Inhibidores de PARP-1 en mujeres con ca ncer de mama metasta sico portadoras de mutaciones BRCA 1/2. Dra. S. López-Tarruella

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1 Inhibidores de PARP-1 en mujeres con ca ncer de mama metasta sico portadoras de mutaciones BRCA 1/2 Dra. S. López-Tarruella

2 Disclosure Information (COIs) Sara López-Tarruella, MD, PhD Consultant or Advisory Role: Celgene, Novartis, Pierre Fabre, Pfizer, Roche, Astra-Zeneca, Eisai Travel Grant: Celgene, Pfizer, Pierre-Fabre, Novartis

3 Racional BL uso inh PARP en CM DNA-damage & repair pathways Lord & Ashworth Science 2017; Nat Rev Cancer 2016; O connor Mol Cell 2015; Pilié et al Nat Rev Clin Oncol 2018

4 Racional BL uso inh PARP en CM Biological PARP functions relevant to cancer Family of 18 members of nuclear proteins, PARP 1 and 2 are involved in celular response to SSB+ PARP-1 & 2 DNA damage sensors (SSBs & DSBs) most active in S-phase Sonnenblick et al Nat Rev Clin Oncol 2015; McCann et al Drug in Context 2018

5 Racional BL uso inh PARP en CM DNA damage response & poly(adp-ribose) polymerase 1 and 2 When PARP is inhibited, SSB persist and result in stalled replication forks and DSBs PARP1 autoparylation finally causes the release of PARP1 from DNA and the restoration of a catalytically inactive state Small molecule NAD+ mimetics inhibit catalytic activity PARP-1 & 2 ART catalytic activity drives the PARylation of PARP1 substrate proteins (branched PAR chains are shown on a target protein), mediating the recruitment of DNA repair effectors, chromatin remodeling, and eventually DNA repair Lord & Ashworth Science 2017; Nat Rev Cancer 2016; O connor Mol Cell 2015

6 Racional BL uso inh PARP en CM Synthetic lethality (the rationale) Two genes ( A and B ) are said to be synthetic lethal if mutation of either gene alone is compatible with viability but simultaneous mutation of both genes causes death 1st clinical exemple of synthetic lethality PARP inhs for the treatment of cancers with defects in the BRCA1 or BRCA2 tumor suppressor proteins, involved in the repair of DNA damage (Farmer & Bryant) BRCA 1/2 & PARP inhibition Lyon et al JNCCN 2018

7 Resurrección de in PARP en CM Inh PARP timeline PFS 3.6 to 5.9 mo PFS 1 mo increase (NS) Lyons et al JNCCN 2018; Pilié et al Nat Rev Clin Oncol 2018 (Oct) FDA approval talazoparib HER2-negative, gbrca1/2 mut BC

8 Desarrollo de los inh PARP Chemical structure of PARP inh Replication arrest results from physical obstruction of replication forks by PARP trapping Catalytic INH (IC50) Iniparib: No effect Talazoparib: 0.57 nm Olaparib: 1.94 nm Rucaparib: 1.98 nm Veliparib: 4.73 nm Synthetic lethality results from unresolved DNA damage Lord & Ashworth Science 2017; Nat Rev Cancer 2016; Mateo et al Nat Rev Clin Oncol 2013; Shen et al CCR 2013; Murai et al Cancer Res 2012 and Mol Cancer Ther 2014

9 Desarrollo de lnh PARP: Olaparib (phii POC) Multicentre phase 2 study to assess the efficacy and safety of oral olaparib at MTD & at a lower dose pharmacodynamically 1 assessment in women with gbrca1 and BRCA2 mut ABC (pretreated at least 1CT régimen) Median PFS: 5.7 mo olaparib 400mg 3.8 mo olaparib 100mg TOXICITY (Study 8/ICEBERG) Manageable G1-2 (nausea, fatigue, anemia vomiting anorexia) Tutt et al Lancet 2010; Fong et al NEJM 2009

10 Desarrollo de lnh PARP: Olaparib (phiii) OlympiAD Stratification by Prior chemotherapy regimens for MBC Hormonal status Prior platinum therapy *93.8% received TPC vs 100% olaparib Robson et al ASCO 2017 NEJM 2017

11 Desarrollo de lnh PARP: Olaparib OlympiAD *100% pts in Olaparib arm and 93.8% in the TPC arm received study treatment CNS 8.3% vs 8.2% Robson et al ASCO 2017 NEJM 2017

12 Desarrollo de lnh PARP: Olaparib OlympiAD PFS2: 13.2 vs 9.3 mo HR 0.57 p= (8.2% TPC arm received olaparib) 7.0 vs 4.2 mo (median PFS) 29.3 vs 26.8% 71 vs 73% *BICR PFS 7.8 vs 3.8 mo HR 0.50 (p<0.0001) 12.7% on olaparib on-going 19.3 vs 19.6 mo (median OS) 50.2 vs 50.5% 49.8 vs 49.5% 19.3 vs 17.1 mo (median OS) HR 0.9 p=0.513 *64% maturity OS analysis 71.2 vs 71.1% 28.8 vs 28.8% Robson et al ASCO 2017 & NEJM 2017 & AACR 2018

13 Desarrollo de lnh PARP: Olaparib OlympiAD Robson et al ASCO 2017 & NEJM 2017 & AACR 2018

14 Desarrollo de lnh PARP: Olaparib OlympiAD Dose reduction: anemia (olaparib 13.7%) vs EPP (SOC 7.7%) Robson et al ASCO 2017 & NEJM 2017 & AACR 2018

15 OlympiAD Desarrollo de lnh PARP: Olaparib *Change from baseline in Global HRQoL favoured pts treated with olaparib vs TPC (3.9 vs -3.6 adjusted mean, p=0.0035) Robson et al ASCO 2017 & NEJM 2017 & ESMO 2017

16 Desarrollo de lnh PARP: Talazoparib (phi & II) ABRAZO PhI tolerable dose 1 mg/day for continuous dosing (fed or fasting) Single-agent activity in prostate, ovarian, SCLC Turner et al ASCO 2017; de Bono et al Cancer Discov 2017

17 Desarrollo de lnh PARP: Talazoparib (phii) ABRAZO Turner et al ASCO 2017

18 Desarrollo de lnh PARP: Talazoparib (phiii) EMBRACA *0.3% pts in Talazo arm and 12.5% in the TPC arm did not received study treatment Litton et al SABCS 2017 & NEJM 2018

19 Desarrollo de lnh PARP: Talazoparib EMBRACA Litton et al SABCS 2017 & NEJM 2018

20 Desarrollo de lnh PARP: Talazoparib EMBRACA Litton et al SABCS 2017 & NEJM 2018

21 Desarrollo de lnh PARP: Talazoparib EMBRACA Litton et al SABCS 2017 & NEJM 2018

22 Desarrollo de lnh PARP: Talazoparib EMBRACA Time to definitive clinically meaningful deterioration in EORTC QLQ-C30 GHS/QoL Ettl et al Ann Oncol 2018; Hurvitz et al EJC 2018

23 Desarrollo de lnh PARP: Niraparib (phiii) BRAVO * BRAVO is unlikely to produce data that is interpretable and therefore suitable for registration in this indication bc a large number of pats in the CT arm did not continue in the trial long enough to receive their first radiological scan, which is required to assess disease progression, resulting in an unusually high rate of censoring in the control arm

24 Desarrollo de lnh PARP: Veliparib combo BROCADE 62.6 vs 76.3 vs 70.2% 0 prior CT 42.4 vs 41.2 vs 40.4% TNBC 53.5 vs 52.6 vs 52.1% gbrca1 mut Han et al Ann Oncol 2017; SABCS 2016; Somlo et al CCR 2013

25 Desarrollo de lnh PARP: Veliparib combo BROCADE High activity for a carbocontaining regimen in gbrca1/2 mut Veliparib modest but significant effect on activity (RR) not translated to PFS Veliparib does not increase expected toxicity Less synergy than expected with TMZ Han et al Ann Oncol 2017; SABCS 2016

26 Desarrollo de lnh PARP: Combinaciones MEDIOLA Dréan et al CRHO 2016; Brown et al BJC 2018; Domchek et al SABCS 2017

27 lnh PARP en el algoritmo de CMM Jan 11, 2018 Olaparib for gbrca mut MBC BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) to ID pts eligible Oct 16, 2018 Talazoparib for gbrca mut MBC & BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) to ID pts eligible LUMINAL HER2-/HR+ Benefit vs CT (optimal sequence?) Benefit vs new targeted therapies (CDK 4/6 inh or Everolimus + ET) Best time for PARPi to be defined Potential combinations with ET/targeted therapies? TRIPLE-NEGATIVE Role in platinum pre-treated? Other CT options vs QoL benefit? Best time for PARPi to be defined Potential combinations with IO or others? Larsen et al PLOS One 2013; Joy et al Curr Oncol 2015

28 lnh PARP en las guías CMM ESMO/ABC 4 A PARPi (olaparib or talazaparib) is a reasonable treatment option for patients with BRCA-associated advanced TNBC or luminal (after progression on ET) ABC, previously treated with an anthracycline with/without a taxane (in the adjuvant and/or metastatic setting), since its use is associated with a PFS benefit, improvement in QoL and a favourable toxicity profile. OS results are awaited. It is unknown how PARPis compare with platinum compounds in this setting and their efficacy in truly platinumresistant tumours NCCN v Patients with HER2-negative disease elegible for single-agent therapy, strongly consider for germline BRCA1/2 testing: Olaparib in an option for patients with HER2-negative tumors and germline BRCA1/2-mutation AGO v.2018 Cardoso et al Ann Oncol 2018, NCCN v2.2018; AGO guidelines 2018

29 CONCLUSIONES Los PARP inh son una nueva terapia de diana que ha demostrado beneficio en SLP & QoL en pacientes con CM HER2-negativo pretratadas portadoras de gbrca1/2 mut y han obtenido su aprobación por las agencias reguladoras representando un HITO en CM avanzado en 2018 (olaparib y talazoparib) La valoración de la determinación del estado de gbrca1/2 mut en pacientes con CM y antecedentes familiares debe ser estándar y tiempo-eficiente para poder contar con esta alternativa terapéutica (impacto en las UCHF) La aprobación de los PARP inh en CM avanzado deja cuestiones abiertas: Cual es el mejor biomarcador predictivo de respuesta a PARP inh? Puede extenderse su uso más allá de las pacientes portadoras de gbrca1/2 mut? Como incorporar los PARP inh en el algoritmo de manejo de las pacientes con CMTN y RH-positivo/HER2-negativo? Se puede mejorar la eficacia de los PARP inh mediante la combinación con otras terapias (ICIs, QT, terapias de diana, DDR inh ) más allá de su uso como monoterapia? Cuales son y como vencer los mecanismos de resistencia a PARP inh? El papel de los PARP inh se expandirá a estadios precoces de la enfermedad? Datos de estudios en (neo) adyuvancia?