Olaparib as Maintenance Treatment Following First-Line Platinum-Based Chemotherapy in Patients With a Germline BRCA Mutation and Metastatic ...
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Olaparib as Maintenance Treatment Following
First-Line Platinum-Based Chemotherapy in
Patients With a Germline BRCA Mutation and
Metastatic Pancreatic Cancer: Phase III POLO Trial
Abstract LBA4
Kindler HL, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ,
Park JO, Hochhauser D, Arnold D, Oh D-Y, Reinacher-Schick A,
Tortora G, Algül H, O'Reilly EM, McGuinness D, Cui KY, Schlienger K,
Locker GY, Golan TMetastatic Pancreatic Cancer
Standard-of-care FOLFIRINOX or
gemcitabine + nab-paclitaxel[a,b]
Median PFS ~6 months[a,b]
Median OS 8–12 months[a,b]
< 50% of patients receive
2nd-line treatment[c]
No targeted treatments for a
biomarker-selected population
validated by phase III trial
FOLFIRINOX = fluorouracil, leucovorin, irinotecan and oxaliplatin; PFS = progression free survival, OS = overall survival
a. Conroy T, et al. N Engl J Med. 2011;364(19):1817-1825; b. Von Hoff DD, et al. N Engl J Med. 2013;369(18):1691-1703; c. Hidalgo M, et al. Pancreatology. 2015;15(1):8-18.
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Metastatic Pancreatic Cancer
BRCA1 and BRCA2 Mutations
Maintenance treatments aim
to delay disease progression
4% to 7% harbor a germline Increased benefit from following chemotherapy
BRCA1 and/or BRCA2 platinum-based without compromising HRQoL
mutation (gBRCAm)[a,b] chemotherapy[c,d]
a. Friedenson B. MedGenMed. 2005;7(2):60; b. Golan T, et al. J Clin Oncol. 2018;36(suppl): Abstract 4115; c. Waddell N, et al. Nature. 2015;518(7540):495-501; d. Golan T, et al. Br J
Cancer. 2014;111(6):1132-1138.
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Overall Survival and Clinical Characteristics of
PDAC in BRCA Mutation Carriers
Probability of OS by Platinum Treatment at Stage III and IV
Number of mOS,
Stage Patients Treatment Months P Value
Probability of Overall Survival
*P < .05 Platinum - 22 22
[6-27]
III & IV 43 .0389
Non Platinum 9
- 21 [4-12]
Golan T, et al. Br J Cancer. 2014;111(6):1132-1138.
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Rationale for PARP Inhibition in
BRCA-Deficient Tumors
Olaparib traps PARP Accumulation of
at sites of DNA DNA double-strand
single-strand breaks breaks
Normal
HRR-deficient cancer cell
cell, eg, gBRCAm
Reliance on Homologous
error-prone recombination
pathways repair
Cell death Cell survival
HRR = homologous recombination repair; ORR = objective response rate; PARP = poly(ADP-ribose) polymerase
O’Connor M. Mol Cell. 2015;60(4):547-560; Kaufman B, et al. J Clin Oncol. 2015;33(3):244-250; Moore K, et al. New Engl J Med. 2018;379(26):2495-2505; Robson M, et al. New Engl J
Med. 2017;377(6):523-533.
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Study 42: Phase II Study of Olaparib in gBRCAm-Associated
Solid Tumors Including Metastatic Pancreatic Cancer
Demonstrated clinical efficacy in gBRCAm ovarian and breast cancers
23 patients previously treated gemcitabine gBRCAm metastatic PDAC
1.0
Ovarian Breast Pancreas Prostate
Proportion
0.8 Median OS, mos 16.6 11.0 9.8 18.4
survival
0.6
(proportion)
Survival,
N 23
0.4
OverallOverall
CR/PR 1/4
Ovarian
(%) (22%)
0.2 Breast
Pancreas 11
Prostate DCR
(48%)
0.0
PFS 4.6 mos
0 3 6 9 12 15 18 21 24 27 27
No. of patients at risk
Time
Time fromFirst
From first dose
Dose,(months)
Months OS 9.8 mos
Ovarian 193 172 154 139 117 78 53 27 14 0 0
Breast 62 50 43 33 25 17 10 6 4 2 0
Pancreas 23 17 14 12 9 6 4 3 1 0 0
Prostate 8 7 6 5 4 4 2 2 1 0 0
CR = complete response; DCR = disease control rate; PDAC = pancreatic ductal adenocarcinoma; PR = partial response
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Study Design
≥ 16 weeks 4-8 weeks Follow-up
First-line chemotherapy Randomizatio Maintenance treatment Discontinuation
n
Key eligibility criteria
Metastatic pancreatic cancer Olaparib
tablets
Deleterious or suspected 300 mg twice Until investigator-
Randomized 3:2
deleterious germline BRCA1 daily assessed disease
or BRCA2 mutation No stratification progression or
≥ 16 weeks first-line factors or unacceptable toxicity
platinum-based chemotherapy Placebo
with no limit to duration,
without progression
(CR, PR or SD)*
38% of gBRCAm patients had disease progression, were ineligible, or declined randomization
*There was no maximum limit to the duration of first-line chemotherapy
SD = stable disease
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Study Endpoints
≥16 weeks 4–8 weeks Follow-up
First-line chemotherapy Randomizatio Maintenance treatment Discontinuation
n
PFS Progression
Primary endpoint:
• PFS using modified RECIST v1.1 by
blinded independent central review Progression on
PFS2 2nd-line treatment
Key secondary endpoints:
• Time to second progression (PFS2)
• Objective response rate
• HRQoL OS Death
• Safety and tolerability
• Overall survival • Prespecified at 87 PFS events from
145 patients
• 80% power at one-sided significance level
of 2.5%
• Assumed PFS HR = 0.54
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Patient Disposition
Olaparib Placebo
N = 92 N = 62
Screened, n 3315
Found to have a gBRCAm, n (%) 247 (7.5)
Excluded, n 93
Disease progression or death 43
Ineligible 22
Patient or physician decision 28
Randomized, n 92 62
Treated, n 90 61
Discontinued treatment, n (%) 60 (65.2) 53 (85.5)
Disease progression by BICR 43 (46.7) 40 (64.5)
Disease progression by investigator assessment 12 (13.0) 9 (14.5)
Adverse event 4 (4.3) 2 (3.2)
Patient decision 1 (1.1) 1 (1.6)
Ineligible 0 1 (1.6)
Continuing assigned treatment at data cut-off*, n (%) 30 (32.6) 8 (12.9)
Median follow-up for progression, mos (range)† 9.1 (0-39.6) 3.8 (0-29.8)
*January 15, 2019. †Censored patients
BICR = blinded independent central review
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Primary Endpoint: PFS by Blinded
Independent Central Review*
Olaparib Placebo
N = 92 N = 62
Median PFS, months 7.4 3.8
HR 0.53
95% CI 0.35, 0.82; P = .0038
Progression-free at data cutoff†:
30 olaparib patients (32.6%)
12 placebo patients (19.4%)
Time Since Randomization, Months
*Dots indicate censorship; †January 15, 2019
CI = confidence interval; HR = hazard ratio
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.PFS at Prespecified Timepoints by
Blinded Independent Central Review*
From 6 months onwards, more than
twice the proportion of olaparib-arm
Patients Free From Disease
Progression or Death, %
patients were progression-free
Time Since Randomization, Months
*Kaplan-Meier method
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Subgroup Analyses of PFS* *Circle size proportional to number of events. Subgroups in which fewer than 5 PFS events had occurred per arm were not analyzed. †By BRACAnalysis CDx® test. PBC = platinum-based chemotherapy Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.
Overall Survival: Interim Analysis,
46% Maturity*
Olaparib Placebo
N = 92 N = 62
Median OS, months 18.9 18.1
HR 0.91
95% CI 0.56, 1.46; P = .68
Subsequent treatment
with a PARP inhibitor:†
1 olaparib patient (1.1%)
9 placebo patients (14.5%) Final OS analysis planned at 106 events
Time Since Randomization, Months
*Dots indicate censorship. †Crossover to olaparib was not permitted during this study; subsequent therapies were given at the investigators’ discretion
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Objective Response* in Patients With
Measurable Disease by Blinded ICR
Two patients in the olaparib Olaparib 5.4 months
23.1% arm had a complete response
Both complete responses were Placebo 3.6 months
ongoing at the data cut-off†
Median time to onset of response
11.5%
Olaparib 24.9 months
n = 18 n=6
Placebo 3.7 months
Olaparib Placebo
N = 78 N = 52
Median duration of response
*By modified RECIST v1.1. †January 15, 2019
ICR = independent central review
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Patient-Reported Global HRQoL Over Time
(EORTC QLQ-C30)*
Average Across All Study Olaparib Placebo
Visits Up to 6 Months* N = 84 N = 54
Global HRQoL Score (0-100)
Adjusted mean change from
−1.20 (1.42) 1.27 (1.95)
baseline (standard error)
Estimated difference (95% CI) −2.47 (−7.27, 2.33)
P = .31
No clinically meaningful change from baseline
in Global HRQoL score in either arm
No clinically meaningful difference in overall
Time From Randomization, Weeks
change from baseline between arms
*Global HRQoL score was not analyzed at time points with less than 20 evaluable patients
HRQoL = health related quality of life; EORTC QLA-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Most Common AEs
Olaparib (N = 91) Placebo (N = 60)
AEs = adverse events
Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.Conclusions • Maintenance olaparib provided a statistically significant and clinically meaningful improvement in PFS to patients with a gBRCAm and metastatic pancreatic cancer whose disease had not progressed during platinum-based chemotherapy • 23% of the patients had a PR/CR on olaparib. Of those patients, median duration of response was 24.9 months • HRQoL was preserved with olaparib treatment and showed no difference between arms, with a trend to improvement in QoL over time in the olaparib treatment arm • In the age of precision medicine: our results are the first from a phase III trial to validate a targeted treatment in a biomarker-selected population of patients with pancreatic cancer • Once again highlighting the importance of gBRCAm testing in this setting Kindler HL, et al. J Clin Oncol. 2019;37(15_suppl): Abstract LBA4.
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