Nuevas estrategias de tratamiento en tumores con mutaciones de BRCA

Transcription

1 Nuevas estrategias de tratamiento en tumores con mutaciones de BRCA Emilio Alba UGCI Oncología Hospital Universitario Regional y Virgen de la Victoria Facultad de Medicina. Málaga IBIMA

2 ÍNDICE DE LA PRESENTACIÓN Mecanismo de acción Magnitud del problema: frecuencia y penetrancia de BRCA Cáncer de mama Cáncer de ovario Otros tumores Conclusiones y perspectivas

3 Mechanisms of Action of Olaparib PARP olaparib SSBs increased by dacarbazine, temozolomide and topotecan Replicating cells Mechanism 2: Potentiation DSBs increased by platinums Normal cell Cancer cell with HRD Repair by Homologous Recombination Survival Mechanism 1: Tumor specific killing by olaparib No effective repair (No HR pathway) Cell death

4 The Concept of Synthetic Lethality (BRCA) (PARP) Ashworth, A. J Clin Oncol; 26:

5 Riesgo de cáncer en personas con mutaciones de los genes BRCA 1/2 BRCA 1 BRCA 2 Mama 65-71% 45-84% Ovario 12-63% 7-27% Mama-varón 3-10% 7% Próstata? % Páncreas 1.2% 1.5-4% Levy-Lahad E. BJC 2007

6 Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) Couch FJ et al. PLoS Genet 9 (3): e

7 Chemotherapeutic Agents: Double Strand DNA Breaks Alkylators DNA interstrand cross-links double strand (DS) DNA breaks Cyclophosphamide Platinums Topoisomerase I poisons Topoisomerase II poisons Bleomycin Forms adducts with DNA Arrest of DNA replication forks DNA interstrand cross-linking, generation of O 2 free radicals Directly damages DNA DS DNA breaks Cisplatin Carboplatin Oxaliplatin Etoposide Irinotecan Topotecan Mitoxantrone Doxorubicin Epirubicin Kennedy R et al. JNCI 2004; 96:

8 TNBC Shares Clinical and Pathologic Features with BRCA-1- Related Breast Cancers ( BRCAness ) Characteristics Hereditary BRCA1 Triple Negative/Basal-Like 1,2,3 ER/PR/HER2 status Negative Negative TP53 status Mutant Mutant BRCA1 status Mutational inactivation* Diminished expression* Gene-expression pattern Basal-like Basal-like Tumor histology Chemosensitivity to DNAdamaging agents Poorly differentiated (high grade) Highly sensitive Poorly differentiated (high grade) Highly sensitive *BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID4 4 1 Perou et al. Nature. 2000; 406: Cleator et al.lancet Oncol 2007;8: Sorlie et al. Proc Natl Acad Sci U S A 2001;98: Miyoshi et al. Int J Clin Oncol 2008;13:

9 Regimen No. pts No. of pcrs % pcrs CMF AC FAC AT Cisplatin J Clin Oncol 2009;28:375-9

10 pcr rate: 22%

11 Predictors of response to cisplatin therapy in triple-negative/basallike tumors Copyright American Society of Clinical Oncology Silver, D. P. et al. J Clin Oncol; 28:

12 Phase I Trial of Olaparib in Patients with Solid Tumors Escalation and expansion phase, n = 60 Recommended phase II dose: 400 mg PO BID Toxicities Nausea (32%), fatigue (30%), vomiting (20%), taste alteration (13%), anorexia (12%), anemia (5%) Clinical activity = 12/19 patients with BRCA mutations Tumor BRCA No. of pts Response Breast CR, 1 SD Ovarian 1 or PRs Fallopian tube 1 1 PR Prostate 2 1 PR Fong PC et al. N Engl J Med 2009; 361:

13 Olaparib in BRCA-deficient Metastatic Breast Cancer: Results Median 3 prior lines of therapy Best percent change from baseline in target lesions by genotype ITT cohort 400 mg BID N = mg BID N = 27 ORR 11 (41%) 6 (22%) CR 1 (4%) 0 PR 10 (37%) 6 (22%) Median PFS 5.7 mo ( ) 3.8 mo ( ) Tutt A et al. J Clin Oncol 2009;27(18S):803s (abstr CRA501)

14 Objective Response Rate (by RECIST) BRCA Mutation-Positive BRCA Mutation-Negative Ovarian 7/17 (41.2%) 11/46 (23.9%) Breast 0/8 (0) 0/15 (0) Gelmon KA et al. Proc ASCO 2010;Abstract 3002.

15 Final Results: Phase II: Gem Carbo +/- Iniparib in TNBC O Shaughnessy J et.al. NEJM 2011

16 Probability of Survival Efficacy Endpoints Overall Survival (OS) ITT Population OS GC (N = 258) GCI (N = 261) HR p-value Median OS 11.1 mos 11.8 mos Prespecified alpha = Months With permission from O Shaughnessy J et al. Proc ASCO 2011;Abstract 1007.

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18 Ovarian Cancer Survival: Effect of BRCA Mutations Cass et.al. Cancer May 2003

19 BRCAness and Response to Chemotherapy Disease Free Survival Overall Survival 34 v 15 mo P = v 41 mo P = Konstantinopoulos PA, et al. J Clin Oncol. 2010;28:3555.

20 Prior response to platinum may predict response to olaparib in BRCA mutated Ovarian Cancer Gelmon K, et al J Clin Onc 2010

21 Phase II: BRCA Mutation Ovarian Cohort Audeh et al, 2009.

22 Percentage change from baseline in size of target lesions Niraparib: Phase 1/2 Ovarian Cancer Anti-tumor Activity * * * * * * ** * * * Platinum Resistant Platinum Recommended Dose Platinum Sensitive * BRCA1/2 mutation carriers Reduction in overall sum of measurable disease but new lesion seen (overall: PD) -Refractory patient (BRCA mutated) not included * * * * * * * * At recommended dose (290/300 mg), 3/4 (75%) platinum sensitive patients achieved RECIST response RECIST response rate in platinum-sensitive patients was 46% (6/13) Response rate (by RECIST and/or GCIG Ca125 criteria) in evaluable platinum-resistant patients was 22% (6/27) Michie Co et al. J Clin Oncol 31, 2013 (suppl; abstr 2513)

23 Proportion of patients progression free Study 19: Progression-free survival 1.0 No. of events: Total patients (%) Olaparib 60:136 (44.1) Placebo 93:129 (72.1) 0.9 Median PFS (months) Hazard ratio 0.35 (95% CI, ) P< At risk (n) Olaparib Placebo Randomized treatment Placebo Olaparib 400 mg bid Time from randomization (months) Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med Apr 12;366(15):

24 Proportion of patients progression-free Study 19: PFS by BRCAm status Number at risk Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt BRCAm (n=136) BRCAwt (n=118) Olaparib Placebo Olaparib Placebo Events: total pts (%) 26:74 (35.1) 46:62 (74.2) 32:57 (56.1) 44:61 (72.1) Median PFS, months HR= % CI (0.11, 0.31); P< Time from randomization (months) HR= % CI (0.33, 0.84); P=0.007 BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance) Presented by: Jonathan Ledermann et al at ASCO 2013

25 Proportion of Patients Progression Free Progression-Free Survival Olaparib 200 mg Olaparib 400 mg PLD *HR < 1 favors olaparib Stats: HR 0.55 (median PFS of 4 to 7.3 mos) N planned: 90 (30/arm) HR* vs PLD (80% CI) Olaparib 200 mg: 0.91 ( ); P = 0.78 Olaparib 400 mg: 0.86 ( ); P = 0.63 Olaparib 200 mg mg: 0.88 ( ); P = 0.66 Median PFS (80% CI) Olaparib 200 mg: Olaparib 400 mg: 6.5 ( ) months 8.8 ( ) months PLD 50 mg/m 2 : 7.1 ( ) months Time From Randomization (months) Number of patients at risk: Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol Feb 1;30(4):372-9.

26 Summary: PARPi in Phase III Development as Maintenance Therapy in Ovarian Cancer 1. AZD 2281 (KU ) = Olaparib SOLO-1 = Front-line HGS maintenance in BRCAmut SOLO-2 = Platinum sensitive HGS maintenance in BRCAmut 2. MK-4827 = Niraparib NOVA = Platinum sensitive HGS maintenance in BRCAmut and BRCAwt 3. CO-338 (AG014699, PF ) = Rucaparib ARIEL-3 = Platinum sensitive HGS and endometrioid maintenance in BRCAmut and BRCAwt

27 PARPi in Phase III Development in Ovarian Cancer 1. AZD 2281 (KU ) = Olaparib 2. MK-4827 = Niraparib 3. CO-338 (AG014699, PF ) = Rucaparib Others with randomized trials in devleopment ABT-888 = Veliparib BMN 673 No direct clinical comparisons!

28 Olaparib in BRCA-deficient Metastatic Breast Cancer: Select Toxicities Olaparib 400 mg BID (n = 27) Olaparib 100 mg BID (n = 27) Grade 1/2 Grade 3 Grade 1/2 Grade 3 Fatigue 15 (56) 4 (15) 15 (56) 2 (7) Nausea 11 (41) 5 (19) 15 (56) 0 Vomiting 7 (26) 3 (11) 6 (22) 0 Headache 10 (37) 0 5 (19) 1 (4) Constipation 6 (22) 0 8 (30) 0 Tutt A et al. J Clin Oncol 2009;27(18S):803s (abstr CRA501)

29 Tumor Response Rates Kaufman B et al. JCO 2015; 33(3)

30 Kaufman B et al. JCO 2015; 33(3)

31 Platinum Sensitive Relapse: Cediranib + Olaparib Phase II open-label randomised study -1:1 randomisation to cediranib/olaparib combination or single-agent olaparib - Platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer Liu J et al. JCO 2014; 32(5S): AbstractLBA5500.

32 Primary Outcome: Cediranib/Olaparib Significantly Increased PFS Compared to Olaparib Alone Liu J et al. JCO 2014; 32(5S): AbstractLBA5500.

33 Cediranib/Olaparib Significantly Increased PFS in Patients Without a BRCA Mutation Liu J et al. JCO 2014; 32(5S): AbstractLBA5500.

34 Response to Chemotherapy Post PARP Inhibitors in BRCA-Carrier Ovarian Cancer Retrospective Study 78 patients (median 3 lines chemotherapy pre-olaparib) - Response rate RECIST 36%, PFS 17 weeks; OS 34 weeks Responses to platinum post olaparib - Response rate RECIST 40%, PFS 22 weeks; OS 45 weeks In 6 cases tested, secondary mutations not observed Responses observed regardless of pre-parp platinum-sensitivity Platinum-to-platinum interval associated with response to post-parp platinum Ang JE et al. Clin Cancer Res 2013; 19(19):

35 RESISTANCE TO PARP INHIBITORS Secondary mutations of BRCA genes altering the reading frame to wild-type 1.-Selection of pre-existing resistance clones 2.-Mutations acquired during treatment in cells genetically unstable due to the lack of HR

36 Mechanisms of PARP Inhibitor Resistance Restoration of HR BRCA Reversion or P53BP1 loss Drug Efflux Upregulation of P-glycoprotein PARP1 Loss Mechanism Unknown PARPi Resistance NEED BIOPSIES TO CLARIFY CLINICAL SIGNIFICANCE

37 CONCLUSIONES BRCA es un biomarcador diferente (riesgo+predictivo) Es necesario una mejor definición del significado de la mutación germinal versus somática Las sales de platino (alquilantes?) parecen ser mas efectivas en presencia de mutación de BRCA Los inhibidores de PARP son eficaces en presencia de mutaciones de BRCA No es conocido si la eficacia es organodependiente Inhibidores de PARP+ QT+ farmacos antidiana +RT Adyuvancia/neoadyuvancia Toxicidad tardía

38 Might Platinum Response Be Predictor of Germline BRCA Mutation? Alsop K, et al. JCO 2012; 30 (21):

39 Maintenance PARP Inhibitors: Current Trials