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
• 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
SINGLE-STRAND BREAKS (SSBs)
DELETIONS and INSERTIONS DOUBLE-STRAND BREAKS (DSBs)
BASE EXCISION
REPAIR (BER)
NUCLEOTIDE EXCISION
REPAIR (NER)
MISMATCH REPAIR (MMR)
HOMOLOGOUS RECOMBINATION
(HR)
NON
HOMOLOGOUS END JOINING
(NHEJ)
PARP XP,
POLYMERASES
MLH1, MSH2, MSH6, MLH3, PMS2
ATM/ATR, BRCA1/2,
CHEK2, RAD51, BRIP1,
PALB2
DNA-PXcs, Mre11, RAD50, NBS1 Reactive Oxygen
Species (ROS)
Replication
Errors X Rays UV Light Alkylating Agents
Spontaneous Reactions
Toss and Cortesi. J Canc Sci Therapy 2013 Cortesi L et al. Curr Cancer Drug Targets 2018
MMR PARP INHIBITORS NER BER
HR
CELL DEATH
BRCA MUTATION CARRIERS
NHEJ REPAIR
REPAIR
SINGLE-STRAND BREAKS
DOUBLE-STRAND BREAKS
Toss and Cortesi. J Canc Sci Therapy 2013 Cortesi L et al. Curr Cancer Drug Targets 2018
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. 2012 Livraghi and Garber, BMC Medicine 2015
Isakoff SJ et al, Future Oncol. 2017 OlympiAD
EMBRACA BRAVO
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
Slide 24
OlympiAD study design
Presented By Mark Robson at 2017 ASCO Annual Meeting
Statistical analysis plan
Presented By Mark Robson at 2017 ASCO Annual Meeting
Primary endpoint: progression-free survival by BICR
Presented By Mark Robson at 2017 ASCO Annual Meeting
Overall survival (interim analysis; 46% data maturity)
Presented By Mark Robson at 2017 ASCO Annual Meeting
Objective response by BICR
Presented By Mark Robson at 2017 ASCO Annual Meeting
Subgroup analyses: PFS by BICR
Presented By Mark Robson at 2017 ASCO Annual Meeting
Subgroup analyses: PFS by BICR
Presented By Mark Robson at 2017 ASCO Annual Meeting
Subgroup analyses: PFS by BICR
Presented By Mark Robson at 2017 ASCO Annual Meeting
Adverse events (any grade) in ≥15% of patients
Presented By Mark Robson at 2017 ASCO Annual Meeting
Grade ≥3 adverse events in ≥2% patients in either arm
Presented By Mark Robson at 2017 ASCO Annual Meeting
● 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 platinum- based 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
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.
ASCO 2018
OLYMPIAD: VISCERAL AND CNS METASTASES
ASCO 2018
ASCO 2018
EMBRACA: CLINICALLY RELEVANT SUBGROUPS
ASCO 2018
ASCO 2018
OLYMPIAD + EMBRACA: A META-ANALYSIS
ASCO 2018
• 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?)
• 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?)
PLATINUM CROSS-RESISTANCE
• 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?)
ASCO 2018
• 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?)
• 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?)
●
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??
