inhibidores de parp en cáncer de ovario · presence of a single allele2 a discrepancy in the 1:1...
TRANSCRIPT
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Coordinación científica:Dr. Fernando RiveraHospital Universitario Marqués de Valdecilla,
Santander
Organizado por: Fundación para el progreso
de la oncología en Cantabria
Inhibidores de PARP en cáncer de ovarioMa Pilar Barretina Ginesta
Servicio Oncología Médica
Hospital Universitari Dr. J. Trueta – Institut Català d’Oncologia
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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
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PARP INHIBITORS DEVELOPMENT
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PARP Mechanism of A ction N ormal Ce ll Deficient Ce ll
MECHANISM OF ACTION
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Cancer discovery 2015
EOC & HRD
Potential
candidates for
iPARPs
Aprox 50% of
HGS EOC
harbor HRD
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PARP INHIBITORS AS MAINTENANCE
THERAPY AFTER PLATINUM BASED
CHEMOTHERAPY AT RELAPSE
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N=265
• ‘Platinum-sensitive’
recurrent high-grade
serous ovarian
cancer
•≥2 prior regimens of
platinum-based
chemotherapy
•Complete or partial
response to most
recent platinum-
based regimen
Olaparib maintenance
monotherapy
(400 mg bid, capsules)
n=136
n=129
Placebo (bid, capsules)
Double-blind
randomization
1:1
Treatment until progression
BRCA testing:
• Previous local germline BRCA testing (case report forms)
• Retrospective germline BRCA testing or tumour BRCA
testing
BRCAm: n=136
BRCAwt n=118
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)
OLAPARIB - STUDY 19
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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
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Lederman JA, et al. Lancet Oncol 2016, Gourley C, et al. ASCO 2017; Lhereux S, et al. Clin Cancer Res 2017.
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).
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SOLO 2 1 ENGOT-OV16 NOVA 2 ARIEL 3 3
Random 2:1
Placebo
Olaparib 300mg bid Niraparib 300mg once
daily
Rucaparib 600mg bid
BRCA status BRCA mut gBRCA /
Non-gBRCA
All comers
Histology HGSC/HGEOC HGSOC HGSC/HGEOC
TFIp >6 months >6 months >6 months
PHASE 3 MAINTENANCE TRIALS
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
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Loss of
heterozygosity (LOH)Telomeric allelic
imbalance (TAI)
Large-scale state
transitions (LST)
Presence of a single allele2
A discrepancy in the 1:1 allele ratio at
the end of the chromosome (telomere)3
Transition points between regions of
abnormal and normal DNA or between
two different regions of abnormality4
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
TAI + LOH+ LST
>42= HRD
NOVA: Myriad My Choice Test
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ARIEL: LOH (NGS)
BRCAmut
BRCA-like
Chromosome No.
Biomarker
Negative
Hypothesis 1:
Ovarian cancer
patients with high
genomic LOH
suggesting BRCA-
like signature will
respond to PARPi.
Hypothesis 2:
Ovarian cancer
patients who are
“biomarker negative”
(ie, with low genomic
LOH) will not
respond to PARPi.
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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
gBRCA mut
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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
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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
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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
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Aditional benefit: TFST&TSST
Morgan RD, et al. Cancer Chemotherapy and Pharmaceutics. 2018;8(14):647-58.
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PARP INHIBITORS AS MONOTHERAPY AT RELAPSE
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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
OLAPARIB: STUDY 42
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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
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NIRAPARIB: QUADRA
Moore KN, et al. ASCO 2018
N=463
At least 3 prior lines
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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
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SAFETY PROFILE: AML & MDS
2.1%
4 %
1(0,5%) MDS & 1 AML
(0,5%) during olaparib
treatment
24/25(96%)
gBRCAm
4/25 (4%)
gBRCAwt
POOLED ANALYSIS
SOLO 2
Korach J, et al. ASCO 2018
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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.
SAFETY PROFILE
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FUTURE STRATEGIES
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OLAPARIB tablets*
Placebo
gBRCA+ or sBRCA+(n=136)
• 1 prior PARPi treatment• 18mo+ after 1st line CT
12 mo+ after 2nd line CT
Stratification factors
• Prior bevacizumab
• <3 vs ≥3 chemo lines
2:1
*300 mg bid or last tolerable dose
RANDOMIZATION
OReO Study: Olaparib Retreatment in Platinum-Sensitive Ovarian Cancer
BRCAve- all-comers(n=280)
• 1 prior PARPi treatment• 12mo+ after 1st line CT
06 mo+ after 2nd line CT
RP/RCPlatinum-based chemotherapy
(no Bev)
PFS
, TFS
T, F
AC
T-O
, Saf
ety,
AES
I, O
S
Powered 80% for PFS primary endpoint. BRCA+ HR=0.5, 74 events.
BRCA- HR=0.65, 191 events.
Enrollment period: •2 ys BRCA+ •3 ys BRCA-ve
Primary Analysis: BRCA+ approx. 42 months after (FSI)BRCA -ve approx. 48 months after (FSI)ClinicalTrials.gov. NCT03106987.
Retreatment
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SOLO-1- in BRCAmut PRIMA: Niraparib in ovarian cancer
1st line Maintenance
ESMO 2018
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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%
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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
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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
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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.
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GRACIAS