Inhibidores de PARP en primera línea de cáncer de ovario

Inhibidores PARP en Cáncer de Ovario.
Resumen Ejecutivo ESMO 2019
Mauricio Lema Medina MD
Clínica de Oncología Astorga, Clínica SOMA, Medellín

Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA
Medellín
Inspirado en: Michael Bierut, 2013, Logo para Mohawk Fine Papers

Conflicts of Interest
Mauricio Lema
Lectures and consulting fees from AZ

Ovarian Cancer
Main slides taken from: clinicaloptions.com
Slide credit: clinicaloptions.com

BRCA Mutations and Ovarian Cancer
 BRCA genes encode enzymes
that repair double-strand
DNA breaks
 Mutations in BRCA1 or
BRCA2
‒ Prognostic marker for
increased risk of ovarian
cancer
‒ Predictive marker for
enhanced PARP inhibitor
activity
Risk of Developing Ovarian Cancer
Mutated BRCA1
39% to 46%
Mutated BRCA2
10% to 27%
Normal BRCA
2%
https://www.acog.org/Patients/FAQs/BRCA1-and-BRCA2-Mutations

HRD and BRCA Mutations
Germline BRCA
mutations
Germline non-BRCA
mutations in HR
pathway
Sporadic (somatic) BRCA
mutations
Sporadic non-BRCA
mutations in HR
pathway
Mutations in HR pathway
↓
HRD

PARP Inhibitor and Homologous Recombination
Survival
Normal cell
Repair by homologous
recombination
DNA SSBs occur all the time in cells
and PARP detects and repairs them
During the replication process,
unrepaired SSBs are converted into DSBs
Replicating cells
PARP
Cancer cell with HRD
No effective repair
(no HR pathway)
Cell death
Tumor-specific
killing by PARP
inhibitors
PARP inhibitor
O’Connor. Mol Cell. 2015;60:547.
Trapped PARP on
single-strand breaks
PARP

Current Treatment Landscape for PARPi in Ovarian
Cancer – Colombia
Not approved
INVIMA approved – gBRCA+ - Platinum-sensitive relapse - only
y
Symptoms
Diagnosis
Chemo
#1
Staging/debulking
Evaluation
Progression
Chemo
#2
Chemo
#3
T
Supportive
care
Death
Chemo
#4+
T
Maintenance M M
Concomitant Concomitant
LaFargue. Lancet Oncol. 2019;20:e15.

Current Treatment Landscape for PARPi in Ovarian
Cancer – Rest of the World
Under investigation
FDA approved
y
Symptoms
Diagnosis
Chemo
#1
Staging/debulking
Evaluation
Progression
Chemo
#2
Chemo
#3
T
Supportive
care
Death
Chemo
#4+
T
Maintenance M M
Concomitant Concomitant
LaFargue. Lancet Oncol. 2019;20:e15.

NOVA: PFS
Mirza. NEJM. 2016;375:2154.
HR: 0.27; P < .0001
Median PFS, Mos
Niraparib: 21.0
Placebo: 5.5
HR: 0.38; P < .0001
Median PFS, Mos
Niraparib: 12.9
Placebo: 3.8
100
50
0
0 16 24
Mos
4 8 12
Non-gBRCAmut Overall
25
75
14 202 6 10 2218
HR: 0.45; P < .0001
Median PFS, Mos
Niraparib: 9.3
Placebo: 3.9
Niraparib
Placebo
100
50
PFS(%)
0
0 16 24
Mos
4 8 12
gBRCAmut
25
75
14 202 6 10 2218
Niraparib
Placebo
100
50
0
0 16 24
Mos
4 8 12
Non-g/sBRCAmut HRD+
25
75
14 202 6 10 2218
Niraparib
Placebo

Phase II QUADRA Trial of Niraparib in Ovarian Cancer
With ≥ 3 Prior Chemotherapy Regimens
 Multicenter, open-label, single-arm phase II trial
Patients with histologically
diagnosed advanced, relapsed,
high-grade serous epithelial
ovarian, fallopian tube, or
primary peritoneal cancer with
≥ 3 chemotherapy regimens
(N = 463*)
Niraparib 300 mg QD
28-day cycles until PD
 Primary endpoint: ORR by RECIST in HRD-positive patients with:
̶ 3-4 lines of prior chemotherapy
̶ Platinum sensitivity
̶ No prior PARP inhibitor
Moore. Lancet Oncol. 2019;5:636.
*After 292 patients enrolled, study limited to those with 3-4 prior chemotherapy regimens and response for ≥ 6 mos to first-line platinum
chemotherapy.

QUADRA: Efficacy Beyond Mutated BRCA
Moore. ASCO 2018. Abstr 5514. Moore. Lancet Oncol. 2019;5:636.
ORR: 28%
Median DoR:9.2 mos
Median PFS: 5.5 mos
Tumor Response in Fourth Line or Later, HRD-Positive, Platinum-Sensitive Patients
BRCA mutated
Non-BRCA mutated
+20%
-30%
160
140
120
100
80
60
40
20
0
-20
-40
-60
-80
-100
BestPercentageChangeFromBaseline

Phase III NOVA Trial of Niraparib Maintenance in
Platinum-Sensitive Recurrent Ovarian Cancer
Patients with no disease > 2 cm,
CA-125 normal or > 90% decrease
during last regimen (≥ 7 days
stable), PR or CR to last or next to
last platinum regimen*
(N = 553)
Niraparib 300 mg QD
(n = 138)
Placebo QD
(n = 65)
Mirza. NEJM. 2016;375:2154.
*Penultimate regimen: CR or PR with no PD within
6 mo of last dose; last regimen: CR/PR after ≥ 4
cycles. After last regimen, no lesions > 2 cm allowed
Niraparib 300 mg QD
(n = 234)
Placebo QD
(n = 116
Germline
BRCA
mutation
(n = 203)
No germline
BRCA
mutation
(n = 350)
Stratified by best response (CR vs PR) to last platinum regimen, TTP
after penultimate platinum regimen, prior bevacizumab/chemo
Treatment
until PD or
death
 Primary endpoint: PFS (> 90% power for 4.8-mo improvement [HR: 0.50])
 Secondary endpoints: PROs, CFI, TTST, PFS2, TTSST, OS
 Randomized, double-blind,
clinical trial
28-day cycles

NCCN Guidelines Version 1.2020
Epithelial Ovarian Cancer…
NCCN.org

Mirza, NEJM, 2019
Maintenance Niraparib After Initial Therapy for
Ovarian Cancer (PRIMA): Phase III Study Design

Maintenance Niraparib After Initial Therapy for Ovarian
Cancer (PRIMA): Phase III Study Design
 Double-blind, randomized, placebo-controlled phase III trial
 Primary endpoint: PFS by BICR
‒ Hierarchical testing in patients with HRD (HR benefit: 0.5) followed by the overall patient population
(HR benefit: 0.65)
 Key secondary endpoint: OS; other secondary endpoints: PFS2, TFST, patient-reported outcomes, safety
Patients with newly diagnosed
advanced ovarian cancer with CR or PR
following first-line platinum-based CT;
high-grade serous or endometroid
pathology; stage III with residual
disease, stage IV, or inoperable
(N = 730)
Niraparib 200-300* mg QD
(n = 484)
Placebo
(n =244)
Stratification by 1L platinum CT,
CR/PR to 1L therapy, HRD status
Tx for 36 mos or
until PD
*Initiated treatment with 300 mg QD for patients ≥ 77 kg
and with platelets ≥ 150,000/μL, 200 mg QD for patients
< 77 kg and/or with platelets < 150,000/μL.
González-Martin. ESMO 2019. Abstr LBA1.

PRIMA: Baseline Characteristics
Characteristic Niraparib (n = 487) Placebo (n = 246)
Median age, yrs (range) 62 (32-85) 62 (33-88)
Median weight, kg 66 66
Stage at diagnosis, n (%)
 III
 IV
318 (65)
169 (35)
158 (64)
88 (36)
Prior neoadjuvant CT, n (%) 322 (66) 167 (68)
Best response to platinum-based CT, n (%)
 CR
 PR
337 (69)
150 (31)
172 (70)
74 (30)
HRD, n (%)
 BRCA mutation positive
 BRCA wild type
274 (51)
152 (31)
92 (20)
126 (51)
71 (29)
55 (22)
Homologous recombination proficient, n (%) 169 (35) 80 (33)
HRD status not determined, n (%) 71 (15) 40 (16)

PRIMA: Summary of AEs
Event, n (%) Niraparib (n = 484) Placebo (n = 244)
AE
 Any
 Grade ≥ 3
478 (98.8)
341 (70.5)
224 (91.8)
46 (18.9)
Treatment-related AE
 Any
 Grade ≥ 3
466 (96.3)
316 (65.3)
168 (68.9)
16 (6.6)
Serious AE
 Any
 Treatment related
156 (32.2)
118 (24.4)
32 (13.1)
6 (2.5)
Leading to treatment discontinuation 58 (12.0) 6 (2.5)
Leading to dose reduction 343 (70.9) 20 (8.2)
Leading to dose interruption 385 (79.5) 44 (18.0)
Leading to death 2 (0.4) 1 (0.4)
González-Martin. NEJM. 2019;[Epub]. González-Martin. ESMO 2019. Abstr LBA1.

PRIMA: Most Common AEs
AE, n (%)
Niraparib (n = 484) Placebo (n = 244)
Any Grade Grade ≥ 3 Any Grade Grade ≥ 3
Anemia 307 (63.4) 150 (31.0) 43 (17.6) 4 (1.6)
Nausea 278 (57.4) 6 (1.2) 67 (27.5) 2 (0.8)
Thrombocytopenia 222 (45.9) 139 (28.7) 9 (3.7) 1 (0.4)
Constipation 189 (39.0) 1 (0.2) 46 (18.9) 0
Fatigue 168 (34.7) 9 (1.9) 72 (29.5) 1 (0.4)
Decreased platelet count 133 (27.5) 63 (13.0) 3 (1.2) 0
Neutropenia 128 (26.4) 62 (12.8) 16 (6.6) 3 (1.2)
Headache 126 (26.0) 2 (0.4) 36 (14.8) 0
Insomnia 119 (24.6) 4 (0.8) 35 (14.3) 1 (0.4)
Vomiting 108 (22.3) 4 (0.8) 29 (11.9) 2 (0.8)
Abdominal pain 106 (21.9) 7 (1.4) 75 (30.7) 1 (0.4)

PRIMA: PFS in HRD and Overall Patient Populations
(Primary Endpoint)
PFS in HRD Population PFS in Overall Patient Population
González-Martin. NEJM. 2019;[Epub]. González-Martin. ESMO 2019. Abstr LBA1
HR: 0.43 (95% CI: 0.31-0.59; P < .001)
Median PFS, Mos
21.9
10.4
Niraparib
Placebo
HR: 0.62 (95% CI: 0.50-0.76; P < .001)
Median PFS, Mos
13.8
8.2
Niraparib
Placebo
100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Mos Since Randomization
PFS(%)
Pts at Risk, n
Niraparib
Placebo
247
126
231
117
215
99
189
79
184
70
168
57
111
34
76
21
66
21
42
11
22
5
19
5
13
4
4
1
0
0
*
** ** * ***
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100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
PFS(%)
Pts at Risk, n
Niraparib
Placebo
487
246
454
226
385
177
312
133
295
117
253
90
167
60
111
32
94
29
58
17
29
6
21
6
13
4
4
1
0
0
*** ** **
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**** **
******
****
*
**
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*
*
***
* *** *
****
** **** ** ** ** ***** ** ******* * ***** * **

PRIMA: PFS in Prespecified Patient Subgroups
Subgroup
All patients
Age
< 65 yrs
≥ 65 yrs
ECOG PS
0
1
Stage of disease at initial diagnosis
III
IV
Neoadjuvant chemotherapy
Yes
No
Best response to platinum therapy
CR
PR
Geographic region
North America
All other regions
Homologous recombination status
BRCA mutation
No BRCA mutation, homologous
recombination deficiency
Homologous recombination
proficiency
Not determined
0.62 (0.50-0.76)
0.61 (0.47-0.81)
0.53 (0.38-0.74)
0.60 (0.46-0.77)
0.69 (0.48-1.00)
0.54 (0.42-0.70)
0.79 (0.55-1.12)
0.59 (0.46-0.76)
0.66 (0.46-0.94)
0.60 (0.46-0.77)
0.60 (0.43-0.85)
0.50 (0.37-0.68)
0.72 (0.54-0.96)
0.40 (0.27-0.62)
0.50 (0.31-0.83)
0.68 (0.49-0.94)
0.85 (0.51-1.43)
Niraparib Better
HR (95% CI)
0.25 0.50 1.00 2.00
232/487 (47.6)
136/297 (45.8)
96/190 (50.5)
146/337 (43.3)
86/150 (57.3)
143/318 (45.0)
89/169 (52.7)
151/322 (46.9)
81/165 (49.1)
146/337 (43.3)
86/150 (57.3)
104/218 (47.7)
128/269 (47.6)
49/152 (32.2)
32/95 (33.7)
111/169 (65.7)
40/71 (56.3)
Niraparib
155/246 (63.0)
86/147 (585)
69/99 (69.7)
107/174 (61.5)
48/72 (66.7)
103/158 (65.2)
52/88 (59.1)
107/167 (64.1)
48/79 (60.8)
100/172 (58.1)
55/74 (74.3)
82/115 (71.3)
73/131 (55.7)
40/71 (56.3)
33/55 (60.0)
56/80 (70.0)
26/40 (65.0)
Placebo
No. of patients with PD or death/N (%)
Placebo Better

PRIMA: PFS and OS in Patient Subgroups
Median PFS, Mos Niraparib Placebo HR (95% CI)
HRD, BRCA mutation positive 22.1 10.9 0.40 (0.27-0.62)
HRD, BRCA wild type 19.6 8.2 0.50 (0.31-0.83)
HR-proficient disease 8.1 5.4 0.68 (0.49-0.94)
Patients who received neoadj CT 13.9 8.2 0.59 (0.46-0.76)
Patients with PR to plt-based CT 8.3 5.6 0.60 (0.43-0.85)
Patients with CR to plt-based CT 16.4 9.5 0.60 (0.46-0.77)
24-Mo OS Probability, % Niraparib Placebo HR (95% CI)
HRD 91 85 0.61 (0.27-1.39)
HR-proficient disease 81 59 0.51 (0.27-0.97)
Overall patient population 84 77 0.70 (0.44-1.11)

PRIMA: Conclusions
 In the phase III PRIMA study, patients who received maintenance niraparib
showed significantly longer PFS compared with patients who received
placebo, regardless of HRD status
 Consistent with existing data on the efficacy of niraparib in recurrent OC,
PRIMA data supported benefit of niraparib treatment in the overall patient
population across all evaluated biomarker subgroups
 No new safety signals were identified and TRAEs were tolerable and
consistent with previous data
 According to investigators, niraparib maintenance therapy may be
considered new standard of care option for patients with advanced OC who
respond to 1L platinum-based CT

PRIMA: Editorial
 ”In this trial, the no-HRD cohort had a very modest benefit over the placebo
group in the time until disease progression.
 Need mature survival data
‒ Whether maintenance therapy after first remission superior to PARP inhibitor
later in the course of the disease.
 Establish the appropriate cut-off for HRD
Longo NEJM, 2019.

NCCN.org
HRD status NOT required

Phase III SOLO2 Trial of Olaparib Maintenance in Platinum-
Sensitive BRCA-Mutated Recurrent Ovarian Cancer
 International, randomized, double-blind clinical trial
Patients with PSR serous
OC and germline BRCA1/2
mutation, ≥ 2 prior lines of
platinum-based therapy,
CR or PR on most recent
therapy
(N = 295)
RECIST assessment
Q12W ± 7 days up to
72 wks, then
~ Q24W until PD or
unacceptable toxicity
Olaparib 300 mg BID
(n = 196*)
Placebo
(n = 99)
 Primary endpoint: investigator-assessed PFS
 Key secondary endpoints: safety/tolerability, PFS2, TFST, TSST, OS,
HRQoL
Pujade-Lauraine. Lancet Oncol. 2017;1274.
*n = 195 received treatment.

SOLO2: Investigator-Assessed PFS
Pujade-Lauraine. Lancet Oncol. 2017;1274.
100
80
60
40
20
0
PFS(%)
Mos
Olaparib
Placebo
HR: 0.30 (95% CI: 0.22-0.41; P < .0001)
Patients at Risk, n
Olaparib
Placebo
196
99
182
70
156
37
134
22
118
18
104
17
89
14
82
12
32
7
29
6
3
0
2
0
0
0
360 3 6 9 12 15 18 21 24 27 30 33

Maintenance Olaparib + Bev After Initial Therapy for
Ovarian Cancer (PAOLA-1/ENGOT-ov25): Phase III trial
Ray-Coquard. ESMO 2019. Abstr. LBA2.

Maintenance Olaparib + Bev After Initial Therapy for
Ovarian Cancer (PAOLA-1/ENGOT-ov25): Study Design
 Phase III randomized trial for patients with newly diagnosed, FIGO stage III-IV, high-grade
serous/endometrioid ovarian, fallopian tube or primary peritoneal cancer (N = 806)
 Primary endpoint: investigator assessed PFS (RECIST v1.1)
 Secondary endpoints: TFST, PFS2, TSST, OS, HRQoL, AE
 Sensitivity analysis: PFS by BICR
Olaparib 300 mg BID for 2 yrs +
Bevacizumab 15 mg/kg on Day 1 Q3W for 15 mos†
(n = 537)
Placebo for 2 yrs +
Bevacizumab 15 mg/kg on Day 1 Q3W for 15 mos†
(n = 269)
Randomized 2:1
Patients who have achieved PR or CR
after upfront or interval surgery,
standard platinum/taxane-based
CT, and ≥ 3 cycles of bevacizumab
(N = 806)
†Bevacizumab administered for a total of 15 mos, including
during treatment with CT.

PAOLA-1/ENGOT-ov25: Patient Characteristics
*Missing data for 6 patients in olaparib group and 4 patients in placebo group. †2 patients with low-grade serous and BRCA mutation.
Characteristic
Olaparib + Bevacizumab
(n = 537)
Placebo + Bevacizumab
(n = 269)
ECOG performance status,* n (%)
 0
 1
378 (70)
153 (28)
189 (70)
76 (28)
Primary tumor location, n (%)
 Ovary
 Fallopian tubes
 Primary peritoneal
456 (85)
39 (7)
42 (8)
238 (88)
11 (4)
20 (7)
Histology, n (%)
 Serous†
 Endometrioid
 Clear cell, undifferentiated, or other histology
519 (97)
12 (2)
6 (1)
253 (94)
8 (3)
8 (3)
Tumor BRCA mutation status, n (%)
 BRCA mutation positive
 BRCA wildtype or unknown
157 (29)
380 (71)
80 (30)
189 (70)
FIGO stage, n (%)
 III
 IV
378 (70)
159 (30)
186 (69)
83 (31)

PAOLA-1/ENGOT-ov25: Patient Surgery Status and
Response to Initial Platinum-Based Chemotherapy
Characteristic, n (%)
(n = 537)
(n = 269)
Upfront surgery
 Residual macroscopic disease
 No residual macroscopic disease
Interval cytoreductive surgery
 Residual macroscopic disease
 No residual macroscopic disease
No surgery
271 (50)
111 (41)
160 (59)
228 (42)
65 (29)
163 (71)
38 (7)
138 (51)
53 (38)
85 (62)
110 (41)
35 (32)
75 (68)
21 (8)
Response after surgery/platinum-based CT
 No evidence of disease
 CR
 PR
290 (54)
106 (20)
141 (26)
141 (52)
53 (20)
75 (28)

PAOLA-1/ENGOT-ov25: Patient Disposition
Characteristic
(n = 537)
(n = 269)
Treated, n (%) 535 (99.6) 267 (99.3)
Discontinued study treatment, n (%)
 Disease progression per RECIST
 Disease progression non-RECIST
 TEAE
 Patient decision
 Death
 Other*
331 (62)
182 (34)
14 (3)
109 (20)
17 (3)
1 (< 1)
8 (1)
194 (73)
155 (58)
13 (5)
13 (5)
10 (4)
3 (1)
0
Median duration of treatment, mos (range)
 Olaparib/placebo
 Bevacizumab
17.3 (0.03-33.0)
11.0 (0.69-21.4)
15.6 (0.07-26.2)
10.6 (0.69-17.1)
Median duration of follow-up, mos 24.0 22.7
* Lost to follow-up, surgery, new comorbidities, and other TEAE.

PAOLA-1/ENGOT-ov25: Most Common and Special
Interest AEs
AEs in ≥ 15% of Patients in Either Arm, n (%)
Olaparib + Bev (n = 535) Placebo + Bev (n = 267)
All Grades Grade ≥ 3 All Grades Grade ≥ 3
Fatigue/asthenia 53 5 32 1
Nausea 53 2 22 1
Hypertension 46 19 60 30
Anemia 41 17 10 <1
Lymphopenia 24 7 9 1
Arthralgia 22 1 24 1
Vomiting 22 1 11 2
Abdominal pain 19 1 20 2
Diarrhea 18 2 17 2
Neutropenia 18 6 16 3
Leukopenia 18 2 10 1
Urinary tract infection 15 <1 10 1
MDS/AML/AA 6 (1.1) 1 (0.4)
New primary malignancies 7 (1.3) 3 (1.1)
Pneumonitis/ILD 6 (1.1) 0

PAOLA-1/ENGOT-ov25: Summary of AEs
AEs, n (%)
Olaparib + Bev
(n = 535)
Placebo + Bev
(n = 267)
All-grade TEAEs 531 (99) 256 (96)
Grade ≥ 3 TEAEs 303 (57) 136 (51)
Serious AEs 167 (31) 83 (31)
Deaths 1 (< 1) 4 (1)
Dose interruptions due to AEs 291 (54) 65 (24)
Dose reductions due to AEs 220 (41) 20 (7)
Discontinuations due to AEs 109 (20) 15 (6)

PAOLA-1: Investigator-Assessed PFS
Olaparib +
Bevacizumab
Placebo +
Bevacizumab
Events, n/N (%) 280 (52) 194 (72)
Median PFS, mos (95% CI) 22.1 16.6
Median time from first cycle of
chemotherapy to randomization = 7 mos
Median follow-up ~ 24 mos
537 513 461 433 403 374 279 240 141 112 55 37 12 03
269 252 226 205 172 151 109 83 50 35 15 9 1 01
Olaparib
Placebo
Patients at Risk, n
100
80
70
60
50
40
30
20
10
0
90
0 3 6 9 12 15 18 21 24 3027
PatientsFreeFromDisease
ProgressionandDeath(%)
33 36 39 42 45
Olaparib + Bev
Placebo + Bev
HR: 0.59 (95% CI: 0.49-0.72; P < .0001)
Ray-Coquard. ESMO 2019. Abstr LBA2

PAOLA-1: Investigator-Assessed PFS
Ray-Coquard. NEJM, 2019

PAOLA-1/ENGOT-ov25: PFS for ITT and by tBRCA
Mutation Status
Subgroup Event Olaparib + Bevacizumab
(n = 537)
(n = 269)
HR (95% CI)
ITT
Events, n (%) [59% maturity] 280 (52) 194 (72) 0.59 (0.49-0.72); P < .0001
Median PFS, mos 22.1 16.6
BRCA
mutation pos
Events, n (%) [59% maturity] 41 (26) 49 (61) 0.31 (0.20-0.47)
Median PFS, mos 37.2* 21.7
BRCA wild
type
Events, n (%) [59% maturity] 239 (63) 145 (77) 0.71 (0.58-0.88)
HRD pos, incl.
tBRCAm pos
Events, n (%) [59% maturity] 87 (34) 92 (70)
0.33 (0.25-0.45)
HRD pos, excl.
tBRCAm pos
0.43 (0.28-0.66)
HRD neg/
unknown
0.92 (0.72-1.17)
*Less than 50% maturity.

PAOLA-1/ENGOT-ov25: Key Sensitivity Analysis
 6% of patients in the olaparib arm and 20% of patients in the placebo arm received
second-line treatment with a PARP inhibitor
Median, mos Olaparib + Bev
(n = 537)
Placebo + Bev
(n = 269)
HR (95% CI);
P Value
PFS 22.1 16.6
0.59 (0.49-0.72);
P < .0001
PFS by BICR 26.1 18.3
0.63 (0.51-0.77);
P < .0001
Time to first
subsequent treatment
24.8 18.5
0.59 (0.49-0.71);
P < .0001
Interim PFS2* 32.3 30.1 0.86 (0.69-1.09)
OS* Data immature
*Results are immature; PFS2: 39% mature and OS: 26% mature.

PAOLA-1/ENGOT-ov25: PFS Subgroup Analysis
Subgroup, n of Events/n of Patients (%) Olaparib + Bev Placebo + Bev HR (95% CI)
All 280/537 (52) 194/269 (72) 0.59 (0.49-0.72)
Age
 < 65 yrs
 ≥ 65 yrs
171/322 (52)
109/205 (53)
126/182 (69)
68/87 (93)
0.61 (0.49-0.77)
0.55 (0.41-0.75)
FIGO stage
 III
 IV
184/378 (49)
95/159 (60)
125/186 (70)
61/83 (83)
0.64 (0.51-0.80)
0.49 (0.36-0.67)
Baseline
ECOG PS
 0
 1
193/378 (51)
85/153 (56)
132/189 (70)
61/76 (80)
0.63 (0.50-0.78)
0.51 (0.37-0.71)
Cytoreductive
surgery
outcome
 Debulking surgery, no residual macroscopic disease
 Debulking surgery, with residual macroscopic disease
 No debulking surgery
135/323 (42)
113/176 (64)
32/38 (84)
104/160 (65)
71/88 (81)
19/21 (90)
0.54 (0.42-0.71)
0.63 (0.47-0.85)
0.56 (0.32-1.01)
Time of
cytoreductive
surgery
 Upfront
 Interval debulking
 No debulking surgery
116/271 (43)
132/228 (58)
32/38 (84)
92/138 (67)
83/110 (75)
19/21 (90)
0.52 (0.40-0.69)
0.66 (0.50-0.87)
0.57 (0.32-1.01)
Response to
first-line CT
 No evidence of disease
 CR
 PR
119/290 (41)
54/106 (51)
107/141 (76)
92/141 (65)
42/53 (79)
60/75 (80)
0.53 (0.40–0.70)
0.44 (0.29-0.66)
0.86 (0.63-1.19)

PAOLA-1/ENGOT-ov25: Conclusions
 In the phase III PAOLA-1 trial, median PFS was significantly prolonged
with the addition of olaparib to maintenance bevacizumab after
frontline platinum-based CT in patients with ovarian cancer, regardless
of BRCA mutation status or initial surgical outcome
 Prespecified subgroup analysis suggested that patients with HRD or
tumor BRCA mutation had the most significant improvement in PFS
‒ Data shows activity of olaparib + bevacizumab in patients who are BRCA
mutation negative but HRD positive
 Safety profile of olaparib + bevacizumab was tolerable and consistent
with previous data

PAOLA-1: Editorial
 Benefit of iPARP established in mutated BRCA ovarian cancer
 Benefit also apparent for high HRD score
 Need mature survival data
‒ Whether maintenance therapy after first remission superior to PARP inhibitor
later in the course of the disease.
 Establish the appropriate cut-off for HRD
‒ MyChoice cut-off of 42 or 33?
Longo NEJM, 2019.

NCCN.org
HRD status NOT required
Ç+

Veliparib + Carboplatin/Paclitaxel for Newly Diagnosed
Ovarian Cancer (VELIA/GOG-3005): Phase III Study Design
Coleman. ESMO 2019. Abstr LBA3.

Veliparib + Carboplatin/Paclitaxel for Newly Diagnosed
Ovarian Cancer (VELIA/GOG-3005): Phase III Study Design
 Primary endpoint: PFS in Arm 1 vs Arm 3 with hierarchical testing in BRCA mutation
positive, HRD positive, and whole population
Patients with newly diagnosed
high-grade serous ovarian
cancer, FIGO Stage III or IV,
ECOG PS 0-2, and no CNS
metastases
(N = 1140)
Carboplatin + Paclitaxel +
Veliparib 150 mg BID
(n = 382)
Placebo
(n = 375)
(n = 383)
Placebo
Placebo
Combination CT: Cycles 1-6 Maintenance: Cycles 7-36
Carboplatin AUC 6 Q3W + paclitaxel 80 mg/m2 QW or 175 mg/m2 Q3W.
Stratification by stage, region, type of cytoreduction,
residual disease, CT regimen, gBRCA status*
*Germline BRCA mutation status added as stratification factor ~ 14 mos after trial initiation due to noted imbalance.

VELIA/GOG-3005: Patient Characteristics
Characteristic CT + Veliparib  Veliparib (n = 382) CT + Placebo  Placebo (n = 375)
FIGO stage III/IV 295 (77)/87 (23) 292 (78)/82 (22)
Surgery received, n (%)
 Primary (69% complete gross resection)
 Interval (71% complete gross resection)
 None
261 (68)
99 (26)
22 (6)
250 (67)
107 (29)
18 (5)
Paclitaxel dosing, n (%)
 Weekly
 Every 3 wks
190 (50)
189 (50)
193 (52)
179 (48)
Deleterious BRCA mutation positive (n = 200), n (%)
 BRCA1 vs BRCA2 (% of BRCAm positive)
 gBRCA vs tBRCA (% of total study arm)
No deleterious BRCA mutation, n (%)
Missing, n
108 (31)
78 (72) vs 30 (28)
80 (23) vs 28 (8)
245 (69)
29
92 (27)
50 (64) vs 31 (36)
63 (18) vs 29 (8)
254 (73)
29
HRD status, n (%)
 HRD positive (includes BRCA mutations), n = 421
 HRD negative, n = 249
 Missing, n = 87
214 (63)
125 (37)
43
207 (63)
124 (38)
44

VELIA/GOG-3005: Summary of AEs
AEs, n (%) CT + Veliparib 
Veliparib
(n = 377)
CT + Veliparib  Placebo
(n = 376)
CT + Placebo 
Placebo
(n = 371)
Any TEAE 377 (100) 376 (100) 371 (100)
Grade 3/4 AEs 332 (88) 329 (88) 285 (77)
Serious AEs 141 (37) 129 (34) 141 (38)
AEs leading to
discontinuation
 PD
 Not related to PD
• Cycles 1-6
• Cycles 7-36*
97 (26)
6 (2)
40 (11)
53 (14)
49 (13)
11 (3)
29 (8)
9 (3)
43 (12)
18 (5)
22 (6)
3 (1)
AEs leading to death 8 (2) 7 (2) 6 (2)
*Most discontinued veliparib between cycles 7 and 8.

VELIA/GOG-3005: AEs During Combination Phase
(Cycles 1-6)
Coleman. ESMO 2019. Abstr LBA3. Reproduced with permission.
100
80
60
40
20
0
Grade 3/4
CT + veliparib  veliparib
CT + veliparib  placebo
CT + placebo  placebo
100
80
60
40
20
0
All Grades
Incidence(%)Incidence(%)

VELIA/GOG-3005: AEs During Maintenance Phase
(Cycles 7-36)
100
80
60
40
20
0
100
80
60
40
20
0
Incidence(%)Incidence(%)
Grade 3/4
All Grades
CT + veliparib  veliparib
CT + veliparib  placebo
CT + placebo  placebo

VELIA/GOG-3005: PFS for Patients With BRCA Mutations
CT + Veliparib  Veliparib CT + Placebo  Placebo
Events, n/N (%) 34/108 (31.5) 51/92 (55.4)
Median PFS, mos
(95% CI)
34.7 (31.8-NR) 22.0 (17.8-29.1)
0
20
40
60
80
100
PFS(%)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
108
92
102
90
99
89
97
88
95
84
90
80
88
74
82
63
80
57
76
50
73
46
65
38
53
29
45
24
38
19
30
13
21
6
14
4
9
2
5
0
1 1 0
Veliparib
throughout
Control
HR: 0.44 (95% CI: 0.28-0.68; P < .001)
Mos From Randomization
Combination Maintenance
Patients at Risk, n

VELIA/GOG-3005: PFS for Patients With HRD (Including
BRCA Mutations)
Events, n/N (%) 87/214 (40.7) 124/207 (59.9)
Median PFS, mos
(95% CI)
31.9 (25.8-38.0) 20.5 (17.8-22.8)
0
20
40
60
80
100
PFS(%)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
214
207
203
199
195
196
191
191
182
183
167
170
161
158
150
134
140
119
130
104
121
97
109
79
82
55
72
47
58
34
44
22
30
11
19
9
14
4
5
2
1
0
1 0
HR: 0.57 (95% CI: 0.43-0.76; P < .001)
Veliparib
throughout
Control
Patients at Risk, n

VELIA/GOG-3005: PFS in ITT Patient Population
(Regardless of HRD or BRCA Mutation Status)
Events, n/N (%) 191/382 (50.0) 237/375 (63.2)
Median PFS, mos
(95% CI)
23.5 (19.3-26.3) 17.3 (15.1-19.1)
0
20
40
60
80
100
PFS(%)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
382
375
352
356
337
340
329
328
308
297
275
260
253
236
228
202
208
172
192
153
172
143
153
119
111
84
95
70
76
55
55
36
38
21
26
16
19
10
7
3
2
0
1 0
HR: 0.68 (95% CI: 0.56-0.83; P < .001)
Veliparib
throughout
Control
Patients at Risk, n

VELIA/GOG-3005: PFS by Subgroup Exploratory Analysis
Median PFS (95% CI)
Subgroup CT + Veliparib  Veliparib CT + Placebo  Placebo HR (95% CI); P Value
ITT (N = 757) 23.5 (19.3-26.3) 17.3 (15.1-19.1) 0.68 (0.56-0.83); P < .001
BRCA mutation positive (n = 200) 34.7 (31.8-NR) 22.0 (17.8-29.1) 0.44 (0.28-0.68); P < .001
HRD positive, with or without
BRCA mutation (n = 421)
31.9 (25.8-38.0) 20.5 (17.8-22.8) 0.57 (0.43-0.76); P < .001
HRD positive, but BRCA wild type
(n = 221)
22.9 (18.2-37.5) 19.8 (16.7-22.2) 0.74 (0.52-1.06)
BRCA wild type, with or without
HRD (n = 499)
18.2 (15.9-21.7) 15.1 (12.6-17.5) 0.80 (0.64-0.997)
HRD negative (n = 249) 15.0 (12.7-18.0) 11.5 (10.1-14.9) 0.81 (0.60-1.09)
Median PFS (95% CI)
Subgroup CT + Veliparib  Placebo CT + Placebo  Placebo HR (95% CI)
ITT (N = 758) --- --- 1.07 (0.90-1.29)

VELIA/GOG-3005: Conclusions
 In this analysis of the phase III VELIA trial, the addition of veliparib to platinum-based CT
followed by veliparib maintenance significantly prolonged median PFS in patients with newly
diagnosed high-grade serous ovarian cancer, regardless of BRCA mutation or HRD status
‒ Risk of recurrence or progression decreased by 56% in patients with BRCA mutations, 43% in
patients with HRD, and 32% in the overall patient population
‒ There was no statistically significant increase in median PFS for patients who received veliparib +
CT without veliparib maintenance
 No new safety signals were observed; AEs were consistent with CT in cycles 1-6 and with
veliparib in maintenance phase
 Investigators concluded that addition of veliparib with CT and veliparib maintenance may be
considered as new first-line treatment option for newly diagnosed, advanced-stage serous
ovarian cancer patients

Cross-Trial PFS Comparisons Impossible due to Different
Patient Populations and Frequency of CT Scans
VELIA PAOLA-1 PRIMA
Inclusion At start CT Maintenance Maintenance
Stage III-IV Stage III-IV Stage III-IV
HGS HGS HGS/EOC
No bev Reimbursement of bev
PDS R+, or NACT, or IV
No bev
PFS, stage III 78% 70% 65%
PFS, stage IV 22% 29% 35%
PDS 67% 50% 67%
NACT 29% 50% 67%
Median follow-up, mos 28 24 14
Slide credit: clinicaloptions.comColeman. ESMO 2019. Abstr. LBA3. González-Martin. NEJM. 2019;[Epub]. Moore. NEJM. 2018;[Epub]. Ray-Coquard. ESMO 2019. Abstr. LBA2.

Conclusions (early iPARP in Ovarian Cancer)
 Maintenance iPARP after PS-OvCa in 1st-line with olaparib or niraparib
an attractive option for:
‒ Either t/gBRCA+, and high HRD score (≥ 42)
‒ If bev used, then olaparib is the iPARP of choice
‒ If no bev, then:
‒ gBRCA+: olaparib or niraparib
‒ tBRCA or High HRD score: niraparib
 Not clear what veliparib concurrent with chemo adds.
None an option in Colombia

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