Robert L. Coleman, MDProfessor & Vice Chair, Clinical ResearchMD Anderson Cancer CenterHouston, [email protected]
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Assessing Currently Available and Emerging
PARP Inhibitors
Disclosures
• Grant funding:• Clovis• Astra-Zeneca• Abbvie
• Scientific Steering Committee• Clovis: ARIEL2 and ARIEL3• Astra-Zeneca: MDACC Alliance• Abbvie: GOG-3005• Tesaro
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PARP inhibitors Clinical Trials
Olaparib
− Study 1 (NCT01078662)− Phase 2 maintenance (NCT00753545)− Phase 2 trial with paclitaxel/carboplatin (NCT01081951)− SOLO-1 (NCT01844986)− SOLO-2 (NCT01874353)− SOLO-3 (NCT02282020)− Olaparib/cediranib (NCT01116648, NCT02446600, NCT02502266)− PAOLA1 (NCT02477644)
Niraparib− PRIMA (GOG 3012; NCT02655016)− NOVA (NCT01847274)− QUADRA (NCT02354586)− AVANOVA (NCT02354131)
Rucaparib− Phase 2 trial (NCT01482715)− ARIEL2 (parts 1 and 2, NCT01891344)− ARIEL3 (NCT01968213)− ARIEL4 (NCT02855944)
Veliparib − Phase 2 trial (GOG 0280, NCT01540565)− Phase 3 trial (GOG 3005, NCT02470585)
Current PARP Inhibitors
4
PARP, poly(ADP-ribose) polymerase
Olaparib: Study 1 Response
• Response rate− Overall response, 34%− Partial response, 32%− Complete response, 2%
• Response duration− Median, 7.9 months (95% CI, 5.6–9.6
months)
Domchek SM, et al. Gynecol Oncol. 2016;140(2):199-203.
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Platinum Sensitivity Status Patients Responders Response Rate (95% CI)
Platinum-sensitive 38 17 45% (29–62)
Platinum-resistant 77 22 29% (19–40)
Platinum-refractory 14 2 14% (2–43)
Unknown 8 5 63% (24–91)
TOTAL 137 46 34% (26–42)
Baseline Patient Characteristics:BRCA2: 22%BRCA1: 77%Pt-resistant: 56%Pt-refractory: 10%
Response by Platinum Sensitivity (n=137)
Efficacy results (n=137)
Olaparib: Study 19 R-Ph2 Maintenance Trial in Platinum-Sensitive Recurrent Serous OC
Ledermann J, et al. N Engl J Med. 2012;366(15):1382-1392.Ledermann J, et al. Lancet Oncol. 2014;15(8):852-861.
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Primary end point: PFSSecondary end points: OS, best ORR, health-related quality of life (TOI), FACT-O, FACT-O symptom index (FOSI), time to progression, disease control rate, and safety and tolerability
• Platinum-sensitive advanced OC• Grade 2–3 serous histology or serous
component• ≥2 previous platinum regimens• CR or PR to just-completed platinum
regimen
Olaparib 400 mg PO bid
(n=136)
Placebo
(n=129)
R
bid, twice daily; CR, complete response; OC, ovarian cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PO, by mouth; PR, partial response; R, randomization
Olaparib: Randomized, Phase 2 Maintenance Trial in Platinum-Sensitive Recurrent Serous OC
Ledermann J, et al. N Engl J Med. 2012;366(15):1382-1392.Ledermann J, et al. Lancet Oncol. 2014;15(8):852-861.
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Parameter Olaparib Placebo HR P-valueAll patients 136 129
PFS 8.4 mo 4.8 mo 0.35 (0.25–0.49) <.001
OS 29.8 mo 27.8 mo 0.88 (0.64–1.21) .44
BRCA mutated 74 62
PFS 11.2 mo 4.3 mo 0.18 (0.10–0.31) <.0001
OS 34.9 mo 31.9 mo 0.73 (0.45–1.17) .19
BRCA wild-type 62 67
PFS 7.4 mo 5.5 mo 0.54 (0.34–0.85) .0075
OS 24.5 mo 26.2 mo 0.99 (0.63–1.55) .96BRCA, breast cancer susceptibility gene; HR, hazard ratio; OC, ovarian cancer; OS, overall survival; PFS, progression-free survival
Olaparib: Randomized, Phase 2 Maintenance Trial in Platinum-Sensitive Recurrent Serous OC (cont.)
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Olaparib Maintenance: All Patients
Ledermann J, et al. N Engl J Med. 2012;366(15):1382-1392.Ledermann J, et al. Lancet Oncol. 2014;15(8):852-861.
HR, hazard ratio; OC, ovarian cancer; OS, overall survival; PFS, progression-free survival
P-value
Ongoing Olaparib Monotherapy Phase 3 Trials
aincluding primary peritoneal, or fallopian tube cancers.
bid, twice daily; BRCA, breast cancer susceptibility gene; CR, complete response; GEM, gemcitabine; HR-QoL, health-related quality of life; ORR, objective response rate; OS, overall survival; PAC, paclitaxel; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PO, by mouth; PR, partial response; RECIST, response evaluation criteria in solid tumors; TDT, time from randomisation to study treatment discontinuation or death; TFST, time from randomisation to first subsequent therapy or death; TSST, time to second subsequent therapy or death
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Patient Population Study Design Study EndpointsSOLO-1 (NCT01844986)− Newly diagnosed stage III-IV ovarian cancera
− Serous or endometrioid high-grade histology− In CR or PR at end of frontline
platinum-based chemotherapy− Deleterious BRCA mutation
− Olaparib(300 mg PO bid) or placebo to progression
− Primary: PFS− Secondary: OS, time to earliest
progression by RECIST or CA-125 or death, PFS2, best ORR, HRQoL,TDT, TFST, TSST, safety/tolerability
SOLO-2 (NCT01874353)
− Platinum-sensitive ovarian cancera
− In CR or PR after ≥2 lines of platinum Tx− Serous or endometrioid high-grade histology− Deleterious BRCA mutation
− Olaparib(300 mg PO bid) or placebo to progression
− Primary: PFS− Secondary: OS, time to earliest
progression by RECIST or CA-125 or death, PFS2, best ORR, HRQoL, TDT, TFST, TSST, safety/tolerability
SOLO-3 (NCT01844986)− Platinum-sensitive ovarian cancera
− In CR or PR after ≥2 lines of platinum Tx− Serous or endometrioid high-grade histology− Measurable disease− No prior PARP inhibitor− Deleterious BRCA mutation
− Olaparib (300 mg PO bid) or physicians choice (weekly PAC, topotecan, PLD, or GEM) to progression
− Primary: PFS− Secondary: OS, time to earliest
progression by RECIST or CA-125 or death, PFS2, best ORR, HRQoL, TDT, TFST, TSST, safety/tolerability
Ongoing Olaparib Combination Trials
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aincluding primary peritoneal, or fallopian tube cancers.bid, twice daily; BRCA, breast cancer susceptibility gene; CARB, carboplatin; CTx, chemotherapy; FIGO, International Federation of Gynecology and Obstetrics; GEM, gemcitabine; HR-QoL, health-related quality of life; OS, overall survival; PAC, paclitaxel; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PO, by mouth; Pt, platinum
Patient Population Study Design Study EndpointsNRG GY004 (NCT02446600)
− Pt-sensitive recurrent ovarian cancera
− Endometrioid or serous high-grade histology or other histology if gBRCAmut
− Measurable disease− ≥1 prior platinum regimens− Prior antiangiogenic Tx first-line only− Progression-free ≥6 mos after last platinum
− Carboplatin-based doublet (PAC or GEM or PLD + CARB) vs Olaparib (400 mg PO bid) vs Cediranib (30 mg PO qd) + Olaparib (400 mg PO bid) to progression
− Primary: PFS− Secondary: OS, safety,
patient-reported outcomes
NRG GY005/COCOS (NCT02502266)
− Pt-resistant or -refractory recurrent ovarian cancera
− Endometrioid or serous high-grade histology or other if gBRCAmut
− ≤2 prior regimens− Prior antiangiogenic therapy first-line only− Progression-free ≤6 mos after last platinum
− Physician’s choice (PAC, PLD, GEM)
− Olaparib+ Cediranib− Cediranib− Olaparib to progression
− Primary: PFS (phase 2); OS (phase 3)
− Secondary: Safety
PAOLA-1 (NCT02477644)
− High-grade epithelial ovarian cancera
− FIGO stage IIIB-IV− At least stable disease after
surgery/chemotherapy for 6–9 cycles
− Olaparib vs placebo + CTx and bevacizumab concurrent with CTx and in maintenance
− Primary: PFS− Secondary: OS, post-
progression survival, HRQoL, safety/tolerability
Current PARP Inhibitors
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PARP, poly(ADP-ribose) polymerase
PARP inhibitors Clinical Trials
Olaparib
− Study 1 (NCT01078662)− Phase 2 maintenance (NCT00753545)− Phase 2 trial with paclitaxel/carboplatin (NCT01081951)− SOLO-1 (NCT01844986)− SOLO-2 (NCT01874353)− SOLO-3 (NCT02282020)− Olaparib/cediranib (NCT01116648, NCT02446600, NCT02502266)− PAOLA1 (NCT02477644)
Niraparib− PRIMA (GOG 3012; NCT02655016)− NOVA (NCT01847274)− QUADRA (NCT02354586)− AVANOVA (NCT02354131)
Rucaparib− Phase 2 trial (NCT01482715)− ARIEL2 (parts 1 and 2, NCT01891344)− ARIEL3 (NCT01968213)− ARIEL4 (NCT02855944)
Veliparib − Phase 2 trial (GOG 0280, NCT01540565)− Phase 3 trial (GOG 3005, NCT02470585)
Niraparib: NOVA Phase 3 Maintenance Study in Platinum-Sensitive Ovarian Cancer
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• Platinum-sensitive ovarian, primary peritoneal, or fallopian tube cancer
• Serous high-grade histology or known to have gBRCAmut
• ≥2 prior platinum regimens • In CR or PR and enrolled within
8 weeks of completion of last platinum regimen
• No prior PARP inhibitor• Planned N=490
Niraparib 300 mg PO daily to
progression
Placebo once daily to
progression
Mirza MR, et al. N Engl J Med. 2016 Oct 7. [Epub ahead of print].ClinicalTrials.gov. NCT01847274. Accessed May 31, 2016.
R2:1
N=490Primary end point: PFSSecondary end points: OS, PFS2, chemotherapy-free interval, health-related quality of life, and safety and tolerabilityAnalysis to include: all patients, gBRCAmut patients, and the non-gBRCAmut cohort (first as HRD+ patients and then all non-gBRCAmut patients)
CR, complete response; gBRCAmut, germline breast cancer susceptibility gene mutation; HRD, homologous recombination deficiency; OS, overall survival; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; PO, by mouth; PR, partial response; R, randomization
aMedian duration of follow-up at time of data cutoff was 16.9 months.
ENGOT-OV16/ NOVA Trial
Mirza MR, et al. N Engl J Med. 2016 Oct 7. [Epub ahead of print].
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Platinum-Sensitive Recurrent High Grade SerousOvarian Cancer
N=553
gBRCAmutn=203
2:1 Randomization
Niraparib n=138
Placebon=65
47 Ongoing
Treatmenta
4 Ongoing
Treatmenta
Non-gBRCAmutn=350
2:1 Randomization
Niraparib n=234
Placebon=116
46 Ongoing
Treatmenta
12 Ongoing
Treatmenta
Prospective Stratification Factors for Randomization
Mirza MR, et al. N Engl J Med. 2016 Oct 7. [Epub ahead of print].
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Characteristic
gBRCAmut Non-gBRCAmutNiraparib(n=138)
Placebo(n=65)
Niraparib(n=234)
Placebo(n=116)
Time to progression after penultimate platinum therapy, n (%)
6 to <12 mo 54 (39.1) 26 (40.0) 90 (38.5) 44 (37.9)
≥12 mo 84 (60.9) 39 (60.0) 144 (61.5) 72 (62.1)
Best response to most recent platinum therapy, n (%)
Complete response 71 (51.4) 33 (50.8) 117 (50.0) 60 (51.7)
Partial response 67 (48.6) 32 (49.2) 117 (50.0) 56 (48.3)
Prior bevacizumab use, n (%)
Yes 33 (23.9) 17 (26.2) 62 (26.5) 30 (25.9)
No 105 (76.1) 48 (73.8) 172 (73.5) 86 (74.1)
gBRCAmut, germline breast cancer susceptibility gene mutation
Progression-Free Survival: gBRCAmut
Treatment
PFSMedian
(95% CI), mo
Hazard Ratio(95% CI)P-value
% of Patients Without
Progression or Death
12 mo
18 mo
Niraparib(n=138)
21.0(12.9, NR) 0.27
(0.173, 0.410)
P<.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.
gBRCAmut, germline breast cancer susceptibility gene mutation; NR, not reached; PFS, progression-free survival
Mirza MR, et al. N Engl J Med. 2016 Oct 7. [Epub ahead of print].
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Progression-Free Survival: Non-gBRCAmut
Mirza MR, et al. N Engl J Med. 2016 Oct 7. [Epub ahead of print].
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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.
gBRCAmut, germline breast cancer susceptibility gene mutation; NR, not reached; PFS, progression-free survival
Treatment
PFSMedian
(95% CI), mo
Hazard Ratio(95% CI)P-value
% of Patients Without
Progression or Death
12 mo
18 mo
Niraparib(n=234)
9.3(7.2, 11.2)
0.45(0.338, 0.607)
P<.0001
41% 30%
Placebo(n=116)
3.9(3.7, 5.5) 14% 12%
Progression-Free Survival: Non-gBRCAmut HRD+
Mirza MR, et al. N Engl J Med. 2016 Oct 7. [Epub ahead of print].
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Treatment
PFSMedian
(95% CI), mo
Hazard Ratio(95% CI)P-value
% of Patients Without
Progression or Death
12 mo
18 mo
Niraparib(n=106)
12.9(8.1, 15.9)
0.38(0.243, 0.586)
P<.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.
gBRCAmut, germline breast cancer susceptibility gene mutation; NR, not reached; PFS, progression-free survival
Ongoing Niraparib Trials
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aincluding primary peritoneal, or fallopian tube cancers.
Patient Population Study Design Study EndpointsPRIMA (GOG 3012; NCT02655016)
− Newly diagnosed stage III-IV ovarian cancera
− HRD+ tumor− In CR or PR at end of at least 4 cycles of
frontline platinum-based chemotherapy− No prior PARP inhibitor
− Niraparib (300 mg PO) or placebo to progression
− Primary: PFS− Secondary: OS, PFS2,
HRQoL, safety/tolerability
QUADRA (NCT02354586)
− Recurrent ovarian cancera
− Serous high-grade histology− ≥3 prior chemotherapy regimens − Disease progression on most recent
chemotherapy
− Niraparib(300 mg PO) to progression
− Primary: ORR− Secondary: DOR, DCR,
PFS, safety/tolerability
AVANOVA (NCT02354131)
− Recurrent platinum-sensitive ovarian cancera
− High-grade serous or endometrioid histology− HRD-positive
− Sequential bevacizumab àniraparb vs niraparib monotherapy vs niraparib+ bevacizumab combination to progression
− Primary: PFS− Secondary: Disease control
rate
Current PARP Inhibitors
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PARP, poly(ADP-ribose) polymerase
PARP inhibitors Clinical Trials
Olaparib
− Study 1 (NCT01078662)− Phase 2 maintenance (NCT00753545)− Phase 2 trial with paclitaxel/carboplatin (NCT01081951)− SOLO-1 (NCT01844986)− SOLO-2 (NCT01874353)− SOLO-3 (NCT02282020)− Olaparib/cediranib (NCT01116648, NCT02446600, NCT02502266)− PAOLA1 (NCT02477644)
Niraparib− PRIMA (GOG 3012; NCT02655016)− NOVA (NCT01847274)− QUADRA (NCT02354586)− AVANOVA (NCT02354131)
Rucaparib− Phase 2 trial (NCT01482715)− ARIEL2 (parts 1 and 2, NCT01891344)− ARIEL3 (NCT01968213)− ARIEL4 (NCT02855944)
Veliparib − Phase 2 trial (GOG 0280, NCT01540565)− Phase 3 trial (GOG 3005, NCT02470585)
ARIEL2: Phase 2, Part 1
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bid, twice daily; BRCAmut, breast cancer susceptibility gene mutation; ORR, objective response rate; PFS, progression-free survival; PK, pharmacokinetics; PO, by mouth; RECIST, response evaluation criteria in solid tumors
• Platinum-sensitive ovarian, primary peritoneal, or fallopian tube cancer
• Serous or endometrioid high-grade histology
• ≥1 prior platinum regimen• Open-label phase 2
Rucaparib 600 mg PO bid to
progression
BRCAmut
Biomarker negative
BRCA-like
Part 1 (COMPLETED) : Evaluation of HRD status/Rucaparib efficacy
Swisher EM, et al. Lancet Oncol. 2017;18(1):75-87.
N=350Primary end point: PFSSecondary end points: ORR (RECIST, RECIST+CA-125), PK, and safety and tolerability
ARIEL2: Phase 2 Study Results
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BRCA, breast cancer susceptibility gene; BRCAmut, breast cancer susceptibility gene mutation; HRD, homologous recombination deficiency; ORR, objective response rate; PFS, progression-free survival; RECIST, response evaluation criteria in solid tumors
HRD Subgroup
Median PFS (90% CI)
ORR RECIST, n (%)
ORRRECIST+CA-125,
n (%)
BRCAmut 9.4 mo (7.3–NR) 27/39 (69) 32/39 (82)
BRCA-like 7.1 mo (3.7–10.8) 22/74 (30) 33/74 (45)
Biomarker-negative 3.7 mo (3.5–5.5) 8/62 (13) 13/62 (21)
McNeish IA, et al. J Clin Oncol. 2015;33(suppl):abstract 5507.
Efficacy and Safety Populations
Criteria- Diagnosis of ovarian cancer (inclusive of primary peritoneal
and fallopian tube cancer)
- Enrolled at 600 mg bid dosing level and received ≥1 dose of rucaparib 600 mg
Criteria- Received ≥2 prior chemotherapies, including ≥2
platinum-based regimens
- Had a deleterious germline BRCA or somatic BRCA mutation
- Enrolled at 600 mg bid dosing level and received ≥1 dose of rucaparib 600 mg
Study 10(NCT01482715)
n=62
n=42
ARIEL2(NCT01891344)
n=315
n=64
Safety Population (n=377)
Efficacy Population (n=106)
Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016). Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016).bid, twice daily; BRCA, breast cancer susceptibility gene
Kristeleit RS, et al. Ann Oncol. 2016;27(suppl 6):vi296.
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Progression-free at 6 months:79%
Progression-free at 12 months:41%
Progression-Free Survival in the Efficacy Population
Kristeleit RS, et al. Ann Oncol. 2016;27(suppl 6):vi296.
23
Median (months) 95% CI Range10.0 7.3–12.5 0.0–22.1+
+ Censored; Censoring rate: 47%
• Of 106 patients, 50 did not have an event of disease progression or death by the data cutoff dates– Of these 50 patients, 32 were still on treatment, and 18 discontinued treatment for reasons other than disease
progression or death at the data cutoff dates
Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016).CI, confidence interval
Prob
abili
ty o
f Pro
gres
sion
-Fre
e Su
rviv
al
MonthsAt risk
(events) 106 (0) 93 (9) 85 (14) 69 (19) 43 (37) 31 (40) 21 (43) 14 (49) 8 (54) 3 (55) 3 (55) 2 (56) 0 (56)
Investigator-Assessed ORR in the Efficacy Population
Kristeleit RS, et al. Ann Oncol. 2016;27(suppl 6):vi296.
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Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016).CR, complete response; GCIG, Gynecologic Cancer InterGroup; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable diseas
Parameter
Study 10n=42
ARIEL2n=64
Efficacy Populationn=106
n (%)[95% CI]
Investigator-assessed RECIST ORR(confirmed CR+PR)
25 (60)[43.3–74.4]
32 (50)[37.2–62.8]
57 (54)[43.8–63.5]
CR 4 (10) 5 (8) 9 (9)
PR 21 (50) 27 (42) 48 (45)
SD 12 (28) 24 (37) 36 (34)
PD 2 (5) 7 (11) 9 (9)
NE 3 (7) 1 (2) 4 (4)
Investigator-assessed RECIST/GCIG CA-125 ORR
75 (71)[61.1–79.2]
Ongoing Rucaparib Trials
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Patient Population Study Design Study Endpoints
ARIEL3 (NCT01968213)
− Recurrent ovarian cancera
− High-grade serous or endometrioid histology− 1 prior non-platinum regimen− Platinum sensitive− In a CR or PR at end of just-completed platinum
regimen − No prior PARP in ≥2 prior platinum regimens− No more than 1 nonplatinum chemotherapy
regimen
− Rucaparib (600 mg PO bid) or placebo to progression
− Primary: PFS− Secondary: OS, HRQoL,
safety/tolerability
ARIEL4 (NCT02855944)
− Grade II-III ovarian cancera
− ≥2 prior chemotherapy regimens and have relapsed or progressive disease
− Rucaparib (600 mg PO bid) or chemotherapy to progression
− Primary: PFS− Secondary: OS, safety/tolerability
aincluding primary peritoneal, or fallopian tube cancers.
Current PARP Inhibitors
26
PARP, poly(ADP-ribose) polymerase
PARP inhibitors Clinical Trials
Olaparib
− Study 1 (NCT01078662)− Phase 2 maintenance (NCT00753545)− Phase 2 trial with paclitaxel/carboplatin (NCT01081951)− SOLO-1 (NCT01844986)− SOLO-2 (NCT01874353)− SOLO-3 (NCT02282020)− Olaparib/cediranib (NCT01116648, NCT02446600, NCT02502266)− PAOLA1 (NCT02477644)
Niraparib− PRIMA (GOG 3012; NCT02655016)− NOVA (NCT01847274)− QUADRA (NCT02354586)− AVANOVA (NCT02354131)
Rucaparib− Phase 2 trial (NCT01482715)− ARIEL2 (parts 1 and 2, NCT01891344)− ARIEL3 (NCT01968213)− ARIEL4 (NCT02855944)
Veliparib − Phase 2 trial (GOG 0280, NCT01540565)− Phase 3 trial (GOG 3005, NCT02470585)
Veliparib: Phase 2 Study Design
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N=50Primary end point: investigator-assessed ORRSecondary end points: PFS, EFS, PFS6/EFS6, OS, safety/tolerability
bid, twice daily; EFS, event-free survival; gBRCAmut, germline breast cancer susceptibility gene mutation; ORR, objective response rate; OS, overall survival; PARP, poly(ADP-ribose) polymerase; PO, by mouth
• Recurrent ovarian, primary peritoneal, or fallopian tube cancer
• gBRCAmut present• <3 prior treatment regimens • Prior biologic therapy but no prior PARP
inhibitor allowed• Measurable disease
Veliparib 400 mg PO bid to
progression
Overall Best Response Patients, n (%)
RECIST (n=40)
CR 2 (5)
PR 11 (27.5)
SD 14 (35)
PD 7 (17.5)
Indeterminate 6 (15)
Disease control rate 27 (67.5)
Results
Coleman RL, et al, Gynecol Oncol. 2015;137(3):386-391.ClinicalTrials.gov. NCT01540565. Accessed June 2, 2016.
GOG 3005: Frontline Phase 3 Trial
28
AUC, area under the curve; CNS, central nervous system; DRS, disability rating score; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; OS, overall survival; PFS, progression-free survival; q3wk, every 3 weeks; qwk, every week
CHOICE OF THERAPYCarboplatin AUC 6 q3wk +Paclitaxel qwk (80 mg/m2) or paclitaxel q3wk (175 mg/m2)Primary or interval cytoreductive surgery
Veliparib
PlaceboHigh-grade serous carcinoma
• Ovary, fallopian tube, primary peritoneal
• FIGO stage III or IV• No prior systemic therapy• ECOG 0-2• No CNS metastases
Arm 2veliparib PO bid +
carboplatin/paclitaxel
Arm 3veliparib PO bid +
carboplatin/paclitaxel
Arm 1placebo PO bid +
carboplatin/paclitaxel
(1:1:1)
N=1100R
ClinicalTrials.gov. NCT02470585. Accessed May 31, 2016.
Primary end point: PFSSecondary end points: OS, DRS scores
§ 2 PARP inhibitor currently approved (olaparib, rucaparib)
§ 2 others in active clinical trials (niraparib, veliparib)
§ Current use outside trials: gBRCAmut
Current status
§ Increasing number of agents: relative merits
Defining new patient groups to benefit§ Defining BRCA-like patients§ Combination with other targeted
agentsScope of roles in ovarian cancer§ Monotherapy in recurrent disease§ Monotherapy as maintenance after
chemotherapy § Combination therapy with
chemotherapy
Immediate future issues
PARP Inhibitors: Summary
29
gBRCAmut, germline breast cancer susceptibility gene mutation; PARP, poly(ADP-ribose) polymerase