FOCUS SULLA TERAPIA CON OLAPARIB

Marilena Di NapoliOncologia Medica Uro-Ginecologica

IRCCS - Fondazione “G. Pascale”

Napoli

Ovarian cancer: not unique disease

Selected genomic alterations and their

frequencies in high-grade serous ovarian

Konstantinopulos PA, et al Cancer Discovery 2015

TCGA Consortium. Nature 2011;Turner, et al. Nat Rev Cancer 2004; Patch, et al, Nature 2015

Prevalence of BRCA mutations in ovarian

cancer

Approximately 50% of HGSOCs exhibit genetic or epigenetic alterations

of HR pathway genes.

Germline BRCA1 and BRCA2 mutations are the most common

alterations, and are present in:

14–15% of all EOCs

22.6% of HGSOCs

Somatic BRCA1 and BRCA2 mutations have been identified in 6-7% of

HGSOCs

Up to 44% have no family history

Konstantinopulos PA, et al Cancer Discovery 2015

PARP Inhibitors

Olaparib indications: US vs Europe

US approval:

PAST: Olaparib monotherapy in patient with germline mutated BRCA OC who have

received > 3 or more chemotherapy treatments together with a companion diagnsostic

test (BRCA analysis CDx). 1

PRESENT: maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tubeor primary peritoneal cancer, who are in a complete or partial response to platinum-basedchemotherapy.

European approval:

Olaparib monotherapy for the maintenance treatment of adult patient with

platinum-sensitive relapsed BRCA-mutated (Germline/somatic) OC, high grade

sereous, fallopian tube, or primary peritoneal cancer who are in response

(compleate or partial) to platinum-based chemotherapy. 2

From February 2018 Lynparza is indicated as monotherapy for the maintenancetreatment of adult patients with platinum-sensitive relapsed high-grade epithelialovarian, fallopian tube, or primary peritoneal cancer who are in response (complete orpartial) to platinum-based chemotherapy

1. Kaufman B, et al. J Clin Oncol 2015

. 2. Ledermann J et al. New Engl J Med 2012

Study 19: Phase II trial design, endpoints and

BRCA testing

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=129Placebo (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)

*BRCAwt patients did not have a detected BRCAm or had a BRCAm of unknown significance

bid, twice daily; BRCAwt, BRCA1/2 wild type; RECIST, Response Evaluation Criteria in Solid Tumors

Statistically significant

improvement in

progression-free

survival with

olaparib1,2

BRCAm subgroup:

Median PFS (olaparib vs placebo): 11.2 months vs 4.3

months HR=0.18, P<0.0001

Overall population:

Median PFS (olaparib vs placebo): 8.4 months vs 4.8

months HR=0.35, P<0.0001

Study 19: Progression free survival results

CI, confidence interval; DCO, data cut-off; FSI, first subject in

OS data maturity: 77%

Alpha (two-sided) = 0.95%

Additional follow-up since

previous analysis = 3 years

28 Aug 2008 31 Oct 2011 26 Nov 2012

FSI

OS data maturity: 38%

Alpha (two-sided) = 0.1%

HR=0.94

95% CI 0.63–1.39, P=0.751

OS data maturity: 58%

Alpha (two-sided) = 3%

HR=0.88

95% CI 0.64–1.21, P=0.442

30 Sep 2015

DCO DCO DCO

. Ledermann J et al. New Engl J Med 2012;366:1382–1392; 2. Ledermann J et al. Lancet

Oncol 2014;15:852–861 Jonathan A Ledermann at ASCO 2016

Study 19 OS analyses

Final analysis of the long-term benefit of

olaparib in pts with PSR SOC in Study 19

CI, confidence interval; DCO, data cut-off; FSI, first subject in. Ledermann J et al. New Engl J Med 2012;366:1382–1392; 2. Ledermann J et al. Lancet

Oncol 2014;15:852–861 Jonathan A Ledermann at ASCO 2017

79% data maturity

DCO, median OS follow-up was 78.0 months

Key slides ESGO 2017

© 2018– FSE/ANM

Biomarker characterization in patients receiving olaparib for ≥6 years

Patients receiving

olaparib for ≥6 years

n=15

sBRCAm

n=3

BRCAm

n=9

RAD51B

mutation

BRCAwt

n=5

gBRCAwt;

tBRCA unknown

n=1

BRCA2m

n=5

BRCA1m

n=3

BRCA1m and

BRCA2m

n=1

HRR

uncertain

n=5

HRRwt

n=2

HRRm

n=1

HRD +ve

n=1*

HRD -ve

n=1*

HRD +ve

n=1

= Foundation Medicine T5 panel result

= Myriad HRD score result

*2/5 BRCAwt patients had no available Myriad HRD score resultgBRCAwt, germline BRCA wild type; HRRm, HRR mutation; HRRwt, HRR wild type; tBRCA, tumour BRCA.

Olaparib OVAIO

Mod. da Friedlander M, et al. ESGO Annual Meeting 2017

Long-term exposure to treatment

Charlie Gourley, et al 2017 ASCO Meeting

SOLO-1, -2, -3

Randomized phase III studies of Olaparib in OC

*Primary endpoint for HRQoL was trial outcome index (TOI) of the FACT-O (Functional Assessment of Cancer Therapy – Ovarian)

Sensitivity analysis: PFS by blinded independent central review (BICR)

• Key secondary endpoints:

Time to first subsequent therapy or death (TFST), time to second progression (PFS2),

time to second subsequent therapy or death (TSST), overall survival (OS)

Safety, health-related quality of life (HRQoL*)

SOLO2/ENGOT-Ov21: study design

Placebo

n=99

Olaparib

tablets

300 mg bid

n=196Primary endpoint

Investigator-assessed

PFS

Patients

• BRCA1/2 mutation

• Platinum-sensitive relapsed

ovarian cancer

• At least 2 prior lines of

platinum therapy

• CR or PR to most recent

platinum therapy

Random

ized

2:1

Presented by Pujade-Lauraine at SGO 2017 annual meeting

No. at risk

OlaparibPlacebo

19699

18270

15637

13422

11818

10417

8914

8212

327

296

30

20

00

100

90

80

70

60

50

40

30

20

10

0

Pro

gres

sio

n-f

ree

surv

ival

(%

)

Months since randomization

0 3 6 9 12 15 18 21 24 27 30 33 36

19.1

Olaparib

Placebo

5.5

Olaparib

(n=196)

Placebo

(n=99)

Events (%) 107 (54.6) 80 (80.8)

Median PFS, months 19.1 5.5

HR 0.30

95% CI 0.22 to 0.41

P<0.0001

Median follow-up was 22.1 months in the olaparib group and 22.2 months for placebo

Presented by Pujade-Lauraine at SGO 2017 annual meeting

PFS by investigator assessment

Subgroup analysis of PFS

Olaparib better Placebo better

Presented by Pujade-Lauraine at SGO 2017 annual meeting

Months since randomization

Pro

gres

sio

n-f

ree

su

rviv

al (%

)

100

90

80

70

60

50

40

30

20

10

00 3 6 9 12 15 18 21 24 27 33

30.25.5

30

No. at risk

OlaparibPlacebo

19699

17662

14826

12818

11216

10314

8814

8211

306

285

30

10

Olaparib

(n=196)

Placebo

(n=99)

Events (%) 81 (41.3) 70 (70.7)

Median PFS, months 30.2 5.5

HR 0.25

95% CI 0.18 to 0.35

P<0.0001

PFS sensitivity analysis using BICR

Olaparib

Placebo

Presented by Pujade-Lauraine at SGO 2017 annual meeting

Total adverse events

Characteristic, n (%)Olaparib

(n=195)

Placebo

(n=99)

Any AE 192 (98.5) 94 (94.9)

Any AE grade ≥3 72 (36.9) 18 (18.2)

Any SAE 35 (17.9) 8 (8.1)

Any AE leading to dose reduction 49 (25.1) 3 (3.0)

Any AE leading to discontinuation of study treatment 21 (10.8) 2 (2.0)

Any AE with an outcome of death 1 (0.5) 0

AE, adverse event; SAE, serious adverse event Presented by Pujade-Lauraine at SGO 2017 annual meeting

Most common hematologic adverse events

Event, n (%) Olaparib (n=195) Placebo (n=99)

All grades Grade ≥3 All grades Grade ≥3

Anemia* 85 (43.6) 38 (19.5) 8 (8.1) 2 (2.0)

Neutropenia* 38 (19.5) 10 (5.1) 6 (6.1) 4 (4.0)

Thrombocytopenia* 27 (13.8) 2 (1.0) 3 (3.0) 1 (1.0)

MDS/AML: 4 cases in olaparib group (2.1%), including one case of CMML

4 cases in placebo group (4.0%)

*Grouped termsPresented by Pujade-Lauraine at SGO 2017 annual meeting

Most common non-hematologic adverse events

All grades (frequency ≥20%)

Olaparib Placebo

100 75 50 25 0 0 25 50 75 100Adverse events (%)

Dysgeusia 7.126.7

Headache 13.125.1

Decreased appetite 11.122.1

Nausea 33.375.9

Fatigue/asthenia 39.465.6

Vomiting 19.237.4

Constipation 23.220.5

Diarrhea 20.232.8

Abdominal pain 31.324.1

Grade ≥3 (frequency ≥2.5%)

Other AEs of interestElevated ALT: 10 patients in olaparib group (5.1%) vs 4 patients in placebo group (4.0%)Elevated AST: 4 patients in olaparib group (2.1%) vs 4 patients in placebo group (4.0%)

2.6

1.02.6

2.04.1

3.0

1.0

2.6 3.0

0.5

Presented by Pujade-Lauraine at SGO 2017 annual meeting

Health-related quality of life: TOI of the FACT-O

TOI over first 12 months Olaparib (n=185) Placebo (n=94)

Change from baseline, adjusted mean −2.90 −2.87

TOI, trial outcome index; FACT-O, Functional Assessment of Cancer Therapy – Ovarian

Estimated difference in adjusted means = −0.03 (95% CI −2.19 to 2.13, P=0.98)

Presented by Pujade-Lauraine at SGO 2017 annual meeting

WHAT ABOUT RECHALLENGE?

Olaparib in first line:SOLO-1 Phase III trial- BRCAm population only

First-line maintenance

Response to platinum-

based chemotherapy

Olaparib

300mg os bid

Placebo

344 patients

PFS/PFS2/OS + QoL

Randomization

2:1

Olaparib in first line: PAOLA 1 study design

MITO 31

A phase II trial of Olaparib in patients with recurrent ovarian cancer wild type for

germline and somatic BRCA mutations: a MITO translational study

QoL !!!!!

In conclusione….

QoL !!!!!

In conclusione….