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
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
PARP INHIBITORS DEVELOPMENT
PARP Mechanism of A ction N ormal Cell Deficient Cell MECHANISM OF ACTION
EOC & HRD Aprox 50% of HGS EOC harbor HRD Potential candidates for iparps Cancer discovery 2015
PARP INHIBITORS AS MAINTENANCE THERAPY AFTER PLATINUM BASED CHEMOTHERAPY AT RELAPSE
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
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
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.
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;18:1274-1248; 2.Mirza MR et al. N Engl J Med.2016;375:2154-2164; 3.Coleman R.L. et al. The Lancet. 2017;390:1949-1961
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):3764-3773. 2. Abkevich V, et al. Br J Cancer. 2012;107(10):1776-1782. 3. Birkbak NJ, et al. Cancer Discov. 2012;2(4):366-375. 4. Popova T, et al. Cancer Res. 2012;72(21):5454-5462. Telli ML, et al. Clin Cancer Res. 2016;22(15):3764-3773
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.
gbrca mut SOLO 2 1 ENGOT-OV16 NOVA 2 ARIEL 3 3 19.1 vs 5.5 m 21.0 vs 5.5 m 16.6 vs 5.4 m HR 0.3 HR. 0.27 HR 0.23 IC 95% 0.22-0.41 IC 95% 0.17-0.41 IC 95% 0.16-0.34 1.Pujade-Lauraine E et al. Lancet Oncol.2017;18:1274-1248; 2.Mirza MR et al. N Engl J Med.2016;375:2154-2164; 3.Coleman R.L. et al. The Lancet. 2017;390:1949-1961
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% 0.34-0.61 IC 95% 0.24-0.59 IC 95% 0.36-0.92 Mirza MR et al. N Engl J Med.2016;375:2154-2164
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;375:2154-2164
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% 0.29-0.66 IC 95% 0.40-0.85 Coleman R.L. et al. The Lancet. 2017;390:1949-1961
Aditional benefit: TFST&TSST Morgan RD, et al. Cancer Chemotherapy and Pharmaceutics. 2018;8(14):647-58.
PARP INHIBITORS AS MONOTHERAPY AT RELAPSE
OLAPARIB: STUDY 42 193 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
RUCAPARIB: ARIEL 2 N=106 HGSOC BRCAmut At least 2 prior lines Rucaparib monotherapy ORR was 53.8% (95% CI, 43.8 63.5); 8.5% CR 45.3% PR Median DOR 9.2m Oza AM, et al. Gyn Oncol 2017
NIRAPARIB: QUADRA N=463 At least 3 prior lines Moore KN, et al. ASCO 2018
SAFETY PROFILE 1.Pujade-Lauraine E et al. Lancet Oncol.2017;18:1274-1248; 2.Mirza MR et al. N Engl J Med.2016;375:2154-2164; 3.Coleman R.L. et al. The Lancet. 2017;390:1949-1961
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
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.
FUTURE STRATEGIES
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. NCT03106987. Enrollment period: 2 ys BRCA+ 3 ys BRCA-ve Primary Analysis: BRCA+ approx. 42 months after (FSI) BRCA -ve approx. 48 months after (FSI)
1 st line Maintenance SOLO-1- in BRCA mut PRIMA: Niraparib in ovarian cancer ESMO 2018
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%
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
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
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.
GRACIAS