Download Rucaparib in Patients with Relapsed, Primary

Rucaparib in Patients with Relapsed, Primary Platinum-Sensitive
High-Grade Ovarian Carcinoma with Germline or Somatic
BRCA Mutations: Integrated Summary of Efficacy and Safety
from the Phase 2 Study ARIEL2 (NCT01891344)
Gottfried E. Konecny,1 Amit M. Oza,2 Anna V. Tinker,3 Robert L. Coleman,4
David M. O’Malley,5 Lara Maloney,6 Kenton Wride,6 Lindsey Rolfe,6
Iain McNeish,7 Elizabeth M. Swisher8
1University
of California Los Angeles, Los Angeles, CA; 2Princess Margaret Cancer Centre, University Health Network,
Toronto, Canada; 3British Columbia Cancer Agency, Vancouver, Canada; 4The University of Texas MD Anderson
Cancer Center, Houston, TX; 5The Ohio State University, James Cancer Center, Columbus, OH; 6Clovis Oncology, Inc.,
Boulder, CO; 7Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
8University of Washington, Seattle, WA
Disclosures
• Speakers’ bureau:
– AstraZeneca, Clovis Oncology
• Research funding:
– Amgen, Merck
• Honorarium:
– Novartis
PARP Inhibitors Are Synthetically Lethal
to BRCAmut Tumor Cells
Cell
proficient in
HR
Cell
deficient
in HR
P
A
R
P
Cell
survival
I
N
H
I
B
I
T
O
R
Cell
death
BRCAmut, BRCA mutant; HR, homologous recombination; HRD, HR deficiency; PALB2, partner and localizer of BRCA2; PARP, poly(ADP-ribose)
polymerase; RAD51, homolog of the bacterial RecA protein.
Kristeleit R, et al. ECC-ESMO 2015. Abstract 2700.
Background
• The PARP inhibitor rucaparib is approved in the US as monotherapy for the treatment
of patients with deleterious BRCAmut (germline and/or somatic) associated advanced
ovarian cancer who have been treated with 2 or more chemotherapies1
• The US approval of rucaparib was supported by integrated data from 2 studies:
Study 10 (NCT01482715) and ARIEL2 (NCT01891344)
ORR, objective response rate; PFS, progression-free survival; US, United States.
1. Rucaparib tablets [prescribing information]. Boulder, CO: Clovis Oncology, Inc.; 2016.
Study Objectives
• To assess ORR and PFS in patients from ARIEL2 with germline or somatic BRCAmut
ovarian cancer
• To determine the effect of platinum sensitivity status and number of prior lines of
chemotherapy on ORR and PFS
ORR, objective response rate; PFS, progression-free survival; US, United States.
1. Rucaparib tablets [prescribing information]. Boulder, CO: Clovis Oncology, Inc.; 2016.
ARIEL2
• Eligibility criteria
• Diagnosis of ovarian cancer (inclusive of primary peritoneal and fallopian tube cancer)
• RECIST measurable disease
• ECOG Performance Status 0–1
• Study Criteria
• All patients initiated treatment with oral rucaparib 600 mg BID
• Treatment continued until disease progression or discontinuation
• Investigator-assessed response (RECIST version 1.1)
ORR, objective response rate; PFS, progression-free survival; US, United States.
1. Rucaparib tablets [prescribing information]. Boulder, CO: Clovis Oncology, Inc.; 2016.
ARIEL2 HGOC Patients
ARIEL2 (n=493)
Germline/somatic BRCAmut or BRCA wild-type
ARIEL2 Part 1 (n=206)
• ≥1 prior platinum-based therapy
• Platinum as their last treatment
• Platinum-sensitive*
ARIEL2 Part 2 (n=287)
• 3–4 prior chemotherapies
• Platinum-sensitive, platinum-resistant, or platinum-refractory*
*Platinum-sensitive: disease progression ≥6 months after last platinum; platinum-resistant: disease progression <6 months after last platinum with best
response other than PD; platinum-refractory: best response of PD on last platinum, which occurred during or up to 2 months after treatment.
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
BID, twice daily; ECOG, Eastern Cooperative Oncology Group; HGOC, high-grade ovarian carcinoma; PD, progressive disease; RECIST, Response
Evaluation Criteria In Solid Tumors.
ARIEL2 HGOC Patients
ARIEL2 (n=493)
Germline/somatic BRCAmut or BRCA wild-type
Present analysis (n=134)
Germline/somatic BRCAmut
ARIEL2 Part 1 (n=206)
ARIEL2 Part 1 (n=41)
• ≥1 prior platinum-based therapy
• Platinum as their last treatment
• Platinum-sensitive*
• ≥1 prior platinum-based therapy
• Platinum as their last treatment
• Platinum-sensitive*
ARIEL2 Part 2 (n=287)
ARIEL2 Part 2 (n=93)
• 3–4 prior chemotherapies
• Platinum-sensitive, platinum-resistant, or platinum-refractory*
• 3–4 prior chemotherapies
• Platinum-sensitive, platinum-resistant, or platinum-refractory*
*Platinum-sensitive: disease progression ≥6 months after last platinum; platinum-resistant: disease progression <6 months after last platinum with best
response other than PD; platinum-refractory: best response of PD on last platinum, which occurred during or up to 2 months after treatment.
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
BID, twice daily; ECOG, Eastern Cooperative Oncology Group; HGOC, high-grade ovarian carcinoma; PD, progressive disease; RECIST, Response
Evaluation Criteria In Solid Tumors.
Patient Characteristics
Patients with BRCAmut HGOC
n=134
Median age (range), y
ECOG Performance Status, n (%)
0
1
Cancer type, n (%)
Epithelial ovarian
Fallopian tube
Primary peritoneal
Other
BRCAmut, n (%)
Germline
Somatic
Origin uncertain
BRCA gene mutation, n (%)
BRCA1
BRCA2
60 (33–82)
68 (50.7)
66 (49.3)
110 (82.1)
12 (9.0)
10 (7.5)
2 (1.5)
78 (58.2)
23 (17.2)
33 (24.6)
86 (64.2)
48 (35.8)
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
Patient Characteristics (continued)
Patients with BRCAmut HGOC
n=134
Median number of prior chemotherapies (range)
1 prior therapy, n (%)
2 prior therapies, n (%)
≥3 prior therapies, n (%)
Median number of platinum-based therapies (range)
1 prior platinum-based therapy, n (%)
2 prior platinum-based therapies, n (%)
≥3 prior platinum-based therapies, n (%)
Platinum-sensitive status, n (%)
Platinum-sensitive (no intervening therapies)
Platinum-sensitive (intervening therapies)
Platinum-resistant
Platinum-refractory
3 (1–6)
18 (13.4)
14 (10.4)
102 (76.1)
2 (1–5)
20 (14.9)
52 (38.8)
62 (46.3)
57 (42.5)
14 (10.4)
49 (36.6)
14 (10.4)
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
ORR by Platinum Status and Line of Treatment:
BRCAmut Ovarian Cancer
ORR by prior lines of therapy,
% (95% CI)
Patient population
Platinum status
Median (range) number
of intervening
non-platinum regimens
Platinum sensitive (n=57)
(Immediate prior treatment =
platinum therapy)
0 (0–0)
Overall*
1 prior line
(n=18)
2 prior lines
(n=14)
3 prior
lines*
70
(57–82)
83
(59–96)
86
(57–98)
52
(31–72)
Platinum sensitive (n=14)
(Immediate prior treatment =
non-platinum based therapy)
1 (1–2)
Platinum resistant (n=49)
1 (0–2)
Platinum refractory (n=14)
0 (0–2)
*Patient subgroup size varies depending on platinum status.
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
CI, confidence interval; N/A, not applicable.
43
(18–71)
N/A
25
(13–39)
0
DCR by Platinum Status and Line of Treatment:
BRCAmut Ovarian Cancer
DCR by prior lines of therapy,
% (95% CI)
Patient population
Platinum status
Median (range) number
of intervening
non-platinum regimens
Platinum sensitive (n=57)
(Immediate prior treatment =
platinum therapy)
0 (0–0)
Overall*
1 prior line
(n=18)
2 prior lines
(n=14)
3 prior
lines*
81
(68–90)
94
(73–100)
86
(57–98)
68
(47–85)
Platinum sensitive (n=14)
(Immediate prior treatment =
non-platinum based therapy)
1 (1–2)
Platinum resistant (n=49)
1 (0–2)
Platinum refractory (n=14)
0 (0–2)
57
(29–82)
N/A
*Patient subgroup size varies depending on platinum status.
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
CR, complete response; DCR, disease control rate (CR, PR, or SD >12 weeks); PR, partial response; SD, stable disease.
39
(25–54)
29
(8–58)
PFS and Platinum Sensitivity
All Patients with BRCAmut Ovarian Cancer
+
+
+
+
Subgroup
(1) Plat sensitive (immediate prior tx=Plat; PFI ≥6 mo)
(2) Plat sensitive (immediate prior tx=non-Plat)
(3) Plat resistant
(4) Plat refractory
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
PFI, progression-free interval; Plat, platinum; tx, treatment.
Median, mo
12.7
7.4
7.3
5.0
95% CI
9.0−14.7
3.7−11.4
5.5−7.7
1.9−5.7
+ Censored,
%
30%
29%
27%
21%
PFS and Degree of Platinum Sensitivity (PFI)
+
+
+
+
Subgroup
(1) Plat sensitive (immediate prior tx=Plat; PFI ≥18 mo)
(2) Plat sensitive (immediate prior tx=Plat; PFI ≥12 mo)
(3) Plat sensitive (immediate prior tx=Plat; PFI ≥6 mo)
(4) Plat sensitive (immediate prior tx=non-Plat)
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
NR, not reached.
Median, mo 95% CI
25.1
5.5−NR
16.9
9.0−25.1
12.7
9.0−14.7
7.4
3.7−11.4
+ Censored,
%
56%
38%
30%
29%
PFS and ORR: Germline vs Somatic BRCAmut
Platinum-Sensitive Patients
+
+
+
Subgroup
Median, mo
mut
(1) Plat sensitive (immediate prior tx=Plat; germline BRCA )
12.8
mut
(2) Plat sensitive (immediate prior tx=Plat; somatic BRCA )
12.7
mut
(3) Plat sensitive (immediate prior tx=Plat; indeterminate BRCA )
7.1
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
95% CI
8.9−16.6
6.2−18.2
5.5−NR
+ Censored,
%
31%
21%
50%
PFS and ORR: BRCA1 vs BRCA2 Mutation Status
Platinum-Sensitive Patients
+
+
Subgroup
(1) Plat sensitive (Immediate prior tx=Plat; BRCA1mut)
(2) Plat sensitive (Immediate prior tx=Plat; BRCA2mut)
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
Median, mo 95% CI
12.8
8.1−18.2
11.2
7.3−16.6
+ Censored,
%
26%
35%
Secondary Somatic Mutations Restoring BRCA1/2 Have
Been Reported as a Mechanism of Platinum Resistance
• An example of a secondary
BRCA2 mutation identified in
the recurrent carcinoma of a
patient who became resistant
to platinum chemotherapy
Heterozygous germline
mutation
Lymphocyte
Loss of wild-type allele
Duplicated mutant allele
with secondary mutation
Primary ovarian
carcinoma
Recurrent ovarian
carcinoma
• Secondary mutations
restoring BRCA1/2 were more
frequently found in platinumresistant than platinumsensitive carcinomas
Graph reprinted with permission. Norquist B, Wurz KA, Pennil CC, Garcia R, Gross J, Sakai W, Karlan BY, Taniguchi T, Swisher EM. Secondary somatic mutations restoring BRCA1/2 predict
chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011;29(22):3008-15. © 2011 American Society of Clinical Oncology. All rights reserved.
Effect of Secondary BRCA mutations on PFS:
Platinum-Resistant/Refractory Patients with BRCAmut
• Secondary somatic mutations were detected in 8 of 55 patients with BRCAmut platinumresistant/refractory HGOC by NGS of screening tumor biopsy and/or ctDNA analysis
• Plasma sample from one patient contained 8 secondary BRCA mutations that restore the
open reading frame
+
+
Subgroup
Median PFS, mo 95% CI + Censored, %
(1) Cases without secondary mut (n=47)
7.3
5.4−9.0
26%
(2) Cases with secondary mut (n=8)
1.7
1.6−3.2
0%
HR=0.12 (95% CI: 0.05−0.29); P<0.0001
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
ctDNA, circulating tumor DNA; NGS, next generation sequencing.
Treatment-Emergent AEs: ≥20% All Grades
Patients with BRCAmut HGOC
n=134
All grades, %
Grade 3/4, %
78
5
78
10
49
5
48
29
40
0
39
10
39
3
38
2
35
<1
34
2
25
7
23
0
23
2
20
4
Term
Nausea
Asthenia/fatigue*
Vomiting
Anemia*
Dysgeusia
ALT/AST increased*
Decreased appetite
Abdominal pain
Constipation
Diarrhea
Thrombocytopenia*
Blood creatinine increased
Dyspnea
Urinary tract infection
• 1 patient died due to intestinal obstruction
• 1 patient died due to generalized edema and general physical health deterioration
*Combined terms.
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
AEs, adverse events; ALT, alanine transaminase; AST, aspartate aminotransferase.
Treatment Exposure, Dose Reductions, and
Treatment Discontinuations
• Median duration of treatment was 7.6 months (range, 0.1–32.7)
• Treatment-emergent AEs led to dose reductions in 49% of patients and
included:
– Anemia/hemoglobin decreased (25%), asthenia/fatigue (11%), and
thrombocytopenia/decreased platelets (10%)
• Treatment-emergent AEs led to treatment discontinuation* in 13% of patients
and included:
– Nausea, vomiting, and anemia (2% each)
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
*Excludes 4 patients who discontinued due to adverse event of disease progression.
Hematologic Laboratory Parameters
Laboratory parameter*
Worsening shift in grade from baseline, %
Maximum shift to grade 3/4, %
Hemoglobin (n=132)
66
20
Platelets (n=133)
41
4
Absolute neutrophil count (n=133)
34
5
Decrease in:
*Data are shown for patients with baseline and postbaseline results.
Dotted lines in graphs show the upper and lower limits of normal for each laboratory parameter.
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
C, cycle; SEM, standard error of the mean.
Chemistry Laboratory Parameters
Laboratory parameter*
Worsening shift in grade from baseline, %
Maximum shift to grade 3/4, %
Creatinine (n=134)
94
0
ALT (n=125)
70
11
AST (n=125)
70
4
Bilirubin (n=125)
21
2
Increase in:
*Data are shown for patients with baseline and postbaseline results.
Dotted lines in graphs show the upper and lower limits of normal for each laboratory parameter.
Last patient with BRCAmut ovarian cancer enrolled: Jun 30, 2016. Data analysis cutoff date: Jan 4, 2017.
ALT, alanine transaminase; AST, aspartate aminotransferase; IU, international unit.
Conclusions
• The ORR in patients with BRCAmut (germline or somatic) relapsed HGOC was greatest in
platinum-sensitive patients (range 52–86% depending on number of prior therapies)
• Median PFS was 12.7 months in patients with platinum-sensitive BRCAmut HGOC vs 7.3
months and 5.0 months in platinum-resistant and platinum-refractory HGOC, respectively
• Secondary somatic BRCA reversion mutations were seen in 8/55 in platinumresistant/refractory HGOC
• The most common treatment-emergent AEs included nausea, fatigue, vomiting, and anemia
• The most common grade 3/4 treatment-emergent AEs included anemia, ALT/AST increased,
fatigue
• Randomized, phase 3, confirmatory study investigating single-agent rucaparib is ongoing in
patients with relapsed BRCAmut (germline or somatic) HGOC (ARIEL4; NCT02855944)
Acknowledgments
All study patients and their families and caregivers
Iain McNeish, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK and
Elizabeth Swisher, University of Washington, Seattle, WA – Co-coordinating Investigators for ARIEL2.
Additional ARIEL2 Investigators and Sites: C. Aghajanian (Memorial Sloan-Kettering Cancer Center), D. Armstrong (Johns Hopkins Kimmel Cancer Center), S. Banerjee
(The Royal Marsden NHS Foundation Trust; Royal Marsden Sutton Hospital), S. Baron-Hay (Royal North Shore Hospital), J. Brenton (Addenbrooke's Hospital), M. Buck
(Sir Charles Gairdner Hospital), C. Castro (Massachusetts General Hospital), A. Cervantes (Hospital Clinico Universitario de Valencia), S. Chambers (University of Arizona
Cancer Center), J. Chan (California Pacific Medical Center), T. Chan (British Columbia Cancer Agency, Fraser Valley Cancer Centre), L.m. Chen (University of California
San Francisco), A. Clamp (Christie Hospital), R. Coleman (The University of Texas MD Anderson Cancer Center), G. Colon-Otero (Mayo Clinic), J. Cragun (University of
Arizona Cancer Center), M. Davy (Royal Adelaide Hospital), B. DiCarlo (Coastal Integrative Cancer Care), R. Dichmann (Central Coast Medical Oncology), O. Dorigo
(Stanford University Hospital and Clinics), Y. Drew (Northern Centre for Cancer Care), E. Eisenhauer (University of Cincinnati), A. Floquet (Institut Bergonié/GINECO), G.
Freyer (Centre Hospitalier Lyon Sud), M. Friedlander (Prince of Wales Hospital), P. Ghatage (Tom Baker Cancer Center), L. Gladieff (Institut Claudius Régaud), J. Goh
(Royal Brisbane and Women's Hospital), M. Gordinier (Norton Cancer Institute), P. Grant (Mercy Hospital for Women), W. Harb (Horizon Oncology Center), M. Hardesty
(Providence Alaska Medical Center), P. Harnett (Westmead Hospital), R. Holloway (Florida Hospital Cancer Institute), G. Kichenadasse (Flinders Medical Centre), G.
Konecny (University of California Los Angeles), P. Konstantinopoulos (Dana Farber Cancer Institute), D. Kredentser (Women's Cancer Care), R. Kristeleit (University
College London), A. Kumar (British Columbia Cancer Agency, Fraser Valley Cancer Centre), S. Lau (Jewish General Hospital), A. Leary (Institut Gustave
Roussy/GINECO), A. Lortholary (Centre Catherine de Sienne), J. Lotz (Hôpital Tenon), L. Ma (Rocky Mountain Cancer Center), L. Martin (Fox Chase Cancer Center), N.
McKenzie (Orlando Health), J. Medioni (Hôpital Européen Georges Pompidou), M. Millward (Sir Charles Gairdner Hospital), D. Mirchandani (British Columbia Cancer
Agency), K. Moore (University of Oklahoma Medical Center), M. Morgan (University of Pennsylvania), D. Mutch (Washington University School of Medicine), A. Oaknin
(Hospital Vall d'Hebrón), A. Olawaiye (Magee-Womens Hospital), D. O'Malley (The Ohio State University), A. Oza (Princess Margaret Hospital), D. Park (St Jude Heritage
Medical Center), M. Plante (Centre Hospitalier Universitaire de Quebec), B. Pothuri (New York University Langone Medical Center), A. Poveda (Instituto Valenciano de
Oncología-Fundación), D. Provencher (Centre Hospitalier de L'Université de Montréal), E. Pujade-Lauraine (Hôpital Européen Georges Pompidou), I. Ray-Coquard
(Centre Léon Bérard; GINECO), C. Saenz (University of California San Diego), C. Scott (Peter MacCallum Cancer Centre - Melbourne), B. Slomovitz (Sylvester
Comprehensive Cancer Center), J. Tangir (Altus Research), A. Tinker (Vancouver Cancer Centre, British Columbia Cancer Agency), K. Tonkin (Cross
Cancer Institute), T. Vanderkwaak (Hope Women’s Cancer Centers), A. Wahner Hendrickson (Mayo Clinic), J. Weberpals (Ottawa Health Research
Institute), S. Welch (London Regional Cancer Centre), B. You (Centre Hospitalier Lyon Sud)
Medical writing and editorial support funded by Clovis Oncology were provided by
Nathan Yardley, PhD, and Shannon Davis of Ashfield Healthcare Communications.