ovarian carcinoma: diagnosis and systemic treatment€¦ · •5th cancer in women • 4th cause of...
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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