clínica diagonal. barcelona - foro de debate en oncología , hrd, all? •when?: first-line,...
TRANSCRIPT
Dr. Josep M. Del Campo Clínica Diagonal. Barcelona
Nuevas Oportunidades en Cáncer de Ovario
Cancer de Ovario: Es una enfermedad única?
Tratamiento inicial: sin cambios
• Cirugía primaria/intervalo: ausencia de T. Residual
• Tratamiento sistémico
– Quimioterapia: Carboplatino + Paclitaxel
– Bevacizumab
• Bevacizumab Neoadyuvante?: en pacientes no operables (ASCO 2017)
Cáncer de Ovario: Tratamiento actual
Tratamiento de la recidiva
• Tratamiento sistémico: ILT, trat. Previos,
– Quimioterapia
– Bevacizumab (recidiva sensible o resistente)
– BRCAmut: Olaparib mantenimiento en enf. Sensible (2016)
• Cirugía: citorreducción secundaria?
– Desktop-3 (ASCO 2017)
• PFS: 19.6 vs 14 meses
• TFST: 21 vs 13.9 meses
• Pend OS
Cáncer de Ovario: Tratamiento actual
Cáncer de Ovario Recurrente: Donde estamos?
BRCAmut / HRD: PARPi Inmunoterapia
gBRCA-mutated 14%
sBRCA-mutated 6%
20%
HRD-deficient 30%
Cáncer de Ovario: Mutaciones
Agents with efficacy demonstrated in relevant trials:
• PARP inhibitors: Olaparib, Rucaparib, Niraparib
Agents/Targets in earlier development:
• Mutant p53 (APR-246)
• AKT (afuresertib)
• DNMT (epigenetic) inhibitor (guadecitabine)
• ATR/ATM; CHK ½, DNA-PK
DNA Repair Inhibitors in Ovarian Cancer
PARPi: Clinical Data
• Which patients?: BRACmut, HRD, all?
• When?: First-line, recurrent sensitive, resistant
• Toxicities
• Future combinations: which partners?
• Integration in the current clinical practice
PFS: 11.2 vs 4.3 HR: 0.18
PFS: 8.4 vs 4.8 HR: 0.35
Olaparib in ROC (sensitive): Study 19 Updated OS
Olaparib in BRCAmut ROC (US study)
RR: 34% RD: 7.9 m
December 19, 2014 Olaparib caps accelerate approval NOT approved as maintenance Germline BRCA mutation >3 prior lines Approval DOES NOT distinguish
between platinum sensitive or resistant
Approval also for companion diagnostic (Myriad BRCA analysis CDx)
December 18, 2014 Olaparib caps accelerate approval Approved as maintenance Germline or somatic BRCA mutation >2 prior lines Sensitive patients in remission
following platinum-based therapy
Olaparib in ROC
Olaparib in ROC: 2017 Data
PARP inhibitors: Part Two
Rucaparib
Ariel 2: tBRCAmut and tBRCA-like* vs biomarker negative patients
*BRCA-like: BRCA methylated (12.7%) and RAD51C methylated 2.4%
*PFS: 7.3 m (BRCA-like with redefinition of LOH cut-off at 16%); HR: 0.48
12.8
5.7 7.3*
5.3 4.7*
December 19, 2016 Rucaparib accelerate approval Deleterious BRCA mutation (germline and/or somatic) >2 prior lines Approval also for companion diagnostic
(FoundationFocusTM BRCA analysis CDx)
Rucaparib in ROC
PARP inhibitors Part Three The most recent news: Niraparib
Niraparib: ENGOT-OV16/ NOVA Trial
PFS benefit in all subgroups: • gBRCA or sBRCA • 6-12, >12; prior beva; best Pt response; number of lines
Treatment
PFS Median (95% CI)
(Months)
Hazard Ratio (95% CI) P value
% of Patients without Progression or Death
12 mo 18 mo
Niraparib (N=35)
20.9 (9.7, NR) 0.27
(0.081, 0.903)
P=0.0248
62% 52%
Placebo (N=12)
11.0 (2.0, NR)
19% 19%
PFS: germline vs somatic BRCAmut
sBRCAmut
Pro
gre
ssio
n-f
ree
Su
rviv
al (
%)
Treatment
PFS Median (95% CI) (months)
Hazard Ratio (95% CI) P value
% of Patients without Progression or Death
6 mo
12 mo
18 mo
Niraparib
(N=138) 21.0
(12.9, NR) 0.27
(0.173, 0.410)
P<0.0001
80% 62% 50%
Placebo
(N=65) 5.5
(3.8, 7.2) 43% 16% 16%
Niraparib: PFS in BRCAwt
HRD pos HRD neg
mPFS (months): 12.9 vs 3.8 HR: 0.38; p= 0.001
mPFS (months): 6.9 vs 3.8 HR: 0.58; p= =0.02
March, 2017 Niraparib accelerate approval BRCA mutation, HRD and wild-type >2 prior lines Companion diagnostic (Myriad)
Niraparib in ROC
PARPi: Open questions
• Strategy – Maintenance, Single agent
– First-line (ongoing trials)
• Resistance • Somatic or epigenetic reversion, secondary mut……
• How to increase susceptibility to PARPi – Increased DNA damage (cytotoxics, radiation)
– Induce HRD through hypoxia (tumor microenvironment)
– Downregulation of HRR (VEGFi)
– BRCAmut higher response to checkpoint inhibitors
• Combination: Which partners? – Angiogenesis, PD1/PDL1 inhibitors
– PI3K, WEE1, ATR
OC: Ongoing Phase III Trials With PARP inhibitors
Combination: Which partners?
– Angiogenesis, PI3K, WEE1, ATR, PD1/PDL1 inhibitors
PARPi in OC: Which one? (Spain)
TOXICITY Olaparib Rucaparib Niraparib
Nausea 1% 5% 3%
Fatigue 7% 10% 8%
Vomiting 4% 4% 2%
Anemia 15% 23% 25%
neutrop 7% 10% 19%
thrombocytopenia 3% 6% 34%
Hypertension 8%
Reduct/Discont 26% / 7% 49% /3% 66% / 14%
EFFICACY Olaparib/19 Olaparib/SOLO 2 Rucaparib Niraparib
PFS (mo) 11.2 19.1 (30.2 BICR) 12.8 / 7.3 / 4.7 21 / 12.9 / 6.9
OS Δ 5 months inmature - Ongoing
BRCAm BRCAm HRD BRCAm, HRD, BRCAwt
Ovarian Cancer
More treatments other than:
• Antiangiogenics
• PARPi
Immunotherapy
Overview of Several Anti-PD-1/PDL-1 Therapies Currently in Development
Pembrolizumab KEYNOTE-028 ASCO 2017
Nivolumab Atezolizumab
Immunotherapy: Rational Combinations
• Chemotherapy
• VEGFi
Choice of Second-Line Therapy and
Later
Duration of response to
initial platinum therapy
BRCA mutation
status
Previous agents used
Toxicities experienced in
first-line setting
Patient’s performance
status
Patient and physician
preference
• Anti VEGF • PARP inh • Approvals
• Neurotoxicity
• Hypersensitivity
• Hematotoxicity
• PFI vs TFI • p/np • b
• Ascitis • Pain •Urgent response
Hysto-type
Biology Factors
Criteria for Selecting Therapies in ROC
From DuBois A, personal presentation
Ovarian Cancer: Summary-1
• Median Survival >5 years (21/2 only ten years ago)
• Antiangiogenics still play an important role
• BRCA appears to be the best target
– Genetic testing for all OC patients (exc: mucinous)
• PARPi: Significant Clinical Benefit
– Benefit correlates with PFI and prior lines
• Olaparib (approved in EU) as maintenance
– Niraparib and Rucaparib coming soon
– Niraparib also in BRCAwt
– Need for better predictive markers
Ovarian Cancer: Summary-2
• Immunotherapy: the next
– Few patients benefits (but for a long time)
• ORR: 15%
– Are other than PD1/PDL1 expression predictive markers?
• MSI, immune microenvironment
• Combination strategies ongoing
• The best treatment: NO NEED FOR TREATMENT
– Early diagnosis remains a challenge
Muchas gracias