clínica diagonal. barcelona - foro de debate en oncología , hrd, all? •when?: first-line,...

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