Prostate and Urologic Cancers Disease Aligned Research Team

June 08, 2021

Yale Cancer Center Grand Rounds | June 8, 2021

Daniel P. Petrylak, MD

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00:00It's my pleasure to be host today.
00:04I'm Roy herbst.
00:05Today, we're very fortunate we
00:07have Doctor Daniel Petre lack who's
00:10professor of medical oncology and
00:12urology and the leader of our GPU program.
00:15He also of course is the leader of
00:18the signal transduction.
00:20One of those years of the signal
00:23transduction program for the care center.
00:26Dan's well known to most of us course.
00:29He spent many years.
00:31I'm at Columbia University.
00:32Before he was recruited here,
00:34now 7 plus years ago,
00:37almost eight and Dan is really, you know,
00:40been a leader in urologic cancers,
00:42bladder and prostate cancer.
00:44Just in the last year with some of his
00:48major studies working with the PROTAC
00:50with Crag Cruzen Arvinas Anthy in
00:53fortunate event and in bladder cancer.
00:55Published in the new internal
00:58medicine to name a few.
01:00He is a world leader.
01:02In this area,
01:03he's also built a team in Geo
01:06Oncology that is putting patients
01:08on protocol and raising the bar
01:11for these diseases around our care
01:14centers and around our entire
01:17network and at the main center.
01:20So then we're really excited.
01:22You know,
01:22one of the things we've been doing
01:24lately is having the different
01:26dogs presented grand rounds as
01:27a chance to sort of integrate.
01:29You know,
01:30the clinical translational
01:31program with the basic science
01:32and hopefully will have a plenty
01:34of time today for discussion.
01:35And with that I'll turn it over to you.
01:38Dan, and thank you for coming today.
01:41Thanks Roy. It's it's a pleasure being
01:43here today and thank you for inviting.
01:45You know it's actually about nine years.
01:47It's going to be September of 2012 that I
01:50came on board and it was the best decision
01:53I've ever made from a career standpoint.
01:55And I thank you and an all the
01:57leadership of the Cancer Center for
01:59being supportive over the years.
02:01And a lot of the work we're going to
02:04present here today was done by our group,
02:06including jochim, Mike Hurwitz,
02:08and but I'd like to give a first
02:10a little bit of an overview as to
02:13what is going on in prostate cancer
02:15and how do we think about it.
02:18So as we know, prostate cancer
02:20is really two different diseases.
02:22There's the disease that you die with,
02:24and this is the prostate cancer
02:26die from the Gleason 6 carcinoma,
02:29which is not none really.
02:31In some some editorials have been
02:33thought to not to be even a cancer.
02:36There was some thought about taking away
02:38from that particular classification that
02:40was in the JC a couple of years ago.
02:43That's none.
02:44That's really not going to cause
02:46a patient's demise.
02:47Even 90% chance of being biochemically free.
02:50A relapse at five years,
02:52no matter what local therapy
02:53you go forth with,
02:55we're going to focus today on
02:57the castrate resistant disease.
02:59And it's important to think about this
03:02disease in terms of clinical states.
03:04As I mentioned before,
03:06there's a clinically localized prostate
03:08cancer which can be cured with local
03:11treatment despite local treatment.
03:13No matter what you receive
03:15with its radiation therapy,
03:16hormonal therapy about one in three men in
03:20unselected cases will have a rising PSA.
03:22This can result in a biochemical relapse
03:25or eventual clinical metastases,
03:27which is the hormone sensitive state.
03:30In the non castrate disease,
03:31as we see in the upper portion of this
03:34this particular slide you also can
03:36have a rising PSA without metastatic
03:38disease and this group of patients
03:40is somewhat problematic and and when
03:43you install hormone therapy because
03:45there's some men that may never need
03:47to go on engine deprivation therapy
03:49and this of course has significant
03:51side effects including weight gain,
03:53loss of muscle mass, fatigue,
03:54loss of sexual function.
03:56So this can have a significant impact
03:58on the patient's quality of life.
04:00It's questionable whether implementation
04:03of hormone therapy at this state
04:06will improve survival.
04:08We then go on to the clinical metastases
04:10in the castrate state and there are
04:13multiple treatments that we have
04:15available and eventually we have pre
04:17chemotherapy and post chemotherapy patients.
04:20The landscape has changed and I think
04:22the important thing to remember is that
04:25this was at Doctor Charles Huggins
04:27presentation above prize in 1966.
04:29He was the person that discovered that
04:32prostate cancer is a hormone sensitive
04:34disease that if you give androgens
04:36the disease will be stimulated.
04:38But this is not curative,
04:40despite regressions of great
04:42magnitude is obvious that there are
04:44many failures of endocrine therapy
04:45to control the disease in
04:47cirrhotic that some of the greats of
04:49prostate cancer, including Doctor Huggins,
04:51actually died from Ictact disease themselves.
04:54So this is how we look
04:57at the disease in 2021.
04:59If you think back to 2004 when Docetaxel
05:02was approved was pretty simple,
05:04you had one treatment and this was useful
05:06for metastatic castration resistant disease.
05:09And then you went on to 2nd hormones
05:12or or two to palliative bodies antra.
05:15Now we have a variety of different
05:18treatments immunotherapy which will be
05:20talking bout with sipuleucel T as well
05:23as other agents agents that affect.
05:25DNA repair other chemotherapeutic agents,
05:27as well as other hormonal agents
05:29that show improvements in survival.
05:32But the key point is,
05:34is that we're not curing anybody with
05:37this particular approach and the
05:39meeting survival is generally about
05:41increments of anywhere between three
05:44and five months in this situation.
05:46So with this massive data,
05:48how do I like to think about this disease?
05:51Well, like to think of this in
05:53terms of classes of agents.
05:55We have really 4 main classes that
05:57we use from a therapeutic standpoint
05:59for castration resistant disease.
06:01Namely,
06:01immunotherapeutic agents such as
06:03Sipuleucel T Pember lose map for a
06:06small percentage of patients will be
06:08talking about a few minutes hormonal agents.
06:11Castrate resistant disease retains
06:13its hormonal axis and if you look
06:15at androgen receptor expression
06:17in specimens from patients,
06:19castration resistant prostate cancer,
06:21you'll find that about 90% still
06:23have an active androgen receptor
06:25axis and we're going to exploit
06:28that with some of these agents.
06:30In fact,
06:31it's known that some of the
06:33chemotherapeutic agents, such as docetaxel,
06:35may actually work by hormonal mechanism.
06:39What do we mean by that?
06:41Well,
06:41when you bind testosterone
06:43to the Android receptor,
06:44it has to translocate the New
06:46York nucleus and microtubules are
06:48essential to the transport of that
06:50particular complex into the nucleus
06:52I mentioned cytotoxic agents such
06:54as docetaxel cabazitaxel their
06:56isotopes that damage DNA radium 223.
06:58We're not going to get into those,
07:01but focus of investigation recently
07:03have been part inhibitors such
07:05as elaborate Kappa rib and that's
07:08appropriate for about 10 to 20% of
07:10patients with castration resistant
07:12prostate cancer.
07:13So we've been behind the long
07:15investigators as well as the breast
07:18investigators because for a long
07:20period of time we've used clinical
07:23characteristics to determine
07:24how we sequence our agents.
07:27Symptomatic versus asymptomatic,
07:28the tendency was to give hormonal
07:32therapy to those patients who had.
07:35Who are asymptomatic and
07:36safe chemotherapy for later?
07:37That may not be the right way
07:39to sequence patients visceral
07:41versus non visceral disease and
07:42then pre and post those heat.
07:45Axel was initially used as a way
07:47of approving drugs for castration
07:49resistant prostate cancer.
07:50The other issue,
07:51now which is coming into play as we've
07:54seen in breast cancer and I'm not
07:56going to go into the specifics of this,
07:58but agents which have been used
08:00traditionally to treat castration
08:02resistant disease have been moved
08:04up into the hormone sensitive
08:06state. And is actually a greater improvement
08:08in the hazard ratio when drugs such as.
08:17Hazard ratio is about .6.
08:18It's pretty significant so so that state
08:21will affect what you're going to be doing
08:23in castration resistance because the
08:25resistance patterns may be different,
08:27and we're only going to start seeing
08:29now how that may influence the treatment
08:32of castration resistant disease.
08:34Because the downstream effect only
08:36started about three to four years ago.
08:39So as I mentioned,
08:41we've been behind our colleagues
08:43in lung cancer and breast cancer
08:45and using targeted therapy and
08:47molecular markers and the three,
08:49I'm going to focus on today
08:52or the androgen receptor,
08:53those of DNA repair,
08:55and immune markers such as
08:58microcycle instability.
08:59So immune therapy is an
09:02FDA approved category.
09:03Four of the treatment of metastatic
09:06castration resistant prostate cancer and
09:08the agent that's approved in the United
09:11States is something called sipuleucel T.
09:14So this is an ecologist T cell
09:17product that's made by taking
09:19the patient's own immune cells,
09:21culturing them with a fusion protein
09:25that uses both prostatic acid
09:27phosphatase as well as a GM CSF.
09:30Fusion protein prostatic acid phosphates
09:32expressed about 90% of prostate cancer cells,
09:34so this is very specific to prostate cancer.
09:38This APC takes up this particular antigen.
09:40It's presented on the surface and
09:43you have a fully activated T cell
09:46by the time this is reinfused back
09:49to the patient three days later.
09:52So the impact trial was published
09:55in 2010 and this took patients
09:58who had had prior chemotherapy.
10:00All forms of treatment and randomize them
10:05to receive sipuleucel T or a placebo.
10:08And it was shown that there was
10:11significant improvement in overall
10:12survival in the patients who
10:15received this particular product.
10:16It was about the hazard ratio 0.775.
10:19Now what was seen in this trial
10:22and what was not seen as opposed
10:25to classic chemotherapy trials.
10:27You did not see an improvement in
10:30progression free survival and that
10:33led to a lot of skepticism initially
10:36because the PFS did not correlate with OS.
10:39Objective responses and
10:40soft tissue are infrequent.
10:41Now again,
10:42this is a select group of patients,
10:44so those patients were entered in.
10:47The study had bone only disease
10:49or a minimal lymph node disease.
10:51They did not have visceral disease.
10:53He really couldn't see whether
10:55there was a response,
10:56but generally the soft tissue
10:58disease did not respond.
11:00PSA responses were rare.
11:01We do see them.
11:03We do see predominantly PSA stabilization,
11:05but despite this we do see a correlation
11:08between the PSA quartiles at study
11:10entry or on this particular trial.
11:12So those with low PSA's have higher
11:15hazard ratios of survival or better
11:17hazard ratios than those with high
11:20PSA's and again leading to the fact
11:22that we want to use immune therapy
11:25early in the course of disease.
11:28So for number of years we tried to
11:30explain why this happens and Ravi Medan
11:32at the NCI is actually published.
11:35A very very elegant paper in
11:37the oncologist in 2010.
11:38Looking at the differences in
11:40terms of how we look
11:42at outcomes and in an immune therapy
11:44as well as cytotoxic therapy.
11:46So on the Y axis we see tumor burden X axis,
11:50the time. And as we see here,
11:53we expect the patient to be progressing
11:55rapidly if you give cytotoxic therapy,
11:58you have a decline in your tumor
12:01volume or two to our burden
12:03and then you see a take off.
12:06Once they become resistant and
12:08often you see a parallel or an
12:10increased slope to what you've seen.
12:13When these patients were prior
12:15to their chemotherapy.
12:16With immune therapy or vaccine therapy,
12:19what you tend to see is a
12:21blunting of that PSA curve.
12:23So what you're actually doing this,
12:25but potentially missing progression
12:27events or seeing progression events
12:28and missing an overall effect.
12:30So really, the hazard ratio
12:32is what I think is important,
12:34and the overall three year survival,
12:36and unfortunately with the
12:38sipuleucel T trials they did not
12:40follow patients past three years,
12:42and I've actually been after the company
12:44to look at that particular question.
12:47To see whether there is a
12:49difference in five year, survivals.
12:52The question of molecular markers, well,
12:54we know that immune therapy with PDL one,
12:58an prostate cancer,
12:59really doesn't have a great response rate.
13:02Generally about 5 to 10% at best in terms
13:05of objective response in unselected patients.
13:08So this is a study that came out of
13:11Memorial Sloan Kettering Cancer Center,
13:13looking at 1033 patients who had
13:16MSI high in prostate cancer.
13:18It's only about a 3%.
13:22Yeah,
13:22but hit rate with that particular marker.
13:25But what's interesting is
13:27that you can see this,
13:29develop overtime that if you look at
13:32sequential specimens in patients with
13:34castrate resistant prostate cancer,
13:36you can see up regulation
13:38or development of MSI.
13:40So this is something that you really
13:42do need to check regularly and in
13:46our patients with castrate resistant
13:48disease and also seven of those 32 MSI
13:52high patients had a dream sideline
13:54mutation in Lynch's assistance.
13:56Syndrome associated gene.
13:59Does this have an effect on response
14:01to checkpoint inhibition therapy?
14:03The answer is yes. This is their series.
14:06Looking at both PDL one as well as PD.
14:09One inhibitors and castrate resistant
14:11disease and about half of patients
14:14will have objective soft tissue
14:16responses and a higher percentage
14:18of patients will have PSA declines.
14:21So in my opinion,
14:22and I think that many thought
14:24leaders feel the same way,
14:26all patients with castrate resistant
14:28prostate cancer need to be checked
14:30for microsatellite instability.
14:32Pember Lism AB is an FDA approved
14:34drug in this state of disease and
14:37this it can be administered in those
14:39patients who have that particular marker.
14:42Rushan ion has looked at CDK 12 in
14:45these patients in castrate resistant
14:47patients as well as we know,
14:50BIALLELIC mutations are formed a
14:52distinct class of prostate cancer.
14:53This leads to genomic instability as
14:56well as the development of neoantigens,
14:58and rule is also demonstrated with
15:01this particular marker that you can
15:04see increased T cell infiltration and.
15:07Also, responses in men with
15:10castrate resistant prostate cancer.
15:12So we actually LED a phase
15:14one study of atezolizumab,
15:16an castrate resistant disease.
15:17This was published in clinical
15:19Cancer Research earlier this year.
15:21Joe Kim and I were coauthors on this patient.
15:24This particular study and we
15:26had two different cohorts.
15:28In initial phase, one cohort of 10 patients,
15:31and then a 15 patient expansion cohort.
15:33As we can see here,
15:35the response rates with a Tesla some
15:37AB were somewhat disappointing.
15:39About 50%.
15:40These are patients who had multiple.
15:42Prior chemotherapies or immunol hormonal
15:45therapies and we did see a fairly
15:48good meeting survival of 14.7 months,
15:50but this is unselected and there were two
15:54partial responses by resist criteria.
15:56Overall now we tried to look for.
16:01Molecular characterization that
16:02may lead us to understand better
16:05why these patients responded.
16:07We saw some higher levels of CD8
16:10in these patients after treatment.
16:13We did not see any significant
16:16PDL one expression,
16:18nor did we find microsatellite instability.
16:21And this is one of our responders
16:24who is microsatellites.
16:26Table had really not a particularly
16:29higher level 22 mutation rates.
16:31But he did have a mutation
16:34in ATM which you know.
16:36Again, there been others.
16:37Some others have correlated responses
16:39with these DNA repair enzymes,
16:41but this was really 2 number too
16:44small to make any great conclusions.
16:48So where are we moving and
16:50immunotherapy yellow?
16:51And what's or some of the
16:53trials that are open right now?
16:55Well, we've been looking at it,
16:57Ralph, up with a bio excel and
16:59this is in resistant patients,
17:02both newer,
17:02castrate resistant as well as small
17:04cell carcinoma of the prostate.
17:06Looking at DP 8-9 inhibition with
17:08the Excel 701201 combined with the
17:11volume in this trial is ongoing
17:13and occurring patients right now.
17:14Joe Kim in the Phase one group.
17:17Is looking at a novel combination of
17:19ateez allusion mab, along with cables,
17:21and which is a TKI which is which
17:24actually was originally looked in.
17:26Prostate cancer number of years ago.
17:30But really, a failed phase, three studies.
17:32And as we saw before,
17:34it is losing members and 8% response
17:36rate cables got a 5% response rate.
17:38You put the two of them together.
17:41They've got a 30% response rate
17:43and Joe is working in the phase.
17:45One group is also designing a phase one
17:48study to look at biological markers.
17:51Small select group of patients
17:53with this combination,
17:54we've completed a vaccine study of
17:57APSA construct with Tremolux Moab.
17:59The interesting thing about this trial,
18:01it was just presented yesterday.
18:03Tasco is that we saw responses in
18:06patients who are hormone sensitive
18:08with a rising PSA.
18:09Really didn't see any really significant
18:12activity in castrate resistant disease,
18:14but unless we did have a couple of
18:17responses were still looking some
18:19of the biologic korelitz and then.
18:22Finally.
18:22We completed accrual in a phase
18:24three trial of Docetaxel plus and
18:27minus pember Lism AB International
18:29Pi on that and hopefully we'll
18:32see a positive result of that
18:34particular study.
18:36Now I mentioned before that in the
18:39castration resistant state you still
18:41have an active androgen receptor and
18:43there could be a different number
18:45of ways in which we can see this
18:48receptor receptor become activated.
18:50In fact, Jack Keller,
18:51who was actually in the lab till his mid 90s,
18:55believe it or not who was at UCSD,
18:58was one of the first people to
19:01describe the fact that if you took.
19:04Prostate cancer specimens an measure
19:06them for testosterone after these
19:08patients had undergone either chemical
19:11or physical castration that you
19:13would find that there was increased
19:15levels of testosterone overtime.
19:17So there's an interesting
19:19pathway of androgen synthesis.
19:20There are also alternative
19:22splicing mechanisms.
19:23There's aberrant function these mutations,
19:25which will give you gain of function,
19:28which will will talk about in a few moments.
19:31But all these particular pathways
19:33can lead to deregulation of the
19:36androgen receptor despite the fact.
19:38That there are serum levels of
19:41testosterone that are castrated.
19:42So one way that we can overcome
19:45this of course,
19:46is shutting down testosterone
19:47synthesis completely.
19:48Testosterone is predominately
19:49made with from the testicles,
19:51but as I mentioned before,
19:53the prostate cancer cells can make
19:56their own testosterone as well as the
19:59adrenals that is actually about 20% of
20:01all the testosterone is created so you
20:04drink or text to peripheral tissues.
20:06You can shut down these particular
20:09pathways by 1720 lyase inhibition
20:11with a drug called abiraterone.
20:14And this is the chemical
20:16structure of Apparate, Rhone.
20:17There's a second way of blocking
20:19the Android receptor pathway,
20:21which is FDA approved.
20:23And that's using anti androgens
20:24which directly antagonized the
20:26receptors enzalutamide was rationally
20:28designed from a series of different
20:30compounds that was selected for
20:32androgen receptor antagonism.
20:33The interesting thing about this drug,
20:36although overtime it's been shown
20:38that we see very very we see
20:40this occasionally is that there's
20:42no known agonist.
20:44Activity see this occasionally with patients.
20:46There is some of these anti
20:48androgens when you stop them.
20:49The PSA actually goes down and we
20:51still have not been able to correctly
20:54explain that particular effect.
20:55So you can decrease testosterone
20:57levels and block the receptors.
20:59Now the fact is these both of
21:01these drugs are FDA approved.
21:03They both improve survival again
21:04by about three to four months.
21:06As we've seen before.
21:08Do we sequence them because
21:10these drugs in terms of toxicity,
21:13seemed to be less toxic than giving
21:15attack scene such as kabasi,
21:17Taxol, docetaxel, unfortunately?
21:19This cross resistance between these
21:21agents PSA responses are generally 10 to 20%,
21:24and you see a progression free survival
21:26of about three to four months.
21:29If you sequence Abby after ends
21:31or ends after Abby.
21:33And also refining to that,
21:35taxing's are less effective and vice versa.
21:38These drugs are also less effective.
21:41Act after Taxing's and there may
21:44be some slight cross resistance.
21:46So kimchi at University of Vancouver
21:49is actually summarized this data,
21:52and if we look across the board
21:55as I mentioned
21:56before, a best we see a survival
21:59of 8.7 about 12 months.
22:02If you give these drugs sequentially.
22:06And PSA decline rates of 20 to 30%,
22:08whereas the single agent drugs
22:10are about 50 to 60% overall.
22:12So how do we look at this in
22:15terms of resistance resistance?
22:17I mentioned before,
22:19you could have upregulation
22:21of different pathways.
22:23And particularly CYP 17 you could
22:25also see these splice variants.
22:28You can see induction of glucocorticoid
22:30expression that also may be related
22:32to enzalutamide resistance,
22:34so they again are multiple pathways
22:36that we can go forth with.
22:39One is error V7.
22:42Play RV 7 is is a truncated
22:44version of the androgen receptor.
22:47The Android receptor has
22:49three different components.
22:50One is the the DNA binding region,
22:53the other one is the liggen binding region
22:57and then the other is the hinge region.
23:00So the login biting region is deleted
23:03in a RV 7 so this can be constituency
23:07activated and then 'cause activation
23:09of the androgen receptor pathway.
23:12It has to dimerize.
23:14So that's actually important
23:16fact as we see here.
23:18From this particular slide,
23:19this is from my colleague Daniel
23:21Interactice at Johns Hopkins.
23:23If you look at those patients
23:25who are AR V7 negative versus
23:28those who are very 7 positive,
23:31they have a better progression free
23:33survival when you're treating these drugs
23:35in patients with abiraterone enzalutamide,
23:38you also better PSA responses.
23:40So if you make a RV 7.
23:42You're less likely to respond
23:44to these particular drugs now.
23:46Taxing's are a little bit more responsive,
23:49but the response rate with
23:51taxes or not as good.
23:53But again,
23:54you see a difference between the RV,
23:567 positives and the negatives,
23:58but overall taxes do have a better
24:01response in those who are positive,
24:03so this data was performed
24:06in patients with CTC's so.
24:09This is associated with primary resistance.
24:12The positive patients may still
24:14become sensitive to taxanes,
24:16but in positive men,
24:18taxanes may be more effective.
24:20Acacius and there may be comparative
24:23efficacy with targeted agents in the
24:26negative patients compared to the.
24:29The the these next generation ages,
24:31such tabron enzalutamide.
24:33So this leads us to a trial called card.
24:37And this is important political
24:40implications to our patients because
24:42What Car did was it took patients
24:44who had received abiraterone or
24:46enzalutamide for one year or less,
24:49then went on to receive docetaxel.
24:51And of course,
24:52the dilemma that physicians have
24:54in the situation is whether you
24:57treat with an alternative anti
25:00androgen or to give a chemotherapy
25:02agent such as cabazitaxel.
25:04And this trial,
25:05I think,
25:05lends credence to the fact that
25:07these AR V7 mutants may actually
25:09persist for a period of time,
25:11because if you give a second androgen
25:13signaling agent so the opposite agent,
25:15if they've got Abby first,
25:16then they get enzalutamide.
25:18If they get enzalutamide,
25:19then they get abiraterone.
25:22You have a better survival with
25:24cabazitaxel then with the secondary agent,
25:27and that's both in terms of
25:29both progression free as
25:31oh as well as overall survival
25:33at the hazard ratio of 0.64.
25:35So in sequence we tend to use
25:38chemotherapy earlier in these patients.
25:40So what are we working on at Yale?
25:43That may be a way of moving forward
25:45with this particular pathway?
25:47Well, number of years ago?
25:49Roy, you know,
25:51one of the things I think.
25:53You need about Yale,
25:54and I think the pandemic is really.
25:57As really hurt is this seminar we
25:59used to have on Tuesday afternoons
26:01between the chemistry department
26:02and the Medical oncology department.
26:04Roy was really instrumental in getting
26:07this going forward forward and Craig
26:09Crews came up to me at one of these
26:11meetings and said you have a need
26:14for Brooke drugs and prostate cancer,
26:16and it's absolutely he's would you want
26:18to go forth with another hormonal age.
26:20And I said absolutely,
26:21there's room for that because there's
26:23a mechanistic approach to it,
26:25and it turns out that the company
26:27that Craig previously had founded.
26:29CEO had died from metastatic prostate cancer,
26:32so he was on a mission to find
26:34other agents and this was really
26:37the perfect collaboration between
26:38a bench and Ben's bedside.
26:41So this is a novel drug.
26:43This is a RV110 and what's
26:45the science behind this?
26:47Well, we're trying to degrade the proteins,
26:50so there's a natural pathway.
26:53The proteasome pathway,
26:54which we basically can degrade
26:57proteins with a bug within our body.
26:59Soap Protex are ways of basically
27:02accelerating this ubiquitin based pathway,
27:04so you have a disease causing protein.
27:07E3 ubiquitin ligase will bind to that.
27:11The Pro tech will actually accelerate
27:13that and then this induces
27:15ubiquitination of the target protein.
27:18And this,
27:19I think the neat thing about
27:21this drug is it's recycled.
27:23You can have as many as 400.
27:26Throat androgen receptors proteins
27:28that can be taken out by this pro tech.
27:32In a given cell and then it basically
27:35is destroyed by the protein cell.
27:38So why is this called a dumbbell?
27:41Well, this is the shape of it.
27:44There's a protein login domain which is
27:46the warhead targets a specific protein.
27:49It's linked to the ligase Lagann
27:52which recruits the E3 ubiquitin
27:54ligase and so all three of these
27:57play a role in protein degradation.
28:00So how is this related to prostate
28:03cancer with a RV?
28:05110 is a pro tech that targets
28:07the engine receptor.
28:09So as we mentioned before,
28:11you can have amplification and
28:13receptor mutations and this this was
28:15developed both in an in androgen
28:18insulin resistant as well as
28:20sensitive cell lines.
28:21So there are variety of different
28:24mutations that this pro tech will
28:27degrade the T878H75Y the F877L
28:29the MV895 point mutations but not
28:32L 2702 an AR V7.
28:33So does that mean that it's not going
28:36to work in these particular subtypes?
28:40The answer is no because if you look
28:43at Doctor Interactice paper carefully
28:45for New England Journal of Medicine
28:48you'll find that in addition to having.
28:52The air B7.
28:53This usually amplification
28:54of and wild type
28:55and receptor which could be
28:57affected by the different Protex.
29:00So this may also affect amplification of
29:02the wild type receptor as we see here.
29:06It's going to degrade 90% of
29:08the engine receptor in vitro.
29:11So two years ago we opened up the phase
29:14one study that looked at AR V110IN men
29:18with castrate resistant prostate cancer.
29:20They had to have at least
29:23two prior therapies.
29:24We did not basically eliminate those
29:26patients who had extensive treatment.
29:29We had required that they have
29:31either abiraterone or enzalutamide.
29:35It took us a little while to
29:38get to the 140 milligram dose,
29:40which is what was important in the
29:43laboratory to achieve activity.
29:45So this is the minimal efficacious dose.
29:48As I mentioned before on the day 15
29:51AUC and Cmax this was achieved at
29:54140 milligrams or greater orally.
29:57So here's some some evidence
29:59that we are hitting the target.
30:01This is a patient of ours that
30:04was treated with ARVs 110 and we
30:06have both a baseline and it big
30:09posttreatment biopsy that shows
30:11downregulation of the Android receptor.
30:14Remember these are heavily
30:15pretreated patients.
30:16This is our presentation from last year.
30:18We see that there is one patient
30:20out at 35 weeks of duration of
30:23treatment and we did see responses.
30:26As measured by a PSA decline,
30:29we saw two patients with PSA
30:32declines of at least 50% an.
30:35Lo and behold,
30:37these patients had degradable engine
30:41receptor mutations T87A at 875Y.
30:44And we see here that that one
30:46patient with the RV 7 did have
30:49a very minor PSA decline,
30:50but he also had a concomitant mutation.
30:53So are responding.
30:55Patient here at Yale head.
30:57Multiple treatments,
30:58including docetaxel,
30:59abiraterone,
31:00radium and enzalutamide,
31:01he had eight eight 7597-A mutation
31:05and he had a 74% PSA reduction after
31:08his treatment was administered and
31:10his time of the presentation is.
31:13Duration of response was 30 weeks.
31:16This is a patient from
31:18Nick Vogelsang at Nevada,
31:20also with a very with the same mutation
31:25pattern showing a PSA reduction of 97%.
31:29And soft tissue responses.
31:31So where are we going with
31:33this particular treatment?
31:34We still have two.
31:36We have a phase two trial
31:38with two open sub cohorts.
31:40Those patients who harbored a RT
31:427-8 or 75 mutation were taking up
31:45to 20 patients were still accruing,
31:47and then those patients who received
31:50a prior second generation and
31:51androgens and no prior chemotherapy.
31:53The subgroup,
31:54one subgroup force are now close to accrual.
31:57At least there an accrual hold it.
32:00This particular point,
32:01so hopefully will open those
32:03in the near future,
32:05and I'd like to know the last minutes
32:07of this talk talk about some of Jochems
32:10work in in with with PARP inhibitors.
32:13As we know,
32:14DNA repair mutations are present
32:16in about 10% of patients with
32:18castrate resistant prostate cancer.
32:20These are predominantly
32:21bracket one and bracket twos,
32:23but we see a variety of other other
32:27mutations such as ATM check too.
32:30Powerbi Tunan rad 51.
32:32As we know,
32:34Prop inhibitors work by the mechanism
32:36of synthetic lethality where this is
32:39involved in single stranded DNA repair,
32:41whereas other agents are involved in
32:44double stranded breaks and the two of
32:47them combined together can cause synergy.
32:50So elaborate has been evaluated
32:52in castration resistant prostate
32:54cancer in a phase two trial.
32:56This was published in the journal
32:59by Joe Johann de Bono's group,
33:0149 patients.
33:02Overall,
33:03the response rate was 32.7% when
33:05they went back retrospectively
33:07looked at genomic analysis.
33:09They found that third of
33:11patients with mutations in DNA
33:13repair 2/3 did not.
33:1514 of those 16 patients with the
33:18DNA repair mutations responded.
33:20Where is only two patients who did not
33:22have that repair mutation responded.
33:24This led to the profound trial
33:26which looked at aerolab rib.
33:28And two different cohorts of patients,
33:31both those who are a bracket,
33:33one bracket, two or ATM positive,
33:35or other DNA repair mutations in these
33:39patients were randomized to receive either
33:41a lap RIV or physicians choice of therapy.
33:45The trial did meet its primary endpoint,
33:47which was radio graphic
33:48progression free survival.
33:49This was in the bracket one bracket,
33:52two or ATM cohorts.
33:53There was about a four month difference in
33:55radio graphic progression free survival,
33:57and when you look at all
33:59cohorts of DNA repair,
34:00there was about a two month difference,
34:03but the hazard ratio was 0.49.
34:06Now this I think,
34:08is one of the important slides from this.
34:11This paper we see that those
34:13patients who have ATM mutations
34:14really don't have a particularly
34:16great response to PARP inhibitors.
34:19In fact,
34:20their hazard ratio is one for death,
34:22and that's that's really different
34:24than what we see with the bracket.
34:27One and bracket twos and the PR2 3RA's
34:30actually do worse with partition.
34:32This is the survival from the trial.
34:35We see that there is a.
34:37Improvement in overall survival
34:39has ratio 0.64 and big difference
34:42in response rate 33% versus 2.3%.
34:44So this drug is FDA approved.
34:47The second FDA approved drug is recap rib
34:49in a slightly different group of patients,
34:53whereas patients in the profound
34:55trial were either refractory to
34:57chemotherapy or two next generation.
34:59And are androids.
35:01This study was a phase two trial,
35:04not a phase three trial that
35:06led to accelerated approval.
35:08In those patients who had
35:11DNA repair mutations,
35:12who would be progressed after either a
35:16Apparate Ronan's little mind or apalutamide?
35:20As we see from this slide here,
35:23we predominantly have those patients
35:25who have bracket one bracket choose an.
35:28Not surprisingly,
35:29a similar response rate with CAP ribbon.
35:32The Bracco Bracco one bracket use
35:3444% but again the same pattern.
35:36No real difference in no objective
35:39responses in those patients have
35:41ATM mutations and the same as far
35:43as biochemical responses concerned
35:4551% bracket one bracket,
35:47two said at least a 50% PSA decline.
35:50Where is none,
35:51had declines in ATM.
35:54So in this time just click add a
35:57little bit and think about what
35:59we've been thinking about it.
36:01Yale in terms of strategy as far as
36:04how we can potentially improve the OR
36:06at least expand the use of part numbers.
36:10Well,
36:10there are variety of different
36:12agents that will synergize with
36:14PARPAN inhibitors in in vitro.
36:16These include Becca Mecca, hitters,
36:18bet inhibitors, PR, 3 kinase inhibitors,
36:20androgen receptor pathway.
36:21That is, we're planning a trial of of.
36:24Everyone 10 plus abiraterone but also
36:27antiangiogenic agents and Joakim is
36:30and and his also looked at the trial
36:32of this of elaborate combined with
36:35Sadir nib Ancaster resistant disease,
36:38as we see here, it's an inducer
36:41of hypoxemia, sadir treatment.
36:42Patient treated cells do have
36:45more hypoxi than the vehicle,
36:47and we know that elaborate works in about
36:5010 to 20% of all prostate cancer patients.
36:54And from the data from Doctor Bender's
36:57laboratory in preclinical data showing
36:59that angiogenesis may be involved,
37:01the combination of elaborate and steered
37:03have seemed to be moving illogical
37:06and come forth with this was for a
37:09presentation at ASCO early ask AGERE
37:11earlier in the year looking at a
37:14randomized phase two trial comparing
37:16elaborate plus a deer nib to steerman
37:19along these were non selected patients.
37:21We wanted to look at this in
37:24retrospective pet fashion. This is.
37:26Was spearheaded by Joseph Kim.
37:29Overall, we enrolled 90 patients nationally,
37:3145 in the combination.
37:33Each of the each different arms of the study.
37:36These were patients with a median
37:39PSA of about 60.
37:40They could have had prior anti
37:43androgen such as abiraterone,
37:45enzalutamide and also prior chemotherapy.
37:47So these again are heavily
37:49pretreated group of patients.
37:52So if we look at the prevalence
37:54of DNA or repair mutations,
37:57overall 31% had some form of
38:00DNA repair mutations,
38:01either bracket one or bracket 2.
38:04The trial did meet its primary endpoint
38:06in unselected patients progression.
38:08Free survival was better in the combination
38:10arm than it was in the single agent arm,
38:13but we started looking at the data.
38:15We see some patterns which I think
38:18could lead us to where we can go
38:21forward with this particular approach.
38:24We don't see really an improvement in
38:26progression free survival in those
38:28patients who are HR proficient.
38:30We do see that in the deficient ones,
38:32be interesting to see whether it does
38:35seem to be somewhat better than what
38:38we see with the POP inhibitor alone.
38:41But there does seem to be in a very,
38:44very small number of patients.
38:46Some response in those patients
38:47at least improvement in PFS in
38:50those patients or ATM positive.
38:51So this may be lead for future
38:54investigation as one would expect
38:56in such a small trial like this,
38:58you're not going to see a survival benefit,
39:01but there is, you know.
39:03But again,
39:04that's something we need to look
39:06at in the properly powered study
39:09so it really does summarize.
39:11We see a difference in the combination
39:13therapy in terms of progression,
39:15free survival and exploratory
39:17analysis is seeing that that in these
39:20particular subgroups there does seem
39:22to be an improvement in our PFS,
39:24so this is something I think this
39:27speaks plourd further in this disease,
39:29so leave some time for questions
39:31so conclusion.
39:32All patients with castrate resistant
39:34prostate cancer in terms of molecular
39:36markers need to be evaluated for
39:39DNA repair enzymes mutations.
39:40As well as Microsoft instability
39:42program should be used early in the
39:45course of castration resistant disease.
39:47Air V110 has clinical activity in
39:50metastatic castration resistant
39:51prostate cancer,
39:52and then we both elaborate in recap,
39:54rip are approved in these patients
39:57with castration resistant disease
39:59and we're looking forward to going
40:01forth with novel combinations to expand
40:04the spectrum of patients who may be
40:06eligible to receive part. In addition.
40:10I'd like to thank all of our colleagues.
40:13I know if miss people in this,
40:16but but Joakim Mike Hurwitz,
40:18inheritance Bondy,
40:19who have really contributed greatly and work
40:22real hard in moving these trials forward.
40:25Our research associates, particularly
40:27Shelby Carleo and Ebony Williams,
40:29who helped to see the patients,
40:31manage the data.
40:32And really,
40:33they're invaluable to our operation map.
40:36Piscatelli leftists about two weeks ago,
40:38but Kristen Fleshman has really
40:40done a great job and in helping
40:43us out during this time period.
40:45I know I've missed a bunch of
40:47different people in this area that have
40:49really helped us, and I apologize.
40:51Apologize to those who have
40:53not included in this slide,
40:55so Roy,
40:55thank you for your
40:57attention and turn it over to questions.
40:59OK thanks Dan. What a wonderful Tour
41:01de force in Geo Oncology I'll start.
41:03Please put your questions into the chat.
41:06But yes, we used to call it the
41:08cancer chemistry colloquium.
41:10And we used to have that on Tuesday
41:12afternoons up on the hill. Scott Miller,
41:14the chair of Chemistry at the time,
41:16and, you know, we organize that.
41:18That's when Julie Boyer was here,
41:19and I'm glad to hear that the pro
41:22tech where it came out of that.
41:23So my question for you is how can
41:26we do more of these here at Yale?
41:28Then you have a great mechanism
41:30for clinical trials.
41:30You know that you've set up.
41:32You have a good patient population.
41:34What are the next step next agents
41:36coming through Yale Science?
41:37Do you
41:37think? Well, I mean, I think that there's.
41:40There's a next generation pro tech.
41:43That looks more active potentially than a RV.
41:45Then the every 110 and we're moving
41:48forth with that in the phase one trial,
41:51but I think that the real next
41:54generation will be had had a sequence.
41:56These had to combine these using
41:58our tumor bank to understand how
42:01to use these particular drugs.
42:03I think also.
42:05I didn't really get into this during
42:08the talk, but but how can we use?
42:11How can we include other ethnic
42:14groups in our treatments?
42:15It's actually an interesting phenomenon.
42:17Vet there have been publications
42:19looking at response rates in
42:21or survival to chemotherapy,
42:23immune therapy and next generation
42:25hormone therapy in African Americans.
42:27And it's actually better.
42:30And so we need to get the word
42:33out that these trials are open,
42:35that all should be included
42:37an that we don't want to see.
42:40People missed their opportunities to get
42:42drugs that they can move forward with,
42:45but I I was really surprised to
42:47see that this data we've actually
42:50been involved with this since our
42:53original swax these 2004 when we
42:55saw a very very big difference
42:57in in favor of African Americans
42:59with docetaxel chemotherapy.
43:01Numbers were too low to to
43:03make any real conclusions,
43:04but Susan Hobby is actually published
43:07on this with combined databases and
43:09this is something we really have to
43:11be to move forward with in terms of
43:14understanding how patients respond.
43:16Right, I can tell you,
43:18in my interim role here in the CTO,
43:20it's been quite noticeable to me that
43:21we do need to have more diversity
43:23in our populations and that means
43:25reaching out and building trust.
43:26And I know you've been doing some of that.
43:29You know, with the cultural ambassadors
43:30and other groups and providing navigators,
43:32we have a question from Darrell Martin.
43:34Renee, do you want to unmute Darrell
43:35so he can ask the question himself?
43:40Darrell.
43:45If not, I'll ask it.
43:51Well, actually I can ask you
43:52'cause you just raised your hand.
44:00OK, any other questions for for Dan Dan tell
44:03me a little bit about about your Darden.
44:06Now with Isaac Kim coming as the new
44:09chair of Urology, any plans to forge
44:12some new collaborations you know?
44:13Build out the multi modality presence?
44:16I know it's still early and he's just
44:19been announced, but some thoughts?
44:21Well, I
44:21I've had a couple of conversations already.
44:24You know he's he's really been one
44:27of the Champions. In looking at.
44:31Local treatment in terms of patients who
44:34have metastatic disease, so this actually
44:36has been known for quite some time.
44:39In fact, one of the sister presentations
44:43that original meeting at presentation of
44:46the texture data at ASCO demonstrated those
44:49patients who had a radical prostatectomy.
44:52As part of their history did better with
44:55chemotherapy than those who did not,
44:57and this may be a selection factor,
44:59but this has been observed
45:01by numerous investigators,
45:02so I zic is actually looking at
45:04a protocol he's bringing.
45:06It was with this with him to evaluate local
45:09treatment in terms of metastatic disease.
45:11Through these patients receive
45:12a radical prostatectomy.
45:13Often my patients will ask me that question
45:15should they get local radiation treatment.
45:18It's actually part of some of our
45:20treatment regimen's already to begin with.
45:23So he's going to bring a unique
45:24look at this particular area,
45:26and we're going to be collaborating
45:27on those trials as brothers as well
45:29as some other trials that will be
45:30targeting the androgen receptor.
45:33Excellent excellent yeah.
45:35He's already called me as to move start
45:38moving it through the CTL so we started OK.
45:40Each young Kim had a question.
45:43Dan at the time of castration resistance,
45:45either primary or secondary, do we do?
45:47We routinely sequence AR androgen receptor?
45:52So I I've been running, you know,
45:54routinely running this as part of
45:55a platform because we're looking to
45:57select these patients for the trial
45:59as part of routine clinical practice.
46:01The answer is no.
46:03I do not look at and receptor
46:06mutations or AR V7 and the reason
46:09why I don't look at it is that the.
46:12We do the trial that extra micro,
46:15which was RPI on this particular
46:17study number of years ago of
46:19a drug called Glitter Own,
46:21which was supposed to be active in a RV.
46:247 positive patients an the selection
46:26criteria where RV 7 positive
46:28ITI and minimally symptomatic
46:30or asymptomatic disease,
46:31and then this is what killed study
46:34because those patients who are air
46:36V7 positive tend to be sicker and
46:38have more rapid progression than
46:40those patients who are in who.
46:42Or not,
46:43so I'm not going to really waste
46:45time on an anti androgen that
46:46I know doesn't work such as
46:48abiraterone enzalutamide go directly
46:50to chemotherapy and we saw that
46:52from the card trial before.
46:55So I think that sequencing should be
46:57done in terms of clinical trials in
47:00terms of understanding the biology,
47:01but not right now in terms of
47:04routine clinical practice.
47:05Thanks Dan, I see that Doctor
47:07Bothwell has his hand raised.
47:08How do you want to unmute and well,
47:11I have you asked your question.
47:16When they will unmute you.
47:23The fear still muted.
47:30OK, any other questions or comments?
47:32So this has been really great.
47:37Then tell us a little bit about you
47:39know the network or most of the trials
47:41open at at at the different sites.
47:44So we've been trying to focus on
47:47what's the best way to balance
47:49things in terms of our portfolio,
47:51so we are the phase three type trials
47:54or open should be open at the clip.
47:57That care centers we did have the
48:00Taxotere Pembroke trial open and we do
48:03have a Pembroke enzalutamide study open
48:05as well at some of the care centers.
48:08So we've been trying to expand those trials
48:11that are are are would normally be seen.
48:14In practice, we doing more.
48:16The phase one is tripe type trials.
48:19Here we actually have been
48:21putting patients on at Greenwich.
48:23One of our tax dear patients.
48:26On the Merck study,
48:28is was on there as well,
48:29so so we are looking to expand these
48:32trials out to all the different care
48:34centers. Great, OK, well we'll give
48:36Doctor Bothwell one more chance.
48:41If not, I think well will end,
48:43but I just have one thought as we end then
48:46it has been nine years and apologized.
48:48But you know, I've been here 10
48:50years and one of the first calls I
48:52got yellows from Jose Milo and who's
48:54house are are hospital bears his name
48:56and he says Roy why do all my friends
48:58have to go to New York to go in
49:01clinical trials for prostate cancer?
49:02And I said they will fix that.
49:04And Dan you certainly have and you
49:06made us the destination for prostate,
49:08bladder and other tumors.
49:09And congratulations on your
49:10program and I think many on the.
49:12The call here today will now perhaps have
49:15opportunities to collaborate with you
49:17'cause and build lab to clinic studies.
49:19So thank you all for coming
49:21to grand Rounds today.
49:23I'll just remind everyone that
49:24on June 25th in the morning we
49:27have our annual ASCO review.
49:28It is virtual again this year.
49:30It's a little shorter,
49:32but we're going to be reviewing many topics.
49:35Dan will be there hopefully as well,
49:37and actually for a very special treat,
49:39we're going to have Vince Devita
49:42interviewed by his daughter.
49:43Talking about the 50th anniversary
49:44of the National Cancer Act,
49:46so that's going to be very special,
49:47so I hope to see everyone there
49:49and have a good day everyone.