New Advances in Prostate Cancer in 2025

Name: New Advances in Prostate Cancer in 2025
Uploaded: 2025-01-23T14:36:51.0766667Z
Duration: 57 min 39 s
Description: Yale Cancer Center Grand Rounds | January 21, 2025 Presented by: Dr. William Oh

January 23, 2025

Yale Cancer Center Grand Rounds | January 21, 2025

Presented by: Dr. William Oh

Information

ID: 12656
To Cite: DCA Citation Guide

Download Transcript

00:00Roy Herbst. Really excited to
00:01introduce our ground round speaker
00:03today.
00:04A special pleasure to introduce
00:06doctor William Oh,
00:07who's just joined us. I
00:09can tell you, Eric has
00:11just texted me and,
00:12wanted me to emphasize how
00:14excited, he and we all
00:15are to have William here.
00:17As you'll see as I
00:18introduce him, he certainly has
00:19a tremendous background, and he'll
00:21be a a great addition.
00:23Doctor O, he's
00:25now the director of precision
00:26medicine for the Yale Cancer
00:27Center
00:28and Smile Cancer Hospital.
00:30He'll be very involved in
00:31in in some of that
00:32work and including our precision
00:34medicine tumor board, and he's
00:36importantly the service line medical
00:38director of Smile Cancer Hospital
00:39at Greenwich.
00:41He received his medical degree
00:42from NYU.
00:44He was actually a Yale
00:45undergraduate in,
00:46BS in
00:48molecular biophysics and biochemistry, and
00:49did his internship and residency,
00:51at the Brigham Women's Hospital
00:53and and his clinical fellowship
00:54at the, Dana Farber, which
00:56is where I first met
00:57him.
00:58Before being at Yale, he
01:00was the chief medical officer
01:01and executive vice president of
01:03the Prostate Cancer Foundation.
01:04We focused on barriers to
01:06delivery of care for prostate
01:08cancer nationally.
01:10William is a genitourinary
01:11oncologist
01:13truly with decades of experience
01:14caring for patients with prostate
01:15cancer.
01:16For over a decade, he
01:17was chief of hematology and
01:19medical oncology,
01:20deputy director of the, Tisch
01:22Cancer Institute and NCI designated
01:24center, and the Ezra Greenspan
01:26professor of clinical cancer,
01:28therapeutics
01:29at the Icahn Medical School.
01:31That's Mount Sinai.
01:33He has a number of
01:34national,
01:35you know,
01:36roles that are quite relevant.
01:38He's chair of the American
01:39Cancer Society's National Prostate Cancer
01:41Roundtable,
01:42whose mission is to improve
01:43prostate cancer outcomes and survivorship
01:45through increasing awareness and equitable
01:47access to prevention, screening, and
01:48treatment.
01:49He's also chair of the
01:50medical advisory council for the
01:52Chemotherapy Foundation.
01:54So, what better way to
01:55welcome William to Yale to
01:57have him give grand rounds.
01:59He's also part of the
02:00QU division. I think Dan
02:02Petrak, I know, is online,
02:04from a meeting he's at,
02:05and he's gonna talk to
02:06us about new advances in
02:07prostate cancer in twenty twenty
02:09five. William, thank
02:13you. Well, thank you, Roy,
02:14and thank you all for
02:15the welcome.
02:20Let's see here.
02:23These are my disclosures.
02:28I wanted to talk a
02:29little bit about my journey
02:30here.
02:32I actually worked with Roy
02:34as a resident. He doesn't
02:35remember that, but we were
02:37residents together. He was a
02:38year ahead of me. And
02:39then subsequently with Eric at
02:40the Dana Farber and many
02:41friends. This was really key
02:43to part of my journey
02:44because as I moved on
02:46in my career,
02:48as you heard, I went
02:49to Mount Sinai about fifteen
02:51years ago
02:51to build a new cancer
02:52center in New York City,
02:54and, ultimately,
02:56we did get NCI designation
02:57and and renewed it.
02:59A part of my goal
03:00in life was to figure
03:02out how we actually deliver
03:03this care better to our
03:04patients because so much was
03:05happening and is happening.
03:07So I left,
03:09my my administrative roles to
03:11join a company called Semaphore,
03:12which was a spin out
03:13of of Mount Sinai, which
03:14was really using genomics, but
03:16really more importantly, clinical data
03:17and AI to try
03:19to improve
03:20the way we deliver care
03:21to patients. And, this will
03:23come up a little bit
03:24in in my decision really
03:26to come back to academia,
03:28to use information and data
03:30to better take care of
03:31our patients.
03:33It's a long story, but,
03:34after two years at, a
03:36publicly traded company, I I
03:37joined, the Prostate Cancer Foundation
03:39as the chief medical officer,
03:41and I'll talk a little
03:42bit about the work that
03:43I did there, in today's
03:45talk. But it all leads
03:46to, I think, a real
03:48opportunity for me to have
03:49joined,
03:50the Yale Cancer Center and
03:51Smilow
03:52to talk about work that,
03:54really in two big domains.
03:55One is, of course, prostate
03:57cancer, which I'm gonna be
03:58focusing on today, and the
03:59second is how we deliver
04:01the care better, not just
04:02in prostate cancer, but to
04:03all cancer patients, and that's
04:05really that title around precision
04:06medicine.
04:08But today, I'm gonna focus
04:09on prostate cancer.
04:11These are the newest data
04:12from the American Cancer Society
04:13about the burden. It is
04:15the number one cancer in
04:16men. Really, by far, thirty
04:17percent of all pros all
04:19cancers are are prostate cancer.
04:21And,
04:22interestingly, even though we sometimes
04:23have a belief that prostate
04:24cancer is not lethal, it's
04:26still the second leading cause
04:27of cancer death. Not only
04:29that, the death rate is
04:30actually rising.
04:31This is as of twenty
04:32twenty five.
04:36Here's the incidence rates, and
04:37it this is, again, really
04:39hot off the press. And
04:40you can see this very
04:41sharp, increase in the, incidence
04:43of prostate cancer. This is
04:45in in and of itself
04:46quite an interesting conversation about
04:48why
04:49it's risen so sharply in
04:50the past decade.
04:52And we can talk a
04:53little bit more in the
04:53q and a about what
04:55the in implications there. And
04:56you can see the parallel
04:57in breast cancer, the breast
04:58cancer incidence rates rising.
05:03But the death rate from
05:04prostate cancer has, in fact,
05:06plateaued,
05:07and there's a lot of
05:07reasons to be concerned about
05:08this plateau. You know, early
05:10when I started in this
05:11field about, twenty five years
05:13ago, I thought the prostate
05:14cancer would actually if you
05:16see this drop that that
05:17you can see on this
05:18graph, I thought prostate cancer
05:19would fall below colo colorectal
05:21and other can cancer death
05:23rates, but in fact, it
05:24has plateaued and in as
05:25I mentioned, it's slowly rising.
05:27Of course, lung cancer death
05:28rates have gone down dramatically
05:29in men since, the surgeon
05:31general's report around, around cigarette
05:34smoking.
05:35And these are some of
05:36the data that have recently
05:38come out about why we're
05:39concerned about the death rate
05:41actually rising.
05:42If you look at,
05:44the rates of, cancer, you
05:45can see again that rise
05:47both both in all groups,
05:49but also specifically in black
05:50men who are denoted by
05:52the green dots here. But
05:54particularly, I wanna point out,
05:55this this graph, the the
05:57distant, metastatic disease, and you
05:59can see two things here.
06:01One is the rate of
06:02metastatic prostate cancer is growing
06:04quite dramatically over the past
06:05decade.
06:07And one question is why?
06:08This is in the US.
06:09This is not worldwide. This
06:10is in a country where
06:11you could see that, that
06:12rates of metastatic disease were
06:14dramatically
06:15dropping before,
06:17before this point. So what's
06:19happened over the past decade?
06:20And then you still see
06:21this huge disparity between black
06:23men and all other races.
06:25And this is gonna get
06:26at some of the work
06:27that I did, particularly at
06:27the prostate cancer foundation.
06:30But, I think a lot
06:31of us are concerned about
06:32these these trends about and
06:33about how we reverse them.
06:36Also last year, the Lancet
06:38Commission published a report
06:40about worldwide rates of of
06:42prostate cancer. And what we
06:43know is that over the
06:44next twenty years or so,
06:46from twenty twenty to twenty,
06:48forty, you can see in
06:49the in the corners here,
06:50the rates of
06:52prostate cancer will double. So
06:54the number of new cases
06:55will double, and the number
06:56of deaths will increase by
06:57eighty five percent. And you
06:59can see a lot of
06:59it is driven in the
07:01orange
07:01bars by by East Asia,
07:04South America,
07:06and, and other parts of
07:07the world. So we're seeing
07:08both an increase in incidence,
07:10but also,
07:11a significant increase in death
07:12rates. And, again, we can
07:14debate and discuss some of
07:15the underlying causes of this.
07:17This is not just a
07:18detection issue. This is a
07:20a a a true concern,
07:21especially in an era where
07:22we have so many new
07:23therapies, which is what I'm
07:24gonna shift my talk to.
07:27So I'm gonna talk about
07:29five different areas today.
07:31I know that's a lot
07:31to cover in a forty
07:33five, fifty minute talk, but
07:34I wanna I'm gonna go
07:35through these because I wanted
07:36to just give you a
07:37sense of how much new
07:39information and new data and
07:40new treatments are really happening.
07:42But I'm gonna start with
07:43this idea that screening
07:45is bad for prostate cancer.
07:46And this is unfortunately
07:48something that has, taken
07:50hold and may be explaining
07:52some of the epidemiologic trends
07:53that you're seeing.
07:55What is risk adapted screening?
07:56Well, I think part of
07:58this is,
08:00conveyed by a very famous,
08:02urologist who is a chair
08:03of urology at, Memorial Sloan
08:05Kettering for many years, and,
08:06unfortunately, himself died of prostate
08:08cancer. But he had a
08:09lot of, wisdom that he
08:11would talk about. One was,
08:13he said, growing old is
08:14invariably fatal. Prostate cancer is
08:16less so. This gets to,
08:18from the nineteen seventies and
08:19eighties, the idea that not
08:20all prostate cancers are lethal.
08:23The other, thing that he
08:24said is, is cure possible
08:26for though in those for
08:27whom it is necessary, and
08:28is cure necessary
08:30for those in whom it
08:31is possible? What he's talking
08:32about is the heterogeneity of
08:33prostate cancer means that some
08:35men should be left alone
08:37to live their lives without
08:38intervention, and other men, no
08:40matter what we do, may
08:41progress and die of their
08:42disease. So when you think
08:43of a disease with such
08:44heterogeneity,
08:45how do we apply the
08:46right treatments and the right
08:48solutions to each of these
08:49patients?
08:51So we we wrote an
08:52editorial. This is Sigrid Carlson
08:54and I really talking about,
08:56screening guidelines, and and you
08:58don't you're not meant to
08:59read this. I can tell
09:00you just just that all
09:02of the major organizations that
09:03actually put out screening guidelines,
09:06put out slightly different ones.
09:08So this is very complicated
09:09and unfortunately on the line.
09:11Now most primary care doctors
09:12and most insurance companies,
09:14fund the recommendations of the
09:15US Preventative Services Task Force,
09:17but the AUA,
09:18the American Cancer Society, the
09:20American Society of Clinical Oncology,
09:22NCCN, they all put out
09:23different guidelines. And you can
09:24see if you dig into
09:26this editorial that, unfortunately, all
09:28of the guidelines differ slightly.
09:31And, you know, who's not
09:32gonna be confused when you
09:33see all of this, variation
09:35in terms of the the
09:36guidelines?
09:38So when I joined the
09:39Prostate Cancer Foundation a few
09:40years ago, even though I'm
09:42a medical oncologist
09:43and I don't necessarily screen
09:45patients, I I asked the
09:46question, where can I make
09:47the biggest difference in terms
09:49of,
09:50reducing mortality from from from
09:52prostate cancer? So one of
09:53the first areas was this
09:54concept of risk adapted screening.
09:56So we know, as I
09:57showed you in that earlier
09:59epidemiologic
10:00graph, black men are one
10:01of the groups that has
10:03the highest rate of both
10:04diagnosis and death from cancer,
10:06and you can see that
10:06here. They actually have about
10:08a two point two fold
10:09higher risk of dying of
10:10prostate cancer. They present at
10:12younger ages, they have more
10:13aggressive disease, and are more
10:14likely to be diagnosed with
10:16advanced disease.
10:17So these racial disparities clearly
10:19exist, and this is clearly
10:20a population at risk.
10:22Now, there's an interesting conversation
10:24about the biology and genetics
10:26behind this and whether this
10:27is truly an access issue,
10:29a socioeconomic issue, or if
10:30it's truly a biological issue.
10:32But the bottom line is
10:33the self reported black men
10:35have the highest rates of
10:36dying of prostate cancer, in
10:37the United States and and
10:39actually in the world.
10:40So what we did was
10:41we simply created a,
10:43an expert group, a panel
10:45here,
10:46to review the evidence.
10:48Now the issue is that
10:49if you try to only,
10:51limit that evidence to randomized
10:53phase three trials, you'll be,
10:55very disappointed because of the
10:57three randomized trials that have
10:59looked at screening, only five
11:00percent of one of the
11:01three trials actually had, black
11:04men enrolled. So here's a
11:05high risk population who have
11:07just not been studied. So
11:08is the absence of evidence,
11:10does that mean that we
11:11shouldn't actually make recommendations that
11:13directly impact this population? And
11:15we decided no. We said
11:16we were gonna look at
11:17all the evidence, but include
11:18evidence that included
11:20modeling evidence and observational data.
11:23So this paper was published
11:24in the NEJM Evidence last
11:25year, and it asked six
11:27questions. You know, should black
11:28men be screened?
11:30What should they know about
11:31screening? At what age and
11:32so on? And I'm not
11:33gonna go into detail about
11:35all this, but, basically,
11:36most men are recommended to
11:37have screening at the age
11:38of fifty to fifty five.
11:40And even though the guidelines
11:42have always put a black
11:43man into an asterisk category,
11:45we took it out of
11:46the asterisk, and we just
11:47basically said black men should
11:48get a baseline PSA between
11:50the ages of forty and
11:51forty five, and they should
11:52also get annual screening. I
11:54think there's a real opportunity,
11:56certainly nationally,
11:57but also here, within the,
12:00the Yale network to really
12:01think about how we can
12:02have an impact on on
12:03patients who are at the
12:04highest risk of both getting
12:06prostate cancer but also dying
12:07of it.
12:10But as I mentioned earlier,
12:12some of the challenges here
12:13are how do we actually
12:14deliver this care.
12:15So, when I left PCF,
12:18really, it was to, as
12:19I thought about coming back
12:21to an academic medical center,
12:22it really requires this kind
12:24of partnership, really community leaders
12:25and academic centers. And I
12:27think that, one of the
12:29organizations that I've been fortunate
12:30to be asked to to
12:31join and lead is the
12:33ACS National Prostate Cancer Roundtable.
12:36And the idea really is
12:37to think about projects that
12:38will actually impact,
12:40the disease in the exact
12:42way that I I first
12:43started when I joined PCF.
12:45And so this started in
12:46September. More to come on
12:47this, and I'd love to
12:49interact with the community here
12:50to think about ways in
12:51which we can actually,
12:53address this at risk population.
12:54There are other at risk
12:55populations. For example, those with
12:57a family history or genetic
12:58risk, Not gonna have a
12:59chance to talk about that
13:00today, but I think that
13:02implementation is key. You can
13:04get all the great drugs
13:05in the world. You can
13:06have all these fancy new
13:07bi diagnostic tests. But if
13:08patients who
13:10can have access to a
13:11basic basically, a fifty dollar
13:13test can actually learn if
13:15they might have, a lethal
13:16cancer, I think that the
13:17answer is to try to
13:18to find those patients.
13:21Okay. So we're gonna switch
13:22to, more advanced disease. And,
13:24of course, this is the
13:25other way in which patients
13:27progress and unfortunately die of
13:29the disease. And I'm gonna
13:29first talk about androgen receptor
13:31pathway inhibitors, what I call
13:33the first targeted therapy. You
13:34know, we talk about targeted
13:35therapy now. We have all
13:36these fancy,
13:38biomarkers. But in truth, androgen
13:40receptor
13:41is one of the key
13:42first,
13:43pathways.
13:44And you can see here
13:45that,
13:46in pink are four,
13:48what we call ARPs or
13:49androgen receptor pathway inhibitors that
13:50are proven to improve survival
13:52in multiple disease states within
13:54the treatment landscape of prostate
13:55cancer.
13:57But this history goes back
13:58many years. In fact, there
13:59have been at least two
14:00Nobel prizes awarded for the
14:02discovery that androgen was a
14:03driver of prostate cancer. Now
14:05in twenty twenty five, we
14:06think it's obvious that androgen
14:08drives prostate cancer. But back
14:09when, doctor Huggins
14:11first did orchiectomies,
14:13in patients with metastatic prostate
14:15cancer, it was not obvious
14:16that prostate cancer was driven
14:18by testosterone and and androgen
14:20receptor.
14:21And this is a long
14:22history. The second,
14:24Nobel Prize, by the way,
14:25was for the chemical synthesis
14:27of LHRH.
14:28And the idea here really
14:29is that this is a
14:30big disease for which this
14:32observation has not only led
14:34to a long standing
14:36treatment, which we still use,
14:37so we don't use orchiectomy
14:39here in the United States.
14:40It's still used worldwide as
14:41a very inexpensive way to
14:43deprive the cancer of its
14:44ligand. But LHRH agonists and
14:46antagonists remain a mainstay of
14:48treatment, basically, androgen deprivation.
14:51But what really have we
14:52learned, when I started in
14:54this field, we said, you
14:55know what? We we gave
14:56the patient luprolide. Their testosterone
14:58went down. We're done. We've
14:59maximized it. It turned out
15:01that we were completely wrong.
15:03And the reason we were
15:04completely wrong is that androgen
15:06continued to be an important
15:07driver of these cancers.
15:09And we now know that
15:10there are at least,
15:12four drugs in this category
15:14of ARPII that block the
15:16continued signaling of an androgen
15:19in these cancer cells. And
15:20they are listed here, abiraterone,
15:23apalutamide, darolutamide, and enzalutamide.
15:25We also know that chemotherapy
15:26has an impact when these
15:28cancers first present. We we've
15:29known that for a while,
15:30but in fact, when you
15:31move it early into the
15:33presentation
15:34of metastatic prostate cancer, you
15:36can target this heterogeneity. Heterogeneity
15:38implies that these cancer cells
15:40are not uniform monoclonal like
15:42some leukemias may be. There
15:43are these different colored cancer
15:45cells.
15:46They're not really colored in
15:46real life, but, but they
15:48are driven by different driver
15:50mutations or abnormalities or sensitivity
15:53to androgen signaling.
15:54And if you have a
15:55better androgen androgen signaling inhibitor,
15:58or chemotherapy that you can
16:00actually improve survival in these
16:01patients.
16:02And there have now been
16:03eleven prospective clinical trials. This
16:05is one of the most
16:06studied and most effective randomized,
16:09stories that exist in modern
16:11oncology.
16:12Okay? Eleven randomized clinical trials
16:14that show survival benefit for
16:16combination therapy in metastatic
16:18hormone sensitive prostate cancer. So
16:20we call this HSBC or
16:21hormone sensitive prostate cancer because
16:23we know that if we
16:24actually deprive these patients of
16:26androgen, as I showed you
16:27with doctor Huggins, we can
16:28put these cancers into remission.
16:30But those patients would recur
16:31within a year or two.
16:33But what we've shown with
16:34all of these clinical trials
16:35is that if you do
16:36doublets where you add an
16:38ARPI to androgen deprivation therapy
16:40or you do triplets where
16:41you add an ARPI plus
16:43chemotherapy,
16:44that you can actually improve
16:45survival, and you can see
16:46the hazard ratios there.
16:49You can improve survival by
16:50up to twenty to forty
16:51percent. And all of these
16:52studies were positive.
16:54So the the question is
16:55not if these drugs work.
16:56The question is, is there
16:58an optimal sequence? Is there
16:59one drug better than the
17:00other? But we're not gonna
17:01talk about that. We're gonna
17:02talk about the fact that
17:03all of these trials, including
17:04one that didn't even make
17:05it to this review article
17:07and was presented very recently,
17:09all show that these drugs
17:10should absolutely be used to
17:12improve survival.
17:14So, you know, when I
17:15give talks to patients,
17:16you know, I try to
17:17make the story simple. Right?
17:18So ADT alone, going back
17:20to the nineteen forties, androgen
17:22deprivation alone, therapy alone was
17:24the standard of care.
17:26Then in the past few
17:28years, if you look at
17:28that graphic, we showed that
17:30chemotherapy
17:31plus,
17:32ADT or an r one
17:34RP plus, ADT improved survival.
17:37So two drugs were better
17:38than one.
17:40Now the triplets showed that
17:42if you add,
17:43a third drug
17:44together, if you add ADT
17:46plus docetaxel on either abiraterone
17:48or dalutamide, you improve survival.
17:50So, actually, these two options
17:51should really be off the
17:52table now, and you'd be
17:54surprised.
17:55A lot of patients, in
17:56fact,
17:57do not receive,
17:58these three options here. And
18:00these options are widely available,
18:02and we can talk again
18:03about why they're not always
18:04used. But sometimes it's the
18:06doctors themselves, maybe not in
18:07academic centers like ours, but
18:09in the community who may
18:10or may not appreciate,
18:12how important these drugs are
18:13in terms of overall survival.
18:15If you can live forty
18:16percent longer with these treatments,
18:18why wouldn't you give these
18:19treatments?
18:20So they've asked that question
18:22in real world studies, and,
18:24this includes mostly,
18:25US studies, but also studies
18:27from other countries. And you
18:28can see that,
18:30adding one of these drugs,
18:31either Dositax or one of
18:33these,
18:34it's called the RC here,
18:35but I mean ARP,
18:36the one of these extra
18:37drugs improve,
18:39were were more likely to
18:40be used in white patients,
18:42younger patients, in academic centers,
18:44and more likely by oncologists
18:45and neurologists.
18:46But if you look at
18:47this graph that was published,
18:49it looks like we're doing
18:50pretty well. But if in
18:51fact, if you actually put
18:52it on scale, this is
18:53what it really looks like.
18:54So we're we're lucky to
18:56get to fifty percent. At
18:57at at the time this
18:58was published, which was just
18:59last year, it was only,
19:01it was only about, thirty
19:03to forty percent were receiving
19:04a second drug.
19:05Okay. So this again gets
19:07to the same point I
19:08brought up earlier about implementation.
19:10We can get all these
19:11great drugs, but if patients
19:12aren't receiving it, they're not
19:13getting the survival benefit.
19:16And I wanna call out,
19:18that there are other drugs
19:19coming down this pike, including
19:21work
19:21developed here at Yale by
19:23Craig Cruz, the concept of
19:24PROTACs,
19:25AR degraders, and led by
19:26Dan Petrelac in the original
19:28clinical trials. And this was
19:29pub presented last year at
19:31ASCO, and you can see
19:32that this,
19:33PROTAC that degrades AR,
19:35specifically in patients who have,
19:37mutations in the ligand binding
19:38domain, it's beyond the scope
19:40of this discussion. But these
19:41are patients who do not
19:42respond to the current,
19:44AR, PIs that we have
19:46at this time. And you
19:47can see these waterfall plots,
19:48you see quite a dramatic
19:51benefit to the use of
19:52a degrader. So we're gonna
19:54continue to see androgen signaling
19:56as an important target for
19:58anticancer therapy and prostate cancer.
20:00So here's a a story
20:02that has evolved over not
20:04just a few decades, but
20:05over
20:06almost a century. We're coming,
20:08you know, in the next
20:09sixty, seventy, eighty years we've
20:10been using these treatments. But,
20:12we think we're done, but
20:13we keep getting better and
20:14better, and you're gonna see
20:15more of these drugs in
20:16that setting.
20:18Okay. So how else can
20:19we be better?
20:20You know, biomarkers are a
20:22hot topic. People talk about
20:23it all the time. That
20:24is the key to doing
20:26better precision medicine. Right? So
20:28I'm gonna talk a little
20:29bit about the story here
20:30in prostate cancer with regard
20:31to both molecular biomarkers and
20:33PARP inhibitors in particular.
20:36So, in this graphic, there's
20:38two areas that a biomarker
20:40that are biomarker driven, PARP
20:42inhibitors and pembrolizumab.
20:43And I'll just talk briefly
20:45about both.
20:46But this is an article
20:47from a few years ago
20:49that really shows the FDA
20:51approvals,
20:52over the last twenty years
20:54and how many of them
20:55are really biomarker driven. You
20:57can see that the blue
20:58are biomarker driven approvals.
21:00And I couldn't find a
21:01more recent updated version, but
21:03it's probably continued and even
21:04more so. And you can
21:06see that in in recent
21:07years, at least half of
21:08all drug approvals by the
21:09FDA are actually,
21:11have an associated biomarker. And
21:13what this really points out
21:13is prostate cancer is not
21:15prostate cancer. Lung cancer, we
21:16know that's the prototypical story.
21:18It's not lung cancer. It's
21:19EGFR mutated lung cancer or
21:21it's,
21:22it's,
21:23ROS fusion lung cancer. And
21:25the same thing is true
21:26in prostate cancer except that
21:28we have fewer clear biomarkers.
21:29But I just this is
21:30an interesting paper from,
21:33also, from last year from,
21:35from a a a prominent
21:37group that looked at the
21:38rates of molecularly driven treatment
21:40decisions. So this concept of
21:42targeted precision therapy.
21:44And we know that,
21:46precision
21:48tier one and tier two,
21:49mutations
21:50represent
21:51about,
21:52in twenty seventeen represented about
21:54nine percent of all patients
21:56presenting,
21:57across the board, all cancers.
21:59And that went up to
22:00thirty one point six percent,
22:02five years later.
22:03Okay? And similarly, the number
22:05of,
22:07undetermined,
22:08drivers or drivers without actionability
22:10went down by about half.
22:12So you might say, depending
22:13on your, you know, point
22:14of view in the world,
22:15are you a half full
22:16or half empty person?
22:19Going from nine percent to
22:20thirty one percent in just
22:21five years is pretty dramatic,
22:23but two thirds of patients
22:25still don't have actionable mutations
22:27if you do sequencing of
22:28their tumors.
22:29And this actually this paper
22:30came out of Memorial Sloan
22:31Kettering. So the question is,
22:33in the average community practice,
22:35you know, if they're not
22:35doing all of the sequencing,
22:36are they getting the benefit
22:38of these actionable mutations?
22:41It turns out prostate cancer
22:42is driven by,
22:44molecular alter alterations, most importantly,
22:46DNA damage repair mutations
22:48or DDR mutations. And you
22:49can see here, if you
22:50look at the mutations,
22:52BRCA two is the most
22:54common one. So this sometimes
22:56surprises patients because with BRCA,
22:58of course, BRCA was named
22:59after breast cancer, but this
23:01gene in prostate cancer patients
23:03is associated with,
23:05both a worse prognosis, earlier
23:07diagnosis,
23:07but also significant,
23:11significantly worse outcomes.
23:13And and if you look
23:14at these, about a quarter
23:16of patients with advanced prostate
23:17cancer or CRPC, castration resistant
23:19prostate cancer,
23:20have,
23:21a mutation in in one
23:23of these DNA damage repair
23:24mutations.
23:26Fifty percent of those are
23:27germline, meaning they inherited it
23:28from their mother or father,
23:29and fifty percent are, somatic,
23:31meaning they developed it, during
23:33their lifetime.
23:34One of the things that
23:35we've learned certainly from preclinical
23:37work is that there probably
23:39is a synergy between androgen
23:41signaling and and blocking androgen
23:42signaling
23:43and,
23:44and these DNA damage repair
23:46mutations.
23:47And, and so the the
23:49the hypothesis based on preclinical
23:51work was that combining
23:53an ARP with a PARP
23:54inhibitor would actually improve outcomes
23:57in patients with prostate cancer.
23:59So two trials three trials
24:01recently about a year ago,
24:03actually, a few years ago,
24:04have shown that,
24:05survival is improved if you
24:07actually combine a PARP inhibitor
24:09with,
24:09one of these androgen receptor
24:11pathway inhibitors. And this is
24:12one of the studies, PROPEL,
24:13which combined olaparib with abiraterone
24:16versus, placebo,
24:17plus abiraterone.
24:19And you can see that
24:20particularly in the BRCA sub
24:22mutated subset, a very significant
24:24improvement, in this case in
24:25overall survival.
24:27So we know that if
24:27you carry one of these
24:28mutations, you should be getting
24:30a PARP inhibitor. But more
24:31importantly, you should be getting
24:32it right up front. You
24:33shouldn't be getting it later.
24:35This this drug was approved,
24:37quite a number of years
24:38ago if you progressed after
24:39a drug like abiraterone.
24:41But now this these studies
24:42seem to suggest that you
24:43should be getting them right
24:44up front, right at the
24:45time of metastatic disease.
24:47And the second study that
24:48is really in flight right
24:49at this moment is Talopro
24:51two. Again, a a different
24:53PARP inhibitor called talazoparib,
24:55combined with enzalutamide versus placebo
24:57plus enzalutamide. Again, a very
24:59similar endpoint, which is, radiographic
25:01progression free survival. And you
25:02can see that in all
25:03patients, there is a benefit
25:05to,
25:06to the combo,
25:08but,
25:09more significant in HRR or,
25:12DDR deficient tumors.
25:14They did put out a
25:15press release that suggests that
25:16maybe this, this combination works
25:18in all comers. I think
25:19we have to wait and
25:20see, when that data is
25:22presented.
25:23So the FDA has now
25:24approved,
25:25at least three combinations that
25:26are listed here. I didn't
25:27show you the third study
25:28of niraparib.
25:30But what does this mean?
25:31This means that in patients
25:32certainly with a DNA damage
25:34repair mutation,
25:35most important one being BRCA
25:37one or two, that that
25:38these patients should receive a
25:40combination of an ARP plus
25:42a PARP inhibitor.
25:44But similar to the story
25:45I've been telling you before,
25:47people don't get tested. It
25:48is, this is a real
25:49world evidence study actually from
25:51the Flatiron Group that shows
25:52that about sixty percent of
25:54patients never get tested
25:56for these mutations.
25:57So as of now, in
25:58order to be a candidate,
25:59you have to be tested.
26:00And you can see that
26:01there was a little bit
26:02of a blip down during
26:03COVID. But in general, about
26:05six only about forty percent
26:07of patients nationally get tested
26:08for DNA damage repair mutations.
26:10So you if you don't
26:11get tested, you'll never be
26:12able to benefit from the
26:13treatment.
26:15Okay.
26:17I think, if we haven't
26:18had a PSMA PET talk
26:20in for this group, I
26:22I hope we do have
26:23one soon because it's completely
26:24transformed
26:25the way we treat these
26:26patients. I've been taking care
26:28of prostate cancer for twenty
26:29five years. PSMA PET has
26:31completely
26:32changed the way we visualize
26:33prostate cancer. Now this is
26:35a clinical states model that
26:36I've shown many years now.
26:38If you start present with
26:39clinically localized prostate cancer, you
26:41have, radical prostatectomy by doctor
26:43Kim and you you're cured
26:45or you get radiation and
26:46you're cured. But if you
26:47aren't and at least a
26:48third of patients are not
26:49cured,
26:50they go through these disease
26:51states going from left to
26:52right where,
26:54where you might have a
26:55rising PSA and then you
26:56develop metastatic disease like I
26:58talked about earlier, which is
26:59on the bottom there. At
27:00the top, though, there's this
27:01interesting state that we defined
27:03as nonmetastatic
27:04but hormone sensitive and then
27:06castration resistant. What does that
27:07mean nonmetastatic?
27:08Well, it doesn't mean that
27:09they don't have metastasis. It
27:10means that we can't see
27:11it with traditional scans like
27:13bone scan and CAT scan.
27:14That's really what it means.
27:15It means that our imaging
27:17was not able to detect
27:19what we knew that was,
27:20cancer progressing. How do we
27:22know that their cancers were
27:23progressing? Well, we have a
27:24biomarker that I started this
27:25whole conversation with PSA
27:27that even though it's very
27:28controversial as a as a
27:30biomarker
27:31for,
27:33for screening, it is not
27:34controversial at all as a
27:36biomarker for monitoring.
27:37We use it all the
27:38time to monitor whether patients
27:40are progressing or not. So
27:41as I said, we've actually
27:43gone through this state where
27:44we actually used to use
27:45bone scan and CT scan,
27:46but we've completely shifted to
27:48the use of PET scan
27:49with CT.
27:50Why? I at least I
27:52have. I was on a
27:52panel. I was sitting there,
27:54and I said, I don't
27:55do bone scans anymore. And,
27:57you know, prominent urologist,
27:59you know, kind of tried
28:00to berate me for it.
28:01But in truth, if I'm
28:03able to get a PSMA
28:04PET scan, it is far
28:05superior to what information I
28:07might get from a bone
28:08scan.
28:09Now PSMA is an interesting,
28:11transmembrane molecule because it's not
28:13just an imaging molecule, but
28:15it is a therapeutic one
28:16as I'll talk about in
28:17a second.
28:18It's, highly expressed in prostate
28:20cancer,
28:21but particularly,
28:22almost a thousand fold in
28:24metastatic disease.
28:25And one of the issues
28:26is that this this, new
28:27imaging agent became, you know,
28:29became available relatively recently.
28:31And you can see here,
28:32I I listed the timing
28:33when it became available, twenty
28:34twenty, twenty twenty one, twenty
28:36twenty three. These are three
28:37different types of PSMA reagents.
28:40And so in a very
28:40short time, we've put a
28:42lot of pressure on nuclear
28:43medicine to be able to
28:44get these scans for our
28:45patients because
28:46from the point of diagnosis
28:48all the way to the
28:49point of advanced disease, this
28:50is helping guide exactly where
28:52the cancer is in a
28:53much more sensitive and specific
28:54way than we were able
28:56to do with, with, imaging
28:58like bone scans or or
28:59CT scans alone.
29:01And, it is,
29:03not real it's it's expressed
29:04on other organs, particularly the
29:06salivary and lacrimal glands. You'll
29:07see on some of the
29:08images I show you, which
29:10is important because of the
29:11toxicity of drugs that target
29:12it. So they get dry
29:13mouth, for example,
29:15and the kidneys can also
29:16sometimes take up these, some
29:18of these drugs. But it
29:19is a really important and
29:21excellent target.
29:23So,
29:25so we we do know
29:26that that concept of nonmetastatic
29:28is a disappearing disease state.
29:31So there were drugs that
29:32were approved for nonmetastatic
29:34castration resistant prostate cancer. But
29:36in this study from the
29:37UCLA,
29:38when they looked at patients
29:39who are nonmetastatic,
29:41that is they didn't have
29:42cancer on a bone or
29:43CT scan and they did
29:44a PSMA PET,
29:46ninety six percent of them
29:47were ninety ninety eight percent
29:48of them actually had a
29:49positive PET scan. So how
29:51that's not nonmetastatic. It means
29:52that your old scan was
29:53no good.
29:54And so it is a
29:56disappearing disease state in in
29:57the advent of the PSMA
29:58era.
30:00There was a prior
30:02test that was available a
30:03few years before called fluciclovine.
30:05Fluciclovine is interesting because it
30:07is a metabolic scan. It's
30:08an amino acid, that,
30:11that was used that we
30:12were using before PSMA became
30:13widely available in the United
30:14States. And this was a
30:15head to head study comparing
30:17PSMA to fluciclovine.
30:19And you can see that
30:21PSMA was four point eight
30:23times more accurate in terms
30:24of detecting,
30:26detecting prostate cancer. So, again,
30:29you can't treat what you
30:31can't measure. Right? We have
30:32PSA. We can measure that.
30:34That's a very simple quick
30:35test that we can order
30:36on these patients. It's not
30:37perfect. It doesn't give us
30:38all the information. Certainly doesn't
30:40tell us where the cancer
30:41is, and that's why PSMA
30:44PET in particular has really
30:45transformed the way we think
30:46about this disease.
30:48And, this is a prelude
30:50to the the next section
30:52of my talk, which is
30:53really therapeutics.
30:54Because as you see on
30:55the left, you can see
30:55a patient with metastatic disease
30:57who has a positive PSMA
30:59PET scan. You can see
31:00the the areas in his
31:01bone,
31:02that light up.
31:03You can see the salivary
31:05glands up in the upper
31:06part of his head, and,
31:08and you can also see
31:09that his kidneys light up
31:10because it's being excreted through
31:11the kidneys, and some is,
31:13collecting in the bladder.
31:14On the right side, you
31:15see that,
31:16FDG PET, which has been
31:18around for many years and
31:19and really lights up in
31:20the with the advent of
31:21glucose
31:22and is very useful in
31:23diseases like lymphoma and lung
31:25cancer because those cancers are
31:27very proliferative and use quite
31:28a lot of glucose.
31:29That that sometimes,
31:31in traditionally, FDG PET was
31:33not useful in prostate cancer.
31:34Traditionally, we haven't used a
31:36lot of it, but you
31:36can see that, in fact,
31:38there are some cancers in
31:39including in this patient here
31:41where some of the cancer
31:42cells do express PSMA, but
31:44some don't, and they only
31:46express FDG. And that's as
31:47you'll see in a minute,
31:48that's a real issue as
31:49we learn more about,
31:51the use of these imaging
31:52tech techniques.
31:54So the last section of
31:55my talk is really gonna,
31:56focus on this era of
31:57targeted therapy. I already started
31:59by saying androgen receptor pathway
32:01inhibitors are targeted therapy, and
32:02that's true. But in fact,
32:04we're moving to, an era
32:06of radioligands,
32:07bispecifics, and beyond. So,
32:10so this is, really
32:12in in this case, I'm
32:13gonna talk about LU one
32:14seven seven PSMA,
32:16but we're also gonna talk
32:17about all the treatments that
32:19I think are are on
32:20their way. So this was
32:21a, New England Journal paper
32:23just three years ago now
32:24called the VISION study.
32:26And it really shows you
32:27how PSMA, in particular a
32:28ligand called PSMA six one
32:30seven, binds to the cancer
32:31cell and delivers
32:33a radioactive,
32:35payload. In this case, LU
32:36one seven seven. That's a
32:38a beta particle that is
32:39lethal. So remember the imaging
32:41I showed you earlier was
32:42just to see the pic
32:43where the cancer is. But
32:44if you put a attach
32:46it to a radio,
32:47ligand that actually,
32:49is in endocytosed by the
32:50tumor cell, then it destroys
32:52that that cancer cell. That's
32:53the idea. So it's like
32:54a smart bomb technology
32:56to take PSMA and then
32:58deliver,
32:59a radioactive particle.
33:01And this is a trial
33:02design. You had to just
33:04have one positive PSMA,
33:06PET lesion. And we can
33:07talk a little bit about
33:08the nuances of this, but
33:10this makes it very simple.
33:11When you're doing a large
33:12randomized trials, keep it simple.
33:14If you don't keep it
33:15simple, it's very hard to
33:16accrue patients.
33:17And the the advantage of
33:18this treatment is that the
33:20patients could have had it
33:21anywhere. It works wherever the
33:22cancer is. It works if
33:23it's in the bone, in
33:24the lymph nodes, in the
33:25liver, anywhere.
33:27And the patients were randomized.
33:29These are patients who had
33:30already received the standard of
33:31care at the time, which
33:32included chemotherapy with a taxane
33:35or, an ARPY,
33:36or both.
33:37And they were randomized to
33:39receive standard of care therapy,
33:40which was not further chemotherapy
33:42but anything else, versus this,
33:45treatment, l u one seven
33:46seven six PSMA.
33:47And you can see here,
33:49on the left, radiographic progression
33:51free survival,
33:52hazard ratio of point four
33:54zero,
33:55sixty percent reduction in risk
33:56of project progression. But more
33:58importantly, overall survival, point six
34:00two has a ratio, Forty
34:01percent improvement in overall survival.
34:03And we have seen some
34:04dramatic responses to patients with
34:06this treatment. It is, given
34:08here, and it is, it
34:09has transformed a lot of
34:10my patients',
34:12lives.
34:13It is not curative, at
34:14least in the states we're
34:15giving. Remember, we're giving it
34:17at very late stages right
34:18now.
34:19So we'll talk a little
34:20bit about, what's being done
34:21to move it forward.
34:23So if you look at
34:24PSA response, that's a very
34:26common way that we measure
34:28how efficacious a treatment is.
34:29And you can see that
34:30if you use,
34:32standard of care alone, about
34:33seven percent will have a
34:34fifty percent drop in PSA.
34:36But if you use this
34:37LU one seven seven,
34:39it's about forty six percent.
34:40So, again, this is not
34:41a treatment that works in
34:42every patient. We can talk
34:43about some of the nuances
34:44there, but this is a
34:45group of patients who had
34:46no other therapy available to
34:48them and who were likely
34:49to progress and die.
34:51And we definitely see exceptional
34:53responders. And what you see
34:54here in this patient is
34:55on the left side, his
34:56PSA was,
34:58eight hundred and eighty, and
34:59he had diffuse bone metastases
35:01as you can see there.
35:02And within, one month and
35:04then three months, which you
35:05see on the second to
35:06last and last panel, his
35:07PSA has gone down to
35:08thirty and his bones, his,
35:10PET scan is pretty much,
35:13clear,
35:14almost completely clear. And we've
35:15seen some complete responses with
35:17these treatments.
35:18So
35:19it is a smart way
35:20of delivering targeted radiopharmaceutical
35:22therapy.
35:23But as I mentioned in
35:24that earlier graphic where I
35:26showed it next to FTG
35:27PET, there are still patients,
35:29for example, who don't express
35:30PSMA. That's what you see
35:32in the left panel. Or
35:33patients who have discordance between
35:35PSMA and FDG,
35:37either in bone in the
35:38center panels or in the
35:39right. And you see I
35:40put PSMA at next to
35:41FDG in each of these,
35:43and you can see that
35:44in some patients, the FDG
35:45PET is showing tumors that
35:46don't make PSMA.
35:49This is also as probably
35:50a a a a way
35:51in which these cancer cells,
35:53you know, it's like the
35:54terminator. Sometimes you you you
35:55shrink them as many as
35:56you can, but the cancer
35:57cells that recur
35:59are don't express PSMA. And
36:00and this treatment will not
36:01work if your tumor cell
36:02does not make PSMA.
36:05The side effects are almost
36:06what you'd expect.
36:08Because it's a radiopharmaceutical,
36:10we see bone marrow suppression
36:11and fatigue.
36:12And the dry mouth is
36:13unique to this treatment because
36:15as I showed you in
36:16some of those graphics, you
36:17see this,
36:19this uptake in the salivary
36:20and, glands.
36:22So what about moving this
36:23treatment earlier? Like, why are
36:24we waiting until after the
36:25patient's progressed on chemotherapy and
36:27has the amount of disease
36:28I showed you? Well, that
36:30idea is obviously, moving forward.
36:31And this was a study
36:32called PSMA four. This is
36:34before chemotherapy.
36:36And you can see it's
36:37the same randomization.
36:38You could either get another
36:40ARPI or you could get,
36:41this LU one seven seven.
36:42And you see on the
36:43left side a very strong
36:45PSMA,
36:47PFS benefit. So really a
36:50doubling of the time it
36:51takes to progress.
36:52But on the right side,
36:53you don't really see an
36:54overall survival benefit. So this
36:56is one of the reasons
36:57that the FDA has not
36:58yet approved this. This study
36:59was presented, you can see
37:00here, in twenty twenty three.
37:01And we've seen this data
37:02for quite some time, but
37:03it's expected that the FDA
37:05will actually,
37:07probably approve this in patients
37:08who have not yet received
37:09chemotherapy. But it's, again, a
37:11subject we don't fully understand
37:13why are aren't these patients,
37:15benefiting in terms of overall
37:16survival.
37:17And then the other question
37:18is, you know, if if
37:19this is these are all
37:20patients with metastatic disease,
37:23why wait till they develop
37:24castration resistance? Why not just
37:26treat them upfront?
37:27And this was a study
37:28from your, Australia where they
37:30gave them two cycles of
37:31PSMA treatment in addition to
37:32hormones and chemotherapy. Remember I
37:34told you, in MHSPC
37:36combination therapy with two or
37:38three drugs is the standard
37:39of care. So why not
37:40just give them this, two
37:42treatments of PSMA in addition?
37:44And they looked at, this
37:45endpoint, which was after all
37:47the treatment's done a a
37:48year later, who's more likely
37:49to have a low PSA?
37:50And it was actually you
37:52were four times more likely
37:53to have a low PSA
37:54a year later.
37:55So it suggests actually that
37:57giving this treatment upfront will
37:59have a long term benefit.
38:01Now,
38:02there's another study giving six
38:03of these cycles six of
38:04these treatments.
38:05If if you give a
38:06treatment like hormonal therapy or
38:08chemotherapy,
38:09then the target starts to
38:10go away. Will giving four
38:12more of those cycles of
38:14of of LU one seven
38:16seven get rid of more
38:16cancer? It's not clear. In
38:18fact, when we give these
38:19treatments to patients who have
38:20a negative PET scan, it
38:21doesn't work. It only works
38:23if the target's there.
38:25So I think, what these
38:27studies suggest is earlier use
38:29of these drugs does matter,
38:30but
38:31giving it indiscriminately
38:32probably doesn't.
38:35So this is my summary
38:36of radioligand therapy. And by
38:37the way, this is a
38:38very odd area for drug
38:39development. People are very, very
38:41interested in replicating this. Because
38:43right now, it's just two
38:44diseases where RLTs
38:46are actually approved. One is
38:47prostate cancer like I showed
38:48you, and the other is
38:49neuroendocrine
38:50tumors, okay, which are even
38:52less common. But people are
38:53very interested in this type
38:55of approach in in bladder
38:56cancer, breast cancer, and lung
38:58cancer. And I think the
38:59the ability to deliver this
39:01type of radiopharmaceutical
39:02treatment, I think, will hinge
39:03on how good those targets
39:05are. We happen to have
39:06a really good target with
39:07prostate cancer, which is PSMA.
39:09The other interesting thing that
39:10you'll hear about is alpha
39:12particles.
39:13So, you know, I'm not
39:14a physicist,
39:15but there are better ways
39:17of delivering a lethal dose
39:19of,
39:19of, radiopharmaceutical
39:21that are more able to
39:23kill these cancer cells with
39:24less toxicity.
39:26Okay. So the last part
39:27of my talk is really
39:28about immunotherapy. And, you know,
39:30this was it's hard to
39:31believe it's this was the
39:33breakthrough of the year in
39:34two thousand thirteen. So we've
39:35been living with this now
39:36for almost a dozen years.
39:38And, of course, you know,
39:39lung cancer is the prototypical,
39:41disease,
39:43along with melanoma and and
39:45kidney cancer where immunotherapies made,
39:47important differences.
39:49But prostate cancer actually was
39:50one of the first diseases
39:51where a checkpoint inhibitor was
39:53tested. This was CTLA four.
39:55And you can actually see
39:56that there was a suggestion
39:58that some patients might benefit
39:59from a checkpoint inhibitor even
40:01in prostate cancer, but it
40:02was never developed further. This
40:03was,
40:04predating,
40:05the use of PD L
40:06one or PD one inhibitors.
40:08But there was a suggestion
40:09that maybe some patients with
40:10prostate cancer actually could benefit
40:12from checkpoint inhibitors. But in
40:14the end,
40:15the only approval for checkpoint
40:16inhibitors in prostate cancer right
40:18now are in TMB high
40:19or MSI high tumors,
40:21which, as you know, are
40:22highly mutated prostate cancer. Prostate
40:24cancers in general are not
40:25highly mutated.
40:28The prevalence is probably around
40:29three to five percent,
40:30and the rate of response
40:31is about fifty percent, but
40:33some of these are durable.
40:34You can't really see the
40:35the bottom there. But the
40:36progression
40:37free survival for those with
40:39very high TMBs, you can
40:40see from from upper to
40:42lower, the highest TMBs. You
40:44can see that they're, they
40:45they are not progressing after
40:47two or three years, some
40:48of these patients. So, again,
40:49it behooves us to check,
40:51for for evidence of a
40:53tumor mutational burden or MSI
40:55high or unstable disease.
40:58But I think the real
41:00you know, that's a very
41:01small percentage of patients. So,
41:02you know, I I probably
41:03have seen one or two,
41:04even though I have a
41:05very big practice,
41:07is is really taking a
41:08a page out of the
41:09PSMA handbook and to look
41:11at,
41:12bispecific t cell engagers,
41:14so called BiTE. So remember,
41:16if you have a target
41:17and now you can deliver
41:18a radiopharmaceutical,
41:19maybe you can deliver other
41:20things like T cells. We
41:22know that T cells are
41:23the things that kill cancer.
41:24Right? Why don't they work
41:26in can prostate cancer in
41:27general like in these,
41:29in this curve? Well, probably
41:30because they don't know where
41:31to go. So if you
41:32can be smart and deliver
41:33the T cell directly to
41:34the cancer cell, maybe you'll
41:36have a better,
41:37out outcome.
41:39So this was one of
41:40the first bites that certainly
41:41got a lot of attention.
41:42This was now five years
41:43ago.
41:44And you can see that
41:45a majority
41:46of patients receiving AMG one
41:48sixty, which was a PSMA
41:49directed,
41:50bispecific t t cell engager,
41:52actually had a PSA response
41:54in this waterfall plot. It
41:55had some toxicities that really
41:57killed this drug,
41:58but there was this, you
41:59know, there are a bunch
42:00of other ones that I
42:01showed you on that first
42:02slide. And this was, this
42:04is also something that is
42:05quite, I think, exciting and
42:07interesting, but I think it
42:08reminds us of the toxicity.
42:10You know, it's interesting. We'll
42:11see the same drug used
42:12in breast cancer and lung
42:14cancer and prostate cancer, and
42:15sometimes we'll see more toxicity
42:16in prostate cancer patients. I
42:18don't always understand why. I
42:20have a theory about it,
42:21which relates to androgen deprivation,
42:23but we do see more
42:24toxicity in prostate cancer patients
42:26than we might sometimes expect
42:27with the same drug.
42:29But this is a combination
42:30of a a a bispecific
42:31from Regeneron
42:33that, again, shows
42:35significant
42:36responses, especially when combined with
42:37the checkpoint inhibitor. But it
42:38was toxic, and there were
42:40several deaths. So what they've
42:41done is they've taken away
42:42the checkpoint inhibitor, and they're
42:43just using the bispecific alone.
42:46And this got a lot
42:48of attention last year,
42:49a couple years ago now,
42:51a STEEP one bispecific.
42:53STEEP one is another target,
42:55immune target that,
42:57showed almost a sixty percent
42:59response rate. Again, in highly
43:00pretreated patients, and you can
43:01see the majority of patients
43:03responded.
43:04So I think this concept
43:06has,
43:07has, legs. I think we
43:08really know that we can
43:10deliver a t cell to
43:11the site of cancer as
43:12long as we can control
43:13the toxicity.
43:15And the last point I
43:16would make is really around,
43:18what we know to be
43:19a
43:20a pathway of progression for
43:21prostate cancer, and that's neuroendocrine
43:23differentiation.
43:24This is a,
43:25a cartoon that talks about
43:27kind of the progression from
43:28the left to the right
43:29of a normal prostate gland
43:31to typical adenocarcinoma.
43:32Those are the PSA producing
43:34prostate cancer cells that might
43:35spread to the bone, and
43:37it moves into this so
43:38called neuroendocrine,
43:40phenotype. Neuroendocrine tumor cells are
43:43don't make PSA. They are
43:45not as responsive to androgen.
43:46And what you see by
43:47the time they develop pure
43:48neuroendocrine prostate cancer is that
43:50these cancers may have unusual
43:52patterns to spread. They may
43:53go to the brain, which
43:54almost never happens normally in
43:55prostate cancer, and they're highly
43:57aggressive. They may go to
43:58the liver, for example.
44:00And this has been, unfortunately,
44:02a way in which our
44:03ARPs and the other androgen
44:04pathway drugs that we have
44:06stop working, and these patients
44:08may progress and chemotherapy, unfortunately,
44:10has a very, modest effect.
44:12Now this is something that
44:13has broad implications across lots
44:15of diseases because we know
44:16actually that neuroendocrine carcinoma is,
44:19present all over the body.
44:20These neuroendocrine cells are present
44:22all over the body. And
44:23in fact, you know, probably
44:24the neuroendocrine type of cancer
44:26that we know the most
44:26about is in the lung.
44:28And so a lot of
44:28the things we've done for
44:29neuroendocrine pros can prostate cancer
44:31has come from our understanding
44:32of how lung cancer doctors
44:34treat neuroendocrine,
44:35cancer or small cell cancers.
44:38But there is a target
44:38here too called DLL three
44:40or delta like ligand, three.
44:42And you can see here
44:43that if you look at,
44:44staining for DLL three,
44:46which is in the last
44:47panel,
44:48you can see that, about
44:49seventy six percent of, advanced
44:51prostate cancers, neuroendocrine prostate cancers
44:54express d DLL three, and
44:56they don't express the AR.
44:57They lose AR expression. They
44:58express DLL three. So last
45:00year, there was a new
45:01BiTE that was approved for
45:03small cell lung cancer called
45:05tarlatanib
45:06or tarlatanib.
45:08And,
45:09this is a you can
45:10see they are targeted towards,
45:12delivering a t cell directly
45:13to a,
45:15small cell lung cancer that
45:16might express DLL three. So
45:18this has actually been looked
45:19at in prostate cancer. And,
45:20again, you can see that
45:22in patients who have DLL
45:23three positive neuroendocrine prostate cancer
45:25that there are some long
45:26term responders.
45:27Overall, the response rate was
45:28only ten percent, but I
45:29think this again gets to
45:30the idea that we have
45:31to find and target the
45:33right patients.
45:35So these are my last
45:36couple of slides.
45:38Targeted therapy for prostate cancer,
45:40I think we're seeing it.
45:41AR is the first target,
45:42but we have PARP inhibitors
45:44for DDR mutations.
45:45MSI high tumors should get,
45:47checkpoint inhibitors. But we're seeing
45:49these PSMA directed therapies, certainly
45:51radioligand
45:52therapies, but also,
45:54these BiTEs.
45:55And DLL three is a
45:56promising target for neuroendocrine prostate
45:58cancer.
45:59So I'm gonna end on
46:01the concept that I I
46:02came here for
46:03to Yale, which is how
46:05are we gonna use precision
46:06medicine more accurately? Here's one
46:07disease, a big disease,
46:09that is still lethal for
46:10a subset of patients. How
46:12do we take what we
46:13learn about the patient? And
46:14you can see, this is
46:15from an AACR report. But,
46:17basically,
46:18think about the world we
46:19live in. We're not just
46:20these are not men who
46:22just come in with one
46:23disease. They come in with
46:24a background of genetics and
46:26and lifestyle factors and and
46:28the epigenome and how they
46:30present. And there's so many
46:31factors that we don't account
46:33for when we try to
46:34deliver
46:35the right treatment to each
46:36of these patients. And I'm
46:37not saying that we can
46:39account for all this, but,
46:40you know, we can definitely
46:41put people into categories
46:43that better account for some
46:44of these factors that right
46:45now we're not measuring at
46:46all.
46:48And I think that AI
46:49is an area where we're
46:50gonna learn more about how
46:51to bring this information together.
46:53This is what I was
46:53trying to do at Sema4
46:55when I was there and
46:56what I think we can
46:57do here with with, the
46:58multidisciplinary
46:59excellence we have in pathology,
47:01molecular,
47:02genetics,
47:03with, bioinformatics,
47:05etcetera. So,
47:06you know, this paper came
47:08out a few years ago
47:09where multimodal AI, which is
47:11really using a combination of
47:13histology
47:14plus clinical data from they
47:16used, multiple randomized clinical trials.
47:18They created an AI score
47:21and, basically predicted the outcomes
47:23of of patients. And they
47:24actually reclassified,
47:26forty two percent of patients
47:28compared to clinical risk factors
47:30was was so called NCCN
47:31criteria.
47:33In other words, they were
47:35much more accurate for about
47:36forty percent of the patients.
47:37So we're making decisions based
47:38on clinical factors that I
47:40mentioned earlier, like PSA and
47:41staging.
47:43And this
47:44AI program
47:45was so potent in predicting
47:46this and is now commercially
47:48available that it made it
47:49into the NCCN guidelines this
47:50year,
47:52as a both a prognostic
47:54tool, which, you know, has
47:55limited value, but also as
47:57a predictor of who should
47:58get hormonal therapy with radiation.
48:00So I'm just using this
48:01as an example of where
48:03we're gonna go in the
48:04future as we as large
48:06language models and and information
48:08gets distilled into, bite sized
48:10pieces that we as clinicians
48:12can use, and I'm really
48:13excited to to be part
48:14of that. So I'll stop
48:15there. Thank you very much
48:16for your attention.
48:21Thank you. I have time
48:22for questions,
48:24comments.
48:26The floor is open. I'll
48:27walk the microphone. Doctor Joseph
48:29Kim, and then you can
48:30keep the microphone and help
48:31me. Okay. Thank you. Thank
48:33you, William. This is a
48:34fantastic talk. And, again, welcome
48:36back, to Yale. So my
48:38question I just wanna kinda
48:39probe on the your last
48:40point about the precision medicine
48:42in prostate cancer. Again, in
48:43prostate cancer, that may not
48:44be the most precise term
48:46either because we are still
48:47learning how we define precision
48:48oncology in prostate cancer. So,
48:50you know, now as you
48:51mentioned, we have a lot
48:52of good treatment options available
48:53for metastatic prostate cancer. You
48:54mentioned novel AR integrator, RIP,
48:57chemotherapy,
48:58PSM target therapies, and PARP
49:00inhibitors.
49:01And doctor Roy Herbst, you
49:02know, he when it was
49:03a SWA, he's a SWA,
49:05he designed this master protocol,
49:07the master protocol, big umbrella
49:09protocol. Are we as a
49:10field in prostate cancer, are
49:11we ready for things like
49:13that? Because if you really
49:14make an impact in in
49:15clinical practice, practice, we have
49:16to come up with a
49:17good novel trial design.
49:19I'd like to know what
49:20your views on, on these
49:21issues are.
49:22Yeah. I mean, I think,
49:24I would love to hear
49:24Roy's thoughts too.
49:27When we built this this
49:29graphic, right,
49:30that you can see,
49:32we did it piece by
49:33piece. It was certainly it
49:35was painful, and it was
49:36each clinical trial.
49:37And the biggest problem with
49:39this picture is we don't
49:40know what we should do
49:41when in which order. Right?
49:43This is we have all
49:44these debates about, sequencing of
49:45treatments.
49:47What you're suggesting is that
49:48we move into this kind
49:49of bigger thinking. Right? The
49:51this idea of a an,
49:53an umbrella protocol or a
49:54protocol that's a master protocol
49:56that that, accounts for all
49:58of the different heterogeneity.
50:00The the the the real
50:01reason we haven't done it,
50:02as you know, Joseph, is
50:03that we don't have the
50:04categories for these patients. Right?
50:07Most patients express
50:08AR. Most patients express PSMA.
50:12We don't know who responds
50:13to, to,
50:15chemotherapy. We don't know who
50:16responds to,
50:18to,
50:19some of the treatments that
50:21we give. So that is
50:22the reason we don't have
50:23this. The other thing that
50:24maybe similar or different is
50:26that these tumors evolve over
50:28time. Right?
50:30So, this picture shows that,
50:31in fact, we induce some
50:33of these resistance patterns. That's
50:34not different from lung cancer.
50:36But maybe lung cancer
50:37presents with enough categories that
50:39you can do a master
50:40protocol where you give the
50:42right drug to the right
50:43person right up front. So
50:44I would love to hear
50:45if if that's what's made
50:47them kind of this broader
50:48approach successful in lung cancer,
50:49Roy.
50:50Well, of course,
50:52lung cancer's evolved now with
50:54nine different, you know, genetic,
50:57defects, you know, oncogenes that
51:00we can target that are
51:01addicted,
51:02that are addictive. So that
51:03that opens up the door
51:04there. I think the area
51:05where these master protocols could
51:07come in handy is in
51:08resistance, either primary or acquired.
51:10But you're right. You need
51:10to have a dichotomy. You
51:11can't solve the whole problem
51:13at once.
51:14You would need to find
51:15patients who are resistant to
51:16one therapy. And and then,
51:17of course, there probably are
51:18patients who are probably better
51:19off with one drug than
51:20the other, and that that
51:21is precision medicine. And, we
51:22certainly have the ability to
51:23do that here. Right? One
51:25of the things you'll work
51:25on, William, because we have
51:26the pathology is is amazing.
51:28We have the surgical
51:30colleagues who will co work
51:31with us, radiation oncology. And
51:32then in a multimodality way,
51:34sort of pull that all
51:35together. So I think that's
51:36a good point, Joe. I
51:37wanna ask you another question,
51:38William,
51:39and, other questions, Joe, who
51:41has the other microphone. You're
51:42at Greenwich, and you're setting
51:43up a service line there.
51:45The PMSA,
51:47therapy you mentioned, is that
51:48available there?
51:49Is it available throughout our
51:50network? And, then also the
51:52BiTE therapy. I just came
51:53off a couple weeks on
51:54service, and I can tell
51:55you that that's not the
51:56easiest thing. Are we administering
51:57that at all our centers
51:58as well? Yeah. Well, the
52:00imaging is available there in
52:01Greenwich, and I'm meeting with
52:04the nuclear medicine team tomorrow,
52:06I believe, to talk about
52:08how to make,
52:09some of these treatments available,
52:10in places like Greenwich. But
52:12it is complicated. I think
52:13you need the right expertise
52:15in each site to be
52:16able to deliver it safely
52:17and effectively.
52:18And I have no doubt
52:20that over time, we'll build
52:21that. I mean, one of
52:22the reasons, as you know,
52:23that I came to Greenwich
52:24is that I I saw
52:26its proximity to New York
52:28and our ability to kind
52:29of apply the great science
52:30and the great clinical care
52:32we deliver across the whole
52:33Milo network, but in a
52:34place where there's a high
52:36concentration of people, which is
52:37in the New York area.
52:38I was in Manhattan for
52:39a long time. People would
52:40when I moved to Manhattan,
52:41people were like, why does
52:42Manhattan need another cancer center?
52:44And it turned out Manhattan
52:45needed another cancer center quite
52:47significantly. There were patients who
52:48were really not cared for
52:49by some of the well
52:50known institutions in New York
52:52City because they didn't have
52:53access, because, there's, it was
52:56such a highly concentrated area.
52:58So I think Greenwich represents
53:00a real opportunity for us
53:01to to to do research,
53:03to do clinical care that's
53:04at the highest level,
53:06but we'll start with the
53:07areas of treatment that we
53:09know are safe and effective.
53:10And and in the long
53:11run, I think we want
53:12patients in Greenwich or in
53:14Westerly or anywhere within the
53:15Smilo network to get the
53:17best standards of care. Great.
53:19Any other questions?
53:20Do we have any of
53:21our fellows here?
53:23I didn't think so. I'm
53:25gonna sign an executive order
53:26to get the fellows.
53:27And and and, seriously, we
53:29should have our fellows here.
53:30This was a wonderful talk,
53:31and,
53:32if anyone's listening online,
53:33we're gonna we're gonna exchange
53:35that. But but, William, let
53:35me ask you. The precision
53:36medicine tumor board, which we
53:38started a while back and
53:39then COVID sort of derailed.
53:41But I would think that's
53:42critical for a cancer center
53:43that we get our scientists
53:45and we get the people
53:45that know how to analyze
53:47the DNA and the epigenetics
53:48and and pull that all
53:49together.
53:50You're gonna revitalize that, I
53:52know. Can you tell us
53:52your plans? Well, I think,
53:54first of all, Zenta and
53:55Rick Wilson Zenta Walter and
53:56Rick Wilson have done a
53:58really great job of taking
53:59this over from Qualator. But
54:00I do think that,
54:02the goal is to kind
54:03of
54:04not just teach, but really
54:06affect the care of all
54:07the patients who get this
54:08molecular testing across all the
54:10diseases that we see. We
54:12have an amazing phase one
54:13program. And in a way,
54:14a precision medicine tumor board
54:16is like matchmaking.
54:17It's like finding the genetic
54:19results that would lead patients
54:20to go on trials sooner
54:22and faster. We know the
54:23biggest barrier. I showed that
54:25biomarker slide from the FDA.
54:27The biggest barrier that that
54:28industry has with these drugs
54:30is finding patients to go
54:31on their trials. And cancer
54:33is no longer prostate cancer,
54:34lung cancer, breast cancer. It
54:36is,
54:37increasingly rare diseases because they're
54:39subsetted into these molecular subtypes.
54:41So I think a precision
54:43medicine tumor board is really
54:44critical, and, my goal is
54:45to think about ways that
54:47we can improve it, make
54:48it hybrid,
54:49and think about more frequent
54:50and and really tactical
54:52discussion so that both trainees
54:54and and the docs themselves
54:55really learn from the experience,
54:57including myself. Great. Speaking of
54:58multiple data, we have a
54:59chair of urology, doctor Kim.
55:01Well, again, thank you so
55:02much for the talk. I
55:03just wanna go back to
55:04the, the disparity issue with
55:06the black man. So, again,
55:07I think we as a
55:08field have been talking about
55:09this for a long, long
55:10time.
55:11So the suggestions in the
55:12I read the your papers.
55:13How do you implement something
55:14like that? What are your
55:15thoughts on getting it out
55:16into the community to make
55:17sure that such guidelines are
55:19followed? Because there's still some
55:20huge resistance,
55:22in terms of implementing. So
55:23what challenge do you see
55:24and, your thoughts? I I
55:26yeah. It's a great question,
55:27Isaac, because,
55:29sometimes the people who are
55:30the biggest evangelists for finding
55:31these cancers earlier, like urologists
55:33or oncologists, are not the
55:34ones talking to the patients
55:36in primary care. I think
55:38that there's a way to
55:39implement a smile wide, Yale
55:41wide,
55:42program. This is really not
55:43a cancer issue. It's precancerous.
55:44It's really internal medicine where
55:46we
55:47try to convey this idea
55:48and and to create, maybe
55:50a Yale wide program
55:52for looking at these high
55:53risk populations. That includes black
55:54men. It includes
55:55men with, genetic risk.
55:58And I think this publication
55:59of this guideline, the reason
56:00I think NEJM,
56:01evidence allowed us to publish
56:03it was they recognize
56:05this gap between
56:06this idea that the USPSTF
56:08says there's not enough evidence,
56:10and now we have something
56:12that can justify a program
56:13where we're more aggressive about
56:14screening black men. So I
56:16wanna certainly sit down with
56:17you and your department, but
56:19also internal medicine, primary care,
56:22and, you know, AAFP and,
56:24you know, ACP,
56:25the American College of Physicians,
56:27they're kind of still against
56:28screening.
56:29And this is the problem.
56:30Risk adapted screening is the
56:32key. Don't screen everyone. Don't
56:33screen the ninety year old
56:35guy who comes in a
56:35wheelchair. But a fifty year
56:37old or forty five year
56:38old black man who has
56:40a family history, he's getting
56:41the wrong message. I know
56:43that because they're they're not
56:44being told that they should
56:46be detected trying to detect
56:47this cancer. So I think
56:48it is a huge challenge.
56:49I think ACS is very
56:51interested in creating the the
56:53the the toolkit to be
56:54able to help places do
56:55this, and that's, I think,
56:56another source
56:57of information.
56:59Any other questions? I think
57:00we are at the end
57:01of the hour. I'll just
57:02say that this is a
57:03wonderful example of what,
57:04comprehensive cancer center does. You
57:06know, we go from the
57:07patient,
57:08access, you know, bringing people
57:10in and getting them screened,
57:11taking them all the way
57:12through the new therapeutic
57:14options.
57:15We have wonderful surgery, radiation,
57:17a a large number of
57:18medical oncologists, Dan, yourself, Joe
57:20Kim is here,
57:22many others. We have Sameer
57:23Azadi coming from,
57:25New York who works on
57:26plasticity, right, who works on
57:27the developmental. So we have
57:29so much that we can
57:29do here. So, let you
57:31know, you should start thinking
57:32about, like, a spore in
57:33a few years. So,
57:34really great to see everyone
57:35here. William will stay up
57:37for a few more questions,
57:38and,
57:38enjoy the rest of your
57:39day. Thank you.