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

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 Ce ll Deficient Ce ll

MECHANISM OF ACTION

Cancer discovery 2015

EOC & HRD

Potential

candidates for

iPARPs

Aprox 50% of

HGS EOC

harbor HRD

PARP INHIBITORS AS MAINTENANCE

THERAPY AFTER PLATINUM BASED

CHEMOTHERAPY AT RELAPSE

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

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

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).

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

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

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.

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

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

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

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

Moore KN, et al. ASCO 2018

N=463

At least 3 prior lines

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

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

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

FUTURE STRATEGIES

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

SOLO-1- in BRCAmut PRIMA: Niraparib in ovarian cancer

1st line Maintenance

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