Cáncer epitelial de ovario:

Cómo elegir mantenimiento

en primera línea
Angélica Nogueira-Rodrigues, MD PhD
EVA-GBTG, SBOC, LACOG, UFMG
DOM, ONCOCLÍNICAS
¿Por qué, cuándo y qué testear en cáncer
epitelial de ovario?
Conflictos de interés:
Consultor:
ANVISA (Brazil), Roche, AstraZeneca, MSD, EISAI, Pfizer, GSK, Agenus, Novartis

Investigación científica:
CNPq, FAPEMIG (public research organizations in Brazil)

Entrenamiento educacional:
Roche, AstraZeneca, MSD, GSK, Pfizer, Novartis, Gilead

Acciones en empresas:
DOM Oncologia
Epidemiología del CEO

314,000

GLOBOCAN,
2020
INCA, 2023
JCO, 2020
Incidencia del cáncer de ovario en América Latina.

Globocan, 2020
Primera línea
Cirurgia de qualidade
é parte fundamental

Reitan Ribeiro
 Alquilantes
Platina Platina/taxane
20

Mortality per 100,000 women

15

10

1975 1985 1995 2005 2011

Slide do autor
Quimioterapia neoadyuvante versus cirugía inmediata:
etapas III y IV

▪ Quimioterapia neoadjuvante seguida de cirurgia de

intervalo não foi inferior à citorredução primária
seguida de quimioterapia adjuvante em pacientes com
carcinoma de ovário estadios IIIC ou IV, conforme os
estudos EORTC-NCIC , CHORUS e Scorpion

▪ A ressecção completa de toda doença macroscópica,

na citorredução primária ou de intervalo, deve ser o
objetivo quando a cirurgia citorredutora é realizada.

1. Vergote I et al, NEJM 2010. 2. Kehoe S et al, Lancet 2015.

314,000

Globocan, 2020
El escenario en evolución de la terapia
de mantenimiento del cáncer de ovario.
 Alkylant Taxane
Platin Platin/ Antiangiogenics
20 taxane (maintenance)

Mortality per 100,000 women

15

10

1975 1985 1995 2003 2011

Cambio de paradigma en la comprensión del cáncer de ovario
 BRCAness / BRCA-like /
HRness

Nature Reviews Cancer 16, 110–120 (2016)

Mutations: germline vs. somatics

BRCA mutated cells

tBRCA+
result
BRCA intact cells

Blood or salive: negative Blood or salive: positive

Eoh et al. BMC Cancer (2020) 20:204 https://doi.org/10 .1186 /s12885-020-6693 -y

 Other HRD BRCA1 germline mutations 8%
BRCA1 somatic mutations 3%
BRCA2 germline mutations 6%
BRCA mutations
BRCA2 somatic mutations 3%
Other 21%

CDK12 mutations 3%
FA gene mutations2% Other HRR gene
NER mutations 4–8% Core RAD genemutations1.5% mutations*
HRR DNAdamagegenemutations2% Genomic
HRD
MMR mutations 3% instability
BRCA1 promoter methy lation 10% Altered HRR gene
RAD51C promotermethylation2% expression
Cy clin E1 amplification 15%
HRP
Other
Possibly HRD EMSY amplification 6% unidentified
PTEN homozygous loss 7%
causes

*Not all mutations have been linked to an HRD phenotype; BRCA, breast cancer gene; CDK12, cyclin dependent kinase 12; EMSY, BRCA2-interacting transcriptional repressor; DNA, deoxyribonucl eic acid; FA, Fanconi anaemia; HGSOC, high-grade serous
ovarian cancer; HRD, homologous recombination deficiency; HRP, homologous recombination proficiency; HRR, homologous recombination repair; HRR, homologous recombination repair; MMR, mismatch repair; NER, nucleotide excision repair; PARP, poly
(ADP-ribose) polymerase; PTEN, phosphatase and tensin homolog
1. Konstantinopoul os PA, et al. Cancer Discov 2015;5:1137–1154; 2. Ahmed A, et al. J Pathol 2010;221:49–56; 3. Press JZ, et al. BMC Cancer 2008;8:17
Parp Inhibitor

Synthetic lethality
From t he be nch t o
be ds ide
 Analysis is performed on DNA isolated from FFPE tumour tissue and assesses two factors to determine HRD status

Testing in newly diagnosed ovarian cancer

Tumour BRCA mutation Genomic instability

Example:
Myriad
myChoice®
Presence of genomic
instability
BRCA mutation
Loss of heterozygosity Telomeric allelic imbalance Large-scale state transitions
(LOH) (TAI) (LST)
Presence of a single allele A discrepancy in the 1:1 allele Transition points betw een
Yes No ratio at the end of the regions of abnormal and
chromosome (telomere) normal DNA or betw een tw o
different regions of abnormality

Score out of 100

BRCA, breast cancer gene; DNA, deoxyribonucleic acid; FFPE, formalin fixed paraffin embedded; HRD, homologous recombination deficiency; LOH, loss of heterozygosity; LST, large-scale state transitions; TAI, telomeric allelic imbalance
Myriad myChoice® HRD Technical Specifications. Available at: https://myriad-web.s3.amazonaws.c om/myChoice/downl oads/myChoiceHRDT ec hSpecs.pdf. Accessed 18 August 2020
other causes
FMI FoundationOne CDx
Myriad myChoice CDx
Mantenimiento
SOLO1 PRIMA

H R =0.30
95% CI, 0.23–0.41
P<0.0001

PAOLA VELIA

PRIME ATHENA
SOLO1: Ensayo de fase III de mantenimiento con
olaparib después de quimioterapia basada en platino
en pacientes recién diagnosticadas con cáncer de
ovario avanzado y una mutación en BRCA1/2.
:Kathleen Moore, Nicoletta Colombo, Giovanni Scambia, Byoung-Gie Kim, Ana Oaknin, Michael Friedlander,
1 2 3 4 5 6

Alla Lisyanskaya,7 Anne Floquet,8 Alexandra Leary,9 Gabe S. Sonke,10 Charlie Gourley,11 Susana Banerjee,12
Amit Oza,13 Antonio González-Martín,14 Carol Aghajanian,15 William Bradley,16 Elizabeth S. Lowe,17 Ralph Bloomfield,18
Paul DiSilvestro19
1
Stephenson CancerCenter at the University of Oklahoma, Oklahoma City, OK, USA; 2University of Milan-BicoccaandIEO,EuropeanInstituteof Oncology IRCCS, Milan, Italy; 3Fondazione
Policlinico Universitario A. GemelliIRCCS Università Cattolica, Rome, Italy; 4Samsung MedicalCenter, SungkyunkwanUniversity School of Medicine, Seoul, Korea; 5Vall d'HebronUniversity
Hospital, Vall d'Hebron Instituteof Oncology (VHIO), Barcelona, Spain; 6University of NewSouth Wales Clinical School, Princeof Wales Hospital, Randwick,Australia; 7St Petersburg City
Oncology Dispensary, St Petersburg, Russia; 8Institut Bergonié,Comprehensive Cancer Centre, Bordeaux, France; 9Gustave-Roussy Cancer Campus, Villejuif, France; 10The Netherlands Cancer
Institute, Amsterdam,The Netherlands; 11Cancer Research UK Edinburgh Centre, Instituteof Genetics and Molecular Medicine, University of Edinburgh, Edinburgh,UK; 12The Royal Marsden NHS
Foundation Trust andInstituteof Cancer Research, London, UK; 13Princess MargaretCancer Centre, Toronto, ON, Canada; 14Clínica Universidad de Navarra, Madrid,Spain; 15MemorialSloan
Kettering Cancer Center, NewYork, NY, USA; 16Froedtert and the Medical College ofWisconsin, Milwaukee, WI,USA; 17AstraZeneca, Gaithersburg, MD, USA; 18AstraZeneca, Cambridge, UK;
19
Women &Infants Hospital, Providence, RI, USA
ClinicalTrials.govidentifier: NCT01844986
esmo.org
This study wassponsored by AstraZeneca;partof analliancebetweenAstraZeneca and Merck & Co., Inc.
Conducted in partnership with theGynecologic OncologyGroup (GOG-3004)
Diseño del estudio
Primary endpoint

• Investigator-assessed PFS
• Newly diagnosed, FIGO Olaparib 300 mg bd • Study treatment (modified RECIST 1.1)
stage III–IV, high-gradeserous (N=260) continued until
or endometrioid ovarian, disease progression
primary peritonealor fallopian 2:1 randomization • Patientswith no Secondary endpoints
tube cancer evidence of disease
• Germline or somatic BRCAm Stratifiedby at 2 years stopped • PFSusing BICR
• ECOG performance status 0–1 response to platinum- treatment • PFS2
• Cytoreductive surgery* based chemotherapy • Patientswith a partial • Overall survival
• In clinicalcomplete response response at 2 years • Time from randomization to
or partial response after Placebo could continue first subsequent therapy or
platinum-based chemotherapy (N=131) treatment death
• Time from randomization to
second subsequent therapy
or death
2 years’ treatment if no evidence of disease
• HRQoL (FACT-OTOI score)

*Upfront or interval attempt at optimalcytoreductive surgery for stage IIIdisease andeither biopsy and/or upfront or interval cytoreductive surgery for stage IV disease.
BICR, blinded independentcentral review; ECOG, Eastern Cooperative Oncology Group;FACT-O, Functional Assessment of Cancer Therapy –
Ovarian Cancer; FIGO,International Federationof Gynecology andObstetrics; HRQoL, health-related quality of life; PFS,progression-free survival;
PFS2,time tosecond progression or death; RECIST, ResponseEvaluation Criteria in Solid Tumours; TOI,Trial OutcomeIndex
 PFS by investigator Olaparib
(N=260)
Placebo
(N=131)

assessment Events (%) [50.6% maturity]

Median PFS, months
102 (39.2)
NR
96 (73.3)
13.8
100
90 60.4% progression free HR0.30
progression-free survival (%)

80 at 3 years
Investigator-assessed

95%CI 0.23, 0.41; P<0.0001

70
60 Olaparib
50
40
30
20 26.9% progression free
10 at 3 years Placebo
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

No. at risk Months since randomization

Olaparib 260 240 229 221 212 201 194 184 172 149 138 133 111 88 45 36 4 3 0 0 0
Placebo 131 118 103 82 65 56 53 47 41 39 38 31 28 22 6 5 1 0 0 0 0
CI, confidenceinterval;NR, notreached
 El mantenimiento con olaparib proporcionó un beneficio
clínicamente significativo en la supervivencia global (SG).
Olaparib Placebo
(N=260) (N=131)
100
Events, n (%) 84 (32.3) 65 (49.6)
90
73.1% Median OS, months NR 75.2
80
67.0% HR 0.55 (95% CI 0.40–0.76);
70
Overall survival (%)

P=0.0004*
60 63.4%
Olaparib
50
46.5%
40
30 44.3% of patients in the placebo
Placebo
group received subsequent
20 PARP inhibitor therapy,
10 compared with 14.6% of
0 patients in the olaparib group
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102
Months since randomization
No. at risk
Olaparib 260 252 246 236 227 214 203 194 185 177 170 165 159 157 153 79 21 0
Placebo 131 128 125 114 108 100 97 92 87 80 73 67 60 54 52 21 6 0
*P<0.0001 required to declare statistical significance
PRIMA/ENGOT-OV26/GOG-3012 Trial Design
Patients with newly-diagnosed OC at
high risk for recurrence after
response to 1L platinum-based Stratification Factors
chemotherapy • Neoadjuvant chemotherapy administered: Yes or no
• Best response to first platinum therapy: CR or PR
2:1 Randomization • Tissue HR test status: deficient or proficient/not-determined

Niraparib Placebo

Endpoint assessment • Designed to demonstrate a HR benefit in PFS of 0.5 in HR deficient patients

Primary Endpoint: Progression-free survival* by BICR
Key Secondary Endpoint: Overall Survival
Secondary Endpoints: PFS2, TFST, PRO, Safety
Exploratory Endpoint: Population pharmacokinetics
and 0.65 in the overall population
• >90% statistical power and one-sided type I error of 0.025
• A hierarchical testing method was performed for the primary endpoint in
the HR deficient patients, followed by the overall population.

1L, first-line; BICR, blinded independent central review; CR, complete response; HR, homologous recombination; OC, ovarian cancer; OS, overall survival;
PFS2, progression-free survival 2; PR partial response; PRO, patient-reported outcomes; TFST, time to first subsequent therapy.
*PFS by RECIST or clinical recurrence defined per protocol; tested hierarchically HR deficient then overall population.
 PRIMA Primary Endpoint, PFS Benefit in the Overall Population
100
Hazard ratio: 0.62 (95% CI, 0.502–0.755), p < 0.0001 Niraparib Placebo
90 (n=487) (n=246)
Progression-free Survival (%)

80 Median PFS
70 months 13.8 8.2
(95% CI) (11.5–14.9) (7.3–8.5)
60
Patients without PD or death (%)
50
6 months 73% 60%
40
Niraparib 12 months 53% 35%
30
Initiation Tx Placebo 18 months 42% 28%
20 after
completion
10
of 1L CT
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Months since Randomization

No. at Risk
Niraparib 487 454 385 312 295 253 167 111 94 58 29 21 13 4 0
Placebo 246 226 177 133 117 90 60 32 29 17 6 6 4 1 0

CI, confidence interval; EOT, end of treatment HR, homologous recombination; NE, not estimable; PD, progressive disease; PFS,progression-free
survival
Discordance in PFS event between investigator assessment vs BICR ≈12%
 PRIMA Primary Endpoint, PFS Benefit in the HR Deficient Population
100
Hazard ratio: 0.43 (95% CI, 0.310–0.588), p < 0.0001 Niraparib Placebo
90 (n=247) (n=126)
Progression-free Survival (%)

80 Median PFS
70 months 21.9 10.4
(95% CI) (19.3–NE) (8.1–12.1)
60
Niraparib Patients without PD or death (%)
50
6 months 86% 68%
40
12 months 72% 42%
30 Placebo
Initiation Tx 18 months 59% 35%
20 after
10 completion
of 1L CT
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Months since Randomization

No. at Risk
Niraparib 247 231 215 189 184 168 111 76 66 42 22 19 13 4 0
Placebo 126 117 99 79 70 57 34 21 21 11 5 5 4 1 0

CI, confidence interval; EOT, end of treatment; HR, homologous recombination; NE, not estimable; PD, progressive disease; PFS, progression-free
survival
Sensitivity analysis of PFS by the investigator was similar to and supported the BICR analysis
PAOLA TRIAL
NOT APPROVED Newly diagnosed FIGO stage III–IV high-grade serous or endometrioid
ovarian, fallopian tube or primary peritoneal cancer*

Primary endpoint
Investigator-assessed
Maintenance therapy PFS (RECIST v1.1)
N=806
Sensitivity analysis
Olaparib (300 mg BID) x2 PFS by BICR
FIRST LINE
years

Randomization
. Surgery (upfront NED/CR/PR + bevacizumab Secondary endpoints
or interval) TFST
. Platinum-taxane 2:1 PFS2,TSST
based OS
Placebo x2 years HRQoL
chemotherapy
Safety and tolerability
. >3 cycles of + bevacizumab
Exploratory endpoints
Bevacizumab
Stratification PFS in predefined
• Tumour BRCAmstatus‡ subgroups including
• First-line treatment outcome BRCAm status ‡ and
HRD score§

Ray Coquard, ESMO NEJM 19

PAOLA

HRD-negative/unknown HRD-positive, including tBRCA HRD-positive, excluding tBRCA

(34%) (48%) (19%)

Olaparib + Placebo + Olaparib + Placebo + Olaparib + Placebo +

bevacizuma bevacizum bevacizuma bevacizum bevacizuma bevacizum
b (n=282) ab (n=137) b ab b ab
(N=255) (N=132) (N=97) (N=55)
Events, n (%) 193 (68) 102 (74)
Events, n (%) 87 (34) 92 (70) Events, n (%) 43 (44) 40 (73)

Median PFS, 16.9 16.0 Median PFS, 37.2 17.7 Median PFS, 28.1 16.6
months months months

HR 0.92 HR 0.33 HR 0.43

95% CI 0.72–1.17 95% CI 0.25–0.45 95% CI 0.28–0.66

Ray Coquard, ESMO, NEJM 19

OS subgroup analysisby BRCAmand HRD status
BRCAm* HRD positive‡ excluding BRCAm HRD negative†
100 100 100
90 5-year OSrate 90 90

Patients who survived (%)

80 73.2% 80 80
70 70 5-year OSrate 70
60 60 54.7% 60
50 53.8% 50 50 5-year OSrate
40 40 44.2% 40 32.3%
30 30 30
20 20 20
25.7%
10 10 10
0 0 0
0 12 24 36 48 60 72 80 0 12 24 36 48 60 72 80 0 12 24 36 48 60 72 80
Time from randomization (months) Time from randomization (months) Time from randomization (months)
No. at r isk
97 96 96 96 96 91 87 86 81 76 71 70 66 63 61 59 58 55 52 45 37 29 22 0 192187186179169157146135126 119109100 97 89 77 72 66 62 57 43 30 16 11 5 1
Olaparib +bevacizumab 15715615615515515215014414313913413113012712311811711511299 80 55 42 21 11 2 0 12 5 2 0 0
Placebo +bevacizumab 80 79 78 77 76 74 72 71 68 66 64 61 59 58 58 54 54 53 50 40 3322 17 1 0 1 0
55 54 54 54 54 51 48 46 44 42 40 39 37 36 33 32 29 28 24 21 15 9 6 85 85 84 83 76 74 71 65 60 56 51 48 46 43 41 38 35 33 31 21 17 11 8 5 2
3
Olaparib + Placebo + 2 0 Olaparib + Placebo + Olaparib + Placebo +1

bevacizumab bevacizumab bevacizumab bevacizumab bevacizumab bevacizumab

(N=157) (N=80) (N=97) (N=55) (N=192) (N=85)
Events, n (% ) 48 (30.6) 37 (46.3) 44 (45.4) 32 (58.2)
Median OS, months 75.2 (unstable)† 66.9 NR 52.0
5-year OS rate, % 73.2 53.8 54.7 44.2
140 (72.9) 58 (68.2)
PARPi as subsequent treatment, n (%) 38 (24.2) 44 (55.0) 9 (9.3) 23 (41.8)
36.8 40.4
HR 0.60 (95% CI 0.39–0.93) HR 0.71 (95% CI 0.45–1.13)
C Permission is required for
25.7 re-use.
32.3
46 (24.0) 34 (40.0)

HR 1.19 (95% CI 0.88–1.63)

*By central labs; †Unstable median; <50% data maturity; ‡By Myriad myChoice HRD Plus. NR,not
reported.
Society of Gynecologic Oncology 2020 Annual Meeting on Women’s Cancer : Oral Presentation

35 – Seminal Abstracts
Population adjusted indirect comparison of the SOLO1 and PAOLA-1/ENGOT-ov25 studies of
olaparib with or without bevacizumab, bev alone and placebo in the maintenance treatment of
women with newly diagnosed stage III/IV ovarian cancer with BRCA mutation I.B. Vergotea, K.N.
Mooreb, R. et al
YooNa Kin, et al, SGO 2021
Efficacy of subsequent chemotherapy for patients with BRCA1/2
mutated platinum- sensitive recurrent epithelial ovarian cancer
progressing on olaparib vs placebo. Post-hoc analyses of the
SOLO2/ENGOT Ov-21 trial.

Time to second progression in patients treated with Time to second progressionin patientstreated with

platinum ,excludingpts with PARPimaintenance (n=78) non-platinum-based regimens(n=51)

Olaparib vs Placebo Olaparib vs Placebo

Median: 7.0 vs 14.6 months Median: 6.0 vs 8.3 months
HR=2.33; 95%CI [ 1.27,4.28] HR=1.58; 95%CI [0.86,2.90 ]

Presented by Frenel, ESMO20

Conclusión
Testing

Why?
Testing

What to test for ovarian cancer?

Testing

When ?
47% 59%
Mortality/incidence
0.62 => 0.67