Ovarian Carcinoma:Diagnosis and systemic treatment

Erice, 30 April 2019

Anita Wolfer, MD-PhD

• 5th cancer in women

• 4th cause of cancer death in women

• Median age at diagnosis : 63 years

• Risk factors: poor reproductive history and long reproductive career

• BRCA1: 15-45% lifetime risk; BRCA2: 10-20 % lifetime risk

• No efficient screening test available

ESMO Clinical Practice Guidelines Ann Oncol 24 (suppl 6): vi24-vi32, 2013

Epidemiology

Pathology

Systemic chemotherapy - Carboplatin + Paclitaxel

• Carboplatin (blood count, creatinine):

myelosuppression (thrombocytopenia J14-J21), nausea + vomiting, nephrotoxicity, polyneuropathy

• Paclitaxel (blood count): myelosuppression (leucopenia J10), anaphylaxis, polyneuropathy, mucositis, diarrhea

Anti-PARPWhy PARP : BRCA1/2 in ovarian cancer

Ovarian cancers with BRCA mutations show longer PFS and OS

BRCA1m

BRCA2m

BRCA1/2m

wt

Alsop et al., JCO 2012, 30(21):2654

Prognosis

Improved PFS and OS: meta-analysis

A systematic review included the

role of both germline and somatic

BRCA mutations on the prognosis

of patients with EOC

Progression-Free Survival:

• Analysis of the BRCA1/2 subgroup

showed that BRCA1/2 mutations

predicted statistically significantly

better PFS (HR=0.65)

Adapted from Sun et al. PLoS One. 2014; 9(5):e95285

Higher platinum sensitivity of BRCA mutated tumors

Alsop et al., JCO 2012, 30(21):2654

Significance of BRCA Status in Patients Diagnosed with Ovarian Cancer

Outcome Reference

Improved overall survival Rubin. NEJM. 1996Sun C. PLoS One. 2014Alsop. JCO. 2012

Improved progression free survival Hennessy. JCO. 2010Sun C. PLoS One. 2014Alsop. JCO. 2012

Better outcomes with platinum Dann. Gynecol Oncol. 2012Vencken. Annal Oncol. 2011Alsop. JCO. 2012

Better outcomes with PLD Adams. Gynecol Oncol. 2011

BRCA mutations are not confined to high grade

serous ovarian cancer

Adapted from 1. Vegote I et al. Euro J Cancer 2016;69:127-134;

Study1 Serous % Mucinous % Endometrioid % Clear cell % Undifferentiated % Unspecified %

Alsop 2012

(N=1001)

16.6 0 8.4 6.3 - 8.2

Jacobi 2007

(N=85)

10.8 0 0 0 0 0

Malander 2004

(N=161)

7.6 0 13.0 12.5 - 0

Norquist 2015

(N=1915)

16 (HGS)

5.6 (LGS)

0 8.8 6.9 - 53.5

Soegaard 2008

(N=445)

5.5 0 5.4 9.1 12.5 10.0

• High grade and low grade serous ovarian cancer patients can harbour BRCA

mutations but rates higher in high grade

• All non-mucinous ovarian cancer patients should be tested for BRCA mutation1

BRCA mutation frequency

• Germline BRCA1/2 mutations in 14.1% of all patients

• 16.6% in serous cancer patients

• 17.1% in high grade serous (HGSOC)

• Germline BRCA mutations not associated with specific molecular subtypes of

HGSOC (gene expression profiling)

• Women with BRCA1 mutation were younger at diagnosis than those without

(53.4 years vs 60.5 y; p<0.0001)

• Women with BRCA2 mutations similar age than wt (59.8 y)

• 44% of mutation positive women had no potentially significant family history

Alsop et al., JCO 2012, 30(21):2654

PARP inhibition and tumour-selective

synthetic lethality

Base excision repair (PARP)

Homologous recombination(BRCA)

Homologous recombination deficient

Base excision repair (PARP)

Healthy

XPARP inhibitor

Olaparib maintenance: SOLO2 trial

Mirza MR et al. N Engl J Med. 2016;375:2154–2164.

CI, confidence interval; gBRCAmut, germline breast cancer susceptibility

gene mutation; HR, hazard ratio; PFS, progression-free survival.

ENGOT-OV16 / NOVA: PFS in the gBRCAmutcohort

80

Niraparib

Placebo

00 24

100

Pro

gre

ssio

n-f

ree s

urv

iva

l (%

)

Time since randomisation (months)

60

40

20

20161284

gBRCAmut

Niraparib (n=138) Placebo (n=65)

Median PFS, months 21.0 5.5

HR 0.27

95% CI 0.17–0.41

P<0.001

Coleman et al, The Lancet 2017

Rucaparib Maintenance Therapy in Platinum-sensitive recurrent Ovarian cancer: AIREL3 trial

Who to test

Every women presenting with non-mucinousepithelial ovarian cancer

When to test

At diagnosis:

Germline testing for all the above reasons (prognosis, family

members, treatment); therefore the earlier the better

If germline negative but advanced disease (stage III or IV), go to

tumor testing

At relapse:

on tumor tissue to inform treatment options

PAOLA-1: olaparib vs placebo plus bevacizumab as maintenance treatment in patients with advanced ovarian cancer Phase 3 trial

• Study design

Primary endpoint

• PFS1 (RECIST 1.1)

Secondary

endpoints

• PFS2

• TSST

• OS

• Safety

• PRO/HRQoL

FIGO stage III–IV high-grade

ovarian cancer (serous or

endometrioid)* or non

mucinous BRCAm

No evidence of disease or CR

or PR following first-line

platinum-based chemotherapy

plus bevacizumab

A minimum of 3 cycles of

platinum-based chemotherapy

plus bevacizumab (2 after

interval debulking)

ECOG PS 0–1

*Includes patients with primary peritoneal and/or fallopian tube cancer†Tablet formulation (2 tablets twice daily)

ECOG=Eastern Cooperative Oncology Group; OS=overall survival; po=by mouth; PFS=progression-free survival; PFS2=time to second progression;

HRQoL=Health-related quality of life; TSST=time to second subsequent therapy; Q3W=every 3 weeks; PRO=patient reported outcome

Ray-Coquard I et al. J Clin Oncol 34, 2016 (suppl; abstr TPS5607 and poster presentation); Clinicaltrials.gov identifier: NCT02477644

Olaparib

300mg† po bid

+

Bevacizumab

15mg/kg Q3W

15 months

Placebo

+

Bevacizumab

15mg/kg Q3W

15 months

Randomise 2:1

N≈612 European +

24 Japanese patients

BRCA testing

prior to

randomisation

Status: in follow-up

High level results expected mid’19

Stratification by tumour

BRCA status and first-line

outcome

Summary of BRCA testing recommendations for

ovarian cancer patients

1. Vegote I et al. EJC 2016; 69:127-134

Why:

• To inform treatment – platinum sensitivity, PARP inhibition, immunotherapy ?

• Prognosis

• Identification of mutation carriers (family members)

Who:

• All ovarian cancer patients with non-mucinous epithelial ovarian cancer

When and what:

• At diagnosis

Anti-PD/L-1Why immunotherapy: TILs (tumor infiltrating lymphocytes) in ovarian cancer

T cell infiltrate predicts better prognosis in most cancer types

Fridman et al, Nature Review Cancer, 2012

Zhang, et al. N Engl J Med 2003

TIL Absent40%

CD3+

Stroma

Islet

TIL Present55%

Not all CRC patients have TILs. Why?

Zhang, et al. N Engl J Med 2003

After CR with chemotherapy, only patientswith TILs survive or are in remission long-term

Meta-analysis of intraepithelial TIL impact in ovarian cancer: 10 studies; 1,815 patients

Hwang et al, Gynecol Oncol 2011

TIL favors survivalTIL favors death

ANTI-PD/L-1

Comment ça marche

ADAPTED from: Emerging immunotherapies in ovarian cancer. Ojalvo LS, Nichols PE, Jelovac D, Emens LA.Discov Med. 2015 Sep;20(109):97-109.

Summary of the PD-1/PDL-1 Clinical Trials to date

Drug Target Population No PD-L1 status

ORR DCR CR PR SD References

Nivolumab PD-1 Relapsed PlatRovarian cancer

18 Any 17% 44% 2 1 5 Hamanishi et al., 2014

Pembrolizumab PD-1 Advanced ovarian cancer

26 PD-L1+ 11.5% 34.6% 1 2 6 Varga et al., 2015

Avelumab PD-L1 PlatR or chemoRovarian cancer

124 Any 9.7% 54% 0 12 55 Disis et al., 2016

Atezolizumab PD-L1 Advanced ovarian cancer

12 PD-L1+ 17% ND 0 2 ND Infante et al., 2016

Best overall responses in all patients

in two cohorts with anti–

programmed death 1 (PD-1)

antibody.

Junzo Hamanishi et al. JCO doi:10.1200/JCO.2015.62.3397©2015 by American Society of Clinical Oncology

PARP-inhibitor in

PARP-inhibitor

Immune response

Patients:

• response lasting ≥6 months to first-line platinum therapy

• considered to have PROC per investigator’s assessment (eg, pts not eligible for further platinum)

• ≤ 5 prior treatment lines

• primary platinum-refractory (PRef) disease excluded, not secondary PRef disease

Treatment: niraparib 200 mg orally once daily + pembrolizumab 200 mg IV every 21 days.

Primary and secondary endpoints: ORR = CR+PR and disease control rate (DCR = CR+PR+SD).

Results:

• 60/62 pts evaluable for response assessment (≥1 on-study scan).

• Median age 60 years.

• Median prior lines of chemotherapy 2 (range: 1-5).

• 64% of pts PROC (PFI < 6 months), 19% pts PRef disease (PFI < 30 days), and 17% platinum-sensitive

• 20 pts remain on treatment and 11 have received treatment for ≥6 months.

• 60 evaluable pts, ORR/DCR 25%/68%; 11 tumor BRCA (tBRCA) mut evaluable pts, ORR/DCR were 45%/73%.

• Responses in 11/38 PROC pts, 2/11 PRef pts, and 1/10 PSens pts (platinum status unknown in 1 responder)

Conclusions: With ORR of 25% in all PROC and ORR of 45% in tBRCAmut pts, niraparib + pembrolizumab

appears promising. Additional evaluation of this combination in ROC is warranted. No new safety signals were

identified with the combination

TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib +

pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—Results from ROC cohort.

An open-label, Phase II basket study of olaparib

and durvalumab (MEDIOLA):

Results in germline BRCA-mutated,

platinum-sensitive relapsed ovarian cancer

Yvette Drew,1 Maja de Jonge,2 Sook-Hee Hong,3 Yeon Hee Park,4 Anita Wolfer,5 Jennifer Brown,6

Michelle Ferguson,7 Martin E Gore,8 Ricardo Alvarez,9 Christopher Gresty,10 Helen Angell,10

Kassondra Meyer,11 Maria Learoyd,10 Mei Tang,12 Mark Lanasa,11 Pia Herbolsheimer11

and Susan M Domchek13

1Northern Centre for Cancer Care, Newcastle-upon-Tyne, UK; 2Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, Netherlands; 3Seoul St Mary's Hospital, Catholic University of Korea, Seoul, South Korea; 4Samsung Medical Center, Seoul, South Korea; 5Lausanne

University Hospital, University of Lausanne, Lausanne, Switzerland; 6Beatson West of Scotland Cancer Centre, Glasgow, UK; 7NHS

Tayside, Dundee, UK; 8The Royal Marsden Hospital, London, UK; 9Cancer Treatment Centers of America, Augusta University, Augusta,

GA, USA; 10AstraZeneca, Cambridge, UK; 11AstraZeneca, Gaithersburg, MD, USA; 12Medimmune Oncology, Inc., Gaithersburg, MD,

USA; 13Basser Center for BRCA, University of Pennsylvania, Philadelphia, PA, USA

Funded by AstraZeneca; ClinicalTrials.gov number NCT02734004

*Patient later achieved a PR after receiving durvalumab + olaparib combination

AE, adverse event; CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease

2

2

2

2

1

1

1

3

3

3

1

1

1

2

3

6

3

4

2

2

1

1

1

1

3

3

3

2

1

1

2

1On study treatment

CR

PR

SD

PD (RECIST)

NE

Discontinuation due to AE

Discontinuation due to patient decision

Death

Prior lines of chemo

Time to progression or treatment discontinuation (N=32)

0 28 56 84 112 140 168 196 224 252 280 308 336 364 392 420 448

Study Day

DCR at 12 weeks: 81% (90% CI 66%, 92%)

12 weeks

*

multicenter, randomized, phase III JAVELIN Ovarian 200 trial (NCT02580058),

556 patients with platinum-resistant or -refractory ovarian cancer randomized to receive :

• A: avelumab intravenously (IV) at 10 mg/kg every 2 weeks in 4-week cycles

• B: avelumab IV at 10 mg/kg every 2 w in 4-w cycles plus PLD at 40 mg/m2 IV every 4 w in 4-w cycles

• C: PLD at 40 mg/m2 IV every 4 w in 4-w cycles

Patients:

• histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer

• platinum-resistant/-refractory disease

• ≤ 3 lines of systemic therapy

• measurable disease

1° endpoints were superior OS or PFS for one or both avelumab arms versus PLD

2° EP: objective response rate (ORR)

ORR : 13.3% (95% CI, 8.8%-19.0%) for avelumab combined with PLD (Arm B), 3.7% (95% CI, 1.5%-7.5%) for single-agent

avelumab (Arm A), and 4.2% (95% CI, 1.8%-8.1%) for PLD alone

A Study Of Avelumab Alone Or In Combination With Pegylated Liposomal

Doxorubicin Versus Pegylated Liposomal Doxorubicin Alone In Patients

With Platinum Resistant/Refractory Ovarian Cancer (JAVELIN Ovarian 200)

HR for PFS of 0.78, did not meet the prespecified criteria for superiority (repeated confidence interval [RCI], 0.587-

1.244; one-sided P value = .0301).

OS endpoint with the avelumab combination not met (HR, 0.89; RCI, 0.744-1.241; one-sided P value = .2082).

International, multicenter, open-label, randomized JAVELIN Ovarian 100 trial (NCT02718417) evaluating

avelumab in combination with and/or following platinum-based chemotherapy in treatment-naïve

patients with locally advanced or metastatic epithelial ovarian cancer (adjuvant)

JAVELIN Ovarian PARP 100 (NCT03642132), an open-label, multicenter, phase III study randomizing

patients with previously untreated advanced ovarian cancer to

1. avelumab plus platinum-based chemotherapy followed by maintenance therapy of avelumab in

combination with talazoparib

2. avelumab plus platinum-based chemotherapy followed by maintenance therapy of Talazoparib

3. chemotherapy plus bevacizumab, followed by bevacizumab maintenance

PAOLA1: first-line treatment, platinum-based chemotherapy plus bevacizumab followed by maintenance

bevacizumab +/- olaparib/placebo

Ongoing studies (not exhaustive)

Bevacizumab 15mg/kg q3w

+

atezolizumab 1,200mg q3w

Investigator’s choice

Phase II trial of bevacizumab + aspirin + atezolizumab in platinum-resistant ovarian cancer: trial design

Optional biopsy Bevacizumab 15mg/kg q3w

+

atezolizumab 1,200mg q3w

+

aspirin 325mg/day

Bevacizumab 15mg/kg q3w

Bevacizumab 15mg/kg q3w

+

atezolizumab 1,200mg q3w

Atezolizumab 1,200mg q3w

Recurrent,

platinum-resistant

ovarian, fallopian

tube or primary

peritoneal cancer

Atezolizumab 1,200mg q3w

+

aspirin 325mg/day

Pre-cycle 3

Continue treatment until PD

1:1:1:1

Upon progression:

continue tumour

assessment q9w until PFS2

Mandatory biopsy

(Anita Wolfer)Lana KandalaftGeorge Coukos