Advances in Therapy and Imaging of Metastatic Prostate Cancer

Thank you again for the nice introduction. I think I've never been introduced like like this before, so thanks also to the organizers for putting together this really nice symposium and for inviting me. So I want to spend a few minutes with you on discussion of advances in therapy and imaging of prostate cancer because we have new options here with regard to imaging, but also with regard to treatment. Just to quickly summarize prostate cancer, it's still the most common cancer in men and the third leading cause of cancer death, so it's curable in if it is in a limited stage by surgical removal or radiotherapy. It can also still be cured if it's locally advanced and has penetrated the organ capsule. If we reset the proceed and the surrounding tissue, and potentially add radiation in some cases. Also with hormone therapy. But as soon as metastasis are detected, this in general indicates of palliative situation. So the goal in this situation is to prolong life and to maintain quality of life. In the beginning this is also possible very, very nicely by androgen deprivation therapy which can keep the disease under control for a certain period of time. Button that's the major problem here. The tumor cells proceed. Cancer tumors has developed resistance. In a medium time of about two to three years. So this is not an never ending treatment option, but it ends at some point because the tumor gets resistant and the disease progresses, and we're talking about metastatic castration resistant prostate cancer in this situation. So in that situation, treatment gets more difficult. There's a number of treatments available, but the subsequent expected survival is only between 16 and 18 months. In this situation, there's more recent data that points towards a bit longer period now. Which is already about 2.4 years but still not not really what we would hope for. And so I put together this slide to just demonstrate you all the options therapeutic options that we currently have with regard to metastatic prostate cancer. So starting on the left with this green boxes, this meta static but still hormone sensitive. So this is the situation where we have good treatment options and all the options on the right side are available. So you see, it's a number of potential treatments, but not all of them are really effective in the way we would hope for. So this is the more established options. The entire the new anti androgen therapies. Such as abiraterone and then solution. Might we have two chemotherapies available that are approved and the more novel options, which is radium 223 therapy and also cisium therapy which is PS method which is on the way, not yet an approved procedure. And also I want to talk a little bit on personalized image guided approaches. So individual treatment in this situation of meta metastisized prostate cancer. So starting with the establish therapies, how effective are they? And I show you 2 boxes here on the left and on the right. The left side is the initial therapy with abiraterone absolute, or might and docetaxel as a chemotherapy. Large trials have been performed here. You see, with numbers more than thousand patients included and on the right side we have this box of post chemotherapy, a regiments again operator on an solution might can be applied following those attacks will and also we have a second chemotherapy option with covers that axle available. If you look into the red circles you see the average survival benefit and this. All of these therapies have been approved on the demonstration of this survival benefit, which is in the range of months, so this is between 2:00 and maximum five months, which is good if you have no other options, but of course it is not what we would hope for in the future. So we go one step further to radiotherapy and has been discussed before already. There's an approved drug Xofigo, which is an Alpha emitter which accumulates in the bone in away as we know it from bound from the bone scan, it is repeated six times. As you can see here, it has an effect and demonstrated to prolong survival and the interval to skeletal problems. But also it is not really curing the disease and you see here. Treatment before and after sort of the uptake is going down in the bone skin after radiotherapy, but it is not completely illuminating. The tumor. And of course, this therapy is only directed towards the ball metastasis, and we know that in later stages of patients frequently also have metastasis in lymph nodes and other other organs. So whereas it put in our set of as we can see here at the moment, it is also a third line therapy, so we would have to perform operator online salute image and. Chemotherapy first before we could move to Radium 223, and it should not be combined with abiraterone because they have been side effects reported recently. These are the research from big trials here, the so called a SIM card trial, and on the left side you see that it improves overall survival again by 3.6 months and on the right side you see that it improved time to 1st symptomatic skeletal events by 5.8 months, and again this data has been used for approval of this. This truck so I want to move on to this more innovative approach of a piece. May therapy and most of you of course know what this is about. Peace May is an enzyme that is expressed on prostate cancer cells, so it's in fact glutamate carboxypeptidase. And most most tumor cells expressed this intensely, so it is an ideal target not only for diagnosis that we will also talk about, but also for therapy and for quite a time now it has been tested in experimental settings as labeled with lutetium 100 hundred and 77. We have been doing this now since 2014 in Cologne in selected patients in a compassionate use program with good success. I show you how this is applied in Germany, this and. Inpatient therapy, but can repeat it four to six times depending on the situation of the patient. So we do the operation of the patients in an outpatient setting where the scan the PET scan is performed. Renal function and laboratory tests are performed, and then a week later we perform a three day inpatient treatment, so it's not a long face that the patient has to spend in House what we believe it makes sense to do this in an inpatient setting. According to radiation protection issues, but also to keep an eye on the on these patients. Which, at least at the moment are really Indiana progressive are advanced stage of disease, so some of them are also critically ill and it is good to have an eye on these patient, at least at the beginning of this therapy, which usually is tolerated very very well. So in Germany we have an agreement or consensus with the Cancer competence Center for Oncology, which is responsible, responsible on judging if a therapy can be reimbursed or not, and they basically approved two constellations for this therapy constellation. One is progressive, symptomatic or fracture prone bone metastasis. As mentioned before, all of the other options have to be performed before you can move to lithium therapy here and that of course, defines. That we treat patients really in Unbury advanced stage of disease, and they have seen all kinds of therapies which may also contribute to selecting particularly malignant tumor clones, because all of the others have basically been illuminated. So we're treating at the moment particular set of patients that might not be the ideal set for treatment with peers may therapy. You see an example here of a patient treated with lutein, PS. May 3 cycles with this constellation of polymer test, this is. And you see that there nicely reduced uptake here from the beginning to end of therapy, and the PSA value dropped from 272 PSA of 55 and some talks. You will see these examples where basically all the diseases completely removed by lutetium therapy. We usually in this late setting do not see this. I have to say we see a reduction of uptake. We see a reduction of metastasis, but it's not that it is completely illuminated and disappearing. So I want to show you show you really typical example here. This is constellation two that has been approved. This is loosen older Organa tests which can be with or without bound metastasis. Again, all available therapies have to be performed. Tumor board decision has to be taken and this is again an example from our clinic here by the PSA again dropped from 9 to one here and you nicely see the lymph nodes in the iliac regions. Here that got reduced very nicely. Some of them are still visible and also a few bone metastasis on top that can be still detected but also. Have been reduced in their uptake. So where we put this at the moment? As mentioned, this is really a last line therapy. So basically everything available has to be performed before or has to be contraindicated because the patients do no longer tolerated. So even the second chemotherapy covers that axle has to be performed currently before we can finally move to this last line. Therapy of lutetium, at least in Germany. In the current situation for this treatment. What about effectiveness? There has been a multicenter trial performed in Germany where several groups participated and you see the results here listed. I won't go in detail, but just to quickly summarize, there was a biochemical response regarding the PSA, which you can see on the left side in this waterfall plot, where more than 50% had had a drop in PSA. We had a survival without progress more than 10 months in 50% of patients, which is, I think, very good. And the overall survival, which you can see on the right graph here, was 70% more than 15 months. If you keep in mind the prognosis that I listed before in this situation where really everything has been performed before, this is really quite a good promising result. I need to say this is a retrospective analysis, so this is not an official prospective trial, but nevertheless we believe that this these results are promising and have also contributed to spreading the. Utility of this therapy and starting a number of now ongoing prospective trials that I'm listing here just quickly without wanting to mention all of them in detail. So in international settings, a number of therapies are ongoing and we just saw the example and the AAA talk before as well. So I want to move away from the nuclear medicine therapies a little bit to this concept of a more personalized and image guided therapy. In this stage of metastatic disease by use of peers may pets. We all know and it has been reported in a number of studies. That piece may pad is very valuable to detect recurrence in a situation where the PSA level is rising again in patients treated by proceed resection or radiotherapy. But it's not only good for detecting local recurrence, but also for detecting the test. A system that refers to lymph nodes, and there's quite a nice study that demonstrated that 80% of lymph node metastasis detected in prostate cancer have a diameter below 8 millimeter. So by definition they cannot be detected by means of morphological imaging, where a threshold of 1 centimeter is basically what is used for claiming that something is suspicious. So it is no wonder that there are significantly higher since sensitivities about 80% for PS may. Regarding detection of lymph node as compared to see T or MRI where the range is around 40% and it has been demonstrated that additional lymph node metastasis are detected in about 2/3 of see T negative patients. When you see this nice example on the left side, the patient has recurrence in the prostate which you see on the image below, but also as a single lumen. Testers in the left iliac region, certainly below a threshold that could be detected in this city. So a complete, completely different situation to just local recurrence. It's also highly valuable for M staging detecting metastasis. Also regarding smaller isolated metastasis, as you can see here again in this example also from our clinic again. Local recurrence in the process. A small focus and that can be detected here, but single bone metastasis is detected in the and spinal in a spinal bone, so again a totally different situation. Also with regard to treatment, of course. Also, I think a very important chapter in for PS may imaging is that we learn that there is a typical oligo metastasis that formally in this way has not been been commonly known, and I'll show it to examples here on the left side. This is an isolated bold metastasis, so no other finding in this patient, just a single bone metastasis detected here by peers may and on the right side even more atypical patient with an isolated language test assist which would not have been detected on the see T scan. So this patient underwent surgery and in fact it has been proven by Histology that this was appears, may and lesion, and the PSA while you drop down to oh point 1 three, an anagram for Melinda and this patient in fact is is now stable for two years, since removal of this a typical long metastasis, so quite quite convincing. I believe we collected a number of data in Cologne with regards to detection of metastasis, depending on the PSA value by means of PSM a pet and what we see here is. In fact, a little bit concerning or scary if you look on the left side, this is following radical prostatectomy, but you can see that in a range PSA range of oh .220 point 5 which is really quite low. We already detected metastasis in more than 30%. If you look at this window and this is really critical because so far even according to the guidelines, it was recommended to perform radiation standard radiation therapy of the prostate region. Even though without imaging, so you would certainly treat the number of these patients incorrectly because they already have metastasis interesting also, on the right side, following radiation therapy in our setting, we also found metastasizes in about 20% of patients with a Delta PSA increase of below tool. Again, interesting with regard to the guidelines because according to the guidelines an only a PSA increase of more than two would be considered to be a recurrence at all. So we found even metastasis in patients that. Did not yet fulfill by a chemical a conditions for suffering from a recurrence at all. What consequences does this have with regards to treatment? Obviously, with regard to radiation therapy, which often is a standard treatment for prostate cancer recurrence, you will not cover the entire disease, and this has been nicely demonstrated in this study by Calais and colleagues in the Journal Medicine. What they showed here is in how many patients you would find lesions outside of the standard radiation field and what you see here in green on the right body is the standard radiation field. What you see in yellow is the metastasis detected in this group of patients as well as 200. 70 patients or quite a large population and they found in about 20% of patients, clearly lesions outside of the standard radiation field. So I think a very strong argument to perform imaging before selecting your treatment. This maybe even more interesting with regard to more specialized individual treatments such as cyber knife. We also have a Cyberknife setting in Cologne. What you see here is the patient that had isolated metastasis in the iliac region on the left side. As you can see here. On top, no other findings, so this patient was selected for Cyberknife Therapy on the basis of the imaging. Finding the therapy planning has been carried out and you see the results below in this patient following the Cyberknife Therapy where we don't see any PS may uptake anymore, so it might have been successful in reducing this single manifestation of tumor in this patient. We will have to learn if this is really prolonging survival, so their studies of course required in this regard. Another option with regard to individually tailored therapy is surgery, and you know that that particular in the limited stage of disease. In many centers there are approaches to perform surgery with regard to the lymph nodes that are affected by disease and you see this example here for patient with two lymph node metastasis and that underwent radio guided surgery. Again, another application for imaging because you can use technetium labeled tracers to intra operatively find these metastasis if they are located. In a typical locations and you see this here the same patient we perform the SPECT scan with technetium labeled compound where the metastasis were detectable and intra operatively could be detected by a probes and then then removed. So where do I see options for further improvement? Because we should move to lower PSA evaluation to do even better detection, and I think there are three main reasons how you could further improve detectability. Imaging for image guided therapy one is improved pet camera technology. You may have seen the development recently also with this vision scanner from Siemens that I think might be game changing with regard to higher sensitivity, which we really require in this context with regard to detecting early early metastasis. Also, I think that technology with regard to reconstruction of course has improved. When you see this, everyone of you knows that uses recent technology. This gap from iterative to modern reconstruction using time of flight and point spread function. And also I think that artificial intelligence will be helpful with regard to more sensitive detection in the future. And finally we should work on improvement of tracers. So this is 18 F labeled it traces with no urinary excretion. Our traces with higher affinity. I show you a few examples here. These are five traces. All of them are currently applied in Kelowna. Also, one is regarding the the agent F labeled compounds. The DCF. While that has been developed in the proper group in Hopkins one, the PS May 1007 developed in Heidelberg. Doctor Diesel is also here. You did a lot of work on this tracer that has less urinary execution and we also have the piece May 7 that has been developed in Cologne also within 18 F label which is superior to some extent to the gallium label for a number of reasons. Lower pathway in the in the tissue, longer half-life etc and I want to show you what resource we got here because we did some Corporation abit comparison between the gallium labeled compounds an the 18 F labeled compounds and I showed 2 examples here of patients that have been scanned with gallium. You see the two here and then the same patient scanned with an 18 F analog on the left side. This is the DCF while and on the right side this is the 18 FPS May 7 and in both cases you see the clarity of the findings. Image quality is certainly improved. I have to say here that we injected higher doses of the 18 F labeled tracers, so this is not a completely fair comparison. But on the other hand we have higher doses available with the ATF traces, so it might also be what we do in clinical settings on an everyday basis. We tested this also with regard to sensitivity and found that in fact in a setting a comparative compatible patient populations, the 18 F labeled compound had a higher sensitivity, particular at the lower PSA levels. So at a level of oh point 5 we had 62 detection rate with the 18 F and only 30 three with the gallium peers in May. And that's of course important because the disease is limited. At the lower PSA levels, so further to the right it gets less and less important to have extremely high sensitivity of the traces available. So I reached the end of my talk and just to quickly summarize for metastatic prostate cancer, we have conventional therapies available that are effective, and they proved efficacy in large trials. They can be combined. They can be used in separate orders, however the survival benefits are limited. And disease is develops resistance against this therapy. We have more recently developed therapies for nuclear medicine such as radium therapy, an Alpha emitter that also proved efficacy, but is limited to skeletal disease, and we have experimental therapies on the pipeline, such as solution, PS may therapy, a beta emitter that shows promising results so far clearly in a number of studies it seems to have a benefit regarding the survival. But it is not yet approved. Is currently only used in compassionate use situations. As a last line therapy. So we urgently need trials that prove evidence over efficacy of this substance earlier. And finally, I believe that imaging piece may imaging opens completely new Ave for more personalized therapy concepts with regard to more sensitive detection of metastasis, which we would not have been detected, it would not have detected at all before and particularly detecting disease in a limited. The stage I think the new traces more sensitive camera technology and reconstruction technology will lead to further improvement here and in the future, and that this may support personalized concepts such as image guided surgery or radiation therapy. Particularly in this. What we now call oligo metastatic disease. So with a limited number of metastasis where I believe that at least systemic therapies can be pushed to the back and by this also presumably improve survival. Am off the patients, so I thank you very much for your attention.

UNIKLINIK Please note that the learning material is for training purposes only! UNIKLINIK und UNIKLINIK und Poliklinik KOLN KÖLN für Nuklearmedizin KOLN KÖLN For the proper use of the software or hardware, please always use the Operator Manual or Instructions for Use (hereinafter collectively "Operator Indications for 1771_u PSMA Radionuclide therapy Indications for 177Lu PSMA Radionuclide therapy Cyberknife: isolated lymph node metastasis Cyberknlfe: isolated lymph node metastasis Ideal diagnostlc window for PSMA-PET imaging? Ideal diagnostic window for PSMA-PET imaging? mCRPC: Established therapies mCRPC: Therapeutic options PSMA-Therapy Summary Cologne data: Metastasis depending on PSA-value in patients with biochemical recurrence Cologne data• Metastasis depending on PSA-value in patients with biochemical recurrence Therapy of bone metastases: 223Radium-therapy Indications for 223-Radium therapy [177LulPSMA: Therapy Regime [177Lu]PSMA: Therapy Regime [177LulPSMA• Therapy Regime Prostate Cancer Radium-223 therapy Results Retrospective Multicenter-trial NRW: [Lul 77]PSMA-617 Therapy N-Staging M-Staging Indications for 177-l_utetium PSMA-therapy in mCRPC Indications for 177-Lutetium PSMA-therapy in mCRPC 5 different PSMA-tracers in use at Univ. of Cologne 18F_ 18F- versus 6dGa-labeled PSMA PET imaging versus 6dGa-labeled PSMA PET imaging Opptions for further improvement Thank you very much for your attention! Current indications for PSMA-therapy Salvage Lymphnode Dissection Atypical oligometastasis N-Staging M-Staging Benefits for radiotherapy: Recurrence of lesions outside standard irradiation field Personalized and image-guided therapy: Manual") issued by Siemens Healthineers. This material is to be used as training material only and shall by no means substitute the Operator Conventional therapies (ADT, chemotherapies, antiandrogen therapies) PSMA: Prostate-specific membrane antigene = Glutamat-Carboxypeptidase Il Isolated lung metastasis, PSA-value 1 ng/ml Isolated lung metastasis, PSA-value 1 ,60 ng/ml Overall survival Of lymph node metastases < mm ! PSMA-PET of lymph node metastases < d mm ! PSMA-PET Of lymph node metastases < d mm ! PSMA-PET Progression-free survival progression-free survival Detection of small or isolated metastases, negative in CT or Manual. Any material used in this training will not be updated on a regular basis and does not necessarily reflect the latest version of the Tc99m-PSMA radioguided surgery: Helpful for reliable detection Of PSMA-positive reference lesions and in atypical localizations. ALSYMPCA trial: Radium-223 increased overall survival and time to first symptomatic skeletal event PSA-changes psA-changes mCRPC mCRPC Isolated bone metastasis, mCRPC mCRP rnCR mcR rnCRP mCRPC mpc 270 patients with recurrence following radical prostatectoy, PSA-levels < 1.0 ng/mL 270 patients with recurrence following radical prostatectoy, PSA-levels < ng/mL In men:most common cancer (approx. 70.000/year) and the third leading cause of cancer death 1. In men:most common cancer (approx. 70.000/year) and the third leading cause of cancer deathl. [18 FIPS MA-7 [18F]PSMA-7 Inpatient therapy, injection of ca. 7.4 GBq 177Lu-PSMA 4-6 times (interval 6-8 weeks) ["GalGa-PSMA-HBED-CC ["Ga]Ga-PSMA-HBED-CC [18F]DCFPYL [18F]DCFPyL Urology Nuclear Medicine/Radiochemistry Se-staging PSMA-PET/CT Staging staging PSMA-PET/CT staging "SMA-PET/CT Improved detection of metastatic disease with PSMA-PET (70% >15 months) (50% months) (70% >15 months) Following resection, histological validation and decline of PS- CR shows significantly higher sensitivites (78%) than CT or Improved detection rate at PSA-level 0.5 pg/L (high probability for limited disease) mCRPC -Improve overall survival and can be combined and/or performed subsequently Massively overexpressed on prostate cancer cells bone scan (threshold PSA > 10 ng/ml!). Exclusion Of false- software and hardware available at the time of the training. Following radical prostatectomy Following radiation therapy Local surgery or radiation therapy Consensus with the German Competence Failure/ PSA-value 0,92 ng/ml Bone scan Bone hormone No mild stronger symptoms • „Last-line" therapy: No licensed/FDA- or EMA-approved procedure, individual compassionate use • „Last-Iine" therapy: No licensed/FDA- or EMA-approved procedure, individual compassionate use -prof. M. -Prot. PSMA-PET/CT: In 52 cases (19%) lesions outside of the standard radiation field! prof. A. Heidenreich Developed Univ. of Cologne Collaboration with value to O, 13 ng/ml. DKFZ Heidelberg OKFZ Heidelberg Failure/ NO Post-chemotherapy regimens hormone No mild Advances in therapy and imaging of metastatic prostate cancer Initial therapy MRI (< 40%), Additional LN-metastases deteced in 2/3 of MRI (< 40%), Additional LSI-metastases deteced in 2/3 of MRI (< 40%), Additional LNI-metastases deteced in 2/3 of MRI 40%), Additional LN-metastases deteced in 2/3 of positive lesions. contraindic -However, survival benefits are limited and they lose efficacy over time Ideal target for diagnosis (PSMA-PET) and radionuclide therapy (theragnostics) Symptoms sympto after 1 Center for Oncology 2017 Usually curable if limited to the prostate: Surgical removal of the prostate and/or radiotherapy2. Usually curable if limited to the prostate: Surgical removal of the prostate and/or radiotherapy2 sensitive Sensitive ngoing prospective clinical trials: 223Radium (Xofigo@), Alpha-emitter, accumulating in bone mCRPC mPC CR mCRPC CR al al, J Med al, Histologically proven mCRPC with PSMA-expression éJNMMl 2013) Prof. D. Poster Improved PET-camera technology -Prof. C. Kobe Johns Hopkins university Johns Hopkins University contraindic to after 1 sensitive Stable since > 2 years! . 2nd CTX CT-negative patients CTX The Operator's Manual shall be used as your main reference, in particular for relevant safety information like warnings and cautions. For therapy: labeling with 177-Lutetium (beta-emitter, halflife 6.7 d) hormone No mild stronger symptoms . 2nd CTX *S3-guideline AWMF recommends salvage-RT up to PSA 0,5 gg/l *S3-guideIine AWMF recommends salvage-RT up to PSA 0,5 gg/l *S3-guideIine AWMF recommends salvage-R up to PSA 0,5 gg/l (Szabo 1m 2015) (Szabo al. 1m 2015) (Szabo vol 1m 2015) al. vol 1m 2015) vol 1m 2015) CTX metastases, halflife: 11 ,4d (range < O. 1 mm) metastases, halflife: 11 ,4d (range < 0.1 mm) Preserved bone marrow reserve, kidney and liver function Preconditions: bone marrow reserve, kidney function •z Team Urology -prof. M. Schmidt overall overall survival Survival Xofigo/223-Radium-therapy (alpha-emitter) Survival *S3-Guideline BCR at A PSA *S3-Cuideline BCR PSA *S3-Cuideline BCR at PSA Locally advanced stage (penetration of organ capsule): Resection of prostate and surrounding to First 20 2016 Improved acquisition/reconstruction algorithms atter CTX sensitive Sym ms 18F-DCFPyL CTX Constellation 2: Lymph node or organ symptoms sym Sym study Study Drug OS (MO) study Drug PRINCE (PSMA-Iutetium Radionuclide Therapy and ImmuNotherapy in Prostate Often without imaging! Often Without imaging! OS (MO) Abiraterone (Zytiga@) or ADT- Constellation 1: Progressive symptomatic or 6 x injections of 55MBq/kg, every 4 weeks (outpatient therapy) 0.66 (5S% 066 0.66 Note: Some functions shown in this material are optional and might not be part of your system. -Pain reduction, survival benefit and extension in time to skeletal event, but limited to bone benefit benefit molecular Imagins ADT- tissue affected by tumor cells and/or irradiation (potentially combined with hormone therapy). mestastases (Wit mestastases (with/withoutbone mestastases (With/without bone metasta mestastases (with/without bone mestastases (with/without bone metastases) Enzalutamide (Xtandi@) • therapy Peoom P,oom (T OF, PSF, etc.). Also artificial intelligence! Cancer) (PRINCE), Australia External fracture-prone bone metastases cancer) (PRINCE), Australia I day outpatient 3 days inpatient therapy Indications: Abiraterone (Zytiga@) or Enzalutamide (Xtandi@) COU-AA_ COUI-AA- Abiraterone 1717 14.8 VS 14.8 vs 3,9 SIEMENS .. SIEMENS 177Lu-PSMA-Therapy (beta-emitter) ADT- Prot. Schwaiger, TUM time to 18F COU-AA_ 30.3. vs COUI-AA- COUJ-AA_ COUJ-AA- COIJ-AA_ COLI-AA- Abiraterone best supportive care: best supportive care PSMA PSMA- • Lutetium-177-PSMA-617 in Low Volume Metastatic Prostate Cancer, Radboud Lutetium-177-PSMA-617 in Low Volume Metastatic Prostate Cancer, Radboud Certain products, product related claims or functionalities (hereinafter collectively "Functionality") may not (yet) be commercially available in your 2. 3. Improved tracers (18F-label, no urinary 1088 10.6 1006 Symptomatic bone disease in mCRPC (EMA-approval) 60 Therapys already applied, no longer effective therapy 3.4x10•3 301 302 1088 50 1006 60 suGa Denosumab (Xgeva@), Bisphosphonate (Zometa@) Metastases indicate a palliative situation, goal: prolonging life and maintaining quality of life Prof. Dr. Eiber, TUM 301 302 -Team NucMed 34.7 134.7 34.4 13.6 Therapys already applied, no longer effective or -Promising new theragnostic procedure targeting all types of metastases 100 1006 PET _ country. Due to regulatory requirements, the future availability of said Functionalities in any specific country is not guaranteed. Please contact Alexander Drzezgo Alexander Drzezga diagnostic] diagnostic University, the Netherlands scan diagnostic diagnostic] best supportive care: Denosumab (Xgeva@), Bisphosphonate (Zometa@) No organ metastases (no effect on extra-osseus lesions), NO organ metastases (no effect on extra-osseus lesions), or contraindicated: excretion, higher affinity etc.) Diagnostics J' prof. wester, TUM window contraindicated: 25 50 20 your local Siemens Healthineers sales representative for the most current information. Treatment: androgen deprivation therapy (ADT) with e.g. LHRH analogues, GnRH antagonists -Highly favorable tolerability and risk profile [68Ga1PSMA-PET [68Ga]PSMA-PET Docetaxel Docetaxel vs Docetaxel Cabazitaxel time •o • 177Lu-PSMA-617 and Pembrolizumab in Treating Patients With Metastatic Enzalutamide 1717 19.9 11.9 18.4 vs 30.3. vs no leading lymphatic disease (e.g. > 3 cm visceral metastases) TC-99m-PSMA SPECT (cor) PSMA SPEC or) 30.3. vs 30.2. vs Renal tuncticm Renal tunctim Renal function Renal tunction Renal Prof. Haberkorn, univ. Heidelberg 223Ra-Therapy -Prof. K. Schomäcker, Team Radiopharmacy Docetaxel Cabazitaxel Docetaxel AFFIRM 4B h Cabazitaxel PREVAIL -Benefits regarding PFS and OS are emerging (promising preliminary data) Department of Nuclear Medicin 1717 1771u Problem: resistance after 2—3 years (median) disease progresses. Metastatic castration- Therapy planning PSMA- control Bisphosphonates or Denusomab Re-staging PSMA-PET/CT vs Placebo 11.9 1088 13.6 134.7 1006 19.9 80 Abiraterone or Enzalutamide months Third line therapy (Enzalutamide/Abiraterone, Docetaxel) vs Placebo 34.4 3 cycles with Castration-Resistant Prostate Cancer, UCSF, San Francisco months [18npPSMA-1007 -Prof. Neumaier, IREMB, Team PET-Radiochemistry [18F]PSMA-1007 -prof. Neurnaier, IREMB, Team The reproduction, transmission or distribution of this training or its contents is not permitted without express written authority. Offenders will be moni- 145 patients, 1-4 cycles, 2-8 GBq per cycle mCRPC: Established options [99mTc]PSMA [99mTC]PSMA therapy PSMA-Therapy therap scan scan & -Not yet approved, currently only compassionate use in the „last line", trials ongoing Healthineers • University ot Cologne University of Cologne UJniversity of Cologne, Germany Bone: 223-Radium Bone: 223-Radiurn Bone: 223-Radiumn Analgetic therapy Initial therapy 223-Radium resistant prostate cancer (mCRPC). toring to ring Chemotherapy (docetaxel, cabazitaxel) PSA level Combination with Abiraterone obsolete! Indications: PSA PSMA 16,2 GBq -M. Wild/Dr. M. Hohberg & Team Medical Physics liable for damages. Study of 177Lu-PSMA-617 In Metastatic Castrate-Resistant Prostate Cancer Univ. Heidelberg univ. Heidelberg Heidelberg Very well tolerated, rare side effects: 10% anemia, 8% dry mouth (< grade 4) Very well tolerated, rare side effects: 10% anemia, 8% dry mouth grade 4) dischar Antiandrogen therapy (Abiraterone or Enzalutaminde) tests TIJ 9 IS Lg 9 IS 9 12 15 30 33 9 15 30 33 (Xofig0@V153-SM 39 39 36 (Xofigo@) 9 15 21 9 12 15 21 27 Abiraterone or Enzalutamide Following radiation therapy Local surgery or radiation therapy mCRPC, incl. Lung, liver incl. Lung, liver (Giesel EJNMMI 2017) (Giesel EJNMMI 2-017, 1771_ 177L EJNMMI EJNMMI 2017) J Med 2017 éJNMMl 2013) Lu-177-PSMA Subsequent expected survival 16—18 months from the time of progression. More recent data Preconditions: bone marrow reserve, kidney function 16.5 vs Cabazitaxel vs 75 25 15.1 vs 30.3 vs Docetaxel vs PSMA-imaging based personalized therapy concepts Biochemical response PSA > 50% in 45% of patients JNM 2017) 80 40 60 (VISION), multicenter, international 80 60 25 20 Chemotherapy (2 different types: Docetaxel and Cabazitaxel) TROPIC TAX 327 Chemotherapy (docetaxel, cabazitaxel) atter CTX (Docetaxel &Cabazitaxel) after CTX (Docetaxel &Cabazitaxel) 177Lu Radio frequency ablation of liver Radio frequency ablation Of liver All names and data of patients, parameters and configuration dependent designations are fictional and examples only. Mitoxantrone 19.9 Mitoxantrone 1717 34.7 average survival up to 2.4 years Subgroup with follow-up: 73% stable (28%) or remission (45%) i' -Earlier/more sensitive detection Of metastases, particularly in limited stages of disease -Earlier/more sensitive detection of metastases, particularly in limited stages of disease -Earlier/mnore sensitive detection Of metastases, particularly in limited stages of disease -Earller/more sensitive detection of metastases, particularly in limited stages of disease 33% with 6BGa-PSMA 62% with 18F-PSMA Novel options • If 2nd CT X is or Shows no effect • If 2nd C TX is or no effect If 2nd CTX is or shows no effect If 2nd CTX is contraindicated or Shows no effect Radium-223/Xofigo@orSamarium-153 Radium-223 improved OS PSMA Radium-223 improved OSme metastases All patients and their family members therapy • therapy 9. 68Ga-PSMA-11 18Fa-PSMA-71 18F_PSMA-7 68Ga-PSMA-11 E8Ga-PSMA-11 68Ga- 68Ga-PSMA-11 -New tracers and more sensitive camera technology may lead to further improvement 18F-DCPyL-PET 18F-DCFPyL-PET Survival without progress: 50% > 10 months,Overall survival: 70% > 15 months r, preconditions: bone marrow reserve (option: transfusion), Preconditions: bone marrow reserve (option: transfusion), preconditions: bone reserve (option: transfusion), Preconditions: bone marrow reserve, kidney function Preconditions: bone reserve (option: transfusion), • 223Radium therapy 223Radium therapy 0.2-0.5 0.5-2 PSA-value L PSA-value A PSA-value Sat PSA-value A PSA-value by 3,6 months as compared Local surgery or radiation therapy Following radiation therapy to first symptomatic skeletal All rights, including rights created by patent grant or registration of a utility model or design, are reserved. tSMA-Therapy PSMA-Therapy d weeks 1. 177Lu PSMA, 68Ga PSMA, and other imaging biomarkers referenced herein may not currently be kidney tunction. no urinary obstruction kidney function. no urinary obstruction kidney tunction, no urinary obstruction kidney function, no urinary obstruction Available data suggests survival benefit > 8 months LHRH: luteinizing releasing Robert Koch in Deutschland 2009/2010. 2013; O, Scher LHRH: releasing Robert Koch Krebs in Deutschland 2009/2010. 2013; Scher -May lead to more personalized concepts (image guided surgery/ radiation therapy), particularly in oligometastatic LHRH: releasing Robert Koch in Deutschland 2009/2010. 2013; Rathkopf D, Scher LHRH: luteinizing releasing Robert Koch Krebs in Deutschland 2009/2010. 2013; LHRH: releasing Robert Koch in Deutschland 2009/2010. 2013; LHRH; releasing Robert Koch in Deutschland 2009/2010. 2013; Rathkopf LHRH: hormon releasing Robert Koch Krebs in Deutschland 2009/2010. 2013; Scher LHRH; releasing Robert Koch in Deutschland 2009/2010. 2013; LHRH: releasing Robert Koch in Deutschland 2009/2010. 2013; D,thkopf Scher LHRH: releasing Robert Koch Krebs in 2009/2010. 2013; Rathkopf LHRH: releasing Robert Koch in 2009/2010. 2013; Rathkopf Scher LHRH: releasing Robert Koch in Deutschland 2009/2010. 2013; Scher LHRH: releasing Robert Koch in Deutschland 2009/2010. 2013; Rathkopf Scher LHRH: releasing Robert Koch Krebs in Deutschland 2009/2010. 2013;, LHRH: releasing Robert Koch in Deutschland 2009/2010. 2013; D, Scher LHRH: hormon releasing Robert Koch Krebs in Deutschland 2009/2010. 2013; LHRH: luteinizing hormon releasing GnRH; Robert Koch in Deutschland 2009/2020. 2013; Scher LHRH; releasing Robert Koch in Deutschland 2009/2010. 2013; Rathkopf Scher 177Lu-PSMA therapy (up to ex) (up 6x) (up (up to 6x) vs Placebo to placebo event by 5,8 months Comsensus with the German Consensus with the German Consensus with the German Competence Consensus with the Gerrnan Lassmann and Nosske 2013. Eur J Nucl Med Mol Imaging, Bruland OS, 18F-label: optimized image quality & contrast Grosse Hohkamp etal., Grcßse Hohkamp etal., Grwse Hohkamp et al., Grosse Hohkamp etal_, HI Cancer 2013; 43-49, S3-Letl e HI Cancer 2013; 19: 43-49, Onkologie: e HI Cancer 2013; 19: 43-49, Onkologie: S3-L e HI 2013; 19: 43-49, Leitlinienprogramm Onkologie: SYL e HI Cancer 2013; 19: 43-49, Onkologie: S3-Leltl e HI Cancer 2013; 19: 43-49, Onkologie: S3-Leitlinie 2014, and Clin Cancer 12: 16SS-1E71 20, HI Cancer 2013; 19: 43-49, Onkologie: S3-Letl e Hi cancer 2013; 43-49, S3-Leitlinie 2014, Pienta K] and D clin cancer Res 12: 1665-1671 20, HI Cancer 2013; 19: 43-49, On kologie: S3-Letl e HI Cancer 2013; 43-49, Leitlinienprogramm S3-Leitlinie 2014, K] and D (2006). 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Images: gayer Healthcare et al. Cancer 2006, Images: gayer Healthcare et al. Clin Cancer Rey 2006. Images: gayer Healthcare et al. Clin Cancer Res. 2006. Images: Healthcare iterative UHD UI-ID Heidenreich et al Heidenreich et Pain reduction similar to Samarium-153 Pain reduction smilar to Samarium-153 Tangen CM (2003) Clin prostate Cancer 2: 41—45, Francini al, , Prostate Cancer end prostatic Diseases 201B Tangen CM et (2003) Clin Prostate Cancer 2; 41—45, Francini Prostate Cancer and Prostatic Diseases situations, potentially postpone systemic therapies and improve survival. CM (2003) Clin Cancer 2: 41—45, Francini Prostate Cancer and Prostatic Diseases Tangen CM et (2003) Clin Prostate Cancer 2; 41—45, Francini prostate Cancer and Prostatic CM et (2003) prostate Cancer 2; 41—45, Francini prostate CM et (2003) Clin Prostate Cancer 2; 41—45, Francini prostate and Prostatic Diseases 201B CM et (2003) Clin Prostate Cancer 2: 41—45, Francini prostate Prostatic 201B CM et (2003) Clin Prostate 2; 41—45, Prostate Cancer 201B CM et (2003) Clin Prostate Cancer 2; 41—45, prostate Cancer Prostatic Diseases CM et (2003) Clin Prostate Cancer 2: 41—45, Francini Cancer and Diseases 201B CM et (2003) Clin Prostate Cancer 2: 41—45, Francini prostate and Prostatic Diseases CM et (2003) prostate Cancer 2; 41—45, Francini al, , prostate Prostatic CM et (2003) Clin prostate 2: 41—45, Francjni prostate Cancer and Prostatic Diseases CM et (2003) Clin prostate Cancer 2; 41—45, Francini al, , and Diseases 201B CM et (2003) prostate Cancer 2; 41—45, Francini al, , prostate Cancer Prostatic CM et (2003) prostate Cancer 2; 41—45. Francini prostate Prostatic CM et (2003) prostate Cancer 2; 41—45, Francini prostate Cancer 201B CM (2003) Clin Cancer 2; 41—45, Francini Prostate Cancer and Prostatic Diseases CM et (2003) prostate Cancer 2; 41—45, Francini Crostancer Cander Prostatic 201B CM et (2003) Clin Prostate Cancer 2; 41—45, Francini prostate Prostatic 201B Tangen CM et (2003) Clin Prostate Cancer 2: 41—45, Francini Cancer and Prostatic Diseases CM et (2003) prostate Cancer 2; 41—45, prostate CM (2003) Clin Prostate Cancer 2; 41—45, Fral, ,i Prostate Cancer and Prostatic 201Bases CM et (2003) Clin Prostate Cancer 2; 41—45, prostate Cancer 201B recognized by the U.S. Food and Drug Administration (FDA) or other regulatory agencies as being Personalized image guided approaches (Surgery/Radiation) @ 2015. university Of Cologne @ 2015, University Of Cologne University of Cologne @ 2015. JnlVevsity Of Cologne @ 2015. University Of Cologne @ 2015, Univevsity Of Cologne @ 2015. Of Cologne @ 2015. Jn•vevsity Of Cologne Dienein J Nucl Med. 2017 Dienein et al. J Nucl Med. 2017 et J Nucl Med. 2017 952 et al. J Nucl Med. 2017 Koln, unpublished data 12/2016, Koln. unpublished data 12/2016, Nucl Med 2017 J Med 2017 Med 2017 Copyright O Siemens Healthcare GmbH 2020 Mindy I. Devis et al. PNAS 2005, Cder. ileborkorn. Cisonhutet al. Mir,dy Davis et PNAS 2005. Cder. 'laborkorn. Cisenhutet Mirrdy Davis et PNAS 2005. Cder. 'laborkom. CiW1hutetaI. Mindy I. Devis et PNAS 2005, Cder. [laborkorn. Cisonhutet al. Mindy I Davis et PNAS 2005, Eder. Elaborkom, Mindy I. Davis et al. PNAS 2005. Eder. ilaborkorn. Eisenhut et al. Mindy I. Davis et PNRS 2005. Cder. Haberkorn, Cisonhutet Mindy I. Devis et al. PNAS 2005. Cder. "laberkom. CiW1hutetaI. Mindy I. Davis et al. PNAS 2005. Cder. 'laborkom., Eisenhutet al. Mindy I. Davis et PNAS 2005. Cder. ilaborkorn. Eisenhutet al. Mindy Devis et PNAS 2005. Cder. 'laborkom, Cisenhutet al. Mindy Davis et al. PNAS 2005. Cder. ilaberkorn. CiW1hutetaI. 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IS: 252-60 20C4, C 16: 252-60 20C4, C 2015: 16: 252-60 20C4, C 2015: IS: 252-60 C 2015: 152-60 C 2015: 16: February 2015 J 2015 2015 November 2014 UJniversity of Cologne, Germany e University of Cologne University of Cologne, Germany University of Cologne IJniversity of Cologne, Germany Dietlein,et al. unpublished data Dietlein, Kobe al. Mol 'mg & Biol 2015 Diotlein, Kobe et al. Mol Img & Biol 2015 Rauscher et ah Der Urologc 2016 et ah Der Urologe 2016 Bioconjugate Chemistry 2012. garinka et J Med 2008 Bioconjugate Chemistry 2012. garinka et J Med Chem 2008 diaconjugate Chemistry 2012. Jarinka et aL J Med Chem 2008 dioconjugate Chemistry 2012. garinka et J Med Ch,em 2008 dioconjugate Chemistry 2012. Jarinka et J Med Chem 2008 Bioconjugate Chemistry 2012. gerinka et J Med 2008 Rauscner et ah Der urologe 2016 2016 10.6 1006 et aL Der urologc 2016 et ah Der urologe 2016 @ aaues et al Department of Radiotherapy. University of Cologne @ aaues et al Depart"lent of Radiotherapy. University of Cologne @ aaues et al Departrnent of Radiotherapy. University of Cologne O University Of Cologne of of Col for ml 7 ml 7 ne safe and effective. Siemens does not make any claims regarding their use. Siemens Healthineers Headquarters Alexander Drzezgo Alexander Drzezgc Alexander Drzezga achieved in the customer's unique setting. Since there is no "typical" hospital and many variables The herein illustrated statements made by Siemens' customers and physicians are based on their Siemens Healthcare GmbH UJniversity of Cologne, Germany IJniversity of Cologne, Germany University of Cologne, Germany University of Cologne U-Jniversity of Cologne, Germany I-Jniversity of Cologne, Germany niversl Of Cologne, Ger exist (e.g., hospital size, case mix, level of IT adoption) there can be no guarantee that other own and discrete opinion. 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