TODAY WE HAVE RAVI MADAN AS OUR FIRST SPEAKER TALKING ABOUT PROSTATE CANCER SO HE'S CLINICAL DIRECTOR OF THE BRANCH. HE GOT HIS MD FROM NEW JERSEY MEDICAL SCHOOL THEN COMPLETED HIS RESIDENCY AT THE UNIVERSITY OF HE JOINED. CURRENTLY HOLDS A JOINT APPOINTMENT BETWEEN MEDICAL ONCOLOGY BRANCH AND LAB OR REOF IMMUNOLOGY AND BIOLOGY. HE'S EXPLORING IMMUNE THERAPY TREATMENTS IN RARE TUMORS. AND TITLE OF HIS TALK TODAY IS TREATMENT FORMED STATIC PROSTATE CANCER. >> THANKS. SO, YEAH, WE HOPE THE HURRICANE REALLY DOESN'T CAUSE MUCH DAMAGE WE'LL GET THROUGH THIS LECTURE WITH HOPEFULLY LESS DAMAGE AS WELL. MOST OF MY DAY JOB IS ACTUALLY CENTERED AROUND PROSTATE CANCER œSTRATEGIES.NG IMMUNOTHERAPY THAT WILL NOT BE AT ALL THE FOCUS OF THIS TALK AS IMMUNO THERAPY MAKES UP A SMALL BIT, I WILL TOUCH ON THAT A LITTLE BIT. AFTER THE FIRST TWO SLIDES IF YOU NEED TO PRETEND THAT YOUR EXPERIMENT IS FAILING OR PICK UP YOUR KIDS IS PROBABLY REASONABLE BECAUSE I'LL HIT ON ALL THE APPROVED THERAPIES I'LL GIVE YOU ALL THE BACKGROUND LATER ON. THESE FIRST COUPLE OF SLIDES LAY THE GROUND WORK FOR THE REST OF THE TALK. THIS IS KIND OF THE CLINICAL COURSE FOR PROSTATE CANCER WHERE PATIENTS ARE DIAGNOSED AND POTENTIALLY CURED EARLY ON UN FORTUNATE FORTUNATELY EVEN PATIENTS WHO ARE TREATED WITH CURATIVE INTENT ROUGHLY 0-40% WILL REOCCUR AT THAT POINT IN TIME AS WE'LL TALK ABOUT HORMONE SUPPRESSIONS. WHEN THAT FAILS WE HAVE SOME OTHER OPTIONS THIS WAS THE TREATMENT LANDSCAPE UNTIL SEVEN OR EIGHT YEARS AGO AND ONLY THING THAT WORKED BESIDES EITHER CHEMICAL OR SURGICAL CASTRATION WAS A DOSE OF A CHEMOTHERAPY. AND THAT EXTENDED SURVIVAL BY A FEW MONTHS BASED ON THE MEDIAN OF A STUDY WHICH I'LL SHOW YOU THAT DATA LATER. FOR AWHILE THERE REALLY WERE NOT A LOT OF OPTIONS FOR THESE PATIENTS. HOWEVER WE'RE FORTUNATE TO HAVE HAD LOT OF ADVANCES IN THE LAST SEVEN OR EIGHT YEARS. I'LL SHARE THEM WITH YOU HERE. ACTUALLY EVEN THOUGH IMMUNO THERAPY IS ALL THE RAGE NOW, THE FIRST KIND OF MODERN IMMUNOTHERAPY BESIDES CYTOKINES WAS ACTUALLY APPROVED IN PROSTATE CANCER, IT'S BEEN SOMEWHAT DEBATED OVER TIME ALTHOUGH I BELIEVE THE PHASE THREE DATA I'LL SHARE THAT WITH YOU SHORTLY. SHORTLY THEREAFTER A SECOND LINE TAXING AGENT AFTER THE FIRST LINE TAXING AGENT WAS DEVELOPED. AND DEMONSTRATED IMPROVEMENT AND SURVIVAL FOLLOWED BY TWO ANTI- THERAPIES. WE'LL COME TO WHY BLOCKING IT IS RELEVANT EVEN THOUGH THEY HAVE BEEN CHEM I CAN TREE OR SURGICALLY CASTRATED. DEMONSTRATED OF EXTRA CASEI BEFORE CHEMOTHERAPY. FOLLOWED BY AN AGENT CALLED RADIUM 223 WHICH IS INFUSIONNAL RADIO-PHARMACEUTICAL AGENT. IT'S REALLY INTERESTING, PROS EIGHT CANCER PROBABLY DOESN'T GET AS MUCH PUBLICITY FOR BEING AN EXCITING TUMOR TYPE BUT YOU SEE OVER RELATIVELY SHORT PERIOD OF TIME WE HAD SEVERAL THERAPIES APPROVED THAT REALLY CROWDED THIS LANDSCAPE. THEY'RE NOT JUST THERAPIES, THEY'RE DIFFERENT MODALITIES. YOU GOT RADIATION-BASED THERAPIES, IMMUNOTHERAPY, AND CHEMOTHERAPIES. WITH ALL THIS OPPORTUNITY, LOT OF THIS HAS BEEN INVESTIGATED IN EARLIER STAGE DISEASE AND TO THAT END, ENZALUATMIDE WERE USED IN PATIENTS BEFORE THE METASTATIC DEVELOPMENT OF DISEASE IN PATIENTS WHO WERE CASTRATION RESISTANT. I'LL SHARE THAT DATA WITH YOU AT THE END IF WE HAVE TIME. THIS WAS JUST APPROVED THIS YEAR AGAIN, YOU SEE HOW THIS LANDSCAPE HAS BECOME VERY CROWDED. THEN LOOKING AT A LITTLE BIT EARLIER STAGE OF DISEASE, THESE ARE PATIENTS WHO ARE DIAGNOSED WITH METASTATIC DISEASE AND DO NOT UNDERGO SURGERY OR RADIATION WITH CURATIVE INTENT OR THEY HAD THAT MANY YEARS AGO THEN COME BACK TO THEIR DOCTORS THEN HAVE METASTATIC DISEASE. BUT NORMAL TESTOSTERONE. THERE HAVE BEEN STUDIES THAT DEMONSTRATED THAT MOVING TWO AGENTS TO THIS EARLIER STAGE OF NEWLY DIAGNOSED PATIENTS DEMONSTRATED SURVIVAL. BUT AGAIN THESE ARE PATIENTS WHO ARE DIAGNOSED WITH METS WHICH IS PATIENTS WHO ARE DIAGNOSED WITH LOCALIZED DISEASE THAT IS THE BIG DIFFERENCE HERE. YOU CAN MAKE NOTATION OF THAT. SO WHAT I'M GOING TO DO WITH THE ALLOTTED TIME LEFT TRY TO GO THROUGH ALL THESE DIFFERENT THERAPIES, THE TRIALS THAT LED TO THEIR APPROVAL, RELATIVE TOXICITIES. HOPEFULLY GIVE YOU BETTER UNDERSTANDING OF WHERE WE'VE BEEN SO WE CAN FIGURE OUT WHAT THE NEXT STEPS ARE. LET'S START OFF WITH SOME NECESSARY BASICS OF UNDERSTAND ING. SO WHAT IS CAT STATION RESISTANT PROSTATE CANCER OR CRPC? THIS IS CANCER THAT GROWS DESPITE CASTRATE LEVELS OF TESTOSTERONE. I MENTIONED THAT CHEMICAL OR SURGICAL CASTRATION IS FIRST WAY TO INTERVENE IN THIS DISEASE THAT'S BECAUSE DECEMBER TOSS -- TESTOSTERONE FUELS THE GROWTH. THAT ONLY WORKS TO CONTAIN THE CANCER FOR RELATIVELY SHORT PERIOD OF TIME ON AVERAGE MAYBE ONE OR TWO YEARS, MUCH LONGER IN THE INDIVIDUAL PATIENT. IT'S POSSIBLE. BUT AT SOME POINT EITHER IT'S GOING TO GROW BASED ON IMAGEING OR PSA AND AT THAT POINT WHEN YOU HAVE EVIDENCE OF CANCER GROWTH THERE ARE EITHER OF THESE TWO ASPECTS DESPITE CASTRATE LEVELS OF TESTOSTERONE IT IS ACYLATION RESISTANT. YOU'LL SEE THAT ACTUALLY THROUGH MECHANISMS OF RESISTANCE, ANDROGEN VERY MUCH DRIVE THESE DISEASE AND TARGETING THE RECEPTORS VERY MUCH A RELEVANT TARGET. THAT GETS US TO THIS NEXT SLIDE WHICH IS WHY DO WE USE ANTI- ANDROGEN THERAPIES IN PATIENTS WHO ARE CASTRATION RESISTANT. THAT IS BECAUSE THESE RESISTANT MECHANISMS THAT DEVELOP THAT DRIVE CASTRATION RESISTANCE ARE AR MEDIATED. SO, YOU CAN SEE AMPLIFICATION OF THE ANDROGEN RECEPTOR WHICH I THINK SPEAKS FOR ITSELF. BUT ALSO SECONDARY PRODUCTION OF ANDROGEN. THIS COULD OCCUR FROM OTHER GLANDS, SUCH AS AS A ADRENAL GLAND, THAT'S RELATIVE BECAUSE MOST OF THE CHEMICAL CASTRATION OR SURGICAL REALLY ONLY ADDRESSES TESTICULAR PRODUCTION BUT NOT OTHER TISSUES. BUT ALSO IN VERY KIND OF SINISTER WAY, CANCER CELLS CAN PRODUCE THEIR OWN ANDROGEN THAT'S RELATIVELY NEW UNDERSTAND ING OVER THE LAST FIVE OR TEN YEARS. THERE'S SECONDARY PRODUCTION OF ANDROGEN WITHIN THE MICRO ENVIRONMENT THAT LEADS TO DRIVEN TUMOR GROWTH THAT'S WHY BLOCKING THESE PATHWAYS IS STILL RELEVANT IN PATIENTS WHO ARE CASTRATION RESISTANT. THERE'S ALSO MECHANISMS BY WHICH SUPPLIES VAIRIAN DRIVES GROWTH OF PROSTATE CANCER OR LIGAND INDEPENDENT GROWTH PATHWAYS. THIS MEANS THAT DESPITE ANDROGEN RECEPTOR PATHWAY THAT IS TRIGGER ED LEADING TO CELLULAR PROLIFERATION AND GROWTH IT MAY BE IRRELEVANT WHETHER OR NOT THERE'S SOMETHING BOUND TO THAT LIGAND. BECAUSE OF A SPLICING CHANGE, THE LIGAND ACTUALLY ISN'T REQUIRED FOR THAT PATHWAY'S ACTIVATION. THAT'S SOMETHING WE'LL TOUCH ON BRIEFLY AS WELL IN CLINICAL IMPLICATIONS L. CAN BE OTHER DOWNSTREAM AFFECTS. DESPITE THE FACT THAT THESE PATIENTS ARE CASTRATION RESISTANT MANY STILL HAVE AR OR ANDROGEN RECEPTOR DRIVEN TUMORS. ALSO WORTH NOTING THAT THERE ARE MUTATIONS. THERE'S SOME DISCUSSION ABOUT MUTATIONNAL BURDEN, THOUGHT THAT PROSTATE CANCER DOESN'T HAVE A LOT BUT LOOKS LIKE THERE ARE OBVIOUSLY MUTATIONS OF PATIENTS WITH CANCER IN THIS STUDY THAT WAS STUDIED, AVERAGE PATIENT HAD THREE AND A HALF. THE MOST SURPRISING OUTED COME HERE WAS THAT SOME OF THESE ARE DNA DAMAGE REPAIR MUTATIONS AND ROUGHLY THIRD OF THESE PATIENTS WHICH CAN BE TARGETED. BUT OBVIOUSLY YOU CAN SEE THE PREPONDERANCE OF ANDROGEN RECEPTOR MUTATION BUT THINGS LIKE P53 AND P10 AS WELL. THEN FINALLY IT'S WORTH NOTING ONE LAST ASPECT OF THE HOUSE RULES OF TREATING PROSTATE CANCER AND THAT IS EVEN THOUGH YOU'LL HEAR CONTROVERSIES ABOUT PSA SCREENING IT IS NOT A CONTROVERSY IN FOLLOWING PATIENTS WHO HAVE CANCER. BUT WHAT IS A LITTLE BIT TRICKY IS HOW THAT PLAYS IN TO YOUR MANAGEMENT OF PATIENS. WHAT HAS BEEN ACCEPTED BOTH HERE IN OUR GROUP PROBABLY MORE HAPTEN YEARS EXTERNALLY FOR THAT PERIOD OF TIME. THROUGH PROS EIGHT CANCER WORK ING GROUP AND CITATION HERE IS THAT P SA IS NOT THE SOLE MARKER OF PROGRESSION. YOU HAVE A PATIENT ON THERAPY IF THEIR PSA IS RISING SHOULD NOT BE THEIR SOLE DETERMINATE. FROM A PERSONAL STANDPOINT LIKE THIRD OR FOURTH ON MY LIST. RADIO GRAPHIC PROGRESSION SHOULD BE THE PRIMARY EVIDENCED. OBVIOUSLY SYMPTOMS AND TOLERABILITY OF THE GIVEN THERAPY ALSO PLAY INTO ACCOUNT BUT JUST BECAUSE YOU HAVE A RISING PSA AND YOU'RE MANAGING A PATIENT WITH PROT TATE CANCER THAT DOESN'T MEAN THE TREATMENT IS FAILING OR YOU SHOULD MOVE ON TO NEXT THERAPY. I SHOWED YOU THAT CROWDED LANDSCAPE, IF THIS, THEN THAT. THERE REALLY ISN'T. WHAT I'VE SEEN SOMETIMES IN SOME PATIENTS WHO ARE REFERRED TO US THERE SEEMS TO BE A SENSE, WE GOT A LOT OF OPTIONS HERE SO YOUR PSA IS GOING UP AND TRY ANOTHER THERAPY WE HAVE THESE DIFFERENT OPTIONS AND REALITY THAT COULD SHORT CHANGE THE CLINICAL BENEFIT TO THE PATIENT BECAUSE A LOT OF THE TRIALS THAT DEMONSTRATED THESE PATIENTS IMPROVED SURVIVAL PRIMARILY RELIED ON RADIO GRAPHIC RE PROGRESSION, THAT'S TRUE FOR ALL THE TRIALS THAT I'LL TALK ABOUT EXCEPT FOR THE THE TRIALS WHICH PREDATED THAT RECOMMENDATION. WE DON'T HAVE A CLEAR TREATMENT SEQUENCE. ONGOING TRIALS ARE EVALUATING THE CURRENT TREATMENTS EITHER IN SEQUENCE OR COMBINATION. SO, IN THE AB SENSE OF THAT I WILL GO THROUGH EACH OF THESE TREATMENTS AND PROPOSE WHAT AT LEAST IS MY OPINION ON HOW THESE AGENTS COULD BE SEQUENCEED. IT'S NOT A FLOW CHART, YOU'LL FIND THAT LARGELY DEPENDS ON THE PATIENT YOU'RE LOOKING AT IN THE CLINIC. THAT IS THEIR PERSONAL PREFERENCES COME INTO PLAY. HOW THE SIDE EFFECTS OF THE GIVEN TREATMENT INTER-PLAYS WITH THEIR EXISTING COMORBIDITIES AS WELL AS HOW FAST THEIR DISEASE IS MOVING HOW SYMPTOMATIC THEY ARE. IN PATIENT WHO HAS LOT OF SYMPTOMS YOU MAY BE INCLINED TO USE CHEMOTHERAPY EARLY ON BUT IN PATIENT WHO DOS NOT YOU MAY HAVE OTHER OPTIONS. AGAIN, THERE'S NOT A STRICT FLOW CHART, THERE'S NOT AN ALGORITHM WHICH IS I KNOW WHAT EVERYBODY WOULD LIKE TO HAVE BUT HOPEFULLY WHAT I'LL PRESENT TO YOU IS A RATIONAL APPROACH BUT REALIZE THIS IS MY OPINION AND REALLY THERE'S NO HARD DATA TO SUPPORT THIS STRATEGY. FOR A FEW YEARS NOW I'VE USED THIS APPROACH OR ALMOST AT DINNER TIME, HOPEFULLY IT DOESN'T GET ANYONE TOO HUNGRY BUT GENERALLY KIND OF LAYS OUT YOUR TREATMENT OPTIONS IN HOW I THINK ONE WAY TO VIEW IT AS YOU LOOK AT A PATIENT GOING THROUGH THE NATURAL HISTORY OF PROSTATE CANCER IN METASTATIC DISEASE. WE'RE FOCUSED ON METASTATIC DISEASE TODAY, I'M NOT A RAID ACHES ONCOLOGIST OR SEWAGE ON I RESERVE THOSE TO THEM. THESE ARE HOW WE CONTAIN THE DISEASE ONCE WE REALIZE IT SPREAD BEYOND THE PELVIS IS NO LONGER CURABLE. I HIGHLIGHTED HERE THESE DIFFERENT OPTIONS AGAIN I'LL WORK THROUGH THIS HOPEFULLY THIS WILL MAKE SENSE TO YOU. IT LAYS OUT KIND OF THE DIFFERENT POSSIBLE OPTIONS HOW YOU CAN LINE THEM UP IN A GIVEN PATIENT AND WE'LL START OFF WITH THE IMMUNOTHERAPY IN PROSTATE CANCER AND APPETIZER, APPETIZERS AREN'T FOR EVERYONE. IT'S NOT GOING TO FILL YOU UP I'M GOING TO CARRY THIS ANALOGY TOO FAR I'M SORRY IF I HAVE ALREADY. IT'S NOT GOING TO BE SUFFICIENT FOR THE WHOLE MEAL BUT I THINK THAT IN SOME PATIENTS IT MAY BE A NICE ADDED THING THAT DOES BENEFIT. THIS IS PREFERENTIALLY USED IN PATIENTS WHO HAVE EARLY METASTATIC CASTRATION RESISTANT PROSTATE CANCER, MINIMAL SYMPTOMS AND LOW VOLUME OR LOW PACE OF DISEASE. THIS IS A THERAPY, IT'S ACTUALLY IMMUNOTHERAPY THAT'S DERIVED FROM A PATIENT'S OWN PERIPHERAL IMMUNE CELLS. WHEN THIS TREATMENT WAS DEVELOPED THEY TOOK A PATIENT'S WHITE BLOOD CELL THROUGH LEUKO FEWER RECESS. WHERE THEY'RE EXPOSED TO GMC ST WHICH IS CTYOKINE AS WELL AS ACID PHOSPHOTASE AN ANTIGEN TARGET. THEN AFTER TWO OR THREE DAYS OF IMMUNOLOGIC BOOT CAMP, IF YOU WILL, EXPOSURE OF YOUR IMMUNE CELLS, TO THIS MILIEU IT'S IN FUSED BACK INTO THE PATIENT. A FULL COURSE OF THERAPY CONSISTS OF THREE INFUSIONS DONE EVERY TWO WEEKS THEN YOU'RE DONE , ONE MONTH'S WORK. THIS IS THE DESIGN OF ACTUALLY THE THIRD PHASE THREE TRIAL THAT WAS DONE WITH THIS AGENT. YOU CAN SEE THAT THERE WAS PLACEBO CONTROLLED COMPONENT. ALTHOUGH THEY WERE LOOKING AT PROGRESSION BASED ON EARLIER PHASE THREE DATA THE PRIMARY ENDPOINT WAS A SURVIVAL ADVANTAGE. YOU SEE IT WAS 500 PATIENT TRIAL THIS WAS THE RESULT OF THIS TRIAL, IT WAS RESULT THAT BASICALLY DEMONSTRATED STATISTICALLY SIGNIFICANT IMPROVEMENT AND SURVIVAL ALSO CLINICALLY MEANINGFUL. I THINK THAT PEOPLE GET CAUGHT UP IN LOOKING AT THIS DATA LIKE, WHAT IS ONLY FOUR MONTHS MEAN. REMEMBER THIS IS MEDIAN. YOU'LL SEE OTHER TRIALS DEMONSTRATE SIMILAR EFFICACY IN THEIR INITIAL PHASE THREE TRIALS THIS WAS ACTUALLY APPROVED IN LIKE I SAID IN 2010 BY THE FDA. BUT CONTROVERSY SURROUNDED THIS THAT'S BECAUSE THERE WERE NO CHANGE IN PROGRESSION FREE SURVIVAL IN THE SHORT TERM OF THESE PATIENTS. YOU CAN SEE THAT HERE BY THESE CURVES WHICH SHOW THAT BASICALLY IF YOU'RE GOING TO DIE IN THE FIRST SIX MONTHS, THIS TREATMENT MIGHT NOT HAVE BENEFITED YOU. IF YOU LIVE LONGER IT SEEMED TO HAVE DONE THAT. ALSO PSA DECLINES WERE UNCOMMON. FAST FORWARD ALMOST A DECADE IMMUNOTHERAPY WE SEE CROSS IMMUNOTHERAPY TRIALS HAVE CROSS OVER PEOPLE ARE LIKE, IMMUNO THERAPY TAKES TIME. WHEN YOU SAID THAT IN 2010 NO ONE BELIEVED IT FOR THESE REASONS IT'S VERY SPLIT CAMP ON WHETHER OR NOT PEOPLE BELIEVE THIS DATA. PERSONALLY I DO, THERE WAS ACTUALLY PHASE THREE THAT DEMONSTRATED THE SAME SURVIVAL ADVANTAGE, IT WAS SMALLER BUT I DO RECOMMEND THIS FOR PATIENTS WITH EARLY STAGE DISEASE WITH MINIMAL SYMPTOM, AGAIN THERE IS A HINT HERE IF THINGS ARE MOVING QUICKLY IT'S NOT GOING TO BENEFIT YOU. AGAIN, THERE'S ALSO DATA FROM THIS TRIAL THAT SHOWED THAT PATIENTS WITH LOWER PSAs HAD A GREATER DELTA BENEFIT IN TERMS OF SURVIVAL. SO WHAT THIS IS SHOWING YOU IN RED IS BASICALLY THE BENEFIT -- OR SURVIVAL IN MONTHS OF PATIENTS TREATED ON PSA QUARTILE S FROM THE STUDY. PSA IS NOT A PERFECT MARKER OF TUMOR BURDEN WE HAVE TO TAKE A LITTLE BIT WITH THE GRAIN OF SALT. NONETHELESS I THINK THIS IS TELLING US THAT PATIENTS AGAIN WITH LOWER TUMOR BURDEN ONE OF THE REQUIREMENTS FOR THIS STUDY WAS NOT TO HAVE A LOT OF SYMPTOMS. THESE PATIENTS HAD A DELTA IN THEIR SURVIVAL RELATIVELY TO THE CONTROL GROUP THAT'S SUBSTANTIAL HERE. FOR THOSE PEOPLE WHO DIDN'T THINK THE 26 MONTH WAS IMPRESSIVE IN TERMS OF SURVIVAL MAYBE MORE CONVINCED BY THIS. WHO TO USE THIS IN? THERE ARE HINTS OF THIS AGAIN, LABEL KIND OF HINTS THAT WE SHOULDN'T BE USING IT IN HIGH VOLUME DISEASE AND I'M SORRY HIGH SYMPTOM DISEASE THEN PERHAPS LOWER PSAs, LOWER TUMOR BURDEN HINTS AT MAYBE WHICH PATIENT SHOULD BENEFIT OR COULD BENEFIT FROM THIS. BUT AGAIN, YOU'RE NOT GOING TO EXPECT TO SEE PSA DECLINE, MY RECOMMENDATION AGAIN IS NOT HARD DATA ON THIS BUT IF YOU'RE GOING TO USE THIS THERAPY GO AHEAD AND GIVE IT THEN MOVE ON TO YOUR NEXT TREATMENT. THERE ARE SIDE EFFECTS HERE BUT THEY'RE PRETTY MINIMAL, FATIGUE, NAUSEA, HEADACHE, I MENTION STROKES JUST BECAUSE SOMETHING THAT WAS TALKED ABOUT WITH INITIAL PHASE 3 IT REALLY IS NOT SOMETHING THAT HAS COME OUT IN A SUBSTANTIAL WAY IN SUBSEQUENT TRIALS. I DON'T THINK IT'S A BIG DEAL. THIS TREATMENT IS VERY WELL TOLERATED. AGAIN, I RECOMMEND IT FOR PATIENTS WHO HAVE EARLY METASTATIC DISEASE, THINGS ARE MOVING SLOWLY THEY HAVE THE OPPORTUNITY TO DO THAT. BUT ONCE YOU'RE DONE WITH YOUR APPETIZER YOU MOVE TO THE FIRST COURSE BECAUSE YOU KNOW IT'S NOT GOING TO FILL YOU UP. I THINK THAT AGAIN WE'RE LOOKING AT PATIENTS NOW WHO EITHER HAVE GOTTEN IT OR MOVING ON, MINIMAL TO MODERATE SYMPTOMS. IN THESE TYPE PATIENTS WHAT DOES THIS MEAN, IT IS FROM A JUDGMENT CALL BUT IF YOU HAVE PATIENT WITH PAIN SYMPTOMS THEY DON'T REQUIRE REGULARLY SCHEDULED NARCOTICS THEN I THINK THEY'RE PROBABLY REASONABLE CANDIDATES FOR EITHER OF THESE THERAPIES. BOTH OF WHICH DEMONSTRATED SURVIVAL ADVANTAGE IN THIS POPULATION AS WELL AS THE ABILITY TO MITIGATE PAIN. I THINK THAT OF THESE TWO OPTION S WE'LL TALK ABOUT THAT FIRST AND IT'S GOOD FOR PATIENTS WHO HAVE SOME SYMPTOMS BUT NOT SUBSTANTIAL AND AGAIN RELATIVELY LOW TO MODERATE OF THE DISEASE. THE ONE DIFFERENCE BETWEEN THE TWO, IS THAT IN ORDER TO MITIGATE SOME OF THE SIDE EFFECTS, YOU HAVE TO TAKE PREDNISONE UP TO TEN MILLIGRAMS A DAY. CONSIDERING THAT PATIENTS MAY HAVE STABLE DISEASE, MY BIAS IS A LITTLE BIT TOWARDS ENZALUTAMID E IN TERMS OF WHICH WOULD BE PREFER ARENA SHALL. IT BINDS TO THE ANDROGEN RECEPTOR. ANDROGENS BIND TO THE RECEPTOR LEADS TO SIGNAL TRANSDUCTION CASCADE LEADING TO NUCLEAR SIGNAL FOR GROWTH AND PROLIFERATION. WHAT WE SEE HERE COMPARED TO OLDER RECEPTORS, WHICH WAS THE ORIGINAL ENZALUTAMIDE HAS GREATER BINDING ABILITY BUT DOWNSTREAM EFFECTS. JUST A MUCH BETTER VERSION OF SOMETHING THAT WAS MULTIPLE AGENTS THAT WERE DEVELOPED IN THE '80S, ACTUALLY MORE IN THE '80S. ENZALUTAMIDE IS A BETTER MOUSETRAP THAT WAS BUILT, MULTI- BILLION DOLLAR DRUG IF YOU THINK YOU CAN IMPROVE ON SOMETHING THAT'S ALREADY BEING DONE, GO FOR IT. IT CAN PAY OFF HELP MILLIONS OF PEOPLE. THE OLDER VERSIONS OF ANDROGEN RECEPTOR ANTIGENESS DID NOT CLEARLY DEMONSTRATE A SURVIVAL ADVANTAGE ON THEIR OWN OR WITH SUPPRESSION. IT WAS PRETTY EXCITING WHEN THIS DRUG CAME OUT A LITTLE OVER MAYBE TEN YEARS AGO, AGAIN IT CHANGED OUR UNDERSTANDING OF THIS, REMINDED US THAT EVEN IN CASTRATION RESISTANT DISEASE, ANDROGEN RECEPTOR AS I STATED WAS RELEVANT TARGET. YOU'LL SEE THAT A LOT OF INITIAL STUDIES WERE DONE AFTER PATIENTS HAD PROGRESSED WHICH WAS AT THE TIME THE ONLY STANDARD THERAPY. BUT ALSO REALIZE THAT THIS WAS ALSO THE QUICKEST PATH TO MARKET FOR THIS AGENT. IT MADE BIOLOGIC SENSE IN SOME WAYS BASED ON TREATMENT LANDSCAPE BUT ALSO MADE GOOD MARKETING SENSE TO GET YOUR ANSWER QUICKER. YOU'LL SEE THE TIMELINES ARE MUCH SHORTER IN THESE STUDIES. IN THIS PLACEBO CONTROLLED TRIAL , PATIENTS ALREADY HAD ONE STANDARD THERAPY, ENZALUTAMIDE SHOWED SURVIVAL. THREE OR FOUR MONTHS AND ALSO CLEAR EVIDENCE OF TIME TO PROGRESSION OR EIGHT MONTHS VERSUS THREE MONTHS WAS APPROVED IN 2012 FOR PATIENTS WHO HAD ALREADY PROGRESSED. NOW AGAIN I'M GOING TO -- I WOULDN'T CROSS COMPARE THESE. THEY'RE DONE IN SORT OF DIFFERENT WAYS, SOMETIMES IN DIFFERENT POPULATIONS, IT'S JUST WORTH HAVING THAT CAVEAT ACROSS ALL THESE LECTURES PROBABLY. NOW, ONCE THEY DEMONSTRATED THAT THEY ALREADY DEVELOPED TRIALS THAT ARE RUNNING IN PATIENTS WHO ARE CHEMOTHERAPY NAIVE, THEY WANTED DEMONSTRATE THAT IT COULD ALSO IMPROVE THEIR SURVIVAL AND IN FACT IT DID. SO, YES, THEY'RE PROBABLY EXTENDING THE LIFE BUT ALSO WHAT COULD BE CALLED THE LEAD TIME BIAS HERE BY GETTING THEM MUCH EARLIER. THIS SURVIVAL ADVANTAGE WAS ALSO EVIDENT BASED ON THIS. 12 MONTHS PROGRESSION FREE SURVIVAL ADVANTAGE, ANY THOUGHTS AS TO WHY THIS IS SO MUCH SHORTER THAN WHAT WE SAW IN THE POST CHEMO SETTING. ANY QUICK STABS AT THAT? IT'S ALWAYS IMPORTANT TO LOOK AT THESE TRIALS AND UNDERSTAND THE POTENTIAL CONFOUNDING VARIABLES WHEN ANALYZING THIS. YOU'LL SEE THIS WITH OTHER DATA AS WELL. BUT THIS IS VERY IMPORTANT TO UNDERSTAND THIS IS A CROSS OVER AFFECT. NOT A DELIBERATE PART OF THE STUDY DESIGN, I THINK IT MAY HAVE BEEN. IF YOU GOT PLACEBO INITIALLY ULTIMATELY PROGRESSED YOU COULD HAVE GOTTEN CHEMOTHERAPY THEN ENZALUTAMIDE WHICH WAS STANDARD OF CARE. EVEN THOUGH THESE PATIENTS ON THESE TRIALS WERE RANDOMIZED, THAT DOESN'T MEAN THEY GOT THESE AGENTS LATER ON. THAT'S WHY IT'S NOT LIKE SURVIVAL BY TWO MONTHS THAT WOULD BE INAPPROPRIATE WAY TO LOOK AT THIS. IT JUST HIGHLIGHTS MAYBE GETTING IT EARLIER WAS BETTER FOR SOME OF THESE PATIENTS. JUST WORTH UNDERSTANDING. ENZALUTAMIDE IS PRETTY WELL TOLERATED, BIGGEST THING HERE IS FATIGUE. REMEMBER I'M HIGHLIGHTING THESE THINGS NOT BECAUSE YOU HAVE TO MEMORIZE THEM ALL I JUST THINK THAT RELATIVE TOXICITY PLAYS INTO THE CHOICES OF THERAPIES FOR THE PATIENTS IN THE ABSENCE OF CLEAR DATA HOW TO SEQUENCE THIS. FATIGUE IS REALLY THE BIGGEST SIDE EFFECT. IT CAN BE PROFOUND IN SOME PATIENTS, SOME PATIENTS THEY DON'T NOTICE IT AT ALL. GENERALLY SPEAKING, ENZALUTAMIDE VERY WELL TOLERATED DRUG. THERE WAS SOME CONCERN THAT PATIENTS WITH SEIZURE HISTORY RECENT STROKES SHOULD BE EXCLUDE FRED TREATMENT. AND THERE'S SOME THAT'S PERHAPS ENZALUTAMIDE BECAUSE OF CNS PENETRATION LOWERS THE SEIZURE THRESHOLD. YOU SHOULD BE CAUTIOUS WITH PATIENTS ON ANTI-SEIZURE MEDICATIONS. THERE HAS BEEN RECENT STUDY THAT DEMONSTRATED THAT IN PATIENTS AT HIGH RISK FOR SEIZURES THAT THE INCIDENTS WAS ACTUALLY PRETTY LOW WITH ANSWER ROUTE MID. SOMETHING TO BEAR IN MIND. SO, THE ONLY REAL BIG DRAW BACK OF THE DRUG SIDE EFFECT PROFILE IS A LITTLE BIT MORE EXTENSIVE I'LL SHARE THAT WITH YOU. IT REQUIRES THE DALE THAT PREDNISONE TO AGAIN MINIMIZE SIDE EFFECTS FROM THE AGENTS ITSELF. SO, NOT A RECEPTOR BLOCKER, IT BLOCKED THE CYP 17 HYDROXYLASE AND LIGASE. BASICALLY THE LIGASE MORE RESPONSIBLE FOR THIS SECONDARY ANDROGEN PRODUCTION. REMEMBER I SAID ONE OF THE RESISTANCE MECHANISMS THAT WE HAVE IN PROSTATE CANCER IS THAT BASICALLY CANCER CELLS OR OTHER CELLS WITHIN THE TUMOR ENVIRONMENT, WITH EITHER CHEMICAL OR SURGICAL CASTRATION WHICH IS THE FRONT LINE THERAPY THERE'S STILL THIS FUEL FLOATING AROUND THE CANCER CELL. ANTI-FUNG I WILL AGENT THAT PROBABLY NONINTERESTS OF I CANNILY ATTACHED THESE ENZYMES. SO AGAIN IF YOU WANT TO BE RICH OR SCIENTIFICALLY FAMOUS YOU CAN AGAIN BUILD A BETTER MOUSETRAP, IT DOES WORK. THAT'S PROBABLY WHAT THIS IS UPDATE OF VERY OLDER, LESS PROSTATE SPECIFIC DRUG. SO, WHEN THIS WAS DEVELOPED AGAIN EARLY STUDIES JUST LIKE WITH ENZALUTAMIDE, VERY PROMISING. THEY HAD PSA DECLINES WHICH WAS A GOOD MARKER OF EFFICACY THIS WAS A PHASE 3 TRIAL THAT WAS DONE AGAIN IN PATIENTS WHO HAD ALREADY PROGRESSED ON DOCETAXEL AND WE SEE AGAIN THERE'S A SURVIVAL ADVANTAGE HERE OF ABOUT FOUR MONTHS IN THIS LATE STAGE DISEASE POPULATION. THIS LED TO FDA APPROVAL IN PATIENTS WHO HAD ALREADY AGAIN RECEIVED DOCETAXEL. THIS ALL HAPPENED RELATIVELY AGAIN THE SAME TIME AS THE ENZALUTAMIDE DEVELOPMENT IT'S NOT LIKE THEY HAD TO RANDOMIZE AGAINST ONE OR ANOTHER BECAUSE EITHER WERE NECESSARILY STANDARD WHEN THE TRIALS WERE DEVELOPED. AGAIN, YOU SEE ADVANTAGE IN TIME TO PROGRESSION. AS WELL AS PSA RESPONSES. THIS IS FOLLOW-UP STUDY JUST LIKE WHAT THE GROUP WITH ENZALUTAMIDE DID, THE COMPANY THERE, THEY RAN ABIRATERONE STUD AUTO TO PATIENTS WHO ARE CHEMOTHERAPY NAIVE YOU SAW IMPROVEMENT IN THE MEDIAN SURVIVAL HERE OF, AT THIS ITERATION IN 2015 IT WAS ABOUT TEN MONTHS RELATIVE TO THE PLACEBO. AND AGAIN IT'S FDA APPROVED NOW FOR ALL PATIENTS WITH METASTATIC DISEASE REGARDLESS OF PREVIOUS CHEMOTHERAPY. SIDE EFFECT IS MORE POPULATED HERE. YOU JUST BEAR THAT IN MIND WHEN YOU HAVE YOUR PATIENTS. IT CAN BECAUSE OF THE 17 HYDROXYLASE INHIBITION LEAD TO SOME EDEMA AND HYPERTENSION. EDEMA IS IN LOWER EXTREMITIES TO SOME DEGREE STEROIDS ARE SUPPOSED TO MITIGATE THOSE. BUT AGAIN HAVING STEROIDS ON BOARD CAN CONTRIBUTE TO OTHER THINGS LIKE HYPERGLUE SEEM CALIFORNIA IF YOU HAVE DIABETIC, IT'S HARD TO CONTROL THEIR SUGARS DON'T WANT TO GIVE THEM ABIRATERONE IF YOU DON'T HAVE TO BECAUSE MAYBE PREDNISONE IS GOING TO GLYCEMIC CONTROL MORE DIFFICULT. ABIRATERONE MAY BE PREFERENTIAL WITH PATIENTS, OR AS WE TALKED ABOUT SEIZURE RISK ISSUES. WHY IS THIS RELEVANT. WHY AM I TALKING LIKE YOU CAN ONLY USE ONE OF THESE THERAPIES. WELL, IN SOME WAYS THERE'S DATA THAT'S COME OUT IN REBOUND YEARS THAT SAYS THERE IS CROSS RESISTANCE BETWEEN THESE TWO THERAPIES. SO PATIENTS WHO GET ONE OF THESE AGENTS ARE LIKELY TO BENEFIT BUT IF THEY GET THE SECOND AGENT THEY MAY NOT OR THAT BENEFIT MAY BE SUBSTANTIALLY DIMINISHED BASED ON THE PHASE THREE DATA THAT I SHOWED YOU. THAT MAKES SENSE BECAUSE BASICALLY THESE ARE VERY GOOD INHIBITORS OF THE ANDROGEN RECEPTOR OR ACTIVATION LEVEL AND SO RESISTANCE MECHANISMS THAT IMPACT ONE THERAPY ARE GOING TO PROBABLY IMPACT BOTH. SO ONE OF THE ONES THAT'S BEEN VERY EXTENSIVELY STUDIED IS CONCEPT THAT I MENTIONED EARLIER WHICH IS THIS CONCEPT OF THE ANDROGEN RECEPTOR SUPPLIES VARIANCE. THESE ARE ANDROGEN RECEPTORS THAT POST TRANSLATIONALLY ARE MODIFIED OR SPLICED IN MANNER THEY DON'T HAVE RECEPTOR YOU DON'T NECESSARILY NEED ANDROGEN FLOATING AROUND TO HAVE THE RECEPTOR BE ACTIVE. SO IT'S ALMOST LIKE HAVING A LIGHT SWITCH BUT THE SWITCH IS BROKEN AND WIRES ARE CROSSED LEAVING THE LIGHTS ON ALL THE TIME. A WEAK ANALOGY BUT BEST I CAN COME UP. HOPEFULLY IT'S OKAY. BASICALLY WHAT THIS MEANS IS THAT EVEN IF YOU BLOCK THE ANDROGEN RECEPTOR OR THE LIGHT SWITCH OR DIMINISH THE ABILITY FOR THE BODY OR CANCER CELLS TO PRODUCE THEIR OWN TESTOSTERONE IT DOESN'T MATTER BECAUSE THAT WIRING IS ALREADY CROSSED BECAUSE OF THE SPLICING. THAT PATHWAY IS GOING TO BE CONSTITUENTLY ACTIVE. THIS IS PROBABLY, DEFINITELY NOT THE ONLY MECHANISM OF RESISTANCE BUT ONE EXAMPLE AND IT GOT A LOT OF GOOD, APPROPRIATELY GOT LOT OF NOTORIETY BASED ON THIS NEW ENGLAND PUBLICATION HIS GROUP AT HOPKINS A FEW YEARS BACK WITH THE SPLICE THAT ANDROGEN RECEPTOR VARIANT 7 SO WHAT YOU SEE HERE IS PATIENTS TREATED WITH ENZALUTAMIDE F. THEY HAD PREVIOUS AB RAD REASON. THEY WERE VERY UNLIKELY TO RESPOND TO ABIRATERONE WHEN THEY RECEIVED IT AFTER ENDS LUTED MID SIMILAR YOU SEE SAME THING WITH PATIENTS WITH WENT ON ON TO GET ENZALUTAMIDE. ALSO WORTH NOTEING THAT NOT EVERYBODY HAD THIS, WE'RE STILL TRYING TO FIGURE OUT EXACTLY HOW RELEVANT THIS IS, THIS IS NOT THE ONLY MECHANISM OF RESISTANCE THIS IS WHY YOU ARE SOMEWHAT LIMITED TO USING BOTH THESE AGENTS SO YOU ARE PROBABLY GOING TO GET MUCH LONGER RUN OUT OF ONE THAN THE OTHER. DEPENDING HOW THEY DO. YOU MAY STILL TRY THE OTHER ONE SEE HOW THEY DO CLINICALLY. THERE'S A LOT OF WORK BEING DONE DEVELOPING BIOMARKERS TO UNDERSTAND WHETHER ARV7 IS PRESENT AND SOME INTERESTING DATA PRESENTED THIS YEAR. WE'LL SEE HOW THAT EVOLVES OVER TIME. AS WE MOVE ON THE PATIENTS WHO HAVE MORE MODERATE OR SUBSTANTIAL SYMPTOMS WITH THEIR PROSTATE CANCER THEN THERE'S LESS DATA SHOWING THAT ENZALUTAMIDE IS EFFECTIVE. THESE TRIALS MORE MODERATE SYMPTOM PATIENTS WE DON'T HAVE AS GOOD DATA SUGGESTING THAT THEY CAN REALLY IMPROVE PAIN IN PATIENTS WITH EXTREME PAIN OR LOT OF SYMPTOMS. ALSO FROM A DOCETAXEL STANDPOINT , YOU MAY FIND THAT TO BE A BETTER THERAPY IN THE SHORT TERM TO SLOW THINGS DOWN. OTHER THING THAT DOESN'T COME INTO PLAY WITH A TUMOR BURDEN STANDPOINT BUT IF YOU HAVE PATIENT, HAVEN'T TALKED A BOUT IT IN THIS CONTEXT THE FRONT LINE THERAPY FOR PROSTATE CANCER THAT'S NO LONGER CURABLE IS ANDROGEN SUPPRESSION ALONE. THAT'S AGAIN CHEMICAL OR SURGICAL CASTRATION F. PATIENTS PROGRESSED WITHIN SIX MONTHS OR A YEAR YOU MAY HAVE CONCERN THAT ALREADY IN THOSE PATIENTS THAT THE ANDROGEN RECEPTOR PATHWAY IS LESS RELEVANT. IN THOSE PATIENTS YOU MAY WANT TO LOOK AT MOVING RIGHT TO CHEMOTHERAPY. AGAIN, IT'S NOT A FLOW CHART BUT YOU HAVE LOOK AT NOT JUST PATIENT IN FRONT OF YOU, TREATMENT HISTORY AND RESPONSE HISTORY AND COMORBIDITY. DOCETAXEL WAS FDA APPROVED BACK IN 2004 AND IT STILL MAY BE A VERY GOOD THERAPY FOR PATIENTS WITH FAST MOVING DISEASE. FOR PEOPLE WHO SAY YOU SHOULDN'T CUT DOWN THE RAIN FOREST, DOSE IT COMES FROM A TREE IN THE PACIFIC NORTHWEST, I KNOW THERE'S NO AT LEAST WET RAIN FOREST IN THE PACIFIC NORTHWEST, BUT THAT'S LED TO THE DEVELOPMENT OF AGENT CALLED PACL ATAX,L IT'S A SYNTHETIC THAT INHIBITS MICRO HUMAN BRAIN WALLS FOR YEARS IT WAS THOUGHT THAT THEY WERE NECESSARY FOR CELLULAR PROLIFERATION AND BY BLOCKING THOSE AND BASICALLY CAN LIMIT CELLULAR PROLIFERATION IN THAT MANNER. SOME RESEARCHERS ACTUALLY HAVE SUGGESTED THAT IT REALLY IS ALL ABOUT THE ANDROGEN RECEPTOR THAT BASICALLY MICRO TUBULES ARE NECESSARY TO TRANSPORT TO THE CONSTITUENT PATHWAY FROM THE CELLULAR MEMBRANE ACTIVATION TO THE NUCLEUS THAT INHIBITING THEM ACTUALLY YOU'RE INHIBITING THE ANDROGEN RECEPTOR PATHWAY THAT IS JUST INTERESTING TO REMIND US THAT HOW IMPORTANT THE ANDROGEN RECEPTOR REALLY IS IN PROSTATE CANCER. SO THIS WAS A STUDY DONE IN PREVIOUS ERA BEFORE ABIRATERONE THIS IS -- PROBABLY DEVELOPED IN THE EARLY 2000s. AND THEY WERE LOOKING AT THREE SCHEDULES, AT THIS TIME THERE WAS NOTHING IN PROSTATE CANCER THAT COULD EXTEND SURVIVAL IN MEN WITH METASTATIC DISEASE BEYOND REALLY CASTRATION. THAT WAS THE ONLY THING. COUPLE OF THINGS HERE. THEY LOOKED AT DOCETAXEL 2 SCHEDULES EITHER EVERY THREE WEEKS OR LOWER DOSE WEEKLY THEN LOOKED AT IT COMPARISON NOT TO PLACEBO BUT TO PREDNISONE. I HAVEN'T MENTIONED IT YET IT WAS APPROVED BY THE FDA IN THE '90s FOR PAL QUAKES. IT DIDN'T EXTEND SURVIVAL BUT DID IMPROVE SYMPTOMS THIS WAS SOMETHING THAT WAS BEING USED IN THE CLINIC AT THAT TIME. WHY PREDNISONE? I MENTIONED ABIRATERONE COMBINED WITH PREDNISONE IT MITIGATES SOME OF THE TOXICITIES. THAT MAY BE THE CASE HERE. BUT REALISTICALLY THE PREDNISONE WAS INCLUDED HERE AS ARTIFACT OF CLINICAL TRIAL DESIGN. SO WHEN MITOXANTRONE. MIGHT SAN TESTOSTERONE LET'S KEEP EVERYTHING EQUAL THEN ADD PREDNISONE AS WELL THAT'S WHY THE PREDNISONE IS INCLUDED IT'S A RELEVANT THING IF YOU HAVE PATIENTS WITH TOXICITY. YES, WE HAVE A QUESTION. PREDNISONE, IT'S A STEROID. GLUCOCOCOURTOID OR STEROID HAS ROLE IN PROSTATE CANCER, AT LEAST PALLIATIVE WAY, ANTI- INFLAMMATORY, THERE'S SOME HINTS MAY HAVE ANTI-TUMOR EFFECTS AS WELL. YOU'LL SEE THAT IN PLACEBO ARMS OF STUDIES, IT'S A STEROID. GOOD QUESTION. THESE ARE THE RESULTS OF THE STUDY, YOU SEE HERE THAT DOCETAXEL EVERY THREE WEEKS, NOTHING DEMONSTRATED SURVIVAL ADVANTAGE AT THAT POINT. PROBABLY LIVED 10-1 MONTHS THAT WAS ABOUT IT. IN THIS STUDY, WITH SUPERIOR TO THE OTHER TWO ARMS AND PATIENTS LIVED FOR ABOUT 19 MONTHS. I CAN'T TELL YOU HOW MANY TIMES PEOPLE COME INTO MY OFFICE OUR CLINIC SAYS, I'M NOT GOING TO GET CHEMOTHERAPY BECAUSE I'M NOT GOING TO TAKE CHEMOTHERAPY AM THE SIDE EFFECTS THAT GO WITH IT FOR ONLY TWO OR THREE MONTHS OF SURVIVAL. I'LL SHOW YOU LONG LIST OF SIDE EFFECTS, DOCETAXEL PRETTY WELL TOLERATED I'VE TREATED MEN IN THEIR 90s WITH IT. THEY DO PRETTY WELL. MOST STILL GO TO WORK ON THIS REGIMEN. BUT UNFORTUNATELY DOESN'T COME ACROSS IN THIS DATA THIS GETS PERPETUATED TOO OFTEN EVEN THOUGH OLDER DATA THAT CHEMO DOESN'T DO ANYTHING MEANINGFUL, WHAT IT MISSES IS THAT THERE WAS A CROSS OVER HERE. PATIENTS WHO PROGRESSED ON MITOXANTRONE COULD GET DOCETAXEL ANY TIME YOU HAVE A BUILT IN CROSS OVER WITHIN STUDY YOU'RE UNDERESTIMATEING THE TREATMENT AFFECT. SO THE REALITY IS IT WAS QUITE SURPRISEING THAT THE MITOXANTRONE LIVED 16 AND HALF MONTHS, HISTORICAL DATA SUGGEST ED THEY LIVE CLOSER TO TEN MONTHS. USUALLY WITH THAT INFORMATION THE PATIENTS ARE A LITTLE MORE OPEN-MINDED. BUT IT IS VERY IMPORTANT HOW YOU INTERPRET THESE STUDIES AND THESE DELTAS IF YOU WILL. ALWAYS LOOK OUT FOR EITHER FUNCTIONAL BUILT-IN CROSSOVERS OR LIKE ONE I MENTIONED EARLIER WITH ENZALUTAMIDE WHICH MAY HAVE BEEN MORE REAL WORLD CROSS OVER. AGAIN, LONG LIST OF TAXIS TEASE THAT CERTAINLY THE CASE. MOST PROFOUND SIDE EFFECTS ARE REALLY NEUTROPENIA. WHICH COULD LEAD TO DEATH JUST HAVE TO HAVE SOME EDUCATION OF THE PATIENTS THAT IF THEY -- NEED TO EXPLORE, DO WORK UP MOST TIMES ARE NOT INFECTED. THAT IS SOMETHING TO BE A WEAR OF AS WELL. I THINK LOT OF THESE SIDE EFFECTS ARE REVERSIBLE. IN THIS INITIAL STUDY PATIENTS ONLY GOT TEN CYCLES OF DOCETAXEL TO THIS DAY SOME PEOPLE ONLY STILL GET TEN CYCLES. OUR PRACTICE HERE AND OTHER PEOPLE HAVE DONE THIS AS AS WELL TO CONTINUE IT UNTIL BASICALLY THERE IS DISEASE PROGRESSION IN MEDICATION. YOU CONTINUE DOCETAXEL UNTIL IT STOPS WORKING, WAY TO GET PATIENTS THROUGH THIS IS TO GIVE THEM BREAKS FROM THE CHEMOTHERAPY BECAUSE LOT OF THESE SIDE EFFECTS CAN REVERSE THEMSELVES. SO DATING BACK TO WHEN THEY DIDN'T HAVE ABIRATERONE WE HAD SOME PATIENTS WHO HAD TREATMENT WITH DOCETAXEL FOR UP TO FIVE OR SIX YEARS ON AND OFF. THESE ARE WERE MEN IN THEIR 70s OR 80s. ONLY GET THEM THROUGH IT BECAUSE GIVING THEM MOM DICE THINGS -- CHEMOTHERAPY HOLIDAYS OR BREAKS THEY'RE SIDE EFFECTS COULD RESOLVE. I DO THINK AGAIN THAT IN PATIENTS WITH FAST MOVING DISEASE THAT CHEMOTHERAPY IS STILL MAYBE EVEN FRONT LINE AGENT DESPITE THESE NEWER OPTION S. RADIUM 223 REPRESENTS AN ALTERNATIVE OPTION FOR PATIENTS WHO ARE SYMPTOMATIC, CLINICAL TRIALS DID NOT EVALUATE PATIENTS WITH LARGE VISCERAL DISEASE SO MOST PEOPLE WILL AVOID IT, YOU'LL SEE BASED ON MECHANISM, THERE'S NOT REALLY RATIONAL FOR WHY IT WOULD WORK IN PATIENTS WITH VISCERAL DISEASE BUT REALLY FOR PATIENTS WITH SYMPTOMATIC BONE DISEASE. I DIDN'T GET INTO THAT JUST FOR NATURAL HISTORY STANDPOINT BUT IT IS WORTH NOTING, 90% OF MEN WITH PROS FATE CANCER HAVE DISEASE IN THEIR BONES AND MOST MEN HAVE DISEASE ONLY IN THEIR BONES. IT IS A BONE DOMINANT DISEASE. VISCERAL DISEASE ALONE IS LIKE I SAID ABOUT 10% AND PATIENTS WITH LYMPH NODE DISEASE IS RARE THOSE PATIENTS DO THE BEST. IT'S JUST SOMETHING WORTH UNDERSTANDING WHEN WE'RE TALKING ABOUT WHY A RADIO PHARMACEUTICAL THAT LOCALIZES TO THE BONES IS SO VALUABLE. I'M NOT A PHYSICIST BUT I WILL TRY TO PRETEND TO PLAY ONE FOR THE NEXT COUPLE SLIDES AS I TELL YOU WHAT RADIUM 223 IS. IT IS PARTICLE EMITTING AGENT BASICALLY BINDS HIGH AREAS OF ACTIVITY WITHIN THE BONES SUCH AS AREAS WITH GROWING PROSTATE CANCER. LIKE I SAID RADIUM 223 ADMITS ALPHA PARTICLES. THAT IS RELEVANT BECAUSE OLDER BIO-- I'M SORRY RADIO PHARMACEUTICAL WERE BETA EMITTING AGENTS. BOTH OF WHICH WERE APPROVED FOR PATIENTS WITH BONE-BASED CANCERS BUT ONLY FOR PALLIATION. BECAUSE THOSE AGENTS WERE BETA EMITTING THE DESTRUCTION RADIUS OF THOSE LIGHTER BETA PARTICLES WITHIN THE BONE WERE LARGER. YOU HAD GREATER IMPACT ON INNOCENT BYSTANDER CELLS LIKE RED BLOOD CELLS. YOU GOT INTO TOXICITY ISSUES REAL QUICK. WITH ALPHA PARTICLES, YES, YOU CAN STILL HAVE DROPS IN COUNTS BUT BECAUSE DESTRUCTION RADIUS IS SMALLER IT'S NOT AS MUCH OF TREATMENT LIMITING AFFECT. OF COURSE IF YOU HAVE PATIENTS WITH A TON OF BONE DISEASE YOU'RE GOING TO HAVE LOT OF ALPHA PARTICLES ON THE BONES THAT COULD BE AN ISSUE. CERTAINLY BETTER TOLERATED IN THE OLDER AGENTS. AGAIN, SOME WAYS YOU SEE HOW THIS IS A RATIONAL UPDATE OF OLDER STRATEGY. THIS DID THIS TRIAL AGAIN AROUND THE TIME THAT DOCETAXEL WHERE THEY RANDOM RANDOMIZED IT'S COME OUT SINCE THAT BASICALLY NUMBER OF INFUSIONS AND DOSE THAT THEY USED WAS ACTUALLY PRETTY ARBITRARY. THEY PRETTY MUCH LOCKED PEOPLE IN HOTEL ROOM UNTIL THEY REAL ESTATE GREED ON SOMETHING THIS IS WHAT THEY CAME OUT WITH THERE'S STILL SOME DISCUSSION IF THIS IS OPTIMUM DOSE. IN PHASE 3 PATIENTS LIVED LONGER IF THEY RECEIVED RADIUM 223 VERSUS PLACEBO, THIS WAS REGARD LESS OF CHEMOTHERAPY. YOU SEE HERE THAT SUBGROUP ANALYSIS, THE OVERALL SURVIVAL BENEFIT OCCURRED REGARDLESS OF PREVIOUS CHEMOTHERAPY OR NOT. IT'S WORTH NOTING THAT YOU DON'T NECESSARILY NEED CHEMOTHERAPY TO BENEFIT FROM THE AGENT. THE PALLIATIVE HELP WAS MORE ADVANCED HAD HAD CHEMOTHERAPY BUT WAS EVIDENCE IN PATIENTS WITH EARLIER STAGE DISEASE WHERE RADIUM 223 IMPROVED I AM TOMS. THIS WAS IMPORTANT UPDATE BECAUSE PREVIOUSLY RADIO PHARMACEUTICALS WERE PALLIATIVE NOW SOMETHING WITH SURVIVAL ADVANTAGE AND WE'RE STILL TRYING TO PROBABLY FIGURE OUT THE EXACT NICHE OF THIS AGENT, THE PRIMARY SIDE EFFECTS THAT WE SEE WITH IT ARE HOME TOE LOGIC AS I SAID BUT NOT -- HEMATOLOGIC. WHAT WE SAW WITH OLDER VERSIONS. RECENTLY THERE WAS DATA THAT CAME OUT THAT SAID WHEN YOU COMBINE RADIUM 223 WITH ABIRATERONE YOU HAVE INCREASED FRACTURES, NO ONE UNDERSTANDS THIS YET, THE COMPANY HAS BEEN LOOKING AT THIS ARE IF A LITTLE WHILE. THEY ALERTED EVERYBODY ABOUT A YEAR AGO. THERE'S OTHER DATA THAT DIDN'T RAISE THAT CONCERN BUT IT'S JUST SOMETHING TO BE AWARE OF WITH RADIUM 223. BUT ON ITS OWN, I THINK IT'S STILL EVIDENCE THAT THERE'S A VIABLE TREATMENT OPPORTUNITY FOR PATIENTS. AS WE MOVE ON ON TO OUR THIRD COURSE OF THERAPY HERE, THESE ARE PATIENTS WHO HAVE ALREADY PROGRESSED ON DOCETAXEL. SO REMEMBER I'VE ALREADY SHOWN YOU DATE THE FROM ENZALUTAMIDE THAT THEY ALL WORK AFTER DOCETAXEL. IF PATIENTS HAD DOCETAXEL AND HAD NOT HAD THOSE AGENTS THEY CAN GET IT IN THEIR THIRD COURSE SPECIFICALLY FOR PATIENTS WHO PROGRESSED ON DOCETAXEL. WHAT IS IT? WELL IT'S A TAXANE THAT DIFFERS ONLY BY TWO HYDROXYL GROUPS. SO, PEOPLE WERE LIKE, ALL RIGHT, THEY DEVELOPED THIS, SAID LET'S DO PHASE THREE IN PATIENTS WHO HAD DOCETAXEL, I DON'T THINK THERE WAS A LOT OF EXPECTATIONS THAT THIS WOULD WORK, THIS IS ANOTHER AGENT THAT UPDATE OF DIFFERENT VERSION. DEMONSTRATED SURVIVAL ADD HANG IT'S WORTH NOTING THAT GROWTH FACTOR WASN'T MANDATED PROBABLY UNDER UTILIZED MAYBE COULD HAVE LIMITED SOME OF THOSE NUTROPINIC INFECTIONS BUT PEOPLE COMMONLY BEEN REDUCING THE DOSE DO 20 MILLIGRAMS JUST I THINK WITHOUT DATA SO ACTUALLY THE COMPANY THAT MAKES DOCETAXEL ALSO MAKES CABAZITAXEL. IN THE FRONT LINE SETTING SO METASTATIC CASTRATION RESISTANT DISEASE SEE IF CABAZITAXEL IS BETTER, WASN'T CLEAR THAT IT WAS DIDN'T SUPPLANT DOCETAXEL AS FRONT LINE CHEMO AGENT. BUT WHAT IT DID SHOW IS THAT THE 25 MILLIGRAM DOSE AND 20 MILLIGRAM DOSE ARE EQUIVALENT SO YOU CAN PROBABLY GET AWAY WITH A LITTLE BIT OF LOWER DOSE AND NOT HAVE TO WORRY ABOUT AS MUCH SUPPRESSION. I THINK CABAZITAXEL STILL STRUGGLES TO BE USED BECAUSE PATIENTS ARE -- PROVIDERS ARE RELUCTANT, PATIENTS ARE RELUCTANT, I THINK IT CAN BE OPTION AGAIN IN CERTAIN PATIENT POPULATION. AGAIN I'D ALREADY MENTION THAT THESE AGENTS ALL HAVE SURVIVAL DATA AFTER CHEMOTHERAPY AND IT'S WORTH NOTING THAT. I THINK IT LOOKS LIKE WE'VE GOT LOT OF THERAPIES BUT WHEN YOU START BREAKING IT DOWN, YOU'RE ONLY GIVING THIS ONE FOR A MONTH , I'M TELLING YOU JUST MOVE ON TO NEXT THERAPY. YOU PROBABLY CAN ONLY USE ONE OF THESE, BOTH MAY BE POSSIBLE BUT THE PALLIATIVE BENEFITS I THINK BOTH ARE POSSIBLE. YOU QUICKLY SEE HOW IF YOU JUST JUMP FROM ONE TO ANOTHER YOU ACTUALLY START RUNNING OUT OF THERAPIES. HAS IMPLICATIONS FOR YOUR PATIENT'S LIFE SPAN. I THINK YOU WANT TO BE THOUGHT FUL HOW YOU DEPLOY THESE THERAPIES, AGAIN THIS IS WHERE I THINK TAKING ACCOUNT WHAT TREATMENT FAILURE IS WHICH IS RADIO GRAPHIC PROGRESSION NOT JUST RISING PSA YOU DON'T WANT TO COME OFF THESE THERAPIES WILLY-NILLY AND WASTE THESE OPPORTUNITIES FOR PATIENTS. THE ULTIMATE GOAL FOR MY PERSPECTIVE WHEN I TALK TO PATIENTS IS HOW CAN WE LINE ALL THESE THERAPIES UP SO YOU CAN BENEFIT FROM AS MANY AS POSSIBLE , MAXIMIZE YOUR QUALITY, LENGTH OF LIFE BUT ALSO YOUR QUALITY OF LIFE. SO IT'S NOT A FLOW CHART BUT HOPEFULLY PRESENTED RATIONAL WAY TO LOOK AT THIS, OTHER PEOPLE HAVE THEIR RATIONAL WAYS AS WELL BUT I THINK JUST GETS YOU STARTED DOWN THE PATH TO UNDERSTAND HOW WE DEAL WITH THIS DISEASE. THE SPECIAL ON OUR MENU SAME SPECIAL WE HAD LAST YEAR BECAUSE STILL HAS BREAK THROUGH STATUS. I MENTIONED IT HAS BREAK THROUGH STATUS WITH THE FDA. I MENTION THAT ABOUT 30% OF MEN HAVE EVIDENCE OF DNA DAMAGE RE PAIR MUTATIONS WHICH CAN BE TARGETED BY INHIBITORS THIS WAS DEMONSTRATED IN CLINICAL TRIAL BY A DOCTOR AND HIS GROUP OVER IN ENGLAND WHAT THEY DEMONSTRATED. SORRY. GOING THE WRONG DIRECTION. I'M SORRY. I MISSED COUPLE OF SLIDES IN HERE. WHAT THEY WERE ABLE TO DEMONSTRATE THAT PATIENTS WHO HAD THIS MUTATION BENEFITED GREATLY FROM PARP INHIBITION, THERE'S HIGH LIKELIHOOD WHEN I GIVE THIS TALK NEXT YEAR OR SHORTLY THEREAFTER WE'LL HAVE PHASE THREE DATA FOR THIS. SO, I ALREADY SHOWN THIS JUST GOING TO SKIP AHEAD HERE. TO NEWER DATA THAT'S OUT I MENTION, I'VE BEEN TALKING ABOUT CASTRATION RESISTANT PROSTATE CANCER UNTIL NOW. AGAIN THAT'S PATIENTS WHO IS TREATED WITH HORMONE SUPPRESSION NOW WE'RE TALKING ABOUT HOW DO WE TREAT PEOPLE WHO HAVE METASTATIC DISEASE THAT IS CASTRATION SENSITIVE. WHO ARE THESE REASONS. THESE ARE PATIENTS WHO EITHER WAKE INTO THEIR DOCTOR CAN'S OFFICE, DIDN'T KNOW THEY HAD PROSTATE CANCER UNFORTUNATELY HAD IT SPREAD THROUGHOUT THEIR BODY. IT'S A DIFFERENT POPULATION, DOES THAT MAKE SENSE? REMEMBER IF YOU HAVE NOT BEEN TREATED FOR PROSTATE CANCER THE OTHER PATIENT GROUP IS PATIENTS WHO HEY HAVE BEEN TREATED THREE OR FOUR YEARS AGO ARE NOT AN R ON ANY THERAPY HOPE IS THEY WERE CURED BUT THEY COME IN, PSA IS HIGHER THEY HAVE SYMPTOMS OR THEY DON'T. THEY LOOK HAVE METASTATIC DISEASE IN NORMAL TESTOSTERONE. EVERY OTHER ONE HAS BEEN IN PATIENTS WITH CASTRATE LEVELS OF TESS TOSS TORE REASON THEY HAVE GONE THROUGH FRONT LINE CASTRATION. IN THIS POPULATION, THERE WAS A STUDY THAT WAS DONE SHORTLY AFTER DOCETAXEL WAS APPROVED LOOKING AT COMBINING THE STANDARD THIS WOULD HAVE BEEN HORMONE SUPPRESSION WITH THE DOCETAXEL REGIMEN THAT I JUST DESCRIBED EVERY THREE WEEKS THAT WAS DEVELOPED FOR CASTRATION RESISTANT DISEASE AND THIS DATA CAME OUT IN 2015 THAT WAS PUBLISHED THEN, HAD SOME INKLING A YEAR OR TWO BEFORE. A PROFOUND AFFECT OVER A LONG TIMELINE THESE PATIENTS ARE GOING TO LIVE FOUR TO FIVE YEARS WITH METASTATIC DISEASE IN ALL THE THERAPIES THAT ARE AVAILABLE YOU SEE IF THEY GOT JUST SIX INFUSIONS OF CHEMO UP FRONT THEY HAD 13 MONTH IMPROVEMENT. THIS THEN BECAME STANDARD OF CARE FOR THIS POPULATION BEYOND JUST HORMONE SUPPRESSION ALONE. THAT IS EVIDENCE IF WE MOVE TREATMENT IN LATER CASTRATION RESISTANT DISEASE EARLIER, TO CASTRATION SENSITIVE DISEASE IT WORKED BETTER. THERE ARE SOME ASPECTS OF THIS THAT IS WORTH UNDERSTANDING WITHOUT GETTING INTO TOO MUCH DETAILS THEY DIVIDED THE GROUP INTO HIGH VOLUME AND LOW VOLUME. RELATIVELY ARBITRARY THERE'S SOME SUGGESTION THAT LOW VOLUME PATIENTS DID VERY WELL ON THEIR OWN WITH JUST ANDROGEN SUPPRESSION. I WOULD BE A LITTLE CAUTIOUS OVER INTERPRETING THAT, I THINK SOME OF THESE VOLUME MARKERS ARE KIND OF IMPERFECTLY APPLIED PROBABLY BROADER DISCUSSION WHEN THERE'S MORE TIME. LYMPH NODE DOESN'T FACTOR IN. PERSONALLY I THINK DOCETAXEL STILL MAY BE RELEVANT FOR PATIENTS WITH METASTATIC CASTRATION. THAT IS LOW VOLUME PATIENTS, I THINK IT'S WORTH NOTING TWO THINGS ONE IS THIS IS A MUCH SMALLER GROUP YOU SEE THIS IS ONLY COUPLE HUNDRED PATIENTS. I'M NOT SURE WE HAVE POWER TO DO THIS TO LOOK AT THIS COMPARISON. BUT ALSO THERE'S SOME OTHER NUANCES HERE THAT AT LEAST I HAVE SOME QUESTIONS ABOUT. I THINK THIS IS PART OF YOUR DISCUSSION WITH YOUR PATIENTS, ESPECIALLY IF THEY HAVE LOW VOLUME DISEASE ON WHETHER OR NOT THEY WOULD GET CHEMOTHERAPY IN THEIR NEWLY DIAL NOSED METASTATIC STATUS. TOLERABILITY OF SIX INFUSIONS OF CHEMOTHERAPY WAS ACTUALLY VERY GOOD. BECAUSE IT'S VERY LIMITED IN NUMBER OF THERAPIES. SIX INFUSIONS OVER 18 WEEKS. CAME OUT TO ROUGHLY 85-87% OF PATIENTS. I THINK THAT SPEAKS TO ITS TOLERABILITY AGAIN WHY I'M COMFORTABLE OFFERING IT TO PATIENCE. ABIRATERONE IS CYP 17 INHIBITOR HAS BEEN TESTED IN THIS POPULATION. AND WE HAD DATA FROM THAT LAST YEAR FROM TWO TRIALS I'LL SHARE WITH YOU ONE OF THEM. THIS IS PATIENTS WITH HIGH RISK METASTATIC DISEASE AGAIN CASTRATION SENSITIVE. CASTRATION SENSITIVE DISEASE VERY SIMILAR TO THE LAST STUDY ALTHOUGH THEIR DEFINITION OF WHO COULD COME ON WAS A LITTLE DIFFERENT. HIGH RISK WAS ANYONE WITH HIGH SCORE WITH PATHOLOGY SCORE MORE THAN THREE SITES OF DISEASE. AGAIN VERY ARBITRARY BUT BENEFITS WERE CLEAR. AS COMPARED TO PLACEBO YOU DID BETTER. THIS IS NOT -- WORTH NOTING IT'S ADT OR ANDROGEN RECEPTOR, NOT JUST A STRATA SEE BOW ARM. THE DIFFERENCE HERE THAT IS WORTH NOTING ALSO IS THAT YOU'RE ON ABIRATERONE UNTIL YOU PROGRESS. WHERE AS YOU GOT THE SIX INFUSION TO CHEMOTHERAPY THAT OTHER STUDY YOU WERE DONE. I THINK THAT INFLUENCES, TOO, SOME PEOPLE'S DECISIONS ON WHICH OF THESE THERAPIES TO USE. IT DOES MINE TO SOME DEGREE. GENERALLY WELL TOLERATED, YOU CAN SEE HOW THERE CAN BE EVENTUALLY PATIENTS WITH GRADE THREE OR FOUR ADVERSE EVENTS SOME CARDIAC ISSUES, SOME LIVER FUNCTION ISSUES, BUT GENERALLY PRETTY WELL TOLERATED. IT IS WORTH NOTING THIS, THOUGH. THIS IS I THINK OPEN QUESTION FOR BOTH THESE STUDIES. THIS WAS NOT A STUDY OF ABIRATERONE EARLY VERSUS ABIRATERONE LATE. IN OTHER WORDS, I'M SEEING PATIENTS GOT NEWLY DIAGNOSED, DOES THAT -- DEFAULT ASSUMPTION IS LIKE, WELL, JUST GIVE IT AS EARLY HATS YOU CAN IT'S GOING TO WORK BETTER. THAT'S NOT WHAT THIS STUDY WAS ABLE TO EYE VALUE WAIT. THIS STUDY WAS DONE BEFORE ABIRATERONE WAS LARGELY AVAILABLE AND APPROVED YOU SEE IF YOU BREAK IT DOWN ONLY 25% OF THE PATIENTS, I GUESS IT WAS 27, IN THIS STUDY WITH ABIRATERONE, THAT'S STUDY HERE. IN THIS STUDY ONLY 27% OF THESE PLACEBO PATIENTS WENT ON TO GET ABIRATERONE OR ENZALUTAMIDE. I TALKED ABOUT THE CROSS OVER AFFECT. THERE'S REALLY NOT -- IT'S NOT LIKE EVERYBODY GOT IT WHEN THEY WERE METASTATIC. THERE'S NOT MUCH OF A CROSS OVER AFFECT HERE SO THERE FOR I'D BE VERY CAUTIOUS TO SAY THAT WE SHOULD JUST GIVE IT EARLIER TO EVERYBODY AND THIS PROVES THAT IT WORKS EARLIER. DOES THAT MAKE SENSE? I'M SEEING SOME NODS HERE, THAT'S GOOD. I THINK WE JUST HAVE TO BE CAUTIOUS HOW WE INTERPRET THAT. I STILL THINK IT'S OPEN QUESTION OF WHETHER OR NOT YOU BENEFIT MORE AT THAT POINT OR TO GET IT LATER, I THAT ALSO FACTORS IN WHETHER YOU CHOOSE DOCETAXEL OR ABIRATERONE. THERE'S NO HEAD TO HEAD DATA WHICH OF THESE IS BETTER, THERE IS SOME INDIRECT EVIDENCE FROM ENGLAND THAT THEY MIGHT BE EQUIVALENT FROM STUDIES DONE THERE. DEFINITELY NEED ADT WITH BOTH OPTIONS THAT'S WORTH NOTING. I DISCUSSED THIS WITH PATIENTS, MY BIAS FOR VARIOUS REASONS USE IT BECAUSE YOU YOU GET YOUR SIX INFUSIONS AND YOU'RE DONE FOR AT LEAST A LITTLE WHILE WHERE AS. >>Abernethy: RAT REASON YOU'RE ON THAT EVERY DAY UNTIL IT STOPS WORKING. I THINK ALSO YOU PROBABLY CAN COME BACK TO THE DOCETAXEL HE LATER ON DOWN THE ROAD IF YOU PROGRESS A YEAR AFTERWARDS OR EVEN SIX MONTHS. THAT'S AN OPEN RESEARCH QUESTION WE DON'T REALLY KNOW HOW GETTING THE DOCETAXEL UP FRONT OR EVEN ABIRATERONE CHANGES THIS. THESE ARE JUST SOME QUESTIONS THAT ARE UNANSWERED AND AGAIN PART OF OUR DISCUSSION WITH THE PATIENTS. IN THE LAST COUPLE OF MINUTES I'LL SHARE WITH YOU THE NEWEST DATA WHAT WE CALL M0 PROSTATE CANCER. SHIFTING BACK TO CASTRATION RESISTANT CANCER UNLIKE THE FIRST TWO GROUPS THAT I TALKED ABOUT THESE PATIENTS ARE NOT METASTATIC UNCONVENTIONAL. THESE ARE PATIENTS WHO HAVE RISING PSA, THEY ARE CASTRATE BUT NO EVIDENCE OF DISEASE ON SCAN. CASTRATION RESISTANT METASTATIC DISEASE MEANS, CASTRATE LEVELS OF TESTOSTERONE, PROGRESSION, CASTRATION SENSITIVE MEANS YOUR TESTOSTERONE IS NORMAL. IN THESE PATIENTS, IT'S SUPPRESSED BUT PSA RISING THAT THEIR CANCER IS MOVING. THESE PATIENTS MAY HAVE FIVE TO TEN YEARS -- PROBABLY NOT TEN BUT FIVE YEARS OR MORE TO LIVE BASED ON SOME LITERATURE PREVIOUSLY WE HAD USED VARIOUS STRATEGIES ON HOW TO TREAT THESE PATIENTS, TWO PHASE THREE TRIALS THAT WERE PRESENTED EARLIER THIS YEAR THAT DEMONSTRATED THAT AGENTS COMPARED TO PLACEBO, DEMONSTRATED OVERALL SURVIVAL ADVANTAGE, AGAIN IN THESE PATIENTS PREVIOUSLY SOME PEOPLE USED OLDER VERSIONS OF THE AGENTS I'VE TALKED TO YOU ABOUT, OLDER ADD CROW GENERAL RECEPTOR ORS CYP 17 INHIBITORS. ENZALUTAMIDE, I WON'T GET INTO -- IT WAS DEVELOPED BY SAME CREATORS SO HERE IS STUDY AGAIN IN THIS M0 POPULATION THERE WAS NO FDA APPROVED THERAPY IN ADDITION TO ADT THEY JUST GOT PLACEBO. WHAT THEY WERE ABLE TO GET AGREEMENT ON FROM THE FDA WHICH IS A BIG DEAL FOR FIRST DIME THE FDA AGREED TO SOMETHING THAT WASN'T SURVIVAL IN A PROSTATE CANCER STUDY. THEY AGREED TO METASTASIS FREE. ABLE TO DEMONSTRATE IN THIS IT'S WORTH NOTING WHO THESE PATIENTS ARE. THERE ARE SEVEN OR EIGHT YEARS REMOVED, THEY'RE MUCH OLDER. IN THE MET STAT TRICKS CASTRATION RESISTANT DISEASE ARE OFTEN IN THEIR 60s THESE GENTLEMEN IN THEIR 70s. WANT TO FACTOR IN THEIR LONG EVENT WHEN YOU TALK ABOUT THESE AGENTS AND THEIR USE. PATIENTS PATIENTS HAD GOTTEN OLDER VERSIONS OF THESE AGENTS ABOUT THREE QUARTERS OF THE TIME HERE IS THE EVIDENCE THAT IT APPROVED METASTASIS. AND BASICALLY LED TO FDA APPROVAL BASED ON THIS. THEY ALSO EVALUATED PATIENTS GAVE THEM ABIRATERONE AFTER THIS YOU KNOW, DO THEY STILL DO OKAY WITH AB ROT REASON, SURVIVAL OR PROGRESSION FREE SURVIVAL CURVE BASED ON PREVIOUS THERAPY WITH PLACEBO SUBTLED THAT YOU ARE NOT SEEING A CROSS OVER AFFECT WHERE THESE CURVES ARE COMING TOGETHER I STILL THINK THERE'S PROBABLY OVERLAPPING MECHANISMS RESISTANCE. THIS IS ENCOURAGING DATA ALTHOUGH PROBABLY NOT PERFECT BUT CERTAINLY BE WORTH FOLLOWING FOR A LITTLE BIT LONGER HERE. IT WAS APPROVED FOR THIS YOU HAVE TO LOOK A THIS GUY GOING TO LIVE LONG ENOUGH TO BENEFIT FROM THIS TREATMENT WITH ALL THESE SIDE EFFECTS WITH THE OTHER CO MORBIDITIES. THEY SAID WE CAN DO SIMILAR STUDY, I DON'T KNOW FOR SURE BUT THEY CERTAINLY DID VERY SIMILAR PROP PEW LAKES, THIS M0 GROUP USING THESE PATIENTS, PSA GREATER THAN TWO AND DOUBLING TIME OF TEN MONTHS. VERY SIMILAR POPULATION AGAIN MEDIAN AGE IS 74. THERE WERE AGAIN SIDE EFFECTS THAT WERE SEEN, IN THIS STUDY THAT THEY ARE WORTH NOTING BUT THEY ALSO GOT THE SAME AGREEMENT FROM THE FDA TO HAVE METASTASIS FREE SURVIVAL AS ENDPOINT. NOT SURPRISINGLY, THESE AGENTS ARE REALLY GOOD. NOT SURPRISINGLY COMPARED TO PLACEBO THEY DID VERY WELL YOU SEE HUGE HAZARD RATIOS THIS ALSO HAS BEEN ADDED TO THE LABEL FOR ENZALUTAMIDE NOW THEY CAN BE USED EARLIER. THEY'RE FOLLOWING THESE PATIENTS LONG TERM, AGAIN WE DON'T KNOW WHETHER THEY ARE GETTING THESE TREATMENTS EARLY IS BENEFICIAL. OVERALL SURVIVAL ANALYSIS WILL BE INTERESTING LONG TERM. SO, IT IS WORTH NOTING, IT'S A WEIRD THING, THAT THERE WAS A HIGHER DEATH RATE WITHIN BASICALLY THREE MONTHS OR FOUR MONTHS OF COMPLETING THE STUDY. SOME OF THAT MAY COME FROM THE FACT THAT IF YOU'RE PROGRESSING OVER THREE YEARS AS OPPOSED TO ONE YEAR YOU FOLLOW PATIENTS LONGER YOU CAN HAVE MORE ADVERSE EVENTS OR DEATHS UNFORTUNATE IN OLDER POPULATION. BUT THIS IS AN OPEN QUESTION WORTH FOLLOWING. AGAIN JUST PAY ATTENTION TO YOUR PATIENTS. I'LL JUST SKIP OVER THIS, MY THOUGHTS, BECAUSE I THINK YOU'VE BEEN HEARING MY THOUGHTS FOR AN HOUR NOW. JUST TO GIVE YOU A HINT OF WHERE THE FIELD IS GOING, WE'RE STILL AS I SAID NUMBER OF TIMES DON'T KNOW THE BEST SEQUENCE OF THERAPY. WE DON'T HAVE THE BEST BIO MARKERS YET WE'RE STILL TRYING TO IDENTIFY THAT. WHETHER COMBINATIONS ARE BETTER THAN INDIVIDUAL THERAPIES. IMAGEING, I DIDN'T GET INTO THAT AT ALL BUT IMAGEING IS BECOMING MORE SENSITIVE WITH NEW TECHNOLOGIES AND THAT WILL CHANGE HOW WE SEE PROSTATE CANCER SO WE'LL DIAGNOSE IT PERHAPS METASTATIC EARLIER THAT WILL CHANGE PERHAPS SOME OF OUR STRATEGIES. THERE'S A VERY LARGE EMPHASIS IN DETECTING OLIGO METASTATIC DISEASE WHICH IS PATIENTS WITH A FEW LESIONS ON P.E.T. IMAGEING TRY TO GO AFTER CUREING THOSE PATIENTS. I THINK RIGHT NOW IT'S STILL AN OPEN QUESTION. I WENT THROUGH A LOT OF THIS TALK DIDN'T TALK ABOUT HOTTEST FIELD IN ONCOLOGY WHICH IS AMINO THERAPY. DATA I HAD WAS TEN YEARS AGO THAT'S PART OF WHAT I DO HERE WITH MY COLLEAGUES IN THE FIELD HERE AND ELSEWHERE. WE'RE TRYING TO DEVELOP ROLE FOR IMMUNOTHERAPY AND PROSTATE CANCER WHY THAT IS TOUGH NUT TO CRACK IS KIND OF WHOLE LECTURE IN AND OF ITSELF. MAYBE THAT'S FOR ANOTHER DAY. I THANK YOU EVERY TON FOR YOUR ATTENTION I KNOW THERE'S HALT ANOTHER LECTURER, I'LL CEDE THE FLOOR, I'LL JUST STEP OUTSIDE FOR A SECOND FOR ANY QUESTIONS. [ Applause ] THE QUESTION WAS, ARE THERE ANY BIOMARKER TESTS OR GENTLEMAN KNELT PARTICULAR TESTS WE CAN USE. I THINK THAT'S WHERE THE DNA DAMAGE REMAYOR MUTATIONS ARE COMING IN TO PLAY. AND SO NOW THAT WE KNOW THAT THIRD OF PROSTATE CANCER PARENTS HAVE DNA DAMAGE REPAIR MUTATIONS AND 12-15% HAVE GERMLINE MUTATIONS THAT IS GOING TO BE AN INDICATOR FOR THERAPY. I WOULD TEST FOR THAT PROBABLY IN THE METASTATIC SETTING. PATIENTS STILL SEEM TO DO OKAY. BUT WHEN PATIENTS ARE STARTING TO PROGRESS PROBABLY WORTH DOING GENETIC TESTING AT THAT TIME. SOME OTHER BIOMARKERS PEOPLE ARE LOOKING FOR CIRCULATING MARKERS OF AR7. THINGS LIKE THAT. THERE ARE A LOT OF OTHER THINGS BEING EXPLORED. CIRCULATING TUMOR CELLS ARE ALSO BEEN ANOTHER CIRCULATING BIO MARKER THAT HAVE BEEN OF INTEREST HAVE BEEN DEVELOPED IN CANYON WITH SOME OF THESE THERAPIES. [ INAUDIBLE ] THE DISTINCTION WAS BASICALLY FOUR LESIONS. BASICALLY FOUR LESIONS, AT LEAST ONE WHICH HAD TO BE OUTSIDE THE PELVIS OR SPINE. BUT IT'S A VERY ARBITRARY DECISION THAT THEY MADE. I THINK YOU CAN SEE WHERE PATIENT WOULD HAVE TON OF DISEASE IN THE SPINE AND SOMEHOW IT WOULD STILL COUNT AS LOW VOLUME BECAUSE THEY DIDN'T HAVE ANYTHING OUTSIDE THE SPINE. ARBITRARY DECISION BUT WORTH DISCUSSING IN THAT CONTEXT OF THAT DATA. THANK YOU. THE TRACO NEXT WEEK WILL BE ON MONDAY. AND I SENT E-MAILS ABOUT THE CORE FACILITIES SO YOU CAN VISIT THE GENOMICS CORE, PATHOLOGY CORE OR THE SMALL MOLECULE CORE THEN YOU CAN VISIT TUMOR BOARDS, NEUROLOGIC ONCOLOGY BRANCH AND MEDICAL ONCOLOGY BRANCH. IF YOU ARE INTERESTED YOU HAVE TO TIM OUT THE SHEET AND RETURN IT TO ME BY THE END OF THE MONTH THEN IN OCTOBER WE'LL START DOING THE CORE VISITS. OUR NEXT SPEAKER, HE GOT HIS MD DEGREE FROM SHANGHAI MEDICAL UNIVERSITY. HE THEN CAME TOLT U.S. AND GOT A PhD FROM NEW YORK UNIVERSITY. HE WAS A RESEARCH ASSISTANT PROFESSOR AT NEW YORK UNIVERSITY FOR SEVERAL YEARS AND COMPLETED INTERNAL MEDICINE RESIDENCY IN BROOKLYN. HE CAME TO NICK IN 2013 -- NIH, HE'S ASSISTANT CLINICAL INVESTIGATOR IN SURGERY BRANCH. HE'S INVESTIGATING NOVEL EPI GENETIC THERAPIES FOR SMALL CELL LUNG CANCER. SO THE TITLE OF HIS TALK IS >> HELLO, EVERYONE. IT'S -- I'M VERY HAPPY TO COME BACK HERE TO TALK ABOUT A SMALL CELL LUNG CANNER AGAIN. THANK YOU SO MUCH FOR THE NICE INTRODUCTIONS. THIS IS OUTLINE OF TODAY'S TALK. OUR FIRST GIVE YOU INTRODUCTION ABOUT SMALL CELL LUNG CANCER HOW WE TREAT A SMALL CELL LUNG CANCER IN CLINICS ALSO WHAT KIND OF CHALLENGE WE HAVE FOR THE SMALL CELL LUNG CANCER. THEN I'LL TALK ABOUT UNIQUE FEATURE OF THE SMALL CELL LUNG CANCER ALSO GIVE YOU TWO EXAMPLES ABOUT THE DRUG COLORADO FOR SMALL CELL LUNG CANCER FINALLY I'LL TOUCH A LITTLE BIT ABOUT EXTRA -- CARCINOMA. LET'S DIVE IN. ACTUALLY THE SMALL CELL LUNG CANCER GOT ITS NAME BECAUSE MORPHOLOGY OF THE CELLS LOOK PRETTY SMALL COMPARED TO THE OTHER CANCER YELLS IN THE LUNG. JUST GIVE YOU A FEELING HOW SMALL THE SMALL CELL LUNG CANCER CELLS ARE ARE, I HAVE -- OF THE SMALL CELL TUMOR SPECIMEN HERE. THE ARROWS POINT OUT IS THE CELLS OF SMALL CELL LUNG CANCER AND WHETHER THE ARROW POINT OUT IS THAT LYMPHOCYTES IN THE BLOOD VESSEL, YOU CAN SEE THAT SMALL CELL LUNG CANCER CELLS ARE JUST A LITTLE BIT BIGGER THAN THE LYMPHOCYTES IN THE BLOOD VESSEL. THEN WE COMPARE TO THE STROMA CELLS IN THIS TUMOR YOU CAN SEE THAT THE TUMOR CELLS IS MUCH SMALLER. THAT'S HOW SMALL CELL LUNG CANCER GOT ITS NAME. WE CANNOT ADJUST, MAKE DIAGNOSIS OF SMALL CELL LUNG CANCER BASED ON ITS TUMOR SIZE. WHEN PATHOLOGY SEES THESE, THEY WERE ACTUALLY THROUGH IMMUNO HISTOCHEMICAL SCANNING. IT'S KNOWN THAT SMALL CELL LUNG CANCER HAS NEUROENDOCRIN FUTURE, EXPRESS THE NEUROENDOCRINE MARKERS. SUCH AS -- AND -- THE PATHOLOGIES CAN STAND FOR THOSE MARKERS IF IT'S POSITIVE IT WILL SUPPORT DIAGNOSIS OF THE SMALL CELL LUNG CANCER. SMALL CELL LUNG CANCER IS ONE TYPE OF LUNG CANCER. SO CONVENTIONALLY, LUNG CANCER IS ACTUALLY DIVIDED INTO TWO GROUPS. SMALL CELL LUNG CANCER AND OTHER GROUP IS NON-SMALL CELL LUNG CANCER. NON-SMALL CELL LUNG CANCER ACTUALLY INCLUDE SEVERAL HISTOLOGY TYPES SUCH AS CARCINOMA, ALSO LARGE CELL CARCINOMA. YOU MAY WONDER WHY WE MAKE SUCH A KIND OF THE NOMENCLATURE AS SMALL CELL LUNG CANCER IN THE NON-SMALL CELL LUNG CANCER. BECAUSE IT HAS VERY DIFFERENT -- COMPARED TO THE NON-CELL SMALL CELL LUNG CANCER. WHAT IS DIFFERENT IS THAT SMALL CELL LUNG CANCER IS MUCH MORE AGGRESSIVE AND ALSO PATIENT OFTEN DEVELOP METASTASES VERY EARLY. THE SURVIVAL OF THE PATIENT WHO HAS NON--- WITH A SMALL CELL LUNG CANCER IS MUCH SHORTER THAN PATIENTS WITH NON-SMALL CELL LUNG CANCER. THAT'S WHY TO HAVE THIS DIFFERENT NOMENCLATURE. BECAUSE SMALL CELL LUNG CANCER IS VERY AGGRESSIVE AND METASTASIZE VERY EARLY, SURGELY DO NOT PLAY A MAJOR ROLE IN THE TREATMENT OF THE SMALL CELL LUNG CANCER. SO IN CONTRAST SURGERY IS MAJOR TREATMENT MODALITY FOR NON- METASTATIC, NON-SMALL CELL LUNG CANCER. BESIDES, SMALL CELL LUNG CANCER ALSO IS VERY UNIQUE THAT IT'S ASSOCIATED WITH THE ENDOCRIN. THE SMALL CELL LUNG CANCER IS ABLE TO EXCRETE THE NEURO ENDOCRIN TRANSMITTERS. SUCH AS ACTH. SO IT CAN LEAD TO THE OVER PRODUCTION OF CORTICOSTEROIDS IN THE ADRENAL GLANDS. THAT CAN LEAD TO CURBING SYNDROME. ANOTHER SYNDROME THAT IS 'SAYS IS CALLED A LAMB BERT-EATON MICE TEEN IN THIS CASE SYNDROME. PATIENT HAS DIFFICULTY OF THE EMITTING THE ACETOCHOLINE IN THE MEMBRANE. PATIENT STARTED WITH THE IN ABILITY TO MOVE THE EXTREMITY AND OVER EXERCISE PATIENT ACTUALLY CAN MOVE BETTER SO THAT IS BECAUSE OVER TIME THEN EXERCISE THE CAPABILITY OF ACETO CHOLINE RELEASE IS IMPROVED SMALL CELL LUNG CANCER IS DIFFICULT CANCER TO TREAT. IN 2014, NIH DESIGNATED AS ONE TO HAVE RECALCITRANT CANCERS. THE OTHER IS PANCREATIC CANCER. IT IS ONLY ABOUT A 7%. MEANTIME EVERY YEAR IN THE U.S. THERE'S ABOUT A 30,000 CHANCE DUE TO THE SMALL CELL LUNG CANCER. YOU ALSO HAVE QUITE A HUGE IMPACT ON THE AMERICAN'S HEALTH SO THAT'S WHY IT'S DESIGNATED AS RECALCITRANT CANCER. ACTUALLY NIH IDENTIFIED FOUR MAJOR OBSTACLES TO PROGRESS IN 2014. THE FIRST OBSTACLE IS THAT THE PATIENT -- ACTUALLY THE SMOKERS ARE AT CONTINUOUS RISK OF DEVELOPING THE SMALL CELL LUNG CANCER EVEN DECADES AFTER MAKE IT QUITE DIFFICULT TO FOLLOW THOSE HIGH RISK SUBJECTS AND BECAUSE EVEN TEN YEARS OR 20 YEARS AFTER SMOKING CESSATION THIS MAY DEVELOP SMALL CELL LUNG CANCER. SECOND, THE OBSTACLE WE MENTIONED ABOUT MOST PATIENT ACTUALLY HAVE METASTATIC DISEASE AT THE TIME OF THE DIAGNOSIS. THE THIRD OBSTACLE IS THAT SMALL CELL LUNG CANCER IS PRETTY SENSITIVE TO THE RADIATION AND ALSO CHEMOTHERAPY. HOWEVER THEY DEVELOP A RESISTANCE VERY QUICKLY. SO THAT WHEN PATIENT DEVELOP RESISTANCE THEN THEY'RE NOT TOO MANY TREATMENT OPTIONS FOR THEM. FOURTH OBSTACLE IS THAT BECAUSE SMALL CELL LUNG CANCER IS NOT DISEASE THAT CAN BE TREATED WITH SURGERY SO WE ACTUALLY DON'T HAVE MANY SPECIMENS FOR RESEARCH ACTUALLY SINCE 2014 THERE HAS BEEN A LOT OF COLLABORATION IN THE SCIENTIFIC COMMUNITY OVER SHARING THE DATA SO THIS ISSUE IS GETTING GRADUALLY RESOLVED. IF YOU ARE RESEARCHER WHO IS INTERESTING STUDYING ABOUT SMALL CELL LUNG CANCER THEN YOU WANT TO TRY TO TACKLE ALL THESE OBSTACLES. FOR EXAMPLE, FOR THE PATIENT WHO CONTINUE TO BE AT A RISK OF DEVELOPING SMALL CELL LUNG CANCER YOU WANT TO IDENTIFY SOME MARKERS MAKE EARLY DIAGNOSIS OF THE SMALL CELL LUNG CANCER OR PREDICT THE RISK. FOR PATIENT WHO -- TO ADDRESS THE QUESTION OF RESISTANCE TO THE THERAPY THEN YOU WANT TO DEVELOP NORMAL THERAPY OR COMBINATORY THERAPY THAT CAN DELAY THE DEVELOPMENT OF THE RESISTANCE. THE STAGING OF THE SMALL CELL LUNG CANCER IS RELATIVELY SIMPLE WE ONLY HAVE TWO STAGES OF SPAT CELL LUNG CANCER. FIRST STAGE IS LIMITED DISEASE AND SECOND ONE IS EXTENSIVE DISEASE. THE DISTINCTION BETWEEN THESE TWO IS QUITE SIMPLE. IF ALL OF DISEASE THAT YOU CAN DETECT ON IMAGEING CAN BE INCORPORATED INTO ONE RADIATION PORT THEN WE CALL IT A LIMITED STAGE. THEN THE PATIENT CAN BE TREATED WITH BOTH RADIATION AND ALSO SYSTEMIC CHEMOTHERAPY F. A PATIENT HAS EXTENSIVE DISEASE MEANING THAT A PATIENT HAS PRETTY WIDESPREAD DISEASE YOU CANNOT COVER ALL THE DISEASE WITH ONE RADIATION PORT, IN THAT CASE PATIENT CAN ONLY BE TREATED WITH CHEMOTHERAPY. APPARENTLY PATIENT HAS MORE ADVANCE DISEASE AND PROGNOSIS IS ALSO WORSE IN THE PATIENT WITH EXTENSIVE DISEASE. SO, IN AVERAGE SURVIVAL OF THE PATIENT WITH SMALL CELL LUNG CANCER OF DIAGNOSIS IS AROUND A YEAR. HOW DO WE TREAT A SMALL CELL LUNG CANCER, SYSTEMIC CHEMOTHERAPY IS MAIN TREATMENT MODALITY FOR THIS DISEASE. IT ACTUALLY WAS LEARNED QUITE EARLY IN 1970s THAT THE SINGLE AGENT IS NOT AS EFFECTIVE AS COMBINATORY TREATMENT. SO ACTUALLY HELPING RESEARCH OF TESTING THE TWO DRUG COMBINATION VERSUS THREE DRUG COMBINATION. IT WAS FOUND THREE DRUG COMBINATION WAS MORE EFFECTIVE HOWEVER IT WAS ALSO MORE TAXIS TEE. BALANCE THIS OUT LIKE TWO DRUG COMBINATION IS MORE EFFECTIVE. OVER THE PAST 30-ISH YEARS THE -- DRUG COMBINATION FIRST LINE THERAPY. SO FAR WE HAVEN'T IDENTIFIED A MORE EFFECTIVE FIRST LINE THERAPY, THIS IS NOT BECAUSE BECAUSE OF LACK OF TRYING, WE FOUND THE ADDITION OF THIRD AGENT IS EITHER NOT AS EFFECTIVE OR A LITTLE BIT TOO TOXIC TO REL LY JUSTIFY THE BENEFIT IT CAN BRING. IN THE SECOND LINE THERAPY FOR PATIENT WHO HAS PROGRESSED AFTER THE FIRST LINE CHEMOTHERAPY IS T OPOTECA. EFFECTIVE IN THE SECOND LINE SETTING. HOWEVER IN THE U.S. TOE POE TEAK CAN'T IS ONLY ONE THAT'S APPROVED BY THE FDA. TO TREAT A PATIENT WHO HAS PROGRESSED AT THE FIRST LINE OF CHEMOTHERAPY PLUS ANOTHER LINE OF THERAPY. THIS IS IN THE THIRD LINE SETTING THAT PATIENT CAN BE TREATED WITH IMMUNE THERAPY IN THIS CASE CHECKPOINT INHIBITOR. I MENTION EARLY THAT SMALL CELL LUNG CANCER TENDS TO METASTASIZE VERY EASILY. SO WHEN PATIENT TREATED WITH THE SYSTEMIC CHEMOTHERAPY AND AFTER CERTAIN MONTHS THEN PATIENT HAD RECURRENCE OF DISEASE. AT THAT TIME PATIENT OFTEN DEVELOP METASTASES IN THE BRAIN. THIS IS NOT SURPRISING BECAUSE THE BRAIN IS A CENTURY SITE MEAN ING THAT THE CHEMO DRUG DOES NOT PENETRATE THROUGH BLOOD- BRAIN BARRIER VERY WELL. IN THE BRAIN YOU HAVE A VERY LOW CHEMO DRUG CONCENTRATION. SO THAT'S REASON WHY IF THERE IS A METASTASES IN THE BRAIN, SYSTEMIC CHEMO MAY NOT BE ABLE TO TOUCH THE CANCER CELL IN THE BRAIN. ACTUALLY IN THE 1980s, THERE HAVE BEEN SOME ATTEMPTS TO TREAT PATIENTS WHO HAD A GOOD RESPONSE TO THE SYSTEMIC CHEMO WITH THE RADIATION THERAPY OVER THE BRAIN THE IDEA IS THAT, IF WE CAN GIVE THE RADIATION TO ALSO TO KILL THE TUMOR CELLS IN THE BRAIN, MAYBE THOSE PATIENTS WON'T HAVE RECURRENCE WITH THE BRAIN METASTASES THAT EASILY. IN THE 1990s, ACTUALLY ANALYSIS SHOW THAT PROPHYLACTIC RADIATION, WHICH PROPHYLACTIC BRAIN RADIATION, ACTUALLY HELP TO IMPROVE THE SURVIVAL OF THE PATIENTS WHO HAD COMPETE RESPONSE FOUND INITIAL CHEMOTHERAPY. THEN TRIAL WAS INITIATED. IN THIS TRIAL, THEY ACTUALLY SELECT PATIENT WHO HAD A RESPONSE FOUND SYSTEMIC CHEMO. BUT AT THAT TIME IT WAS NOT A POPULAR TO DO THE BRAIN IMAGEING THE PATIENT WHO ON THE TRIAL WAS UNKNOWN TO HAVE BRAIN MASS OR NOT. OVER SEVERAL YEARS, RESULT CAME OUT SHOWING THAT PROPHYLACTIC RADIATION ACTUALLY HELPED TO DECREASE THE OCCURRENCE OF BRAIN METASTASES. MEANTIME ALSO HELPED TO IMPROVE PROGRESSION FREE SURVIVAL, ALSO IN THE PATIENTS WHO HAD RESPONSE TO THE INITIAL CHEMOTHERAPY. AS DATA WAS SHOWN ON THE RIGHT SIDE, YOU CAN SEE THAT THE SURVIVAL CURVE OF THE PATIENT WHO RECEIVED PROPHYLACTIC RADIATION DOES MUCH BETTER THAN THE PATIENT WHO RECEIVE THE PCI INITIALLY. HOWEVER, AS I MENTIONED THAT THE PATIENT WHO WERE ON THESE TRIALS DID NOT HAVE A MAIN IMAGEING BEFORE IRRADIATION. NOW WE KNOW -- ACTUALLY IMAGEING IS VERY COMMON. HOW ABOUT THE PATIENT WHO WAS NOT FOUND TO HAVE BRAIN METASTASIS, WHETHER THOSE PATIENTS SHOULD HAVE RECEIVED RADIATION OR NOT. THE REASON TO ASK THAT QUESTION IS BRAIN RADIATION IS NOT SOMETHING THAT DENY BECAUSE IN PATIENT ACTUALLY AFTER RADIATION CAN FEEL VERY FATIGUED AND OVER LONG TIME PATIENT ALSO BE DEVELOP MEMORY ISSUES. CANNOT FIND THE RIGHT WORDS AND SO ON. IT'S ACTUALLY EFFECTIVE PATIENTS COGNITIVE CAPABILITY. IF IT'S NOT NECESSARY, WE REALLY TRY TO AVOID THIS THERAPY. TO ADDRESS THAT QUESTION, ACTUALLY, THIS IS A JAPANESE GROUP DID THIS TRIAL TO SELECT A PATIENT WHO HAD MAGNETIC RESONANCE IMAGEING OF THE BRAIN. AND WHO NOT FOUND TO HAVE BRAIN METASTASIS. RANDOMIZE INTO THE PROPHYLACTIC RADIATION VERSUS NO RADIATION. ACTUALLY FOUND QUITE A DIFFERENT RESULT. SO UP HERE IT SHOWS THE SURVIVAL OF THE PATIENT. RIGHT CURVE REPRESENT PATIENT WHO RECEIVED THE PROPHYLACTIC RADIATION. YOU CAN SEE THE PATIENT WHO RECEIVED RADIATION ACTUALLY DID A LITTLE BIT WORSE THAN PATIENT WHO DID NOT RECEIVE RADIATION. ALTHOUGH DIFFERENCE IS NOT A STATISTICALLY SIGNIFICANT, AT LEAST THERE'S NO CLEAR BENEFIT. IN THE LOWER PART IT SHOWS THAT THE PATIENT WHO RECEIVED RADIATION DOES HAVE LESS CHANCE TO DEVELOP A BRAIN METASTASES COMPARED TO THE PATIENT WHO DO NOT RECEIVE RADIATION. BUT THIS IS JUST POINT OUT THAT -- WE ACTUALLY ARE CAPABLE OF STRATIFIED PATIENTS BASED ON THE RISK. SO THAT -- IT WILL BE POSSIBLE TO PROVIDE MORE PROCEED SIGHS THERAPY SO THAT YOU ONLY SELECT A PATIENT WHO WILL BENEFIT FROM THE TREATMENT THEN GIVE THE TREATMENT SO THAT YOU AVOID UN NECESSARY HARM TO THE PATIENT WHO MAY ACTUALLY MAY NOT BENEFIT FROM THE TREATMENT. NOW I'M GOING TO SWITCH GEAR AND TALK ABOUT UNIQUE GENETIC FEATURES OF THE SMALL CELL LUNG CANCER. WAS VERY EARLY THAT SMALL CELL LUNG CANCER HAS PRETTY SIGNIFICANT ABNORMALITY. IT WAS FOUND THAT SMALL CELL LUNG CANCER ALSO HAS DELETION OF THE CHROMOSOME 3P21. WHAT IS SHOWN HERE ON THE LEFT SIDE IS CHROMOSOME 3 OF ESTABLISHED BY DIFFERENT PATIENTS WITH SMALL CELL LUNG CANCER. AS YOU CAN SEE THERE'S SOME DIFFERENCE IN THE LANES. THAT SUGGEST THE CHROMOSOME. WHAT IS COMMON ABOUT ALL THESE CELL LINES IS THAT THEY ALL HAVE DELETION OF CHROMOSOME REGION 3P 21. THAT IS QUITE INTERESTING. IN THAT THE CHROMOSOME REGION ACTUALLY CLOSE TO 100 GENES. SO TO THIS DATE WE STILL HAVEN'T FIGURED OUT IF WHAT GENE IS ACTUALLY CRITICAL FOR THE DEVELOPMENT OF THE SMALL CELL LUNG CANCER IN THAT REGION. COULD THIS BE USED TO MAKE A DIAGNOSIS OF SMALL CELL LUNG CANCER BUT THE ANSWER IS, NO, BECAUSE THIS IS NOW SOMETHING THAT'S VERY SPECIFIC TO THE SMALL CELL LUNG CANCER. ALSO BE FOUND IN THE EPITHELIUM INJURED BY THE SMOKE, TOBACCO SMOKE. WE CANNOT REALLY USE THESE TO MAKE THAT -- TO MAKE EARLY DIAGNOSIS OF THE SMALL CELL LUNG CANCER BUT THIS IS JUST A VERY INTERESTING FINDING. BESIDES CHROMOSOME 3B21 DELETION , THERE'S OTHER REGIONS SUCH AS CHROMOSOME 13 AND CHROMOSOME 17P DELETED IN THE SMALL CELL LUNG CANCER. SO ACTUALLY THIS IS BACK IN 1980 s, SO THAT'S ACTUALLY ONE OF THE NIH RESEARCHERS, DOCTOR KAY HE ACTUALLY HAD IDEA THAT BECAUSE THE RBG IS LOCATED IN THE CHROMOSOMAL 13Q SO HE ACTUALLY CHECKED TO SEE WHETHER THE RB GENE IS COMMONLY DELETED IN THE SMALL WELL LUNG CANCER. HERE IS DATA OF THE NORTHERN BLOCK WHICH IS A WAY TO DETECT EXPRESSION OF A GENE. NOW WE ALWAYS USE THE QUANTITATIVE RTPCR TO CHECK THE EXPRESSION. THAT'S BACK IN THE 1980s WHAT HE FOUND WAS THAT COMPARED TO THE NOW SMALL CELL LUNG CANCER AS SHOWN HERE, THE SMALL CELL LUNG CANCER OFTEN HAVE NO SIGNAL OF THE RB, JUST DELETION OF THE RB. THIS WAS ALSO FOUND WHICH IS A TYPE OF NEUROENDOCRIN TUMOR. RELATIVELY LOW GRADE. THEN EXPANDED HIS ANALYSIS INCLUDED MORE SMALL CELL LUNG CANCER CELL LINES. AND HE FOUND THAT MAJORITY OF THE SMALL CELL LUNG CANCER HAVE LOTS OF RB. IN THE MEANTIME, JOHN, WHO WAS ALSO AT NIH AT THAT TIME ASKED QUESTION WHETHER P53 IS AFFECTED WE KNOW THAT P53 IS LOCATED IN THE CHROMOSOME 17P. ACTUALLY DID ANALYSIS FOUND P53 WAS DELETED OR MUTATED IN THE SMALL CELL LUNG CANCER. YOU CAN SEE THAT, SMALL MUTATION , SOME MAY HAVE DELETION THAT LEADS TO THE NORMAL SIZE OF THE MRA. THERE'S ALSO SOME SMALL CELL LUNG CANCER CELL LINE WHICH WAS STARTED NOT TO HAVE ANY DETECT ABLE ABNORMALITY NOW A DEEPER SEQUENCING AND THESE CELL LINES OFTEN FOUND TO HAVE MUTATION IN P53 AS WELL. THESE STUDIES ESTABLISH A CORRELATION BETWEEN THE MUTATION OR DELETION OF RB AND P53 WITH SMALL CELL LUNG CANCER. IT DOESN'T ESTABLISH THE CAUSATION RELATIONSHIP. WHETHER THE DELETION OR MUTATION OF RB AND P53 LEADS TO THE SMALL CELL LUNG CANCER. THIS IS QUESTIONS ANSWERED BY USING TRANSGENIC ANIMAL MODELS. IN THIS STUDY, DOCTOR BURR AND ACTUALLY ESTABLISHED TRANSGENEIC MOUSE MODEL WITH CONDITIONING IN ACTIVATION. IN THE OPEN MOUSE MODEL. OVER TWO MONTHS PERIOD OF TIME HE ACTUALLY WAS ABLE TO FIND HYPO PLASTIC FOCUS IN THE WAY AS YOU CAN SEE FROM HERE. IF YOU DO THE BRDU STANDING WHICH ACTUALLY HELPED TO ANALYZE THE PROLIFERATION YOU CAN SEE THAT, THE CELLS IN THIS REGION ARE HAVING PROLIFERATED. IF YOU WAIT LONG ENOUGH ABOUT SIX MONTHS TO ONE YEAR, THESE MICE ACTUALLY CAN DEVELOP THE SMALL CELL LUNG CANCER. JUST THE LATENT PERIOD IS QUITE LONG. SO LATER ON HE ACTUALLY ADD ADDITIONAL GENE MUTATION SUCH AS ACTIVATED, ACTUALLY DEVELOPMENT OF THE SMALL CELL LUNG CANCER CAN BE GREATLY ACCELERATED. WITH THIS DATA ACTUALLY SUGGESTS THAT DEACTIVATION OF P53 AND RB1 CAN LEAD TO THE SMALL CELL LUNG CANCER. THERE'S ACTUALLY ANOTHER PIECE OF DATA FROM CLINIC TO SUPPORT THE IMPORTANCE OF THE P53 AND RB ACTIVATION FOR THE SMALL CELL LUNG CANCER. AND THIS IS ACTUALLY VERY INTERESTING PHENOMENON NONE FOR THE PATIENT WHO ARE STARTED WITH NON-SMALL CELL LUNG CANCER WITH THE ACTIONABLE MUTATION, WHEN THEY WERE TREATED WITH OR AGENTS WHEN THE -- WHEN PATIENT DEVELOPED RECURRENCE AND SOME TIME IN THE NON-SMALL CELL LUNG CANCER ACTUALLY CAN BE CONVERTED TO THE SMALL CELL LUNG CANCER. SO THE SMALL CELL LUNG CANCER BECOME A MECHANISM BY DRUG RESISTANCE TO THE TARGETED THERAPY. THIS IS A PATIENT WHO WAS INITIALLY DIAGNOSED WITH ADENO CARCINOMA WITH THE MUSICIAN IN A58R IN THE EGFR. THIS IS SENSITIZING MUTATION. PATIENT ACTUALLY CAN BE TREATED WITH TARGETED AGENT EGFR INHIBITOR. PATIENT WAS TREATED FOR A YEAR THEN DEVELOPED TUMOR RECURRENCE. BIOPSY WAS PERFORMED AND PATIENT WAS FOUND TO HAVE SMALL CELL LUNG CANCER, NOT SMALL CELL BUT SMALL CELL LUNG CANCER. PATIENT REMAINS TO HAVE MUTATION OF THE EGFR SUGGESTING THAT THIS SMALL CELL LUNG CANCER IS ACTUALLY COMING FROM THE SAME THAT LEADS TO THE SMALL CELL LUNG CANCER INITIALLY. PATIENT WAS TREATED WITH CHEMOTHERAPY AND RADIATION. THEN WAS PUT BACK ON EGFR INHIBITOR. EVENTUALLY PATIENT DEVELOPED RESISTANCE TO -- BOTH THE -- HAD RECURRENCE, BECOME RESISTANT TO THE CHEMOTHERAPY THEN PATIENT WAS TREATED WITH BOTH RADIATION, WITH THE CHEMOTHERAPY AS WELL AS TARGET AGENT. AT THIS MOMENT THE TUMORS WERE RESISTANT TO THESE TREATMENTS THEN PATIENT EVENTUALLY PASSED AWAY AND HAD AUTOPSY DONE. HERE TO SHOW GENETIC FEATURES OF DIFFERENT TUMORS OF THESE PATIENTS. AS YOU CAN SEE HERE THIS IS ACTUALLY NON-SMALL WELL LUNG CANCER TUMOR THE PATIENT HAS. PATIENT HAS THE ACTIVATING MUTATION OF THE EGFR AND BECAUSE PATIENT DEVELOPED SECOND MUTATION IS CALLED A P7. PATIENT BECOMES RESISTANT TO THE INITIAL EGFR INHIBITOR. IF YOU LOOK AT THE OTHER GENES STATUS, FOR P53 THERE IS DELETION IN ONE ALLELE BUT THE OTHER ALLELE IS A Y TYPE. OTHER TUMORS, SO THOSE ARE SMALL CELL LUNG CANCER YOU CAN SEE THAT THOSE TUMORS ALSO REMAINS TO HAVE EGFR MUTATION. AGAIN TELLS YOU THAT THESE ARE COMING FROM THE SAME CLONE THAT DEVELOPED -- THAT LEADS TO THE NON-SMALL CELL LUNG CANCER. YOU CAN FIND THAT THERE IS ALSO THE DELETION IN ONE ALLELE. P53 AND THE OTHER ALLELE ACTUALLY IS LOST DUE TO THE LOSS OF HETEROZYGOCITY. THIS IS PRESENT IN BOTH TUMORS IN THE END OF LIVER. IN THE MEANTIME THESE RESEARCHERS ALSO CHECKED EXPRESSION LEVEL OF RB USING THE IMMUNOHISTOMECHANICAL STANDING SO THE DATA IS LISTED HERE. THEY ACTUALLY COMPARED BETWEEN THE TUMOR BEFORE THE TARGETED THERAPY AND TUMOR PROGRESSED AFTER THE TARGETED THERAPY. IF YOU JUST LOOK THROUGH, YOU CAN SEE THAT, WHENEVER THERE'S NEUROENDOCRINE FEATURES THAT SUGGESTS THAT THIS IS A SMALL CELL LUNG CANCER YOU CAN SEE THERE'S RB. MEANING THAT RB IT WAS ALSO LOST IN RECURRENT TUMORS WITH NEURO ENDOCRIN FEATURES. AGAIN, SHOW THAT LOSS OF P53 AND RB ARE VERY CRITICAL FOR DEVELOPMENT OF THE SMALL CELL LUNG CANCER. THIS IS FURTHER CORROBORATED BY THE SEQUENCING DATA OF THE SMALL CELL LUNG CANCER. IN THIS STUDY THE RESEARCHERS ACTUALLY DID WHOLE GENOME SEQUENCING OVER 100 SMALL CELL LUNG CANCER SPECIMENS. THEY ACTUALLY DIDN'T REALLY FIND ANY MUTATION, IS THAT CAN BE TARGETED WITH EXISTING MDICATION. HOWEVER, WHAT THEY FOUND FIRST THEY FOUND P53 AND RB1 ARE MUTATED OVER 90 AND 80% OF THE PATIENTS RESPECTIVELY. THIS IS AGAIN PREVIOUS FINDING. SECOND OF ALL, THEY FOUND THAT EPIGENETIC GENES SUCH AS P300 AND CROWD-PP BOTH GENES ACTUALLY ENCODE FOR THE TRANSFERASE WHICH IS MODIFIED HISTONES AND REGULATE GENE EXPRESSION. THESE OCCUR IN 15% OF THE PATIENTS. ANOTHER INTERESTING FINDING IS THAT NOTCH RECEPTORS ARE ALSO OFTEN MUTATED WITH THE PATIENTS WITH SMALL CELL LUNG CANCER. ON THE RIGHT SIDE, WHICH ACTUALLY SHOWS GENE DELETION AND AMPLIFICATION IN THE SMALL CELL LUNG CANCER PATIENTS. AS I MENTIONED EARLY THAT CHROMOSOMAL 3P IS OFTEN DELETED IN THE SMALL CELL LUNG CANCER. AS YOU CAN SEE THAT HERE, THERE'S A DELETION. RB AND P33 ARE ALSO DELETED VERY FREQUENTLY IN THE SMALL CELL LUNG CANCER. OFTEN AMPLIFIED IN THE SMALL CELL LUNG CANCER. THOSE ARE THE FAMILY GENES THAT INCLUDE MIK. IRSQ INVOLVED IN THE PI3 KINASE PATHWAY THIS IS OFTEN AMPLIFIED. TO SUMMARIZE THEIR FINDING THEY ACTUALLY FOUND FOUR DIFFERENT PATHWAYS ARE OFTEN IMPACT IN THE SMALL CELL LUNG CANCER. THE FIRST PATHWAY IS CELL CYCLE REGULATION AS MENTIONED THAT A P 53 AND RB ARE OFTEN LOST IN THE SMALL CELL LUNG CANCER. SECOND PATHWAY PI3 KINASE. OFTENTIME THE PI3 KINASE PATHWAY IS TURNED ON IN THE SMALL CELL LUNG CANCER PATIENT. THE THIRD PATHWAY IS RELATED TO THE TRANSCRIPTIONAL REGULATIONS, AS MENTIONED THAT EPIGENETIC ENZYMES ARE OFTEN DEACTIVATED, THE MIC A VERY IMPORTANT REGULATOR AMPLIFIED IN THE SMALL CELL LUNG CANCER. LAST PATHWAY IS NOTCH SIGNALLING PATHWAY. IT WAS FOUND THAT NOTCH SIGNALLING ACTUALLY IS OFTEN TURNED DOWN BY THE MUTATIONS OF THE NOTCH RECEPTOR. BUT THE SIGNIFICANCE ACTUALLY ADDRESSED IN THE SAME STUDY AS WELL. HERE JUST VERY RECENT PIECE OF DATA SHOWING YOU THAT IN ACTIVATION OF EPIGENETIC ENZYMES ACTUALLY ACCELERATE THE DEVELOPMENT OF THE SMALL CELL LUNG CANCER IN MOTH MODEL. IN THIS EXPERIMENT, THE RESEARCHER ACTUALLY ADDED A THIRD -- ACTUALLY INACTIVATED -- ON TOP OF THE GENETIC BACKGROUND OF RB1 AND P53. AS YOU CAN SEE THAT, THE MICE WITH THE TRIPLE GENE MUTATION ACTUALLY DEVELOPED SMALL CELL LUNG CANCER MUCH EARLIER THAN THE MICE WITH ONLY TWO GENE MUTATION. ON THE RIGHT SIDE, ACTUALLY SHOW YOU, THIS IS IN THE MICE WITH HE TWO GENE MUTATION. AT THE TIME WHEN THERE'S JUST HYPOPLASTIC LEGION IN THE TRIPLE MUTATION MICE, ADVANCE STAGE OF SMALL CELL LUNG CANCER. WHICH SUGGESTS THAT THE OTHER GENES BESIDES P53 AND RB ACTUALLY CAN HELP FACILITATE THE DEVELOPMENT OF THIS SMALL CELL LUNG CANCER. IN THIS CASE BP1 DOES THAT. NEXT I WANT TO GIVE YOU TWO EXAMPLES ABOUT DRUG DEVELOPMENT IN THE SMALL CELL LUNG CANCER. FIRST IS ABOUT -- AS MENTIONED EARLIER, THE NOTCH RECEPTOR IS OFTEN MUTATED IN THE SMALL CELL LUNG CANCER. HERE IS A CARTOON TO SHOW YOU WHAT IS THE NOTCH SIGNALLING PATHWAY. NOTCH RECEPTORS ARE ACTUALLY THE CELL MEMBRANE RECEPTORS. WHEN THE RECEPTOR BINDS TO LIGAND, WHICH CAN BE ACTIVATING OR INACTIVATING LIGANDS. WHEN IT'S BINDING TO THE ACTIVATED LIGANDS THEN STRUCTURE OF THE NOTCH RECEPTOR IS ALTERED SO THAT IT CAN BE CLEAVEED BY -- AT THE CLEAVAGE THE INTER- CELLULAR DOMAIN OF THE NOTCH RECEPTOR CAN ACTUALLY SERVE AS SIGNALLING MOLECULE AND MIGRATE INTO THE NUCLEUS. IN THE NUCLEUS THESE INTER- CELLULAR OF THE NOTCH RECEPTOR CAN BIND TO OTHER TRANSCRIPTIONAL FACTORS AND THEN THESE TWO ACTIVATION OF THE GENES. TO ANSWER THE QUESTION ABOUT SIGNIFICANCE OF NOTCH SIGNALLING INACTIVATION, RESEARCHERS ACTUALLY USE THE TRANSGENIC MOUSE MODEL AGAIN. IN THIS EXPERIMENT THEY ACTUALLY USED A TRIPLE KNOCK OUT TRANS GENIC MOUSE MODEL TO GENERATE A SMALL CELL LUNG CANCER. IN THE TRIPLE KNOCK KNOCK OUT THEY ACTUALLY KNOCKED OUT P53, R B, ALSO RB1. THEN IN THE SECOND MODEL THEY ACTUALLY ADDED EXPRESSION OF INTER-CELLULAR DOMAIN OF THE NOTCH RECEPTOR 2. IN THAT CASE THE NOTCH SIGNALLING IS ALWAYS TURNED ON. WHAT THEY FOUND IS THAT IN COMPARE THE TUMOR GENERATION BETWEEN THESE TWO DIFFERENT MOUSE MODEL, ACTUALLY THE STRAIN THAT HAVE EXPRESSION OF NOTCH RECEPTOR TWO INTER-CELLULAR DOMAIN HAS LESS NUMBER OF TUMORS IN THE LUNG ALSO IF YOU LOOK AT SURFACE AREA OF THE LUNG IMPACT BY THE TUMOR, AGAIN IT SHOWS THERE'S -- LESS AFFECTED BY TUMORS IN THE STRAIN THAT HAVE EXPRESSION OF NOTCH TWO INTER- CELLULAR DOMAIN. HERE I SHOW SURVIVAL CURVE, AGAIN SHOW THAT THE OVER EXPRESSION OF NOTCH 2 INTER- CELLULAR DOMAIN ACTUALLY PROLONG THE SURVIVAL OVER THE ANIMALS. AGAIN, SHOW THAT ACTIVATION OF NOTCH RECEPTOR OR TURNING DOWN OF THE NOTCH SIGNALLING ACTUALLY FACILITATE THE DEVELOPMENT OF THE SMALL CELL LUNG CANCER. IN THE MEANTIME, ANOTHER GROUP OF RESEARCHERS IN CALIFORNIA ACTUALLY FOUND THAT ONE GENE CALLED DLL3 WHICH ACTUALLY IS ANTAGONIZEING LIGAND IS OFTEN OVER EXPRESSED IN THE SMALL CELL LUNG CANCER. WHAT IS SHOWN HERE, COMPARED TO THE NORMAL LUNG IN THE SMALL CELL LUNG CANCER TUMOR AND ALSO CELL LINES, YOU CAN SEE THAT EXPRESSION OF EOS3 IS ACTUALLY ABOUT ONE HAVE LOG HIGHER THAN EXPRESSION OF DLL3 BEING NORMAL. AS MENTIONED THAT TURNING DOWN THE NOTCH SIGNALLING ACTUALLY FACILITATED DEVELOPMENT OF THE SMALL CELL LUNG CANCER AND THIS DLL3 IS ANTAGONIZEING LIGAND. OVER EXPRESSION OF THIS LIGAND HELPED TO TURN DOWN THE NOTCH SIGNALLING. SO HOW CAN WE USE THIS INFORMATION TO DEVELOP A THERAPY ACTUALLY THIS GROUP OF RESEARCHERS HAD IDEA TO DEVELOP ANTIBODY CONJUGATE. THIS PROTEIN IS A CELL SURFACE PROTEIN. YOU CAN YEARS ANTIBODY TO TARGET OR BINDS TO THESE SURFACE RECEPTOR. SO WHAT THEY DID, THEY ACTUALLY LINKED VERY TOXIC CHEMO DRUG HERE WE CALL IT A PAY LOAD. LINKED THE ANTIBODY THAT CAN RECOGNIZE DL3 ON CELL SURFACE THEY GIVE THE NAME. IDEA THAT ANTIBODY CAN LEAD THE DRUG TO THE TUMOR CELLS BECAUSE CHEMO DRUG ITSELF IS PRETTY TOXIC WHICH YOU CAN NOW REALLY GIVE IN THE PATIENTS WITHOUT THESE MECHANISMS BECAUSE THAT JUST BE TOO TOXIC TO THE PATIENT BUT IN THIS CASE BECAUSE IT'S ACTUALLY GUIDED BY THE ANTIBODY YOU CAN GIVE VERY SMALL AMOUNT OF THE DRUG WOULD BE ENRICHED AS TUMOR SITE. IN THIS CASE VERY TOXIC DRUG CAN EFFECTIVELY KILL THE TUMOR CELLS IN THE ANIMAL MODEL, FOR EXAMPLE , TAKE THIS AS EXAMPLE. THE TUMOR WAS TREATED WITH THE FIRST LINE CHEMOTHERAPY, IN THIS CASE SYS PLAT. BUT OVER TIME TUMOR DEVELOPMENT RESISTANCE. IF YOU DON'T TREAT IT, WHICH WAS REPRESENTED AS BLACK CURVE TUMOR VOLUME CONTINUED TO INCREASE. HOWEVER IF YOU TREAT WITHABLY DRUG CONGUY GAIT. YOU CAN SEE SHRINKAGE OF THE TUMOR AND ALSO THE SHA RICKAGE OF TUMOR CAN LAST OVER ABOUT THREE MONTHS. ON THE RIGHT-HAND SIDE ACTUALLY DID COMPARISON. HOW ABOUT RETREATED THESE MICE WHO DEVELOP RESISTANCE TO THE INITIAL CHEMOTHERAPY. THEN YOU CAN FIND THAT, ALTHOUGH TUMOR SIZE DECREASED AGAIN, BUT APPEAR FASTER THAN THE FIRST ROUND OF THE CHEMOTHERAPY. THIS IS THE POINT THEY WANT TO MAKE IS THAT THIS ANTIBODY DRUG CONJUGATE IS BETTER THAN THE CHEMOTHERAPY. THIS DRUG ACTUALLY WAS TESTED IN THE CLINICAL TRIAL. FOR THE INTEREST OF TIME I'LL JUST BRIEFLY MENTION ABOUT THIS. ACTUALLY -- WHO PROGRESSED AFTER FIRST LINE CHEMOTHERAPY AS WELL AS FIRST TWO LINES FOR THERAPY. BASED ON EXPRESSION LEVEL OF THE DL3. MAJORITY OF PATIENTS HAVE AT LEAST SOME EXPRESSION IN SOME OF THE TUMOR CELLS. THERE'S ALSO ABOUT TWO-THIRD OF PATIENTS WHO HAVE EXPRESSION OF DL3 IN MORE THAN 50% OF THE TUMOR CELLS. THIS IS WATER FAT PLOT WHICH SHOWS RESPONSE OF THE TUMORS TO THIS TYPE OF DRUGS. YOU CAN SEE THAT HERE THE USE OF COLOR TO REPRESENT EXPRESSION LEVEL OF THE DL3. THE PATIENT WHO HAVE THE BARBIE LOW THIS LINE ARE CONSIDERED TO HAVE RESPONSE, MEANING THESE ARE THE TUMORS HAVE MORE THAN 30% OF SHRINKAGE. SO YOU CAN SEE THAT MANY OF THESE HAVE -- MANY OF THESE BARS ARE ACTUALLY IN GREEN COLOR WHICH REPRESENT THEY HAVE EL3 EXPRESSION LEVEL MORE THAN 50%. THERE'S ALSO COUPLE OF PATIENTS WITH LIGHT GREEN BAR WHICH ARE NO AVAILABLE DATA OF THE DL3. SO WHICH DOES MAKE SENSE THE PATIENT WHO HAVE HIGHER EXPRESSION OF THE TARGET ARE MORE LIKELY TO HAVE A RESPONSE TO THE TREATMENT. THIS IS THE DATA SHOWING THE RATE OF OBJECTIVELY SONS MEANING THAT A TUMOR HAS SIGNIFICANT SHRINKAGE VERSUS CLINICAL BENEFIT RATE MEANING THAT THERE'S NO PROGRESSION OF THE TUMOR ON THIS TREATMENT. YOU CAN SEE THAT THE PATIENT WITH HIGH EXPRESSION OF THE MARKER, BUT IN THIS CASE GREATER THAN 50% HAVE BETTER CHANCE TO HAVE A RESPONSE. ALSO THESE PATIENTS HAVE BETTER CHANCE OF CLINICAL BENEFITS AS WELL. THIS TRIAL ACTUALLY WAS INITIALLY DONE IN THE PHASE 1 AND LATER THE DRUG ACTUALLY WAS ACQUIRED BY -- THEY ACTUALLY INITIATE A PHASE TWO TRIAL. ACTUALLY JUST RECENTLY RELEASED DATA OF THE PHASE TWO TRIAL. THE PHASE TWO TRIAL RESULT IS ACTUALLY A LITTLE BIT DISAPPOINT ING. THE DATA ACTUALLY DID REPEAT FINDINGS IN THE PHASE ONE. IN THIS CASE IN THE PATIENTS WITH HIGH EXPRESSION OF THE DL3 ONLY FIND 16% OF RESPONSE RATE COMPARED TO THE PREVIOUSLY 39%. THIS IS BECAUSE OF THE DIFFERENT PATIENT POPULATION. THE COMPANY ACTUALLY IS TRYING TO SEE WHETHER THIS DRUG CAN BE COMBINED WITH OTHER DRUGS IN THE FIRST LINE OR SECOND LINE SETTING. NEXT TALK ABOUT IMMUNE THERAPY IN THE SMALL CELL LUNG CANCER. IMMUNE THERAPY IS A VERY HOT AT THIS MOMENT SO ALSO HAS BEEN MANY ATTEMPTS TO TESTING THIS TYPE OF DRUG IN THE SMALL CELL LUNG CANCER. IMMUNOTHERAPY ACTUALLY COME WITH DIFFERENT FLAVORS. THERE COULD BE VACCINE, COULD BE ANTIBODY CONJUGATED OR JUST SO-CALLED IMMUNOINHIBITORS. WHAT I WOULD FOCUS ON TO TALK ABOUT NEW CHECKPOINT INHIBITORS. THE TUMORS CAN DEVELOP IN PATIENTS BECAUSE IMMUNE SYSTEM CANNOT REALLY TELL THE DIFFERENCE BETWEEN TUMOR CELLS AND THE NORMAL CELLS. SO THE WAY THE TUMOR CELL DOES THAT IS THEY ACTUALLY OVER EXPRESS SOME OF THE PROTEINS SUCH AS PDL1. THE LIGAND 1 WHICH JUST TELL IMMUNE SYSTEM THAT I'M SELF, DON'T ATTACK ME. SO THE PRINCIPLE OF THE CHECKPOINT INHIBITORS IS TO USE ANTIBODY TO REALLY INTERRUPT THE BINDING BETWEEN THE PDL1 WITH THE PD1 ON IMMUNE CELLS. SO THAT SO THAT IMMUNE SYSTEM CAN RECOGNIZE THE TUMORS. THERE ARE MANY OTHER MOLECULES ON THE TUMOR CELLS THAT CAN MEDIATE IMMUNE SUPPRESSION SO WHAT'S RELEVANT TO THIS TALK IS CTLA4 WHICH ALSO IS EXPRESSED IN THE TUMOR AND IMMUNE CELLS THAT CAN TURN DOWN IMMUNE ACTIVATION. IN ORDER TO HAVE IMMUNE RESPONSE SO NEED TO HAVE IMMUNE CELLS. IN THE MEANTIME, IMMUNE CELLS NEED TO BE ABLE TO HAVE TUMOR CELL IS DIFFERENT FROM THE NORMAL CELLS. SO THE WAY IT DOES IT, THE TUMOR CELLS OFTEN HAVE MUTATION. IT MAY EXPRESSION PROTEIN DIFFERENT FROM THE NORMAL CELLS. THAT IS HOW THE IMMUNE CELLS CAN PICK IT UP BE ABLE TO TELL THIS IS DIFFERENT FROM ITS NORMAL CELLS. HERE IS A VERY FAMOUS GRAPH WHICH JUST SHOW TUMOR MUTATION VERDICT IN DIFFERENT TYPE OF TUMORS. JUST WANT TO POINT OUT THAT SMALL CELL LUNG CANCER ACTUALLY CONSIDERED AS TUMOR TYPE WITH HIGH MUTATION BURDEN. OFTENTIMES THE TUMOR, IS THAT ARE CAUSED BY THE SMOKING OR IN THIS CASE MELANOMA WHICH IS CAUSED BY THE UV LIGHTS TENDS TO HAVE HIGHER MUTATION BURDEN. USUALLY, WHEN TUMOR HAVE HIGH MUTATION BURDEN IT'S MORE LIKELY TO EXPRESS A PROTEIN THAT IS DIFFERENT FROM ITSELF. IT'S MORE LIKELY TO BE PICKED UP BY THE IMMUNE SYSTEM SO THAT HAVE IMMUNE RESPONSE. THE EXPRESSION OF THE PDL1 SMALL CELL LUNG CANCER IS ACTUALLY NOT VERY HIGH. ALSO EXPRESSION OF PDL1 OFTEN ON IMMUNE CELL INSTEAD OF TUMOR CELL WHICH POSE A LITTLE BIT OF WHERE CHECKPOINT INHIBITOR WILL ALL BE EFFECTIVE IN THESE TYPE OF TUMORS. IN THE MEANTIME GENETIC STUDY ACTUALLY FOUND THAT IN SOME -- VERY SMALL NUMBER OF THE PATIENTS THERE IS AMPLIFICATION OF THAT PDL1 HERE ACTUALLY SHOW THE TWO PATIENT SAMPLES COMPARED TO 75 PATIENTS WITHOUT AMPLIFICATION. YOU CAN SEE THAT CD 74 STANDS FOR PDL1. THERE'S A VERY -- VERY SIGNIFICANT INCREASE OF GENE EXPRESSION. THIS ACTUALLY IS ALSO CORROBORATED BY IMMUNOHISTO CHEMICAL STANDING SHOWING IN BROWN COLORS THAT PDL 1 OVER EXPRESSED WITH GENE AMPLIFICATION. IN THE CLINICAL TRIAL -- I'LL SKIP THIS SLIDE. THAT PATIENT ACTUALLY WAS TESTED TO BE TREATED WITH JUST A SINGLE AGENT CHECKPOINT INHIBITORS VERSUS THE COMBINATION OF CHECKPOINT INHIBITORS. SO IN THIS CASE THERE ARE INHIBITORS TARGETING PD-L1 AND TARGET THE CTI4. SO AGAIN THEY STRATIFY PATIENT BASED ON EXPRESSION OF THE PDL1 IS PRETTY LOW ONLY ABOUT 14 TO 24% IN THE PATIENTS. WHAT THEY FOUND THAT FOR SINGLE AGENT IN THE PATIENTS NOT STRATIFY BASED ON PDL1 EXPRESSION THERE'S ONLY 10% OF PATIENTS WHO HAVE PARTIAL RESPONSE. IF YOU COMBINE CHECKPOINT INHIBITORS RESPONSE RATE CAN BE DOUBLED TO ABOUT 20%. HOWEVER THE COMBINATORY CHECKPOINT INHIBITOR TREATMENT ARE NOT -- BECAUSE THEY ARE ACTUALLY THEY ARE MUCH HIGHER TOXICITY AND THERE COULD BE SOME OTHER IMMUNE RELATED, RATTED VERSE EVENTS SUCH AS PNEUMO NIGHTS, ALSO THE ENCEPHALOPATHY CAUSED BY ACTIVATION OF THE IMMUNE SYSTEM. CURRENTLY THIS IS COMBINATORY IMMUNE CHECKPOINT INHIBITORS HASN'T BEEN APPROVED BY FDA AS WAITING FOR MORE DATA. WHAT I WANT TO POINT OUT IS THAT IN RETROSPECTIVE ANALYSIS OF THE CLINICAL SPECIMEN, ACTUALLY WAS FOUND THAT PATIENT WITH HIGHER MUTATION BURDEN TENDS TO HAVE BETTER CHANCE TO RESPOND TO THE IMMUNOCHECKPOINT INHIBITOR WHICH DOES MAKE SENSE THAT MORE MUTATIONS SUGGESTS THAT THERE ARE MORE NEW ANTIGENS TO BE RECOGNIZED BY THE IMMUNE SYSTEM. AS SHOWN HERE THIS IS A BLUE REPRESENT SINGLE AGENT AND ORANGE REPRESENTS THE DOUBLE AGENTS. YOU CAN SEE THAT IN THE PATIENT WITH HIGH MUTATION BURDEN, THERE'S MUCH HIGHER RESPONSE RATE IN THE PATIENT WHO GOT A SINGLE AGENT VERSUS DOUBLE AGENT ACTUALLY THIS TOPIC WILL BE FURTHER DISCUSSED IN THE NEXT WEEK LECTURE. JUST TOUCH A LITTLE BIT ON THIS. BESIDES SMALL CELL CARCINOMA CAN OCCUR IN OTHER ORGAN SYSTEMS SUCH AS PROSTATE AND BLADDER AND HEAD AND NECK TUMORS. COMPARED TO SMALL CELL LUNG CANCER THE EX TENSE OF THE CARCINOMA IS MUCH LOWER THERE'S NOT TOO MUCH EXPERIENCE ON THOSE TUMORS. THE FIRST LINE THERAPY IS ACTUALLY BORROWED FROM THE SMALL CELL LUNG CANCER IS ALSO THE SYS PLATTING WITH -- ONE DISTINCTION THAT THE SMALL CELL LUNG CANCER IS NOT AS LIKELY TO METASTASIZE TO THE BRAIN AS SMALL CELL LUNG CANCER. ONLY EXCEPTION IS PROSTATE CANCER SMALL CELL LUNG CANCER IN THE HEAD AND NECK SMALL CELL LUNG CANCER THESE ARE TWO STILL LIKELY TO EXPRESS TO THE BRAIN. FOR THOSE TWO YOU MAY CONSIDER ABOUT PROPHYLACTIC CRANIAL RADIATIN. JUST TO SUMMARIZE IN THIS LECTURE I MENTIONED THAT SMALL CELL LUNG CANCER IS RECALCITRANT CANCER WE NEED A MORE THERAPY FOR THIS TYPE OF CANCER. YOU MAY REMEMBER THAT P53 AND RB 1 OFTEN MUTATED IN THE SMALL CELL LUNG CANCER. FINALLY IMMUNOCHECK POINTED INHIBITOR HAS BEEN RECENTLY APPROVED FOR THE TREATMENT OF SMALL CELL LUNG CANCER IN THE THIRD LINE SETTING. ACTUALLY DUE TO THE TIME ISSUE I DIDN'T GET CHANCE TO MENTION ABOUT OTHER NOVEL AGENTS THAT ARE CURRENTLY BEING DEVELOPED. BUT MORE ARE COMING. THANK YOU. [ INAUDIBLE ] IN THE SMALL CELL LUNG CANCER HAVE NEW FEATURE BUT ALSO A SMALL NUMBER OF TUMORS WHICH DO NOT HAVE NEUROENDOCRIN FEATURE. IT WAS REPORTED IN ONE OF THE CONFERENCE DATA, SMALL CELL LUNG CANCER WITHOUT ENDOCRIN FEATURE HAS HIGH EXPRESSION OF THE PDL1 THEY ARE MORE LIKELY TO RESPOND TO THE CHECKPOINT INHIBITOR. BUT CLINICAL DATA IS STILL LACK ING. [ INAUDIBLE ] THANK YOU. HAVE A GOOD EVENING.