PARP inibitori nel trattamento del carcinoma mammario metastatico: recenti successi e prospettive future.

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1 PARP inibitori nel trattamento del carcinoma mammario metastatico: recenti successi e prospettive future. Dr.ssa Angela Toss Centro Oncologico Modenese Università di Modena e Reggio Emilia

2 MECHANISMS OF ACTION OF PARP INHIBITORS PHASE III TRIALS IN ADVANCED BREAST CANCER OLYMPIAD trial (ASCO 2017) EMBRACA trial (SABCS 2017) RECENT UPDATES (ASCO 2018) FUTURE PERSPECTIVES

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4 Reactive Oxygen Species (ROS) Replication Errors X Rays UV Light Alkylating Agents Spontaneous Reactions SINGLE-STRAND BREAKS (SSBs) DELETIONS and INSERTIONS DOUBLE-STRAND BREAKS (DSBs) BASE EXCISION REPAIR (BER) PARP NUCLEOTIDE EXCISION REPAIR (NER) XP, POLYMERASES MISMATCH REPAIR (MMR) MLH1, MSH2, MSH6, MLH3, PMS2 HOMOLOGOUS RECOMBINATION (HR) ATM/ATR, BRCA1/2, CHEK2, RAD51, BRIP1, PALB2 NON HOMOLOGOUS END JOINING (NHEJ) DNA-PXcs, Mre11, RAD50, NBS1 Toss and Cortesi. J Canc Sci Therapy 2013 Cortesi L et al. Curr Cancer Drug Targets 2018

5 SINGLE-STRAND BREAKS BER NER MMR REPAIR PARP INHIBITORS DOUBLE-STRAND BREAKS HR NHEJ BRCA MUTATION CARRIERS CELL DEATH REPAIR Toss and Cortesi. J Canc Sci Therapy 2013 Cortesi L et al. Curr Cancer Drug Targets 2018

6 PARPi prevent dissociation of recruited PARPs from DNA-damage sites: these stabilized PARP/DNA complexes determine stalling of the replication fork during DNA replication, with subsequent formation of double strand breaks. Murai J et al. Cancer Res Livraghi and Garber, BMC Medicine 2015

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8 BRAVO OlympiAD EMBRACA Isakoff SJ et al, Future Oncol. 2017

9 OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and a germline BRCA mutation Presented By Mark Robson at 2017 ASCO Annual Meeting

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11 OlympiAD study design Presented By Mark Robson at 2017 ASCO Annual Meeting

12 Statistical analysis plan Presented By Mark Robson at 2017 ASCO Annual Meeting

13 Primary endpoint: progression-free survival by BICR Presented By Mark Robson at 2017 ASCO Annual Meeting

14 Overall survival (interim analysis; 46% data maturity) Presented By Mark Robson at 2017 ASCO Annual Meeting

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16 Objective response by BICR Presented By Mark Robson at 2017 ASCO Annual Meeting

17 Subgroup analyses: PFS by BICR Presented By Mark Robson at 2017 ASCO Annual Meeting

18 Subgroup analyses: PFS by BICR Presented By Mark Robson at 2017 ASCO Annual Meeting

19 Subgroup analyses: PFS by BICR Presented By Mark Robson at 2017 ASCO Annual Meeting

20 Adverse events (any grade) in 15% of patients Presented By Mark Robson at 2017 ASCO Annual Meeting

21 Grade 3 adverse events in 2% patients in either arm Presented By Mark Robson at 2017 ASCO Annual Meeting

22 An open-label trial design was made necessary by the use of different treatments in the control group. Heterogeneous study population in terms of hormonal-receptor status, previous use of chemotherapy, and previous use of platinumbased treatments. The trial was not powered to detect any differences in effect that are suggested by subgroup analyses. Since platinum agents were not included as treatment options in the control group, the trial cannot address the relative benefits of olaparib and platinum-based chemotherapy

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30 29 March 2017 BRAVO Clinical Trial Important Notification Following an interim analysis of data by the independent data monitoring committee (IDMC), the BRAVO Steering Committee has concluded that any further recruitment would not be productive in generating a clinically useful endpoint. An unusually high rate of discontinuations occurred prior to the first scan for patients in the physician s choice chemotherapy control arm resulting in an imbalanced censoring between arms. It is important to note that the IDMC has found no new safety concerns with respect to niraparib. The Steering Committee will receive the data from the IDMC to better understand the data, and to assess the benefit of niraparib to patients on study and guidance will be provided to Investigators as soon as it is available. Further enrollment is now being stopped.

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32 OLYMPIAD: VISCERAL AND CNS METASTASES ASCO 2018

33 ASCO 2018

34 EMBRACA: CLINICALLY RELEVANT SUBGROUPS ASCO 2018

35 ASCO 2018

36 OLYMPIAD + EMBRACA: A META-ANALYSIS ASCO 2018

37 ASCO 2018

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39 OVERCOMING THE MECHANISMS OF RESISTANCE (platinum cross-resistance?) ROLE OF MUTATIONS IN DNA DAMAGE REPAIR GENES OTHER THAN BRCA1 and BRCA2 (such as PALB2, CHEK2, RAD51C, and RAD51D) BIOMARKERS OF RESPONSIVENESS BEYOND GERMLINE SETTING (somatic mutations?) COMBINATION STRATEGIES (chemotherapy? immunotherapy?)

40 OVERCOMING THE MECHANISMS OF RESISTANCE (platinum cross-resistance?) ROLE OF MUTATIONS IN DNA DAMAGE REPAIR GENES OTHER THAN BRCA1 and BRCA2 (such as PALB2, CHEK2, RAD51C, and RAD51D) BIOMARKERS OF RESPONSIVENESS BEYOND GERMLINE SETTING (somatic mutations?) COMBINATION STRATEGIES (chemotherapy? immunotherapy?)

41 PLATINUM CROSS-RESISTANCE

42 OVERCOMING THE MECHANISMS OF RESISTANCE (platinum cross-resistance?) ROLE OF MUTATIONS IN DNA DAMAGE REPAIR GENES OTHER THAN BRCA1 and BRCA2 (such as PALB2, CHEK2, RAD51C, and RAD51D) BIOMARKERS OF RESPONSIVENESS BEYOND GERMLINE SETTING (somatic mutations?) COMBINATION STRATEGIES (chemotherapy? immunotherapy?)

43 ASCO 2018

44 OVERCOMING THE MECHANISMS OF RESISTANCE (platinum cross-resistance?) ROLE OF MUTATIONS IN DNA DAMAGE REPAIR GENES OTHER THAN BRCA1 and BRCA2 (such as PALB2, CHEK2, RAD51C, and RAD51D) BIOMARKERS OF RESPONSIVENESS BEYOND GERMLINE SETTING (somatic mutations?) COMBINATION STRATEGIES (chemotherapy? immunotherapy?)

45 OVERCOMING THE MECHANISMS OF RESISTANCE (platinum cross-resistance?) ROLE OF MUTATIONS IN DNA DAMAGE REPAIR GENES OTHER THAN BRCA1 and BRCA2 (such as PALB2, CHEK2, RAD51C, and RAD51D) BIOMARKERS OF RESPONSIVENESS BEYOND GERMLINE SETTING (somatic mutations?) COMBINATION STRATEGIES (chemotherapy? immunotherapy?)

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52 Olaparib e Talazoparib sono i primi inibitori di PARP a mostrare un miglioramento della PFS nel setting mammario avanzato. Attendiamo dati maturi per OS. Diversi temi restano aperti: Tutti i MBC o solo TNBC? Quale ruolo del platino ora? Geni other than BRCA? Mutazioni somatiche? Strategie di combinazione? Vantaggio a fronte di incremento tossicità? A CHI PROPONGO IL TEST BRCA e con quale TIMING??

53 GRAZIE PER L ATTENZIONE