NOVOSTI V SISTEMSKEM ZDRAVUENJU RAKA JAJČNIKOV Erik Škof Onkološki Inštitut, Ljubljana RAK JAJČNIKOV - BOLEZEN SE POGOSTO PONOVI Operacija Kemoterapija Bevacizumab fffff fffff 10-18 mesecev Mediani čas preživetja brez ponovitve bolezni2,3,4 -70% bolnic ima ponovitev bolezni 3 leta od pričetka zdravljenja1 -40% 40 mes. 5-letno preživetje5 Celokupno preživetje' Potrebno je izboljšati učinkovitost primarnega zdravljenja z namenom izboljšanja izhoda zdravljenja bolnic z rakom jajčnikov1-5 83 NOVE EVROPSKE SMERNICE - LETA 2019 1 PVWfl^ ooccsecME Annals of Oncology 30:672- 705,2019 1 «"« »micM dot 10.1093/an nonc/mdz062 ^BM T MJ ,LiI "H™ Published online 2 May 2019 § g QC N l -r ^ -J O CQ S SPECIAL ARTICLE ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease1 I QC CQ O CL £ £ CL S CQ O O N. Colombo1*, C. Sessa2, A. du Bois3, J. Ledermann4, W. G. McCluggage5,1. McNeish6, P. Morice7, S. Pignata8,1. Ray-Coquard9,1. Vergote10,1T. Baert3,1. Belaroussi7, A. Dashora12, S. Olbrecht10,11, F. Planchamp13 & D. Querleu14*, on behalf of the ESMO-ESGO Ovarian Cancer Consensus Conference Working Group4 Original Article gyneMogical cancer ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease N Colombo,1 C Sessa,2 A du Bois,3 J Ledermann,4 WG McCluggage,5 I McNeish,6 P Morice,7 S Pignata,8 I Ray-Coquard,9 I Vergote,10,11 T Baert,3 I Belaroussi,7 A Dashora,12 S Olbrecht,10,11 F Planchamp,13 & D Querleu,14 on behalf of the ESMO-ESGO Ovarian Cancer Consensus Conference Working Group 84 PRIMARNO SISTEMSKO ZDRAVLJENJE > Novosti: > Zaviralci PARP* v L liniji po OP in KT - stadij HI/IV > Raziskava SOLO-l: olaparib1 > Raziskava PRIMA: niraparib2 > Raziskava PAOLA-1: olaparib+bevacizumab3 > Določanje mutacije BRCA 1/2 - za namen zdravljenja > Iz krvi (zarodna) > Iz tumorja (somatska/zarodna) > Določanje okvare HR** - v razvoju.... PARP* - poli ADP riboza polimeraza HR ** - homologna rekombinacija 7-Moore K, et al. N Engl J Med 2018; 2- González-Martín A, et al. N Engl J Med 2019; 3-Isabelle Ray-Coquard, et al. N Engl J Med 2019 85 RAZISKAVA SOLO-1: OLAPARIB V1. LINIJI PRI BRCA 1/2 MUTIRANIH PFS benefit of maintenance olaparib was sustained beyond the end of treatment CD «J —' > 0.7" 9) » 0.6 - » I 0.5" o 04 " h h. 1 0.3" o. 0.2 _ 0 1" 0.0 PFS benefit of maintenance olaparib was consistent in higher- and lower-risk subgroups Higher-risk Baseline characteristic, n (%) Interval debulking surgery CR to pnor chemotherapy* BRCAIm BRCA2m BRCAIm and BRCA2m 2-year treatment cap Median PFS, months Olaparib (N=146) Placebo (N=73) 94 (64) 43 (59) 107 (73) 54 (74) 109 (75) 43 (59) 36 (25) 30 (41) 1(1) 0 (N=142)t (N=72)t 73 (51) 59 (82) 40.6 11.1 HR 0.35 (95% CI 0.25-0.49) -i--1-1-1--1-1-1--1-1-1--1-1-1--1-1-1-r 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 Months since randomization No. at risk Olaparib 142 Placebo 72 131 124 110 114 104 00 05 88 76 67 66 63 60 56 56 52 50 48 46 31 27 15 6 64 52 39 20 23 21 18 18 17 16 12 12 12 11 11 10 10 10 10 6 4 1 1 Lower-risk Baseline characteristic, n (%) Interval debulking surgery CR to pnor chemotherapy* BRCAIm BRCA2m BRCAIm and BRCA2m 2-year treatment Median PFS, months 71% Olaparib (N=114) Placebo (N=58) 0 0 106 (93) 53 (91) 82 (72) 48 (83) 30 (26) 10(17) 2(2) 0 (N=114) (N=58) 43 (38) 40 (69) NR 21.9 HR 0.38 (95% CI 0.25-0.59) -1-1-1-1--1-1-1--1-1-1--1-1-1--1-1-1-r 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 Months since randomization 114 105 102 00 06 05 03 87 83 73 71 67 64 63 57 51 47 47 43 40 27 23 15 58 53 50 43 36 33 32 20 23 22 22 10 18 16 13 13 13 13 12 11 10 10 2 SGO VIRTUAL ANNUAL MEETING 2021 ON WOMEN'S CANCER* *As randomized. tPFS analysis by nsk excludes five patients recruited in China. Investigator-assessed by modified RECIST v1.1. DCO: March 5, 2020. _ CR, complete response. SockW Oncologic Raziskava PRIMA: Niraparib v 1. liniji (ne glede na mutacijo BRCA 1/2) European Network of Gynaecological Oncological Trial groups Grup» FlKiitiñol dc Investigación eil Cancer ele Ovario Gynecologic Oncology Group Niraparib Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer (PRIMA/ENGOT-OV26/GOG-3012) A. González-Martín,1 B. Pothuri,21. Vergote,3 R.D. Christensen,4 W. Graybill,5 M.R. Mirza,6 C. McCormick,7 D. Lorusso,8 P. Hoskins,9 G. Freyer,10 F. Backes,11 K. Baumann,12 A. Redondo,13 R. Moore,14 C. Vulsteke,15 R.E. O'Cearbhaill,16 B. Lund,17 Y. Li,18 D. Gupta,18 B.J. Monk19 1 Grupo Español de Investigación en Cáncer de Ovario (GEICO), Medical Oncology Department, Clínica Universidad de Navarra, Madrid, Spain; 2Gynecologic Oncology Group (GOG), Department of Obstetrics/Gynecology, Perlmutter Cancer Center, NYU Langone Cancer Center, New York, NY, USA; 3Belgium and Luxembourg Gynaecological Oncology Group (BGOG), Department of Gynaecology and Obstetrics, Division of Gynaecologic Oncology University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium; 4Nordic Society of Gynaecological Oncology (NSGO), Research Unit of General Practice, Institute of Public Health, University of Southern Denmark, Odense, Denmark;5 GOG, Gynecologic Oncology, Medical University of South Carolina, Charleston, SC, USA; 6NSGO, Rigshospitalet-Copenhagen University Hospital, Copenhagen, Denmark; 7GOG, Legacy Medical Group Gynecologic Oncology, Portland, OR, USA; Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO), Fondazione IRCCS National Cancer Institute of Milan, Milan, Italy; 9US Oncology Research (USOR), Department of Medical Oncology, BC Cancer - Vancouver, Vancouver, BC, Canada; 10Groupe d'lnvestigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), HCL Cancer Institute Department of Medical Oncology Lyon University, Lyon, France; 11Division of Gynecologic Oncology, Ohio State University, Columbus, OH, USA; "Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), Department of Gynecology and Obstetrics, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany; 13GEICO, Hospital Universitario La Paz-ldiPAZ, Madnd, Spain; 14USOR, Division of Gynecologic Oncology Wilmot Cancer Institute, Department of Obstetncs and Gynecology, University of Rochester, Rochester, NY, USA; 15BGOG, Department of Medical Oncology and Hematology, AZ Maria Middelares, Gent, and Department of Molecular Imaging, Pathology, Radiotherapy & Oncology, Center for Oncological Research, Antwerp University, Antwerp, Belgium; 16GOG, Gynecologic Medical Oncology, Memorial Sloan Kettering Cancer Center, and Department of Mediane, Weill Cornell Medical College, New York, NY, USA; 17NSGO, Department of Oncology, Aalborg University, Aalborg, Denmark; 18TESARO: A GSK Company, Waltham, MA, USA; 14Anzona Oncology (US Oncology Network), University of Arizona College of Medicine, Phoenix Creighton University School of Medicine at St. Joseph's Hospital, Phoenix, AZ, US BARCELONA 2019 ESVEf ongress esmo.org 88 Raziskava PRIMA: Niraparib v 1. liniji (ne glede na mutacijo BRCA 1/2) PRIMA Primary Endpoint, PFS Benefit in the Overall Population 1001> 90- 80 - 70 ■ 3 60 - 70- 3 (/) 60- CD 0) 50- C O 40- (/> (/) <1> 30- U) o Q_ 20- 10-0 Hazard ratio: 0.43 (95% Cl, 0.31-0.59) p<0.001 -W-+--+- Placebo 0 4 Initiation of PRIMA Lafterco mp[et[onqflL CT Niraparib 247 231 215 Placebo 126 117 99 -i—i—|—i—|—i—|—i—|—i—|—i—|—i—|—i—|—i—|—i—|—i— 6 8 10 12 14 16 18 20 22 24 26 28 Months since Randomization 189 184 168 111 76 66 42 22 19 13 4 0 79 70 57 34 21 21 11 5 5 4 1 0 57% reduction in hazard of relapse or death with niraparib Niraparib (n=247) Placebo (n=126) Median PFS months (95% CI) 21.9 (19.3-NE) 10.4 (8.1-12.1) Patients without PD or death (%) 6 months 86% 68% 12 months 72% 42% 18 months 59% 35% BARCELONA 2019 ES vtf ongress 1L, first-line; Cl, confidence interval; CT, chemotherapy; HR, homologous recombination; NE, not estimable; PD, progressive disease; PFS, progression-free survival. Sensitivity analysis of PFS by the investigator was similar to and supported the BICR analysis. 90 RAZISKAVA PRIMA: NIRAPARIB V 1. LINIJI (NE GLEDE NA MUTACIJO BRCA 1/2) PRIMA PFS Benefit in Biomarker Subgroups 100 90 80 "5 > 70 t 3 CO 60 8 50 - C o 40 tn t/t 0) 30 D) O k- 20 Q. 10 0 { Homologous Recombination Deficient (HRd) HRd/ßRC4mut HRd/ßRC4wt Hazard ratio: 0.40 (95% CI, 0.27-0.62) Hazard ratio: 0.50 (95% CI, 0.31-0.83) 4t—I—«tt—t- Placebo H-'-1-'-1-'-1-'-1-'-1-'-1-'-1-'-1-'-1-'-1-'-1-1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Months since Randomization HR-proficient Hazard ratio: 0.68 (95% CI. 0.49-0.94) 6 8 10 12 14 16 18 20 22 24 26 28 Months since Randomization 6 8 10 12 14 16 18 20 22 24 26 28 Months since Randomization Niraparib provided similar clinical benefit in the HRd subgroups (BRCAmut and BRCAwi) Niraparib provide clinically significant benefit in the HR-proficient subgroup with a 32% risk reduction in progression or death OHgrGSS C|, confidence interval; HR, homologous recombination; mut, mutation; PFS, progression-free survival wt, wild-type. BARCELONA 2019 ES 91 RAZISKAVA PAO LA-1: O LA PAR IB + BEVACIZUMAB V 1. LINIJI (ne glede na mutacijo brca 1/2) BARCELONA 2019 □vif ongress (j engot * / European Network erf ■ GYNECOLOGIC CANCIH INTtROROfP ARCAQV - OINECO European Network of Gynecological Oncological Trial groups Phase III PAOLA-1/ENGOT-ov25: maintenance olaparib with bevacizumab in patients with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy and bevacizumab as standard of care Isabelle Ray-Coquard, Patricia Pautier, Sandro Pignata, David PéroL Antonio Gonzalez-Martin, Paul Sevelda, Keiichi Fujiwara, Ignace Vergote, Nicoletta Colombo, Johanna Mäenpää, Frédéric Selle, Jalid Sehouli, Domenica Lorusso, Eva Maria Guerra Alia, Claudia Lefeuvre-Plesse, Ulrich Canzler, Alain Lortholary, Frederik Marmé, Eric Pujade-Lauraine, Philipp Harter ^..... "GCTIC MaNGO VyN5ED-CTU esmo.org ClinicalTrials.gov identifier: NCT02477644 This study was sponsored byARCAGY Research 92 RAZISKAVA P AO L A-1: OLAPARIB + BEVACIZUMAB V 1. LINIJI (ne glede na mutacijo brca 1/2) PFS by investigator assessment: ITT population (., ENGQT \ J EurtpMrHeftwrftof ▼ / (ifMKtiofirjl Onroiogtrji Vul grrwpc GYNECOLOGIC L'ANCtK IV 1 » Hc.WOt1 AflCAOV OINtCO ä- ra —- CD jz a) ro T3 E 2 O <1) 42. "This median is unstable due to a lack of events - less than 50% maturity 94 Dejavniki" ki vplivajo na homologno rekombinacijo OTHER (some may be HR deficient via upregulation of miRNAs or other mechanisms) Other 21% HR DEFICIENT BRCA1 germline mutations 8% BRCA1 somatic mutations 3% NER mutations 4-8% MMR mutations 3% Cyclin E1 amplification 15% HR PROFICIENT BRCA2 germline mutations 6% BRCA2 somatic mutations 3% BRCA1 promoter methylation 10% CDK12 mutations 3% RAD51C promoter methylation 2% FA gene mutations 2% j PTEN j homozygous EMSY \-Core RAD gene mutations 1.5% 1 HR DNA-damage gene mutations 2% loss 7% amplification 6% ^ POSSIBLY HR DEFICIENT 95 SISTEMSKO ZDRAVLJENJE PONOVITVE BOLEZNI ► Novosti: > Uporaba izraza „občutljivost oz. rezistenca na platino" samo na osnovi PFI (platinum-free intervala) je „zastarelo", namesto tega: > Platinum is an option vs. platinum is not an option ► Zaviralci PARP* - vzdrževalno, ne glede na BRCA (EMA) > olaparib - raziskavi SOLO-21 > niraparib - raziskava NOVA2 > rucaparib - raziskava ARIEL 33 > Biološko podobno zdravilo bevacizumaba * PARP - poli ADP riboza polimeraza i-Pujade-Lauraine E, et al. Lancet 2017; 2- Mirza MR, et al. NEJM 2016, 3- Coleman RL, et al. Lancet 2017 SISTEMSKO ZDRAVLJENJE - NOVOSTI V SLOVENIJI (1) > Primarno sistemsko zdravljenje > Vzdrževalno zdravljenje (po OP in KT) - stadij III/IV > olaparib (pri BRCA mutiranih) - 2 leti > niraparib (ne glede na BRCA) - 3 leta > bevacizumab (ne glede na BRCA) - 15 mesecev >► biološko podobno zdravilo bevacizumaba (MVASI®) > olaparib + bevacizumab - sprožen postopek za odobritev ZZS > Zdravljenje ponovitve bolezni > Vzdrževalno zdravljenje (po odgovoru na KT s platino) > olaparib (pri BRCA mutiranih) > niraparib (ne glede na BRCA) > bevacizumab (ne glede na BRCA) >► biološko podobno zdravilo bevacizumaba (MVASI®) SISTEMSKO ZDRAVLJENJE - NOVOSTI V SLOVENIJI (2) >Od januarja 2019: > Določanje mutacije BRCA 1/2 > Iz tumorja (somatska/zarodna) > Iz krvi (zarodna) * Namen testiranja BRCA je: > Izbor optimalnega vzdrževalnega zdravljenja (olaparib, niraparib, bevacizumab) > preventiva raka dojk in jajčnikov > Posodobljena klinična pot za testiranje mutacije v genih BRCA 1/2 > Določanje okvare HR (poleg BRCA) - v fazi raziskovanja... * po predhodnem genetskem svetovanju 98 SISTEMSKO ZDRAVLJENJE - NOVOSTI V SLOVENIJI (3) g ► Naše izkušnje s testiranjem BRCA s o Research article | Open Access | Published: 02 April 2019 QC Cytology material is equivalent to tumor tissue in N 1 ° determining mutations of BRCA 1/2 genes in patients 1 ^ -j I o with tubo-ovarian high grade serous carcinoma CQ S s Andreja Gornjec, Srdjan Novakovic. Vida Stegel. Marko Hočevar. Živa Pohar Marinsek. Barbara Gazic. Mateja Kraje & Erik SkofS QC CQ O BMC Cancer 19. Article number: 296 (2019) Cite this article ■ CL s £ CL Aktualno v primeru, če testiranje iz tumorskega tkiva (FFPA) ni možno ^ CQ O Pi - neprimeren material L-J O to - operacija/biopsija ni možna 99 SISTEMSKO ZDRAVLJENJE - NOVOSTI V SLOVENIJI (4) >► Naše izkušnje z zdravilom olaparib 12 ONKOLOGIJA ISSN 1408-1741 IZVIRNI ZNANSTVENI ČLANEK | LETD XXV ŠT 1 | JUNIJ 2021 Izkušnje z zdravilom olaparib pri zdravljenju recidivnega epitelijskega raka jajčnikov z mutacijami v genih BRCA lin BRCA 2 Experience with olaparib in the treatment of recurrent ovarian epithelial cancer with mutations in the BRCA 1 and BRCA 1 genes