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Dr Anne-Claire HARDY-BESSARDCentre Armoricain d’Oncologie
CARIO HPCAPlérin France
PHASE I
• Escalade de dose– Cohortes 3-6 patients– Dose de 30 à 400 mg/j– Expansion 15 malades a DMTØ60 patientesØDMT : 300 mg/j
• Partie B : 40 patients à DMT– Ovaire résistant et cancer de prostate
• DLT :– grade 3 fatigue (one patient given 30 mg/day),– grade 3 pneumonitis (one given 60 mg/day), and– grade 4 thrombocytopenia (two given 400 mg/day).
• Common treatment-related toxic effects, predominantly grade 1 or 2 :– anaemia (48%), – nausea (42%), – fatigue (42%), – thrombocytopenia (35%), – anorexia (26%), – neutropenia (24%), – constipation (23%), – Vomiting (20%)
• Pharmacokinetics :– dose proportional and – the mean terminal elimination half-life was 36·4 h ( 32·8-46·0).
• Pharmacodynamic analyses confirmed– PARP inhibition exceeded 50% at doses greater than 80 mg/day– antitumour activity was documented beyond doses of 60
mg/day.
• 8/20 (40%) BRCA1 or BRCA2 mutation carriers with ovariancancer had RECIST partial responses,
• 2/4 (50%) of mutation carriers with breast cancer.
NOVA
Study hypothesis
Niraparib, as a selective PARP1/2 inhibitor, will provide a clinical benefit to all patients who have platinum-sensitive recurrent ovarian cancer who are in response to platinum,
regardless of gBRCA mutation status
The myChoice® HRD test measures DNA damageTelomeric allelic imbalance (TAI) Large-scale state transitions (LST)Loss of heterozygosity (LOH)
Platinium-Sensitive recurrent high grade serous ovarian cancer
Traitement avec 4-6 cycles de platinium-based therapy
Response to platinium treatment
gBRCAmut Non-gBRCAmut
Niraparib 300 mg once daily Placebo
Treat until progression of disease
Niraparib 300 mg once daily Placebo
Treat until progression of disease
Tested at 100 events to achieve p < 0,05
• HRD pos population• Tested at 100 events to achieve p<0.05;• If test was positive then:
• Test overall non-gBRCAmut cohort (p<0.05)
Primary Endpoint : PFS by central, blinded review
Niraparib NEJM. Dec 1. 2016
Characteristic
gBRCAmut Non-gBRCAmutNiraparib(N=138)
Placebo(N=65)
Niraparib(N=234)
Placebo(N=116)
Age - years
Median (min, max)
57.0(36, 83)
58.0(38, 73)
63.0(33, 84)
60.5(34, 82)
ECOG PS0 91 (65.9) 48 (73.8) 160 (68.4) 78 (67.2)1 47 (34.1) 17 (26.2) 74 (31.6) 38 (32.8)
Primary tumor site – n (%)Ovarian 122 (88.4) 53 (81.5) 192 (82.1) 96 (82.8)Primary peritoneal 7 (5.1) 6 (9.2) 24 (10.3) 8 (6.9)Fallopian tube 9 (6.5) 6 (9.2) 18 (7.7) 11 (9.5)
Lines of previous chemo – n (%)
2 70 (50.7) 30 (46.2) 155 (66.2) 77 (66.4)
≥3 67 (48.6) 35 (53.8) 79 (33.8) 38 (32.8)
*One patient received one line of prior therapy.
Treatment
PFSMedian(95% CI)(Month
s)
Hazard Ratio
(95% CI)p-value
% of Patients without
Progression or Death12 mo
18 mo
Niraparib
(N=138)
21.0(12.9, NR)
0.27(0.173, 0.410)
p<0.0001
62%
50%
Placebo
(N=65)
5.5(3.8, 7.2)
16%
16%
PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox proportional hazards model, with the stratification factors used in randomization.
NR=not reachedMirza MR et al. N Engl J Med 2016;375:2154-64
Treatment
PFSMedian(95% CI)(Month
s)
Hazard Ratio
(95% CI)p-value
% of Patients without
Progression or Death12 mo
18 mo
Niraparib
(N=234)
9.3(7.2, 11.2)
0.45(0.338, 0.607)
p<0.0001
41%
30%
Placebo
(N=116)
3.9(3.7, 5.5)
14%
12%
PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox proportional hazards model, with the stratification factors used in randomization.
Treatment
PFSMedian(95% CI)(Month
s)
Hazard Ratio
(95% CI)p-value
% of Patients without
Progression or Death12 mo
18 mo
Niraparib
(N=106)
12.9(8.1, 15.9)
0.38(0.243, 0.586)
p<0.0001
51%
37%
Placebo
(N=56)
3.8(3.5, 5.7)
13% 9%
PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox proportional hazards model, with the stratification factors used in randomization.
BRCAwt
Treatment
PFSMedia
n(95%
CI)(Month
s)
Hazard Ratio(95%
CI)p-value
% of Patients without
Progression or Death12 mo
18 mo
Niraparib
(N=71)
9.3(5.8, 15.4)
0.38(0.231, 0.628)
p=0.0001
45%
27%
Placebo(N=44)
3.7(3.3, 5.6)
11% 6%
Treatment
PFSMedia
n(95%
CI)(Month
s)
Hazard Ratio(95%
CI)p-value
% of Patients without
Progression or Death12 mo
18 mo
Niraparib
(N=35)
20.9(9.7, NR)
0.27(0.081, 0.903)
p=0.0248
62%
52%
Placebo(N=12)
11.0(2.0, NR)
19%
19%
sBRCAmut
NR=Not reached
Treatment
PFSMedia
n(95%
CI)(Month
s)
Hazard Ratio
(95% CI)p-value
% of Patients without
Progression or Death12 mo
18 mo
Niraparib
(N=92)
6.9(5.6, 9.6)
0.58(0.361, 0.922)
p=0.0226
27%
19%
Placebo(N=42)
3.8(3.7, 5.6)
7% 7%
HRD-positive HRD-negative
Mirza MR et al. N Engl J Med 2016;375:2154-64
Prog
ress
ion–
free
Surv
ival
(%)
HRD ve+
gBRCAm
HRD ve-
0
25
50
75
100
0 2 4 6 8 10 12 14 16 18 20 22 24
Time Since Randomization (months)
gBRCAm
gBRCAwt,HRD ve+gBRCAwt,HRD ve-
gBRCAmut: FOSI
gBRCAmut: EQ-5D-5L
Non-gBRCAmut: FOSI
Non-gBRCAmut: EQ-5D-5L
• Measured using the Functional Assessment of Cancer Therapy –Ovarian Symptom Index (FOSI) and the EQ-5D-5L
• PRO surveys were collected at:• Screening visit• Every other cycle through
cycle 14• Post progression
• Compliance rates were high, and similar between the two treatment arms• Niraparib: FOSI completion
rate ranged from 75.0% to 97.1%
• Placebo: FOSI completion rate ranged from 77.6% to 97.4%
• PROs were similar for niraparib Mirza MR et al. N Engl J Med 2016;375:2154-64
gBRCAmut Non-gBRCAmut
All patientsAge 18 to <65 years
≥65 yearsRace White
Other (including unknown)Region USA and Canada
Europe and IsraelTime to progression before study enrollment 6 to <12 months
≥12 monthsBevacizumab use Yes
NoBest overall response on last platinum regimen Complete response
Partial responseTotal no. of prior platinum regimens 2
>2Cumulative no. of prior chemotherapy regimens 2
>2BRCA BRCA1
BRCA2Confidence LimitHazard Ratio
HR (95% CI)
0.01 0.10 1.00 5.00
HR (95% CI)
0.01 0.10 1.00 5.00
• Chemotherapy-free interval– gBRCAmut: HR 0.26 (22.8 mths vs 9.4 mths; 95% CI: 0.169, 0.414; p<0.0001)– Non-gBRCAmut: HR 0.50 (12.7 mths vs. 8.6 mths; 95% CI: 0.370, 0.666; p<0.0001)
• Time to first subsequent treatment– gBRCAmut: HR 0.31 (21.0 mths vs. 8.4 mths; 95% CI: 0.205, 0.481; p<0.0001)– Non-gBRCAmut: HR 0.55 (11.8 mths vs. 7.2 mths; 95% CI: 0.412, 0.721; p<0.0001)
• PFS 2 (data are immature)– gBRCAmut: HR 0.48 (25.8 mths vs. 19.5 mths; 95% CI: 0.280, 0.821; p=0.0062)– Non-gBRCAmut: HR 0.69 (18.6 mths vs.15.6 mths; 95% CI: 0.494, 0.964; p=0.0293)
uOverall survival (data are immature)• <20% patient deaths in either treatment arm; HR 0.73 (95% CI, 0.480 to 1.125; p=0.1545)
Event — no. (%)Niraparib(N=367)
Placebo(N=179)
Thrombocytopeniaa 124 (33.8) 1 (0.6)
Anemiab 93 (25.3) 0
Neutropeniac 72 (19.6) 3 (1.7)
Fatigued 30 (8.2) 1 (0.6)
Hypertension 30 (8.2) 4 (2.2)
*There were no Grade 5 events. aThrombocytopenia=thrombocytopenia and decreased platelet count. No grade 3 or 4 bleeding events were associated with thrombocytopenia; bAnemia=anemia and decreased hemoglobin counts; cNeutropenia=neutropenia, decreased neutrophil count, and febrile neutropenia; dFatigue=fatigue, asthenia, malaise, and lethargy.
MDS/AML occurred in 5 of 367 (1.4%) in patients who received niraparib and 2 of 179 (1.1%) in patients who received placebo.
Event — no. (%)
Dose Reductions
(N=367)
Events That Occurred After
Cycle 3(N=296)
DoseDiscontinuation
s (N=367)Thrombocytopeniaa 148 (40.3) 7 (2.4) 12 (3.3)
Anemiab 68 (18.5) 50 (16.9) 5 (1.4)
Neutropeniac 32 (8.7) 8 (2.7) 7 (1.9)
Fatigued 20 (5.4) 9 (3.0) 12 (3.3)
Hypertension 5 (1.4) - 1
aThrombocytopenia=thrombocytopenia and decreased platelet count. No grade 3 or 4 bleeding events were associated with thrombocytopenia; bAnemia=anemia and decreased hemoglobin counts; cNeutropenia=neutropenia, decreased neutrophil count, and febrile neutropenia; dFatigue=fatigue, asthenia, malaise, and lethargy.
Mandatory dose reductions for hematology laboratory abnormalities were required for thrombocytopenia, anemia, and neutropenia
Any Grade Grade 3/4 Any Grade
gBRCAmut: FOSI
gBRCAmut: EQ-5D-5L
Non-gBRCAmut: FOSI
Non-gBRCAmut: EQ-5D-5L
• Measured using the Functional Assessment of Cancer Therapy –Ovarian Symptom Index (FOSI) and the EQ-5D-5L
• PRO surveys were collected at:• Screening visit• Every other cycle through cycle 14• Post progression
• Compliance rates were high, and similar between the two treatment arms• Niraparib: FOSI completion rate
ranged from 75.0% to 97.1%• Placebo: FOSI completion rate
ranged from 77.6% to 97.4%• PROs were similar for niraparib
compared with placebo
AMM POUR TOUTES LES PATIENTES EN RECIDIVE
PLATINE SENSIBLE
AMM POUR TOUTES LES PATIENTES EN RECIDIVE
PLATINE SENSIBLE
Création de TESARO
QUADRA
24
HRD=homologous recombination deficiency; ITT=intent-to-treat; mITT=modified intent-to-treat; PARPi=PARP inhibitor.
Key ObjectivesTo evaluate the safety and clinical activity of niraparib treatment in the tBRCAmut (both germline and somatic) subgroup ofpatients according to their platinum responsiveness.To evaluate clinical activity of niraparib treatment in the subgroup of patients with HRDpos platinum-sensitive disease.Secondary objectives The assessment of efficacy in the intent-to-treat (ITT) population, and a planned subgroup analysis based on BRCA and HRD tumor status, and response to last platinum-based therapy.
• 1. Bruchim I, et al. Eur J Obstet Gynecol Reprod Biol. 2013, 2. Hanker, LC, et al. Annals Oncol. 2012, 3. Domchek, et al. Gyn Oncol. 2016, 4. Matulonis, UA, et al. Annals Oncol. 2016, 5. Konecny. SGO Annual Meeting 2017, 6. Moore, KN, et al. ASCO Annual Meeting, 2018. Abstract #5514.
2525
26
27
28
• The continuum of clinical activity according to platinum sensitivity in patientswith tumors bearing BRCA mutations was further demonstrated byprogression-free survival (PFS) analysis.
• The mPFS was 6.3 months (95% CI 5.4, 8.2) overall. In comparison, PFS inpatients with platinum-sensitive, -resistant and –refractory disease was 11.0months (95% CI 5.5, NE), 5.4 months (95% CI 1.8, 10.1), and 5.7 months (95% CI1.8, NE), respectively
28
AVANOVA
Niraparib 100–300 mg qd + BEV 15 mg/kg q3w
• High-grade serous/ endometrioid PS ROC or BRCAm OC
• Measurable diseasePrimary endpoint: safety & tolerabilitySecondary endpoints: Define Phase 2 dose, PK, PD, ORR
Mirza M, et al. ESMO 2017, abstract 953P
• 3/12 patients BRCA1/2m (germline and tumour)
• 4/12 patients HRD positive (including 3 with BRCA1/2m)
• Recommended phase 2 regimen: niraparib 300 mg/day + BEV 15 mg/kg q3w
• Main toxicities were haematological (one case of grade 4 thrombocytopenia meeting criteria for DLT)
• 50% ORR (CR in 8%); 92% CBR; median PFS 11.3 months
PRIMA
Endpoint assessment
Niraparib 200 or 300 mg
daily*
PlaceboDaily
High risk for progressive disease ovarian cancer stage III or IV and achieved a CR or PR following front line platinum-based
chemotherapy
Progression-free survival (PFS) by central radiologic reviewPrimary Endpoint
2:1 Randomization• Neoadjuvant chemotherapy administered: Yes or No
• Best response to 1st platinum therapy: CR or PR
• HRD status: positive or negative/not determined
Stratification Factors
*Starting dose of 200 mg used for patients <77kg or
with baseline platelet count <150,000/uL
• Body weight <77 kg or baseline platelet count <150,000/μLexperienced grade ≥3 thrombocytopenia at higher rates and were more likely to be dose reduced.
• Importantly, efficacy was not compromised in patients who received a dose reduction.
0
20
40
60
80
100
<77 kg or <150,000/uL
≥77kg and ≥150,000/uL
Inci
denc
e (%
)
Grade 3/4 thrombocytopenia in
NOVA
35
High-grade serous or endometrioid or high-grade predominantly serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer that is stage III or IV according to FIGO criteriaMust be randomized within 12 weeks of the first day of the last cycle of chemotherapySurgical criteria: • All stage IV patients• Stage III patients treated with neoadjuvant chemotherapy • Stage III disease who have visible residual disease after primary debulking
surgeryChemotherapy criteria*: • Must have had ≥6 and ≤9 cycles of platinum-based therapy • Must have had ≥2 postoperative cycles of platinum-based therapy following
interval debulking surgery Patients must agree to undergo central tumor HRD testing
*Bevacizumab not allowed during maintenance
*†Anemia events included anemia and hemoglobin decrease.‡Neutropenia events included neutropenia, febrile neutropenia, and neutrophil count decrease.
Hematological toxicities Grade
Pre-amendment, fixed starting dose
300 mg QD(Pooled niraparib &
placebo)
Post-amendment, individualized starting dose
300 + 200 mg QD(Pooled niraparib
& placebo)
N=480 N=247
ThrombocytopeniaAny grade, n (%) 164 (34.2) 50 (20.2)≥Grade 3, n (%) 110 (22.9) 22 (8.9)Grade 4, n (%) 76 (16.5) 8 (3.2)
Platelet count decrease
Any grade, n (%) 91 (19) 34 (13.8)≥Grade 3, n (%) 51 (10.6) 12 (4.9)Grade 4, n (%) 26 (5.4) 6 (2.4)
Anemia† Any grade, n (%) 229 (47.7) 77 (31.2)≥Grade 3, n (%) 101 (21.0) 27 (10.9)
Neutropenia‡ Any grade, n (%) 148 (30.8) 57 (23.1)≥Grade 3, n (%) 75 (15.6) 23 (9.3)
Symptomatic TEAEs
Pre-amendment, fixed starting
dose300 mg QD
(Pooled niraparib & placebo)
Post-amendment,
individualized starting dose
300 + 200 mg QD(Pooled niraparib
& placebo)
N=480 N=247
NauseaAny grade, n (%) 226 (47.1) 86 (34.8)
≥ Grade 3, n (%) 5 (1.0) 2 (1)
VomitingAny grade, n (%) 84 (17.5) 23 (9.3)
≥ Grade 3, n (%) 4 (0.8) 0
FatigueAny grade, n (%) 144 (30.0) 57 (23.1)
≥ Grade 3, n (%) 6 (1.25) 3 (1.2)
Hypertension*Any grade, n (%) 59 (12.3) 16 (6.5)
≥ Grade 3, n (%) 18 (3.8) 1 (0.4)
InsomniaAny grade, n (%) 95 (19.8) 28 (11.3)
≥ Grade 3, n (%) 5 (1.0) 0
NIQOL
TOPACIO
ASCO 2018 - D’après Kostantinopoulos P et al., abstr. 106, actualisé
Niraparib + pembrolizumab chez des patientes atteintes d’un cancer de l’ovaire en rechute résistante ou réfractaire
5% had been treated with 3 or more prior lines of chemotherapy, 97% with prior taxane, 63% received prior bevacizumab, and 29% were platinum refractory.
The majority (77%) did not have a BRCA mutation BRCA sauvage, n (%) 48 (77)
HRD–, n (%) 32 (52)
PD-L1+, n (%) 35 (57)
Congrès américain d’oncologie clinique 2018 - D’après Kostantinopoulos P et al., abstr. 106, actualisé
Intérêt de l’association niraparib + pembrolizumab chez des patientes atteintes d’un cancer de l’ovaire en rechute résistante ou réfractaire
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Mei
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110
Sujets
907050
3010
-10-30-50-70-90
-30
tBRCA mutéHRD+HRD–/inconnuSous traitementPD-L1+*
*********************************
HRD (déficit en recombinaison homologue)
(n = 60, 2 patientes non évaluables)
• ORR: 25% • Disease control rate : 68%;
• ORR was 24% in the platinum refractory population.
• Response rates were not dependent on biomarker status; – 26% (9/34) in patients without a tumor BRCA mutation – 29% (7/24) in patients with HRD-negative tumors.
FIRST
Treatment21 days cycle
x 5 cycles
MaintenanceUp to 3 years
Newly diagnosed stage III/IV advanced ovarian cancer
N= 720-960
Cycle 1: Carboplatin + paclitaxel
± bevacizumab
Randomization
Carboplatin + Paclitaxel + TSR-042
Double placebo
+/- Bevacizumab
+/- Bevacizumab
Carbo + Paclitaxel+ Placebo
Carbo + Paclitaxel+ Placebo
Placebo (TSR-042) + Niraparib
TSR-042 + Niraparib
Primarydebulkingsurgery
Intervaldebulkingsurgery
OR
• Leading Group: GINECO• Chair: AC Hardy-Bessard
Ø High grade epithelial OC except mucinous adenocarcinomaØ All patients with neo adjuvant chemotherapyØ All patients with FIGO IVØ After primary debulking surgery :
Ø All patients with FIGO high grade stage III without complete resection
Ø All patients with FIGO high grade stage III with complete resection and high risk defined by Aggregate 5 cm extra-pelvic disease during PDS
Ø Concurrent bevacizumab use (investigator choice; yes vs no)
Ø HRR (homologous Recombinant Repair) and BRCAmstatus based on ctDNA with tumorsample as back-upü BRCAmut, ü BRCAwt HRR+ ü BRCAwt HRRneg / inconclusive
Ø FIGO Stage III with residual < 1 cm at PDS versus others
Ø PFS investigator RECIST 1.1
• SOLO1 positif chez patientes mutées
Treatment21 days cycle
x 5 cycles
MaintenanceUp to 3 years
Newly diagnosed stage III/IV advanced ovarian cancer
Cycle 1: Carboplatin + paclitaxel ± bevacizumab
Randomization
Carboplatin + Paclitaxel + TSR-042
Double placebo
+/- Bevacizumab
+/- Bevacizumab
Carboplatin + Paclitaxel + TSR-042
Carbo + Paclitaxel+ Placebo
Placebo (TSR-042)
+ Niraparib
TSR-042 + Niraparib
+/- Bevacizumab
+/- Bevacizumab
BRCAmut BRCAwt
Carbo + Paclitaxel+ Placebo
Carbo + Paclitaxel+ Placebo
Placebo (TSR-042)
+ Niraparib
TSR-042 + Niraparib