colleagues at nci and happy to take any questions for the next five or ten minutes. [applause] [off mic] >> in terms of identifying targets, developing treatment, directing treatments, that's

specifically targets, because in our field that's not been done in the past. patients with lymphomas received chemotherapy treatment and regimens which are very broad in terms of what they do. so they are not directed at one particular pathway, and that's

why the side effects are pretty bad in terms of you have to target everything. everything is targeted but now we have drugs like ibrutinib where it targets one enzyme and is effective. yes? [off mic]

>> that's a very good question. we're making progress in that. so, yeah, i've been talking about conventional gene expression, and that's very complicated. we can do that at nci, it's not something that could be done in the community, but the group

that i mentioned, lymphoma and leukemia and molecular profiling project, they have developed now with nanostring technology a point b gene predictor which they just published recently and this seems like something that could be in the next few years used in the community but it has

to be studied in clinical trials first, but it's pretty inexpensive and appears to be reproducible. it's looking promising we'll be able to use technology like that in the future. more questions? all right.

thank you. >> our next speaker is dr. ravu madan, m.d. from the new jersey medical school in 2001, then did an internal medical residency at rutgers, and then in june 2004 joined the nci medical oncology branch, now an assistant clinical investigator, clinical

director of the genitourinary molecular branch, and today's title is prostate cancer. >> thank you all for coming. yes, thank you all for coming. i don't know that i would have agreed to this as readily if i knew i had to follow dr. dunleavy, a pretty good speaker,

but i'll try to do my best. it's hard to encroach upon a meal so i'll try to keep this on time. i do have a lot of slides. there's been -- prostate cancer, you don't always think about it, it's a dynamic field, five new therapies in the last four or

five years. i'd like to provide information to get you thinking about whatever line of research you're doing. i will try to get you through the background information and scientific struggles at the end and get done with enough time

that you can have questions that are relevant to your own research. we'll go from there. so let me skip through some of we'll figure out where we're going with this. we'll talk about prostate cancer from soup to

nuts, as they say. as i mentioned, it's an interesting few years for prostate cancer research. a lot of things have been developed over the last couple decades, and come to clinical fruition now. this is a clinical course of

prostate cancer, patients where they start off with minimal tumor volume, and then they are usually asymptomatic, the disease is nonmetastatic, has not left the prostate and is castration sensitive, fundamental if the diseases growth is fueled by androgen,

namely testosterone, depriving the tumor of testosterone is a when that's enough to contain the disease, we call castration sensitive. when the disease figures out mechanisms around that, we term it castration resistant. that's just part of the

requisite vocabulary. as you'll hear, the disease is curable, with surgery or radiation, but unfortunately 20 to 40% who have recurrent disease despite radiation and therapy at that point the psa and tumor volumes start to rise, commonly treated with

testosterone lowering therapies, usually called chemical castration second line hormonal therapies, as of 2010, chemotherapy was the only form of treatment for metastatic disease with extended survival. in 2010, therapeutic cancer vaccine demonstrated

survival. also approved in 2010, two therapies in 2011 and 2012, these drugs recently approved in the pre-chemotherapy state and then that's the latest, radium 223, a radio-pharmaceutical, infusion. in the last few years there have

been a lot of advances. we need help from you and researchers, how to combine therapies and use these optimally, hopefully with the background i provide you today you can go and figure out those tough questions and help patients in the future.

prostate cancer is diagnosed in a quarter of a million men each year, roughly 30,000 die of the disease as well. it's something patients can live with for a long time, it's also a lethal disease and very prevalent. people ask what are the risk

factors. it affects one in eight men so it's not clearly defined. there have been a lot of studies looking at genetic predisposition, that's not clearly defined as well. there's always a suggestion that environmental aspects play a

role or rate, hashed to say. asians have far less incidents than northern europeans or north americans and for some reason the disease seems to be more aggressive in african-americans. breast cancer, that aggressive nature in african-americans is sometimes socioeconomically

related, in other words they don't have the access to care, the screening, that's not the case in prostate cancer. it does seem like there's a difference within race as well but a lot of this needs to be fully defined. what about preventing cancer?

i'm going to talk about that. a cautionary tale, five alpha reductase inhibitors, that was theorized to be a possible way to prevent cancer in people with risk factors. two studies were done with two agents, both were positive. there was a 25% reduction in

prostate cancer incidence, these are standard, designed to sling the prostate as well. there was some confounding data when patients were diagnosed after treatment they had more aggressive disease. it's thought that's possibly related to the fact because the

prostate shrunk, if you stuck a needle in there you're more likely to hit cancer, that debate rages a but there was never a reception of, wow, i can reduce my prostate cancer risk by 25% if i take these pills. the public did not want this treatment largely because of

side effects, some of the testosterone-lowering therapies. it's interesting we talk about prevention and want prevention, when you actually get into the wild, so to speak, you try to give a patient a therapy that has side effects for a disease they don't have, it's a lot

harder to get enthusiasm you would think. just something to keep in the back of your mind from a clinical perspective. prostate cancer screening is controversial. i'm not going to go into recommendations, they ebb and

flow, but a rectal exam is one way to detect prostate cancer. you have your scrotum here, penis, bladder, and the rectum here. so with a digital rectal exam you can palpate the prostate. you can palpate a very small portion of the prostate, a

relatively primitive test that there's tumor anteriorally or by the bladder you're probably not going to feel it, or who knows if you'll palpate it appropriately, not the most sensitive of tests. so along tame psa, verybody wants a biomarker, psa is a

biomarker but not a surrogate. the role is controversial. the end result is we're diagnosing more men than may need therapy. this is the actual prevention path, this is a lecture in and of itself on the controversy of screening.

this slide probably says it all with prostate cancer screening. what happened in 1987? well, it's not that everyone all of a sudden got prostate cancer. this is when psa screening became readily available. patients below the baseline got diagnosed.

that's why there's the giant exactly. this shows what some people comment on frequently, the screening works, where is the drop-off in deaths? you can see in this line it's starting to decline, there's some perspective that suggestion

in the last -- decade that followed this, the decline continued but screening is still very controversial. so i'll move on from that just by saying controversial about ten times. now we'll get into more of the meat of the matter with prostate

cancer. one of the ways we look at prostate cancer under the microscope is gleason scoring, a pathological way to assess the aggressive nature of the disease. or more practically a way to assess mobility.

what the pathologists will do is look under the slide, look at the degree of anarchy, if you will, how disruptive is the architecture, more anarchy-related mobile cancer cells. if you get a five score, they

are basically very disorganized, more likely to metastasize, that's why i bring up the mobility. when you hear patient diagnosed with prostate cancer they will get a gleason three-plus score. why can't we add things up? we have calculators now.

the three represents the predominant pathology in a sample. the four represents the secondary. when you see a gleason three plus four, that's exactly what that means. there is really no difference

between a three plus four and four plus three. they both equal seven but if you have a four that's going to be driving the disease. now, it's important in terms of determining primary therapy, i'll show you a slide shortly. you can't have understanding of

a disease without the staging, i'm going into not in painful detail but it's simple. think of surgical staging, tumor in one lobe, it's one. in two lobes, each lobe, that's stage two. if it's kind of broken through the capsule of the prostate,

that's three. if it's metastasized, that's four an generic for all cancer. if you understand that you can get the gist of staging and prostate cancer. i probably confused everybody with this, feel free to ask questions.

so how do we figure out who needs to be treated with prostate cancer? this is the back end of the screening controversy. does everyone have to be treated? if you think a patient is going to live ten years you should

consider therapy. this will get into what we'll talk about shortly, prostate cancer is a disease we live with for years and don't have that luxury with most cancers. if you have a patient at 75 that had their triple bypass surgery and stroke, they are probably

not going to live to 85 unfortunately, maybe checking psa every year makes no sense, maybe you don't have to diagnose prostate cancer, maybe it's something that's not going to kill them, the prospect of competing morbidity. if you have a 60-year-old by

with strokes and heart attacks and probably is going to live five years maybe he shouldn't get his psa checked, this is a primary care doctor conversation. if you have a 75-year-old still liking, good health, maybe his psa should be checked.

there's a thought presses that's necessary. there's different approaches to prostate cancer once you diagnose patients, and one of those is watchful waiting, which is kind of a nice way of saying really do nothing, you diagnose this in a guy and realize they

maybe aren't going to live ten years, we're not going to pay attention, if you have symptoms we'll address it but take a hands-off approach. active surveillance is different. this is where you're not sure if the patient needs treatment,

they have a low grade disease so in the pathological aggressive next, gleason six or lower, they may not need treatment even if they are relatively healthy and young. this is something where you check their psa, maybe rebiopsy every year, that's the different

between watchful waiting and active surveillance. this is confusing until you actually realize what it says, and then it's kind of literally of shades of gray this is developed by dr. parton and colleagues at johns hopkins, older patients from the 90s,

it drives home the point of how age factors in. these are the age divisions. and then here you see the gleason score. you almost never see a gleason five anymore. it's rare pathologists grade anything less than a six.

the dark area here represents patients dying from their disease, light areas here represent patients -- i'm sorry, yes, the dark area is patients dies of disease, light area is patients dying with other causes. as you get higher up in the

gleason score, here is 7, here is 8 to 10, 7 is intermediate, 6 or lower is low risk, you see why based on this. a lot more proportion are dying of their cancers represented by the dark gray area, but if you have a gleason 7 patient intermediate risk, and they are

diagnosed at 74, maybe, again, you have to assess. this drives home that point pretty well, something that is not too annoying to look at. the surgery is better than watchful waiting? it sounds like a weird question but in the '90s they asked

they said yes, surgery is better, but this data says therapy is a therapeutic options for prostate cancer. what are complications from surgery in this is important when we talk about what treatment patients should get. incontinence, electile

dysfunction, infection, complications associated with anesthesia, this is relevant with joan rivers just dying. surgery is only relevant for patients with localized disease who have no evidence the tumor spread beyond the prostate. radiation is another option for

patients with local disease. i'm not a radiation oncologist. i won't go into a lot of details but basically we're very good now, better than before, at targeting tumor with high level radiation to kill the cancer that's essentially the role of radiation.

it's worth noting that there isn't randomized data that says should patients get surgery or sometimes it's easy. sometimes if they have, you know, a baseline characteristic that excludes them from surgery, maybe they can't tolerate patients, maybe in patients over

70, radiation can more commonly done. with a history of bowel disease, radiation could exacerbate that, maybe then in those situations surgery is better. it's actually difficult. patients want to know what to do.

the doctor is like you with do this, you can do that, it's a personal preference. my perspective is take treatment with the side effects you're more comfortable with. a lot of people say it's cancer, i want to cut it out. that's common too.

that's also because people made up their minds, so if they do a trial where you give randomized surgery or radiation, people are like, i don't want radiation, or i don't want surgery. it's hard for people to submit themselves to randomization and that's why a lot of randomized

tests failed. brachy therapy can be done in one setting where they inject the seeds that emit low level radiation and kill the cancer. this is better for low risk disease or patients with small prostates. this is another form of

radiation which is an option in some cases. complications of radiation, again you can have erectile dysfunction, irritation of the bowels, a secondary risk of malignancy, supposedly better with better targeting but still a risk.

what about just giving hormonal therapy? i mentioned that -- i won't get into the molecular basis until later, but prostate cancer is primarily fueled by testosterone, androgen is produced in the body, binds to an androgen receptor, so

dropping testosterone levels will be a form of therapy. for men who are too sick for radiation or surgery, but need palliation from symptoms, primary androgen deprivation therapy is an option for patients. again, it's something that is

definitely very secondary to surgery radiation. surgery and radiation are potentially curative, androgen therapy is not. that's another fundamental difference. i'll cut through this quickly to get to more of the metastatic

data and more discussion at the end. what about combining the therapies? radiation with surgery, does that work? the answer is in some patients it does. what about surgery and androgen

deprivation? in some of the works. and what about radiation and androgen deprivation? some data supports this. i'll share that now. so in a study that looked at basically patients with lymph node positive disease, prostates

taken out, and lymph node sampling, and patients who basically had positive disease in their lymph node were given hormones, that's another way to say androgen deprivation therapy, and patients who didn't get adp earlier live longer. this data is skewed because in

this day and age with psa we don't wait like we did in this study, which was in order for the patient that got randomized, after the disease was metastasized, so this was not a relevant control in the modern area. with a positive lymph node, this

is appropriate. this was just asking the question, could you give hormones to everybody before surgery? the answer here was there was no big difference. i was one slide ahead of myself. there was clear data this did

better, but the control group isn't exactly a real world control group now. what about giving radiation with so they found that basically in this study if you had t-3, a tumor had broken out of the capsule but hadn't extended

widely, it made sense. they took people that are positive margins or evidence the disease had broken through, let's radiate them locally for disease that may have been left behind. this is a population where the disease can benefit from

radiation as we called it, adjudant after surgery. what about if you have a positive lymph node and did radiation, those studies were what you can interpret, if it's in the lymph node, it's probably in other lymph nodes or micro metastatic

easy of disease. androgen deprivation may make sense. this is gleason 8, 9 or 10, two or three years of hormone therapy after radiation, does it improve survival, intermediate risk disease, mostly measured at gleason 7, six months of

hormones, may improve survival outcomes. if you have gleason 6, you get radiation in those settings, no data for hormone therapy. that's just a sense of local therapy and kind of the different approaches in combination.

so i think i'll move on to metastatic disease. any questions about local therapy before i move on? okay. so prostate cancer is relatively meek in that as unique. there's a biomarker before we

have radiographic evidence. off the top of my head, in terms of solid malignancy, colon cancer and other gi malignancy it's not hard care. ovarian cancer is another example. so it creates a unique situation for even 20 to 40% of men who

get radiation or surgery, between there, unfortunately could not be cured and had biochemical recurrence. evidence of psa risings after surgery or radiation. and so again the therapy in these patients commonly used, androgen deprivation, that's the

primary fuel source for cancer cells to grow. how do you use that therapy? there was a large study done in the '90s, they presented this data a couple years ago looking at intermediate -- i'm sorry, intermittent or continuous androgen therapies.

in other words, when you had a psa immediately detectable, did you need androgen deprivation for your life or intermittently until there's evidence of metastatic disease? they randomized patients to intermittent, eight months of therapy versus continuous.

the long term survival here is relatively equal beyond about 11 years, just the difference here that wasn't significant. the answer to the question is both are options. and i think i want to make a couple things clear. one is the -- this is only an

option for nonmetastatic when there's radiographic evidence we can see the disease on bone scan or ct, then unfortunately all patients have to be beyond suppress therapy, otherwise the cancer can grow and you're closer to having symptoms if you have metastatic

disease already. for patients with biochemical recurrence, where this stage of disease, you know, they may not require therapy for a few years so in that situation it's okay to alternate back and forth between the few doses of hormone therapy and then what you do is

take a step back, watch the psa rise slowly, as long as they don't have metastatic disease when you can basically wait for the psa to reach a threshold or velocity and restart therapy. that's how practice is done. does anybody get continuous i'll go over the side effects of

hormones shortly. there are side effects. why would patients want continuous hormone therapy? factor in the side effects of androgen deprivation therapy i'll go over shortly but there's a side effect of not treating, i tell patients if you're all all

night staring at the ceiling because you're not on therapy, continuous therapy is appropriate. you're not going to have more side effects in the long term but there are patients that prefer that, they want it off their plate and not have to

worry about it for a few years. that's how that goes. so again if we look at the biochemical recurrence and what happens, this study gives you a sense of the longevity of these patients, length of time for which the patients live with their cancer.

this was a study after surgery, on average two years for them to develop rising psa, eight years for them to develop the metastasis. this is one study so the numbers vary but this tells you maybe continuous androgen deprivation therapy for an 8-year stretch

may not be a requirement. this is older data without a lot of newer therapies i'll talk about shortly. it's hard to know the complete context. there are newer strategies, this diagnosis of metastatsis may get moved up further not because

patients are getting more metastasis quicker, but more because we're using more high tech scan technology. this gives you a sense of -- this is the time frame with prostate cancer, very different unfortunately for patients with lung and pancreatic cancer where

death and diagnosis often occur in the same year. metastatic prostate cancer, spread beyond the prostate, only about 4% of patients have metastasis with diagnosis, this has a lot to do with screening. two things, one is more fancy imaging techniques that may

common line, and two, as screening goes down, do the numbers go up? in europe where psa screening is not done or the u.s. before 1987, the number is higher. i mean, you wouldn't know you had prostate cancer until you had a bony metastasis.

it also does not mean you have symptoms. it's often years before they have pain symptoms, it's different than other cancers. it's important to realize that system metastasis is not curable. once it's left the prostate,

it's something we can see radiographically, it's very difficult in most cases to cure. generally you consider it incurable. then the aim of therapy becomes kind of maintaining quality of life, delaying death if possible, and decreasing the

morbidity. so this is just something that comes up a little bit. hopefully it's not blurry up there. this is basically showing you the sites of disease in prostate so 90% have metastatic disease in the bone, 10% with no

messages. bone. part of this we already knew. patients with liver disease do worse than without liver disease? this is from a study that shows the therapy, this is pretty mature data from a decade ago.

this is the kaplin-meyer curve. take a step back. oncologists saying the curve, it's what we do, we have to show these throughout the talks. this represents all the patients, 100% survival, this time, over time unfortunately patients died, so that's what

these curves represent. further to the right the better. again, these are a big deal for oncologists like ekg's are big for cardiologists, this is a big deal for oncologists. but as you see here, patients with bone or lymph node and bone disease, pretty much do about

the same in a midline thing. patients with lymph node only disease do better. through the last decade that i've been treating prostate cancer there's the sense of, well, i never see prostate cancer in the lymph node only, the bone scan is negative, this

represents a minority. i never see this. this went along with what we had seen, which is it's not necessarily so. it's very to fall into dogmatic traps, another cautionary tale. let's take a step back and how we talk about met static

prostate cancer, systemically with adt, androgen deprivation therapy, most effectively with the orchiectomy, and the agonistses, telling it to produce more lhrh. antagonists work more

conventionally, blocking pituitary access, degarelix is a new therapy, the older form are these. but i think -- i'll get through this slide quickly in the interest of time. these are the side effects i mentioned with antiandrogen

therapy, a primary way to contain prostate cancer with side effects. get decreased libido and erectile dysfunction. this leads to hot flashes in these men as well. similarly you get weight gain,

as well as decreased bone density. the same thing you see in menopause. you can see gynecomastia in some men. fatigue we see invariably but it's more of like i walk two miles and i'm more tired they

end of those two miles than i used to be. it's important to have that in you can see increased risk of diabetes, about one in 140 patients also increased risk of heart disease, so these are things just to be aware of as we

treat these patients, realize that they still need therapy so there are other metabolic conditions. this is where a lot of research has been improved recently. and this is the disease, metastatic castration-resistant metastatic, we all know that's

spreading, usually to the bones. the castration part is worth discussing to drive that point home, patients who you already removed testosterone from the serum in their body, in other words normal testosterone may be from 200 to 800, with testosterone-lowering therapy

usually less than 20, for some trials they will be less than 50. but unfortunately despite that, the psa is still going up. disease is still growing. mechanisms of resistance later, a huge area maybe you can help with, with your research, but

it's important to understand when i talk about crpc this is the disease state i'm talking about. so different ways to basically limit testosterone from these patients when you lower the body's testosterone, coming in with other therapy that target

androgen receptor directly. lower the testosterone, the tumor may come up with other mechanisms, one can be increasing the number of receptors making it more sensitive to lower levels of testosterone but if you come in with androgen receptor

antagonists, the older drugs, they can basically block the -- they bind in the receptor site and they don't lead to the chain reaction of cellular signaling that leads to cellular ketokonazole is interesting, developed in the '80s, an antifungal, it's provided a

weird nonspecific inhibition of cyp-17, there was talk of decrease androgen production in the adrenal gland, it was thought they must produce or limit testosterone production in the adrenal glands, but it was a variable acceptance of how it works.

with the newer therapies, these have more of a back seat role in metastatic disease, more limited to the patients who are castrate resistant but not yet metastatic, and beyond the data of improving survival with metastatic disease, it's a

little bit gray. so these are the therapies i showed earlier and this is the only vaccine approved. there's antiandrogen therapy, abiraterone. i think it's interesting, it shows how progressive this field is in prostate cancer.

chemotherapy is developed from this tree extract, bark extract, and the way this was thought to work for really many decades, for prostate cancer only one decade, limiting proliferation of the cancer cells which requires mitosis and that's how it prevented cancer cells from

growing. that's well and good but we seem to have forgotten what was discovered in the 1940's, i said it ten times, the androgen receptor drives this disease, not surprisingly it's interesting that in recent years it's become more clear that

docetaxel might be limiting cell growth because the angio receptor requires micro tubules, it explains why the only two chemotherapies approved are taxels. it was surprising when a second taxel was approved. this is the study that was done

that led to the approval of docitexal, a three arm study, every three weeks versus every week, different doses, this is thought to have less side effects. this is a control arm, fda approved in the early '90s, decreased symptoms that didn't

increase survival, commonly used recently for palliative benefits. oncologists love to show this. green is every three weeks, this is every week, and white and yellow is mitoxantrone. in 2004, this improved survival,

2 1/2 months of survival. so this data was actually very momentous in prostate cancer because until then we had no way to improve survival beyond hormone therapy alone, and it actually drew a lot of attention. i wouldn't have spoken to a lot

of patient groups, patients are like 2 1/2 months, chemotherapy is terrible, why would i take this treatment for 2 1/2 months? what would somebody answer to that question, if anyone? is there any reason why you 2 1/2 months is misleading? why would a patient -- the

patient is like, well, i can live with the side effects, the chemotherapy is terrible, i don't need that to make me miserable for ten to twelve months, why should i take it if i'm only going to live two months? any thoughts on this?

so a couple things. it's an average, that's a very good point. that's good. it's a median, so for some patients they are living much longer than 2 1/2 months. any other thoughts? you have to look at the study

design. there's no placebo here. patients got chemotherapy, big deal, i told you that was approved for palliation. you should always ask if you see studies like this, where maybe the survivals are questionably short, in this study there was

crossover. patients got their mitoxantrone there was crossover and they were allowed to get docetaxel. usually when i tell the patients that, their wife gets upset and hits them a little bit and then wind up getting chemotherapy because they didn't really

understand the dynamics of it. i think it's a good sign, general, of another generic lesson and the expectation for survival based on earlier studies was close to ten months. not everybody gets the benefit of crossover but 16-point a months was higher than expected.

any questions? >> good question. a bunch of people created ash contrary metrics of progress. this is used universally for solid tumors, generally if soft tissue disease is greater by 20% in size, cumulative mass, that's your progression.

in this study, bone lesions may have been considered progression. in 2004 probably a rise in psa would have been considered a very good point. i don't go into this into this talk but i'll mention it now. psa is a great marker for

disease but once they are metastatic, the number of lesions, size of those lesions, that's the demarcation. so all the studies done more recently are leading patients on despite rising psa, and are waiting for progression based on metrics just described, so that

way there's not premature discontinuation of therapy. it is very important, this is something that still even though this is a consensus guideline that came out in 2008, six years later this is something not fully understood, progression in metastatic disease should only

be measured by psa, something i think i'll add to the slide for next time. there was also palliative benefit, quality of life i talked about crossover and why that underestimated survival benefits, that's worth always remembering for different

trials. don't be too scared by this slide. we have a lot of therapies in prostate cancer, we don't know how to use it. i thought it was practical to talk about it or show them. there's side effects with

docataxel. you can see here limiting the quality of life but i won't go into this. i just figured since we have so many options, it's important to factor in side effects when you're picking a therapy for this patient.

we shift to the next approved therapy in prostate cancer, therapeutic cancer vaccine, there's a lot of political and dogmatic controversy around this agent, but if you don't know about that i won't go into detail today. basically this is an

immune-stimulating therapy generated from a patient's own peripheral blood immune cells, collected from the patient via leukoapheresis, they are mailed back to the processing center, infused into the patient, the full course consists of three

infusions, one every two weeks over a month. people talk about human checkpoint inhibitors this is the first really modern immunotherapy approved based on this study, where they took patients who had mildly symptomatic disease, this was

called impact. and gave them the vaccine or placebo, randomized them two to one. this was the end result. so the end result was patients who received the vaccine lived 4.1 months longer, statistical significant, that led to fda

approval. the overlapping curve here is the controversy, which basically can also cause confusion because these therapies, like many immunotherapies, including check point inhibitors, don't reduce your psa, don't make your tumor shrink, they don't do anything

in the short-term. this is the focus of my own personal research but for the sake of staying on topic i won't get into detail. immunotherapy has an indirect effect on the cancer, it's not killing cells directly like chemotherapy.

and immunotherapies are better at slowing the growth of tumor as opposed to shrinking down immediately. we're seeing data with checkpoint inhibitors. very different therapy. this caused controversy, i can talk about this at the end, i

have three trials with this hypothesis, these therapies slowed tumor growth, beyond the focus of the talk so i won't go into detail but this is fda approved, that's very well tolerated as well. basically infusion-like reactions, a small concern, but

it's not borne out in clinical practice. if you think the therapies work, which i do, you think it takes time for these to work, the earlier the patients can get them, the better. that's sipuleucel-t. remember i mentioned

ketonaconazole that was thought to inhibit the hormone in the adrenal gland? people used it but there was controversy. smart people i think in england pulled this drug off the shelf and basically said let's do a better version and specifically

targeted sip-17 gliase and hits hydroxylates as well. the reason why this is important, because it prevents androgen synthesis in adrenal land, testicles as well, emerging data in recent years for resistance limits production.

testosterone is how the tumor grows. we can limit this production of testosterone, get patients at castrate level, over time there's still growth of the tumor. there's different mechanisms of resistance, i mentioned one,

upregulation of the an dough general receptor, but another one, perhaps the sinister nature of cancer, cancer cells themselves produce their own androgen, they almost in an autocrine fashion serve as their own fuel source. it's creepy but that's one of

the mechanisms by which the cancer continues to grow. abiraterone blocks the seconder forms of cancer production. these are patients who took the drug from the '70s and '80s and they got a billion dollar drug on their hands or i wouldn't be showing you this

data if it was negative, but this was the trial, phase 3 trial in patients who already are chemotherapy. this was the result, you can't compare the length of survival, these are patients more further along than either the two studies i showed you before, and

also they are done at different timeframes. it's hard to compare. these are placebo arm, a relevant comparison, significant improvement of patients with abiraterone, this was done in patients who already had this study has since been done

in patients chemotherapy naive but had longer timeframes to live, survival was on average 25 months, also approved for patients who haven't had now effectively approved for all patients with metastatic castration resistant disease. this is looking at progression

data versus placebo, and i think we'll move on. you can see that most patients have a decline with their psa, more so than the placebo. side effects, again, don't get too caught up. big side effect, unlike

chemotherapy, edema. it happens in some patients, to a large degree in other patients not at all. we haven't figured out -- this is probably because of the nonspecific gliase, targeting hydroxylate, it would be good to limit the side effects,

hydroxylate leads to increase in other hormones, these are the side effects, joe all overall it's well tolerated. anytime is patient is on a trial, it gets captured and winds up at one of these percentages.

that's why things like constipation and diarrhea are in everything. in you follow enough patients, they will have that. even the placebo arm has this. cabazitaxel is the second line. it differs from -- it's a

taxane, differs with the side chambers. this was off patent for two years and hoped to get lucky with another taxane with a longer patent life. we all hope that wasn't the case but regardless it is surprising a second taxane worked, speaking

to the androgen receptor mechanism. randomized trial, again you see the control arm led to improved progression, from three months to one and a half months, talking about short timeframes in these patients, very advanced disease, survival was 15 months

versus a little under 13 months, again statistically significant. side effect profile was striking, 5% of patients from the original report had infection-related death, that's considerably high. with the advent of newer therapies, it's much less

thought of as a great option for in that study done largely outside the united states, white counts up quicker, probably would have minimized death, it's used in clinical practice in america but because of the related deaths, it did caution the benefit of this and also the

subsequent approval of abiraterone and other therapies. this factors into the clinical synthesis of seeing patients trying to pick out which therapy to use. so like abiraterone, enzalutamide, this is a modern version.

sawyer and his group developed a better mouse trap, it binds to the angio receptor, it has better binding to the androgen receptor and unlike the other agents has better impact at preventing androgen receptor from traveling to the nucleus, sending growth signal, better

version with better clinical outcomes, a study here. about 1200 patients in this study, a large improvement in survival, 18.4 versus 13.6 months, this drug was approved two years ago for patients with again metastatic disease who

already had chemotherapy. i interjected this slide because patients who had not had chemotherapy, you saw an improvement in survival here, basically the median survival is all the way out like 33 months versus 31 months, you can see the separation in curves, starts

off here and is profound. this is again significant statistically and led to approval of this drug in patients who had not already had these were distinctive disease states, so now like abiraterone, this drug is very well this makes this the premier

choice in my opinion for resistant prostate cancer, it will affect their quality of life the least and that factors into my thought process in giving this drug. and the final class of therapeutics, alpharadin, similar to older

radiopharmaceuticals like strontium, it's a radiopharmaceutical agent that delivers basically radioenergy to the tumor microenvironment. the difference, it's based on alpha particle, not beta particle. alpha particles have a shorter

radius which they basically fire off from the radius, more likely to hit the tumor, less likely to hit bone marrow cells, oft when the disease is, prostate cancer is basically in the bone near the bone marrow, if you have far-shooting particles you'll drop the platelets and it limits

ability to give the agents. the older investigatorses were fda approved for palliation, they did improve symptoms but not survival. this was developed with hopes of improving survival, and based on this randomized study, this was a mixed population of patients

that had chemotherapy and had not, so this also improved these are symptomatic patients, that's why survival times are shorter. you see the survival time is 15 months versus 11 months, this led to fda approval. people aren't clear on how to

use this, it's still researched for patients with symptomatic bone disease but that's one of the things we have to figure out how to use all these therapies. pretty well tolerated in you see anemia, neutropena but not to the degree we saw with other pharmaceuticals.

this is where we are now with all the therapies. a lot of options for men with prostate cancer but we don't know the sequence or what combinations work better and something that, again, we need basic science data, clinical data, a lot of trials are

ongoing. how would i treat a man with prostate cancer in general? the way we follow patients if they have metastatic disease we follow them with psa rising, once they have a small area of metastatic disease they become eligible for all these

therapies. my ideal world view, my opinion, not based on randomized data, we think vaccines work, we think they work earlier, i would start with a dose of sipodeuceel-t, and the next one is enzalutamide. again, ar-blocker, well

once there's progression, it becomes unclear. since they are all targeting the androgen pathway, other therapies are less effective, so i think radium-223 is good for patients with symptomatic bone raptly progress saying, you may think it's on the outs,

not well tolerated. we had abiraterone and these men after surgery and radiation showed up years later, and they have normal testosterone, and metastatic this is the difference in patients with a psa or

biochemical occurrence, conventionally treated with androgen deprivation therapy, they are already castration resis tint, these are castration 5 to 10% of patients, this is interesting, remember this is very early on in that disease course i talked about.

patients who got hormones with dose taxel early lived 13 months longer. we're talking about 6-year readouts. if you start in the early going you can show benefits over the long term.

this is relatively new data from just the past year so it was only the patients with high volume disease. these are patients with lesions notice liver, poor prognosis, or multiple bone lesions including one outside the normal distribution of the disease,

outside the spine and pelvis. they had four lesions, one outside the area, considered high volume, those were the patient. others with one random bone lesion, chemotherapy still has an important role despite newer agents.

we have a few minutes to talk about future direction and maybe this can impact research. i alluded to mechanism, ongoing trial, sequence, i'll come back to that in a moment. multiple modality therapy, mechanism of resistance is important.

this is one review of the literature we did recently that looked at patients with chemotherapy after abiraterone, that prevents secondory androgen production, we think this works through translocation of the receptor, and this supports previously docetaxel had a time

correction benefit, if they already got abiraterone survival is about a year. this i think leads to the fact that these patients are less likely to respond to docetaxel. we combine with another agent, dr. dahut is the p.i. on that study.

this is one of the clinical things, how can you improve other therapies by adding to it? cross resistance is something we're looking into. this is with an agent which another inhibitor. this slide is in your packet. i won't go through it.

we're near the end. it highlights the mechanisms of resistance, docetaxel in prostate cancer, we talked about pumps, basically increase pumping of the docetaxel outside of the cancer cell, mutations in the pathway, the angiogenesis pathway, these are mechanisms of

docetaxel. this slide shows the different mechanism of of androgen receptor. so you have secondary production which is very important from the adrenal glands as well as tumor itself. this is not detectable in

systemic circulation but may be relevant in the microenvironment. this is an important part we have to look into, how can we limit secondary pro production of androgens by the tumor, beyond abiraterone. androgen receptor may change,

there can be more of them, which makes perhaps the tumor more testosterone. but i think one of the other ways in which the androgen receptor changes, the pathway changes, is that it loses its receptors. in other words, you basically

have an active androgen receptor essentially because no longer does the require that binding site for activation. so in other words, there's been a lot of data a couple weeks ago documents a slight variance, particularly androgen receptors with variant 7, it doesn't have

a binding domain, you can't block it, and it leads to a constituently active pathway, these are -- this is the understanding with new and improved therapy. we have to figure out perhaps with your help in the future how better to sequence and combine

therapies to overcome resistant pathways and develop new pathways, there's opportunities with immunotherapy, prostate cancer with improved survival, likely targeting the immune system, perhaps immunologic stimulation with other therapies is one way, that's again a focus

of my research and my colleagues here at the nci and some of our lab people who are here with us today. the other thing is that some standard therapies combine well with immunologic therapies, that's something we're also working on.

so a lot of progress in the last five years, the by-product of a lot of basic science research in the decades before. with progress now comes new problems. and new questions and we need to get the answers. so i think the other thing that

we have to ask ourselves, can we move some of these new therapies -- i said they were all approved in metastatic resistant, can we move them to adjudant? can we give enzalutamide or combine it with radiation? what about immunotherapy?

maybe immunotherapy can stimulate immune system and mop up microscopic areas left behind, active areas of research. i think you may look at some of these increments, three months here, four months there, if you move this earlier in the disease

process, your pivot point becomes greater and clinical impact can be profound. i do think some therapies perhaps combined in neoadjudant or adjudant setting could be relevant. please let me know if you have

any questions. [applause] >> right. point to clarify, remember's, most men in this country who don't get by surgery or radiation have a rising psa and are put on therapy before they are metastatic.

roughly 5 to 10%, a small subset diagnosed with metastatic disease before they knew they had prostate canceror new they had recurrent prostate cancer and weren't on therapy, naive to androgen therapy.

i've had some people talk to me about that, it's important but new. i'm glad you asked. ffic] >> you know, it's interesting but there were studies do before docetaxel and they were in mouse models, it does improve

some mouse models. clinical trials did not bear that benefit. perhaps there's something about the way these bind tha are more relevant in androgen receptors. it's interesting, two relatively similar taics, that's a good question.

>> yeah. yes, there have been new active studies on this. i actually with my colleagues have clinical trials in patients newly diagnosed being treated with radiation, patients with rising psa, patients who have nonmetastatic disease, two would

all agree moving it up earlier, i have other studies with colleagues, so do a lot of other this brings up a good point. why were all these studies done here when i told you the most benefit is here? from the pharmaceutical development and timate path to

the clinic or path to market, this is where your -- this is where your clinical end point -- it's where you get your answer the quickest and therefore your financial windfall. it's not surprising that abiraterone and enzalutamide showed here.

if they were negative, the studies may have been shut down. >> there's a lot of political bash backlash, no one seems to be complaining about avastin which improves survival in lung cancer a couple months bu provides just as much, an inhibitor of melanoma is 150

grand, as opposed to 90 grand. cost is a relevant concern for all these therapies, and diluteamide costs roughly $8000 a month. they quote the median at 16 months, it's a lot of math for me. the median was between 10 and

12, it makes the math easier, 80 to $96,000. cost is a relevant issue, particularly a lot of backlash because people were like, you're not making my psa going down, why am i paying $96,000? now everyone is on the immunotherapy bandwagon a little

bit but cost is relevant for all these therapies i'm sure dr. dunleavy thought i'm not smart enough to dress that but we're going to have to address this. studies have been done looking at radiation with doce taxel -- i'm sorry, surgery, studies did

not show long term survival some studies are still being done or done different but to date they have been negative. a very good thought though. thank you for saying. sorry to interrupt your dinner.