Ospedale e Territorio: insieme

contro il carcinoma ovarico

Trattamento di seconda linea e oltrelinea e oltre

Roberta Buosi

Alessandria, 19 settembre 2018

Dimensione del problema

� > 80% of cases diagnosed > 50 years age.

64 per 100,000

� Considering chemotherapy, up to 10% of patients might not respond to first-line chemotherapeutic treatment and, of those who do respond, between 55% and 75% of

� 64 per 100,000in women aged ≥ 85 years.

� with BRCA-deficient tumours, the age of diagnosis can be about 10 years earlier.

respond, between 55% and 75% of people will relapse within 2 years.5

Fattori prognostici e OS

Prognostic factors thought to influence outcome (i.e. response to treatment and survival) are:

� the stage of the disease at diagnosis (FIGO stage)

Relative 5-year survival rate is > 90% for

early stage disease but falls markedly to <

10% for later stages (FIGO stage)

� Age

� patient’s general health (typically referred to as performance status) at the time of presentation

� grade tumour histology.

� residual disease after debulking surgery are considered to be strong predictors.

Relative 1- and 5-year survival rates (%) for two time periods

OS 1year5 years

1971–5 42.0 %

21.0 %

2005–9 72.3 %42.9 %

Obiettivi di cura

Prolungamento della sopravvivenza

riduzione del n di recidive

Controllo dei sintomi (o dilazione della loro comparsa)

Miglioramento della qualità di vita complessiva (o dilazione del peggioramento)

> percentuale delle platino sensibili

CRONICIZZARE

TEAM INTERDISCIPLINARE

INTER -PROFESSIONALE

Analisi costi

An analysis of Hospital Episode Statistics for 2006–8 of patients dying from prostate, breast, lung, upper gastrointestinal, colorectal or ovarian cancer indicates that patients with ovarian cancer and in their last year of life required 53,700 elective bed-days (at a cost of £14,274,623) and 216,723 emergency bed-days (at a cost of £58,606,527).

On a per-person basis, ovarian cancer had a longer elective stay and a longer emergency length of stay than the other cancers.

Ovarian cancer also had the highest overall cost,

at £8000 per person.

Alkeran,

RT

CDDP +doxo,

Carbo +

paclitaxel

Target

Therapy

Immunoterapy

Development of therapy

CTX

monoDoxo lipo,

Topotecan, +doxo,

PECImmunoterapy

1970 1980 1990 2000 2010

mono

1960

Topotecan,

trabectedina

2016

Decisional node PFI

OS PS ovarian cancer

Overall survival for the subgroup of patients with FPS ovarian cancer

Overall survival for the subgroup of patients with PPS ovarian cancer

Studi di fase III

Paz platino

resistenti

C. Aghajanian JCO 2012

PFS OS

NON c’è consenso da parte di molti Panel diesperti per l’uso di Bevacizumab inassociazione alla chemioterapiaDa preferire alternative terapeutiche

Fattori Predittivi?

BRCA1-2 mutation

identified mutations now recognized to be related to the HRR pathway in ap- proximately 30% of high-grade

WILDE TYPE

ap- proximately 30% of high-grade serous ovarian cancers.

This included somatic mutations

in BRCA1/2 (3%), ATM and ATR (2%), the FANC family (5%), and hypermethylation of RAD51C (3%), as well as germlinemutations in BRCA1 (9%) or

BRCA2 (8%)MUTATO

Patients with epithelial ovarian cancerand germline or somatic BRCA1 orBRCA2 mutations demonstrate impairedability to repair double-strand breaksthrough HRR, which likely explains theincreased sensitivity to platinum and

the potentially more favorable

PARP1 and PARP2 are enzymes, activated byDNA damage, which facilitate DNA repair inpathways involving single-strand breaks (SSBs)

and base excision repair (BER)

BRCA – PARP meccanismi cooperatori di riparazione del

DNA

the potentially more favorable

outcome compared with patients who

are wild-type.

these cancers may have sensitivity

to immune checkpoint inhibitors

targeting the PD-1/PD-L1 pathway

and base excision repair (BER)

After binding to altered DNA, PARP1 increases its catalytic activity and uses NAD+ to create polymers of poly(ADP- ribose) (PAR) and transfers it to acceptor proteins, including PARP itself This auto-poly(ADP-ribosyl) ation recruits various other proteins to the site of DNA-

damage, initiating a repair complex.

Meccanismo d’azione di PARP-I

LG AIOM

Olaparib for Maintenance Treatment of BRCA 1 or 2 Mutated, Relapsed, Platinum-

Sensitive Ovarian, Fallopian Tube and Peritoneal Cancer in People Whose Relapsed

Disease has Responded to Platinum-Based Chemotherapy

phase II, double-blind randomised controlled trial that recruited 265 patients with PSRserous ovarian cancerNo selection about BRCA

Primary endpoint PFSPrimary endpoint PFS

olaparib, 400 mg bdPFS: HR 0.35; 95% CI 0.25–0.49; P < 0.00001), extending the median time toprogression or death following chemotherapy by 3.6 months (from 4.8 to 8.4 months).Only 38% BRCA test

OS not different (38% first interim analysis)

96% tested for BRCA1/2 mutation (BRCAm),

PFS HR 0.18 (11,2 vs 6.9 m)

But second interim analysis revealed no

statistically significant overall survival

(OS) benefit (58%)

Olaparib

� Olaparib come mantenimento nelle

� Olaparib di mantenimento nelle recidive platino sensibili

EMA ottobre 2014 FDA dicembre 2014

mantenimento nelle recidive platino sensibili ca ovaio sieroso papillare di alto grado

(studio 19)

mantenimento nelle recidive platino sensibili dopo 2-3 linee di trattamento

(studio 42: 34% pazrispondenti)

Treatment with olaparib monotherapy in the maintenance setting significantly improves progression-free survival in

patients with platinum-sensitive relapsed ovarian cancer:

Eric Pujade-Lauraine,1 Jonathan A Ledermann,2 Richard T Penson,3 Amit M Oza,4 Jacob Korach,5

Tomasz Huzarski,6 Andrés Poveda,7 Sandro Pignata,8 Michael Friedlander,9 and Nicoletta Colombo10

Funded by AstraZeneca; ClinicalTrials.gov number NCT01874353

platinum-sensitive relapsed ovarian cancer:Results from the Phase III SOLO2 study

SOLO2/ENGOT-Ov21: study design

Placebon=99

Olaparib 300 mg bid

n=196 Primary endpoint

Investigator-assessedPFS

Patients• BRCA1/2 mutation• Platinum-sensitive relapsed

ovarian cancer • At least 2 prior lines of

platinum therapy

Random

ized2:1

*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*)

n=99platinum therapy• CR or PR to most recent

platinum therapy

Random

ized

Characteristic

Olaparib(n=196)

Placebo(n=99)

Age, median (range) 56 (28–83) 56 (39–78)

Ovarian 162 (82.7) 86 (86.9)

Demographic and baseline characteristics

Primary tumor type, n (%)

Ovarian 162 (82.7) 86 (86.9)

Fallopian tube or primary peritoneal 31 (15.8) 13 (13.1)

Other/missing 3 (1.5) 0

Prior platinum regimens, n (%)

2 lines 110 (56.1) 62 (62.6)

3 lines 60 (30.6) 20 (20.2)

≥4 lines 25 (12.8) 17 (17.2)

Platinum-free interval, n (%)6–12 months 79 (40.3) 40 (40.4)

>12 months 117 (59.7) 59 (59.6)

Response to platinum therapy, n (%)Complete response 91 (46.4) 47 (47.5)

Partial response 105 (53.6) 52 (52.5)

100

90

80

70

60

50

free s

urvi

val (

%)

Olaparib

Olaparib (n=196)

Placebo (n=99)

Events (%) 107 (54.6) 80 (80.8)Median PFS, months 19.1 5.5

HR 0.3095% CI 0.22 to 0.41

P<0.0001

PFS by investigator assessmentPFS sensitivity analysis using BICR

Olaparib (n=196)

Placebo (n=99)

Events (%) 81 (41.3) 70 (70.7)Median PFS, months 30.2 5.5

HR 0.2595% CI 0.18 to 0.35

P<0.0001Olaparib

No. at risk

OlaparibPlacebo

19699

18270

15637

13422

11818

10417

8914

8212

296

30

20

00

50

40

30

20

10

0

Pro

gre

ssio

n-fr

ee s

urvi

val (

%)

Months since randomization

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

19.1

Placebo

5.5

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

Months since randomization

00 33

30.25.5

No. at risk

OlaparibPlacebo

306

10

Secondary efficacy endpoints

27.9

7.1

18.4PFS2

Time to first subsequent therapy,

or death (TFST)

HR 0.2895% CI 0.21 to 0.38

P<0.0001

HR 0.5095% CI 0.34 to 0.72

Median not reached

Not reached

18.2

0 10 20 30Median (months)

Olaparib

PlaceboData immatureOverall survival

Time to second subsequent therapy,

or death (TSST)

P=0.0002

HR 0.3795% CI 0.26 to 0.53

P<0.0001

Median not reached

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)

Total adverse events

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

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 CMML4 cases in placebo group (4.0%)

*Grouped terms

Most common non-hematologic adverse events

All grades (frequency ≥20%)

Olaparib Placebo

Dysgeusia 7.126.7

Nausea 33.375.9

Fatigue/asthenia 39.465.6

Vomiting 19.237.4

Diarrhea 20.232.8 Grade ≥3 (frequency ≥2.5%)

2.6

1.02.6

2.04.1

1.0

100 75 50 25 0 0 25 50 75 100

Adverse events (%)

Dysgeusia

Headache 13.125.1

Decreased appetite 11.122.1

Constipation 23.220.5

Abdominal pain 31.324.1

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%)

3.0

2.6 3.0

0.5

Study conclusion

• SOLO2 demonstrated a statistically significant PFS improvement in patients receiving olaparib,by investigator assessment and BICR

• The PFS benefit was supported by a significant delay in TFST, PFS2 and TSST in the olaparibgroupgroup

• With the exception of anemia, toxicity was mostly low grade

• SOLO2 is the first Phase III trial of olaparib tablets as maintenance treatment and showed asignificant benefit in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2mutation

DOVE SIAMO ADESSO ….

• PARP-I rappresentano un cambiamento nel trattamento del carcinoma dell’ovaio

• Le mutazioni di BRCA sono i primi fattori predittivi nel carcinoma dell’ovaio per selezionare le pazienti da candidare a Target Therapy

• Resistenza agli PARP-I ?

dell’ovaio per selezionare le pazienti da candidare a Target Therapy

• Il test per valutare le mutazioni germinali è già parte della nostra pratica clinica per la selezione dei tumori dell’ovaio, e i test somatici pa la valutazione delle BRCAness sono stati validati e saranno precocemente introdottotti nell’uso quotidiano

Nuove molecole

ARIEL3: Rucaparib maintenance treatment for recurrentovarian carcinoma after response to platinum therapy

Fase IIICa ovaio recidivato

375 ptsRucaparib 600 mg

bid

PD o tossicità

recidivatoAlmeno 2 linee

di platinumbased CT

RC/RPdopo CT

R2:1

189 ptsPlacebo

bid

PD o tossicità

Stratificazione in base allo stato di BRCA (BRCA-mutated carcinoma or BRCA wild-type and high-LOH carcinoma)

Obiettivo primario PFS Obiettivi secondari: RR, Safety, OS

Caratteristicheal basale

Tossicità

BRCA mutate

Deficit di ricombinazione omologa

ITT population

EFFICACIA: PFS

ENGOT-OV16/NOVANiraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer

MR. Mirza, NEJ Med 2016

Caratteristiche al Basale

EFFICACIA: PFS

PARP-I : PS ITT

Metanalisi – Cochrane 2016

PARP-I : PS Platinum sensitive onlyNessun vantaggio in OSneanche nel solo sottogruppodelle platino sensibili

Combinazioni

Olaparib + Cediranib vs Olaparib

Phase IICa ovaio Platino

sensibile90 pts

Cediranib 30 mg+ olaparib 200 mg bid

PD

inaccettabile

PDO Tossicità

inaccettabile

PDPD90 pts Olaparib 400 mg bid

Stratificazione in base allo stato di BRCA

Endpoint primario: PFS

inaccettabile

PDO Tossicità

inaccettabile

RISULTATI

OLA

+CEDIR

OLA

0RR % 79.6 47.8

PD 0 1

PFS 17.7 m 9 m

Toxicity G3 OLA +CEDI OLA

fatigue 27% 11%

diarrea 23% 0%PFS 17.7 m 9 m

BRCA WTORR %PFS

7616.5 m

325.7 m

BRCA MORR %PFS

8919.4 m

6416.5 m

34% of patients in the cediranib/olaparib arm had baseline

hypertension.

diarrea 23% 0%

ipertensione 41% 0%

J.F Liu, Lancet Oncol 2014

Surgical cytoreduction for recurrent epithelial ovarian cancer PS

surgery with complete cytoreduction (no visible residual disease) is associated with significant improvement in overall survival.

However, in the absence of RCT evidence, it is not clear whether However, in the absence of RCT evidence, it is not clear whether this is solely due to surgical effect or due to tumour biology. Indirect evidence would support surgery to achieve complete cytoreduction in selected women. The risks of major surgery need to be carefully balanced against potential benefits on a case-by-case basis.

quesiti:

Platino Resistenti

Nuove combinazioni? Nuove combinazioni?

IMMUNO CHEKPOINT-I?

Platino Resistenti/refrattarie

Da cosa

dipende la PR?

Dobbiamo ancora

definire la PR solo su

fattore temprale?

Come

superarla?

Fattori

biomolecolari

?

RANDOMI

AURELIA: study designPlatinum-resistant OCa

•≤2 prior anticancer

regimens

•No history of bowel

obstruction/abdominal

fistula or clinical/ Treat to

Treat to

PD/toxicity

Investigator’s

choice

Optional BEV

monotherapyd

BEV 15 mg/kg q3wc

Chemotherapy

ISE

PD = progressive disease.aEpithelial ovarian, primary peritoneal or

fallopian tube cancer; bStratification factors:

selected chemotherapy; prior anti-angiogenic

therapy; Treatment-free interval (<3 vs 3‒6

months from previous platinum to subsequent

PD); cOr 10 mg/kg q2w. d15 mg/kg q3w,

permitted on clear evidence of PD.

1. Adapted from Pujade-Lauraine E, et al. J Clin

fistula or clinical/

radiological evidence of

rectosigmoid involvement

Treat to

PD/toxicitychoice

(without BEV)

BEV 15 mg/kg q3w

+ chemotherapy

1:1

Chemotherapy options (investigator’s choice):

• Paclitaxel 80 mg/m2 days 1, 8, 15, & 22 q4w

• Topotecan 4 mg/m2 days 1, 8, & 15 q4w (or 1.25 mg/m2, days 1–5 q3w)

• PLD 40 mg/m2 day 1 q4w

AURELIA: Progression-free survival

Presented By Elise Kohn at 2017 ASCO Annual Meeting

OS: ITT populationCT

(N=182)

BEV + CT (N=179)

Events, n (%) 136 (75) 128 (72)

Median OS,months (95% CI)

13.3(11.9‒16.4)

16.6(13.7‒19.0)

HR (unstratified)(95% CI)Log rank p value (2-sided unstratified

0.85 (0.66‒1.08)

P<0.174

100

75

50

Ove

rall

su

rviv

al

(%)

Data cut-off: 25 January 2013.

Adapted from Pujade-Lauraine E, et al. J Clin

Oncol 2014; 32(13): 1302-8.

CTBEV + CT

No. at risk:182 130 98 63 29 12 1 0179 148 106 75 39 13 1 0

0 6 12 18 24 30 36 42Time (months)

50

25

0

Ove

rall

su

rviv

al

(%)

Safety and Clinical Activity of the Programmed Death-Ligand1 Inhibitor

Durvalumab in Combination With Poly(ADP-Ribose) Polymerase Inhibitor

Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib

in Women’s Cancers: A Dose-Escalation, Phase I Study

JM Lee, JCO 2017

RISULTATI

Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer

ORR

Efficacia

* Includes ovarian cancer (n = 15), triple-negative breast cancer (n = 2), cervical cancer (n = 2), and uterine leiomyosarcoma patients (n = 1)CI, confidence interval; DCR, disease-control rate; IC, immune cell; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TC, tumor cell; TRAE, treatment-related adverse event, Tx, treatment

1. Hamanishi J, et al. J Clin Oncol. 2015;33(34):4015-4022. 2. Varga A, et al. J Clin Oncol. 2015;33(suppl): Abstract 5510. 3. Disis ML, et al. J Clin Oncol. 2016;34(suppl): Abstract

5533. 4. Infante JR, et al. Ann Oncol. 2016;27(Suppl 6): Abstract 871P. 5. Lee J-M, et al. J Clin Oncol. 2016;34(suppl): Abstract 3015.