the

New Approaches to Metastatic Hormone Sensitive Prostate Cancer

mine is gonna be about treat treating

metastatic hormone sensitive or

endocrine naive patients with metastatic

prostate cancer these are my relevant

disclosures most of them have been you

know more of an ad board type role for

these companies that make advanced

prostate cancer products the gaps here

one patients with metastatic disease

have undergone kind of a an evolution in

their treatments and this doesn't appear

to be the one that correlates with my

talk so I'll just say this one does talk

about patients with newly diagnosed

metastatic prostate cancer both terms of

dividing them up into how they present

in low risk or high risk States because

that often impacts how they behaved in

the clinical trials talk about the added

role of additional androgen ablation in

patients on traditional hormonal therapy

and also to talk about the role of

adding chemotherapy in the referral so

we know that you know the stage of the

presentation has a lot to do with

prediction of outcomes these are just

some historical things but obviously

we're not curing patients with advanced

or metastatic prostate cancer with any

of these treatments but we are

controlling their disease and slowing

their disease and we've made some major

moves forward it used to be that on

average you got about 18 months of

cancer control if you presented with

bone metastases now we can take them

years beyond five years in some cases so

there have been improvements but we're

still not curing them these numbers are

hard to get like okay what number of m0

patients are out there running around

what percentage of newly diagnosed were

pretty good at getting those this is a

little bit old but again I picked it

because it suggested that it was like

10,000 new cases of metastatic prostate

cancer it's probably increased a little

bit with some of the step backwards in

screening for prostate

answer I know at Stevenson Cancer Center

we see a lot more men with advanced and

metastatic disease than then I was used

to seeing in Nashville so I think that's

not just Oklahoma I think that's really

a statement of lack of of prostate

cancer screening and it's kind of

catches up to us there's a whole lot of

patients even 40 to 50 thousand with now

castration resistance in the United

States and so that's reason to focus on

these type of things my talk is going to

focus on metastatic disease as they

present I it's always good to remind

ourselves there we have two Nobel Prizes

in a neurology and this was one of them

for the understanding that there is

antigen responsiveness and dependence

for growth of prostate cancer and that

depriving prostate cancer cells of

androgens results in a remission of the

disease in most cases about 90% probably

maybe 95% of initial prostate cancer

that's metastatic responds to initial

hormonal manipulation those that don't

you should pay attention they usually

have a variant like a neuroendocrine

histology and they need chemotherapy and

they need to referral pretty quick if

they haven't seen an oncologist the

reports of understanding that the extent

of disease impacts the outcome sometimes

as much as the treatment has been known

now for more than twenty years these are

two of the early studies that were

looking at use of orchiectomy plus or

minus flute amide for example and and

what they found was it really the most

important thing was how advanced their

disease was when they presented as to

how they responded it wasn't whether

they got a shot plus a pill or not

charted which is a study that we'll talk

about in a minute was the study that

kind of gave a new modern-day definition

to one surrogate for outcomes and that

was extent of disease and so if they had

more than five for more bone lesions and

one was outside of the axial skeleton or

soft tissue disease they were considered

high ball

so that's one that we'll talk about and

then now that that had a bearing on the

outcomes for the treatment a lot of

subsequent studies are kind of

categorizing patients and subsetting the

analysis of the outcomes we know that

their response to the treatment is often

a predictor of how they're going to do

at about the six-month mark and so this

was just some data from from a Southwest

Oncology trial looking at those patients

who didn't go to less than four but most

of the patients should really go to some

where one or less if they're truly

getting a good response but at around

that six-month mark you start to see

separation of how they ultimately do and

PSA is a surrogate for that in some

instances this is just a menu of what's

out there for treatment most of us are

very familiar with the first four that's

kind of in the urology wheelhouse

there's bone targeted therapies that

were using now and I know that'll come

up in later discussion today

there's the use of chemotherapy which

we've talked about in previous years in

this meeting but I think it's now kind

of becoming a standard of care for all

of us to consider in these patients as

well as new AR signalling medications

and we'll talk about those a lot of us

use intermittent therapy it was

mentioned earlier in the morning this

was a study that tried to determine

whether intermittent or continuous

hormonal therapy was better too

confusing study because their outcomes

were these non-inferiority things but

the bottom line I think is that there is

probably an overall benefit in terms of

patients who present with metastatic

disease for continuous / intermittent

but side effects and things kind of

drive other decisions and certainly it's

not a lot better so that's why many

patients do opt for intermittent therapy

the two general strategies that we have

as we sit here today for metastatic

disease are chemo combined with hormones

or more potent androgen targeting this

was the charted study that kind of got

us for the first time in a the only

thing we had before

this was in castration resistance we had

three months of survival advantage for

men with docetaxel this study took a dt+

docetaxel versus ADT alone and

randomized men with newly diagnosed they

did kind of divide him up into higher

low-volume as I mentioned before and

what they found was that overall the

study was positive and had more than a

year of additional survival outcome but

for those men who had high-volume

disease by those definitions that I

previously described there was about an

18-month overall survival advantage as

compared to just conventional ADT the

lower volume patients really we didn't

see that benefit this was a kind of

follow-up longer term analysis 53 month

median and again that same result was

durable it kind of bore out and the

results for the high-risk high-volume

patients were there and for the low

volume not really so that's kind of been

one of the drivers for a lot of

oncologists that when they see patients

it'd be nicer to have more predictive

tools than just volume of disease but it

is one of the things in the equation the

charted study came out about the same

time is the Stampede study which was

just another similarly designed study

looking at the use of docetaxel and

again a positive study with more than a

year of overall survival benefit by

adding chemotherapy not all studies so

for example there was a French study

that didn't show benefit but but it

actually did show months of benefit it

just wasn't statistically significant in

their trial and there's some may be

differences in the patient selection and

what kind of volume of cancers they had

etc but when you put them all together

you've got two level 1 studies that show

benefit

you've got meta-analysis that favor the

use of docetaxel chemotherapy and so all

of us should consider it a standard of

care for patients with newly diagnosed

metastatic disease

besides chemotherapy what else do we

have

and so another option is the use of a

burrata rune with steroid these were two

back-to-back publications in the

New England Journal that looked at

adding the Zytiga or abiraterone plus

prednisone to traditional hormonal

therapy and they both showed similar

results and the most important there's

you know progression-free on on your

left and an overall survival advantage

is really the the best thing we could

say and so that was evidenced in this

study called latitude and it was

similarly in a stampede study

similarly trial design and similar

results with overall survival advantage

and relative risk reduction in death

from prostate cancer by adding another

androgen synthesis inhibitor if you will

so the caveat on this one is it requires

a steroid it's usually only five

milligrams a day and you have to monitor

them because there's laboratory testing

like liver functions and potassium as

well as keeping an eye on their blood

pressure but those are things that need

to be done and there's a kind of a

formulaic way if you want to do it but

when you start them and then it relaxes

as they get further out in their follow

up so what's new so these studies are

new this year so a polute amide which

you just heard about in the m0 patients

patients with PSA rises after hormonal

therapy well now there's a study looking

at it in newly diagnosed metastatic

disease so the use of a peluda might

Plus LHRH compared to LHRH alone showed

again another significant improvement

both in progression-free survival as

well as overall survival this study was

called the Titan study and again it was

a significant benefit it worked in both

low and high volume patients so it

probably is not surprising to the

oncologist but they do get a lot of

patients who really buy in on the on the

use of chemo sometimes when we present

those options to them though our

patients don't really want chemotherapy

even though we try to convince them that

it would be appropriate

sometimes you need options besides this

the Zytiga or the

Barada rune had a little bit of a

barrier to uptake because of the use of

steroids and some of the complications

of steroids that are urologists weren't

really very comfortable with but here

you this offers you an option that

doesn't require steroids and does give

them a survival benefit

I'll just go quickly because there were

two studies with enzalutamide so I

showed you a pollute amide there are two

studies that came out this year with

enzalutamide as well this one was called

arches again the it's a randomized study

hormones hormones plus enzalutamide and

they looked at survived this one

actually looked at radiographic

progression-free so that's why i'm not

gonna spend a lot of time on it it did

meet its primary end point that the

patients had less radiographic

progression less PSA progression that

sort of thing and that was a move

forward it worked in both low and high

volume and it also worked in patients

who'd previously seen docetaxel but the

higher level study was one kind of

powered for overall survival and this

was an enzalutamide trial looking at it

in addition to LHRH and the enzyme

instead II had over a thousand men again

it did show radiographic

progression-free but most importantly

there was survival advantage by using

enzalutamide with newly diagnosed

metastatic patients it worked in both

but it's better it was better in lower

volume patients based on the publication

in the New England Journal I'm really

gonna accelerate us through this all ago

metastatic because there is not a

standard of care really as we sit here

2019 but we know that some men who

present with metastatic disease are

young healthy and motivated and if there

were treatments that you could direct at

their primary tumor in theory they might

live longer or do better so it is Theory

some of the kind of rationale are listed

here but it's a work in progress they

know from looking at some of the genetic

testing that they've done on primaries

in metastatic

sites and then for that you know the the

primary tumor spawns new metastatic

sites and even the new metastatic sites

spawn additional metastatic sites so

they know that some if we don't treat

the primary we may still be at risk for

continuation of this there have been

retrospective studies that said oh look

the people who had their primaries

treated did better but of course that's

fraught with selection bias and

publication but you can imagine you pick

the best candidates for that and then

compare them to the worst candidates who

didn't get primary treatment there were

two studies last year in radiation

oncology literature that attempted to

look at this horror ad was one of them

I'll go through this pretty quick but

basically patients with metastatic

disease either had their primary treated

or not and they all had systemic therapy

and what they found was that there was

no overall survival benefit in this

group of patients who had radiation to

their primaries compared to those who

didn't there were some kind of trends in

the lower volume metastatic patients

again not statistically significant and

there were some delays and like their

PSA progression so at least that got the

conversation going and then Stampede

which is this multi-armed multi looks

like a horse race they just add a a

treatment to the comparator which is

standard of care don't treat the primary

so stampede had a similar trial design

treating the primary with radiation

therapy and they randomized them and

again they say separated patients in the

low and high volume just like the chart

and study they overall did not see a

survival benefit to treating the primary

with local radiation but they did start

to see some PSA failure free survival if

you will and then when they subset at

these patients into their disease burden

lower high volume again you start seeing

a trend toward some improved outcomes in

patients with low volume disease and so

when they did this subset analysis which

is always fraught with its own

statistical problems they did see a

benefit to adding radiation to the

primary in low volume newly diagnosed

metastatic patients who were also

treated with systemic therapy these are

five trials that are going on in the you

know the world we're participating in

that slog 18:02 study some of them look

at surgery some of them look at

radiation and so the jury's not out are

these trials wouldn't be going on if you

have a patient with metastatic disease

if you refer them we will consider them

for this trial it randomizes patients so

half of them get treatment and half of

them don't to the primary

all of them get the systemic therapy and

then within the treatment group some get

surgery and some get radiation the

patient and you decide that so it's not

like a coin flips on what the local

treatment would be but they're kind of

stacking it for the right amount for

each patient so the take-home messages

here there's kind of new things

developing it used to just be in the CRP

space but now we're getting some

treatments that are being moved back

into metastatic newly diagnosed

treatments that we knew kind of worked

out on the on the castration resistant

now they're showing benefit in patients

with newly diagnosed metastatic disease

of course chemotherapy particularly for

high volume we have more potent androgen

targeting now we have three approved

agents in that space based on new

studies and treatment of the primary is

an evolving concept and best probably

done in in clinical trials if we can so

we can sit here a couple years from now

and be able to tell you likely who might

or might not benefit and if they do

benefit what that treatment should be so

I think that's kind of the changing

landscape design for newly diagnosed

metastatic kind of dovetails with the m0

stuff that you heard from dr. Morgan's

and hopefully that'll be helpful to you

when you see patients with this problem

in your practice

you