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Prostate and Urologic Cancers Disease Aligned Research Team

 .

Prostate and Urologic Cancers Disease Aligned Research Team

June 08, 2021

Yale Cancer Center Grand Rounds | June 8, 2021

Daniel P. Petrylak, MD

ID
6701

Transcript

  • 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.