Financial and Other Disclosures

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1 Financial and Other Disclosures Off-label use of drugs, devices, or other agents: None Data from IRB-approved human research is not presented I have the following financial interests or relationships to disclose: No financial relationships Disclosure code N Immatics BMY Aveo VVUS PTN Investor shareholder shareholder shareholder shareholder 1

2 Radical prostatectomy in oligometastatic prostate cancer Markus Hohenfellner & Luisa Hofer Departement of Urology, University of Heidelberg Luisa Hofer

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4 Definition "Oligometastatic patients" status between local and diffuse metastatic tumor Today: in most studies 1-5 metastasis in distant lymph nodes or bones Hellman and Weichselbaum 1995 J Clin Oncol

5 Diagnosis in high risc PCA patients Standard diagnostic in high risc patients today: bone scintigraphy and CT/MRI abdomen/pelvis Detection of lymph node metastasis: CT 42% sensitivity, 82% specificity MRI 39% sensitivity, 82% specificity Cholin-PET 49% sensitivity, 95% specificity PSMA-PET 65% sensitivity, 96% specificity In combination with CT/MRI as PSMA-PET-CT/MRI also detection of bone and visceral metastasis possible Today: PSMA-PET-CT is the optimal primary diagnostic for high risc patients 06/17, Maurer, Eiber et al Nat Rev Urol

6 Diagnosis in high risc PCA patients "Oligometastasis" is a relative diagnosis probably a lot of undetected- oligometastatic patients received already a radical prostatectomy 06/17, Maurer, Eiber et al Nat Rev Urol

7 EAU guidline

8 Improving OS through cytoreduction Renal cell carcinoma (Nx+interferon vs. interferon, 13.6 vs. 7.8 months median survival) Her2+ breast cancer stadium IV (resection of the primary tumor vs. no surgery, median survival 66 vs. 28 months) Ovarian cancer ( 25% cytoreduction = median survival 22.7 months vs. 75% cytoreduction = 33.9 months) peritoneal metastatic colon carcinoma (HIPEC + cyto- reduction vs. i.v. chemotherapy, median survival 22.4 vs months) Flanigan, Mickisch et al J Urol, Tan, Li et al Oncotarget Bristow, Tomacruz et al J Clin Oncol, Verwaal, van Ruth et al J Clin Oncol

9 Elimination of the primary tumor as possible source of metastasis Haffner, Mosbruger et al J Clin Invest

10 Ways of metastasis Primary tumor as nutrition media for aggressive circulating cells (= Self- Seeding ) Linear metastasis at multiple time points Tumor stem cell as source for metastasis Kim, Oskarsson et al Cell, Turajlic and Swanton 2016 Science, Collins, Berry et al Cancer Res

11 Elimination of the primary tumor as possible source of metastasis Gundem, Van Loo et al Nature

12 Elimination of the primary tumor as possible source of metastasis Understanding the individual situation by: molecular imaging biologic markers liquid biopsy sequencing neuronal BigData management Gundem, Van Loo et al Nature

13 Indication: Survival after local therapy in M1 patients SEER Data Base (n=8185) RPx (n=245) vs. no LT - 5 -year OS: 64% vs. 22.5% (p < 0.001) - CSS: 75.8% vs. 48.7% (p < 0.001) patients in no LT group older (72 vs. 62a) National Cancer Data Base (n= 1470) 3-year overall survival - with vs. without LT: 69% vs. 54% (p < 0.001) - RPx (n=1470) vs. RT: 78% vs. 60% (p < 0.001) Culp, Schellhammer et al Eur Urol Culp, Schellhammer et al Eur Urol; Loppenberg, Dalela et al Eur Urol

14 Indication: Survival after local therapy in M1 patients Tumor registry Munich (n=1538) 5-year overall survivall RPx (n=74) vs. no LT: 55% vs. 21% (p < 0.01) Heidenreich et al: (n=23, <3 bone metastasis) Tumorspecific overall survival after 40 months RPx vs. no LT: 95% vs. 84% (p < 0.05) Gratzke, Engel et al Eur Urol Gratzke, Engel et al Eur Urol; Heidenreich, Pfister et al J Urol

15 RPx in HD in M1 patients ( ): n = 59 Mean age= 62,6 years, preoperative PSA= 23.7 ng/ml, removed lymph nodes= 29 Tumor data base Heidelberg

16 RPx in HD in M1 patients ( ): n = 59 Tumor data base Heidelberg

17 Individual therapies RPX+AHTneo n = 7 RPX+AHTneo+RaL n = 1 RPX+AHTneo+RaP n = 1 RPX+AHtneo+RaP+RaL n= 1 RPX+AHTneo+AHTp n = 14 RPX+AHTneo+AHTp+RaL n = 8 RPX+AHTneo+AHTp+RaP n = 6 RPX+AHTneo+AHTp+RaP+RaL n = 7 RPX n = 2 RPX+RaP n = 1 RPX+orchiectomy n = 2 RPX+AHTp n = 5 RPX+AHTp+RaL n = 3 RPX+AHTp+RaP+RaL n = 3 Tumordatenbank Heidelberg

18 Indication: Survival after local therapy in M1 patients BIAS in all studies: retrospective, selection bias of the better patient, additional therapy

19 Treatment of metachronic metastasis? 1) Theory of indirect metastasis 2) Therapy of metachronic metastasis is possible: radiotherapy of bone, lymphatic and visceral metastasis leads up to 25 months free of AHT, current study: Surveillance vs. Radiatio 3) Ext. LAE in high risc patients prolongs cancer specific overall survival (Gundem, Van Loo et al Nature)(Ost, Bossi et al Eur Urol)(Decaestecker, De Meerleer et al BMC Cancer), (06/17),(Abdollah, Gandaglia et al Eur Urol)

20 Neo-adjuvant therapy No evidence of a longer OS with a neo-adjuvant therapy with AHT and/or chemotherapy in high risc patients BUT Reduction of the ct status Lower rate of positiv surgical margins Reduction of pn+ Individual benefit/risk stratification concerning flush and gynaecomasty in case of AHT (McKay, Choueiri et al Drugs)(Tosco, Laenen et al Prostate Cancer Prostatic Dis)(Shelley, Kumar et al Cancer Treat Rev)(Chi, Chin et al J Urol)

21 Current multicentric study: g-rammp inclusion criteria: 1-5 bone metastasis, PSA < 200 ng/ml Martini-Klinik Hamburg: (06/18)

22 Current studies MD Anderson Cancer Center in den USA: prospective, multicentric, randomised, M1 patients

23 Case report- primary bone metastasis in PCa patient - 53 year old patient - First diagnosis 12/13 - Initial PSA 130 ng/ml - GS 9 - singular (?) metastasis right Os pubis PSMA-PET-CT

24 Case report 12/ /2014 start of a neo-adjuvant antihormonal treatement with Leuprorelin und Bicalutamid davinci-assisted radical prostatectomy with ext. lymphadenectomy (pt3b, pn0/15, R1) 03/ /2014 Sorafenib 07-09/2014 adjuvant radiotherapy of the prostate and the bone metastasis (68 Gy) antihormonal treatement with Leuprorelin und Bicalutamid 03/2015 end of the first cycle of antihormonal treatement 11/2016 biochemical relapse from PSA 0.01 to 2 ng/ml and diagnosis of bone metastasis (5.+6. rib and prox. femur) restart of antihormonal therapy 6 cycles of docetaxel Current PSA under AHT ng/ml, good general condition, good continence

25 Indication: local morbidity Prevention and/or therapy of: macrohaematuria urinary retention obstruction of the ureter infiltration of the rectum => RPx vs. AHT, symptomatic local recurrence 25.7% vs. 75.0% Wiegand, Hernandez et al BJU Int; Won, Gurney et al BJU Int

26 Conclusio RPx in oligometastatic patients No evidence of randomised controlled studies means not that RPx is not efficient in metastatic patients meta analysis show possible better oncological outcome Improving the local situation in a safe operation in patients with intact pelvic floor Careful and individual indication Part of a structured-anticipative multimodale concept (neoadjuvant, adjuvant, salvage)

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