Dr. Josep M. Del Campo Clínica Diagonal. Barcelona
Nuevas Oportunidades en Cáncer de Ovario
Cancer de Ovario: Es una enfermedad única?
Cáncer de Ovario: Tratamiento actual 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) BRCA mut : 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 Recurrente: Donde estamos? BRCA mut / HRD: PARPi Inmunoterapia
Cáncer de Ovario: Mutaciones gbrca-mutated 14% sbrca-mutated 6% 20% HRD-deficient 30%
DNA Repair Inhibitors in Ovarian Cancer 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
PARPi: Clinical Data Which patients?: BRAC mut, HRD, all? When?: First-line, recurrent sensitive, resistant Toxicities Future combinations: which partners? Integration in the current clinical practice
PFS: 8.4 vs 4.8 HR: 0.35 PFS: 11.2 vs 4.3 HR: 0.18
Olaparib in ROC (sensitive): Study 19 Updated OS
Olaparib in BRCA mut ROC (US study) RR: 34% RD: 7.9 m
Olaparib in ROC 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: 2017 Data
PARP inhibitors: Part Two
Rucaparib
Ariel 2: tbrca mut and tbrca-like* vs biomarker negative patients 12.8 5.3 4.7* 5.7 7.3* *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
Rucaparib in ROC December 19, 2016 Rucaparib accelerate approval Deleterious BRCA mutation (germline and/or somatic) >2 prior lines Approval also for companion diagnostic (FoundationFocus TM BRCA analysis CDx)
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
Progression-free Survival (%) PFS: germline vs somatic BRCA mut sbrcamut Treatment Niraparib (N=138) Placebo (N=65) PFS Median (95% CI) (months) 21.0 (12.9, NR) 5.5 (3.8, 7.2) Hazard Ratio (95% CI) P value 0.27 (0.173, 0.410) P<0.0001 % of Patients without Progression or Death 6 mo 12 mo 18 mo 80% 62% 50% 43% 16% 16% Treatment Niraparib (N=35) Placebo (N=12) PFS Median (95% CI) (Months) Hazard Ratio (95% CI) P value 20.9 (9.7, NR) 0.27 11.0 (2.0, NR) (0.081, 0.903) P=0.0248 % of Patients without Progression or Death 12 mo 18 mo 62% 52% 19% 19%
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
Niraparib in ROC March, 2017 Niraparib accelerate approval BRCA mutation, HRD and wild-type >2 prior lines Companion diagnostic (Myriad)
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) BRCA mut 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) 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 BRCA m BRCA m HRD BRCA m, HRD, BRCA wt 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%
Ovarian Cancer More treatments other than: Antiangiogenics PARPi Immunotherapy
Overview of Several Anti-PD-1/PDL-1 Therapies Currently in Development
Nivolumab Atezolizumab Pembrolizumab KEYNOTE-028 ASCO 2017
Immunotherapy: Rational Combinations Chemotherapy VEGFi
Criteria for Selecting Therapies in ROC Patient and physician preference Duration of response to initial platinum therapy PFI vs TFI p/np b Previous agents used Anti VEGF PARP inh Approvals Ascitis Pain Urgent response Patient s performance status Choice of Second-Line Therapy and Later BRCA mutation status Neurotoxicity Hypersensitivity Hematotoxicity Toxicities experienced in first-line setting Hysto-type Biology Factors
From DuBois A, personal presentation
Ovarian Cancer: Summary-1 Median Survival >5 years (2 1/2 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 BRCA wt 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