Inhibidores de PARP en cáncer de ovario

Transcription

1 Inhibidores de PARP en cáncer de ovario Ma Pilar Barretina Ginesta Servicio Oncología Médica Hospital Universitari Dr. J. Trueta Institut Català d Oncologia Coordinación científica: Dr. Fernando Rivera Hospital Universitario Marqués de Valdecilla, Santander Organizado por: Fundación para el progreso de la oncología en Cantabria

2 INDEX 1. PARP INHIBITORS DEVELOPMENT 2. MECHANISM OF ACTION 3. PARPi AS MAINTENANCE TREATMENT AT RELAPSE 4. PARPi AS MONOTHERAPY AT RELAPSE 5. SAFETY 6. FUTURE 7. CONCLUSIONS

3 PARP INHIBITORS DEVELOPMENT

4 PARP Mechanism of A ction N ormal Cell Deficient Cell MECHANISM OF ACTION

5 EOC & HRD Aprox 50% of HGS EOC harbor HRD Potential candidates for iparps Cancer discovery 2015

6 PARP INHIBITORS AS MAINTENANCE THERAPY AFTER PLATINUM BASED CHEMOTHERAPY AT RELAPSE

7 OLAPARIB - STUDY 19 N=265 Platinum-sensitive recurrent high-grade serous ovarian cancer 2 prior regimens of platinum-based chemotherapy Complete or partial response to most recent platinumbased regimen n=136 Double-blind randomization 1:1 n=129 Olaparib maintenance monotherapy (400 mg bid, capsules) Treatment until progression Placebo (bid, capsules) Primary endpoint: Progression-free survival (PFS) by RECIST 1.0 Secondary endpoints included: Overall survival (OS), safety and tolerability Exploratory endpoints: Time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST) BRCA testing: Previous local germline BRCA testing (case report forms) Retrospective germline BRCA testing or tumour BRCA testing BRCAm: n=136 BRCAwt n=118

8 Lederman J, et al. N Engl J Med 2012 & Lancet Oncology 2014 OLAPARIB - STUDY 19 No differences in OS No differences in QoL Exploratory analysis: Increased TFST & TSST

9 OLAPARIB - STUDY 19 LONG TERM OUTCOMES Clinical Factors: olaparib, complete response to CT (not for TFIp) Univariate Analysis, Markers of response to Olaparib: HRD statuys by MyChoice, BRCA mut (not for BRCA methylation). Lederman JA, et al. Lancet Oncol 2016, Gourley C, et al. ASCO 2017; Lhereux S, et al. Clin Cancer Res 2017.

10 PHASE 3 MAINTENANCE TRIALS Random 2:1 Placebo SOLO 2 1 ENGOT-OV16 NOVA 2 ARIEL 3 3 Olaparib 300mg bid Niraparib 300mg once daily BRCA status BRCA mut gbrca / Non-gBRCA Rucaparib 600mg bid All comers Histology HGSC/HGEOC HGSOC HGSC/HGEOC TFIp >6 months >6 months >6 months 1.Pujade-Lauraine E et al. Lancet Oncol.2017;18: ; 2.Mirza MR et al. N Engl J Med.2016;375: ; 3.Coleman R.L. et al. The Lancet. 2017;390:

11 NOVA: Myriad My Choice Test Loss of heterozygosity (LOH) Presence of a single allele 2 Telomeric allelic imbalance (TAI) A discrepancy in the 1:1 allele ratio at the end of the chromosome (telomere) 3 Large-scale state transitions (LST) Transition points between regions of abnormal and normal DNA or between two different regions of abnormality 4 TAI + LOH+ LST >42= HRD 1. Telli ML, et al. Clin Cancer Res. 2016;22(15): Abkevich V, et al. Br J Cancer. 2012;107(10): Birkbak NJ, et al. Cancer Discov. 2012;2(4): Popova T, et al. Cancer Res. 2012;72(21): Telli ML, et al. Clin Cancer Res. 2016;22(15):

12 ARIEL: LOH (NGS) BRCA mut BRCA-like Hypothesis 1: Ovarian cancer patients with high genomic LOH suggesting BRCAlike signature will respond to PARPi. Biomarker Negative Chromosome No. Hypothesis 2: Ovarian cancer patients who are biomarker negative (ie, with low genomic LOH) will not respond to PARPi.

13 gbrca mut SOLO 2 1 ENGOT-OV16 NOVA 2 ARIEL vs 5.5 m 21.0 vs 5.5 m 16.6 vs 5.4 m HR 0.3 HR HR 0.23 IC 95% IC 95% IC 95% Pujade-Lauraine E et al. Lancet Oncol.2017;18: ; 2.Mirza MR et al. N Engl J Med.2016;375: ; 3.Coleman R.L. et al. The Lancet. 2017;390:

14 NOVA: gbrcawt population BRCA wt HRD pos(+sbrcamut) HRD neg 9.3 vs 3.9 m 12.9 vs 3.8 m 6.9 vs 3.8 m HR 0.45 HR 0.38 HR 0.58 IC 95% IC 95% IC 95% Mirza MR et al. N Engl J Med.2016;375:

15 NOVA: gbrcawt/sbrcamut Somatic BRCA testing should be determined as the benefit of maintenance with PARPi is similar to gbrca patients Mirza MR et al. N Engl J Med.2016;375:

16 ARIEL 3: g/s BRCA wt POPULATION BRCA wt LOH High BRCA wt LOH Low 9.7 vs 5.4 m 6.7 vs 5.4 mm HR 0.44 HR 0.58 IC 95% IC 95% Coleman R.L. et al. The Lancet. 2017;390:

17 Aditional benefit: TFST&TSST Morgan RD, et al. Cancer Chemotherapy and Pharmaceutics. 2018;8(14):

18 PARP INHIBITORS AS MONOTHERAPY AT RELAPSE

19 OLAPARIB: STUDY OC: gbrca1 mut 77% / gbrca2 mut 23% At least 3 prior lines Olaparib Monotherapy ORR: 31,1% Median PFS 7,0 months, OS 16,6 months Patients with 3 previous lines: ORR 34% & median duration 7,9m Kaufman JCO 2015

20 RUCAPARIB: ARIEL 2 N=106 HGSOC BRCAmut At least 2 prior lines Rucaparib monotherapy ORR was 53.8% (95% CI, ); 8.5% CR 45.3% PR Median DOR 9.2m Oza AM, et al. Gyn Oncol 2017

21 NIRAPARIB: QUADRA N=463 At least 3 prior lines Moore KN, et al. ASCO 2018

22 SAFETY PROFILE 1.Pujade-Lauraine E et al. Lancet Oncol.2017;18: ; 2.Mirza MR et al. N Engl J Med.2016;375: ; 3.Coleman R.L. et al. The Lancet. 2017;390:

23 SAFETY PROFILE: AML & MDS SOLO 2 1(0,5%) MDS & 1 AML (0,5%) during olaparib treatment 2.1% 4 % POOLED ANALYSIS 24/25(96%) gbrcam 4/25 (4%) gbrcawt Korach J, et al. ASCO 2018

24 SAFETY PROFILE QUALITY OF LIFE STUDY 19 & SOLO 2 TRIALS: NO STATISTICALLY SIGNIFICANT DIFFERENCES (ASCO 2017) NOVA ENGOT-OV16 TRIAL: NOT STATISTICALLY SIGNFICIANT DIFFERENCES (ESMO 2017) ARIEL 3: Publication.

25 FUTURE STRATEGIES

26 PFS, TFST, FACT-O, Safety, AESI, OS Retreatment OReO Study: Olaparib Retreatment in Platinum-Sensitive Ovarian Cancer gbrca+ or sbrca+ (n=136) 1 prior PARPi treatment 18mo+ after 1 st line CT 12 mo+ after 2 nd line CT BRCAve- all-comers (n=280) 1 prior PARPi treatment 12mo+ after 1 st line CT 06 mo+ after 2 nd line CT Platinum-based chemotherapy (no Bev) RP/RC R A N D O M I Z A T I O N 2:1 OLAPARIB tablets* *300 mg bid or last tolerable dose Placebo Stratification factors Prior bevacizumab <3 vs 3 chemo lines Powered 80% for PFS primary endpoint. BRCA+ HR=0.5, 74 events. BRCA- HR=0.65, 191 events. ClinicalTrials.gov. NCT Enrollment period: 2 ys BRCA+ 3 ys BRCA-ve Primary Analysis: BRCA+ approx. 42 months after (FSI) BRCA -ve approx. 48 months after (FSI)

27 1 st line Maintenance SOLO-1- in BRCA mut PRIMA: Niraparib in ovarian cancer ESMO 2018

28 PARPi + IT TOPACIO: niraparib + pembrolizumab (ASCO 2018) N= 62 (49% Platinum resistant, 23% Platinum refractory) ORR 25% DCR 63% mdor: 9.3m MEDIOLA: olaparib + durvalumab (SGO 2018) N= 32 gbrcamut relapsed EOC DCR at 12m: 81% ORR 72%

29 PARPi +/- Antiangiogenics +/- IT PAOLA: olaparib + Bevacizumab 1st line maintenance. Cediranib + Olaparib: As maintenance after platinum therapy at relapse (ICON 9) As treatment without chemotherapy MITO 25: Niraparib + rucaparib FIRST: 1st line CT + Niraparib + TSR042 ATHENA: 1st line CT + Rucaparib + Nivolumab DUO-O: 1st line CT + Olaparib + Durvalumab

30 CONCLUSIONS PS relapse Maintenance after platinum based CT BRCA mut PS relapse Maintenance after platinum based CT All comers Monotherapy OLAPARIB * EMA FDA RUCAPARIB ** EMA FDA NIRAPARIB EMA FDA * Monotherapy after 3 previous lines ** Monotherapy after 2 previous lines

31 CONCLUSIONS PARPi as maintenance treatment have showed increased PFS across all groups of patients who respond to platinum therapy: - greatest effect in g/sbrcamut >> test must be performed in all patients - significant but lesser benefit in BRCAwt - Benefit regardless of HRD status Long term benefit in about 11% of patients. Also active as single agent therapy (even in patients heavily pretreated) Active in combination. Toxicity generally low and manageable.

32 GRACIAS