- ARIEL3 study successfully achieved
its primary endpoint of improved progression-free survival (PFS) by
investigator review in each of the three populations studied (tumor
BRCA-mutant, HRD and overall intent-to-treat)
- ARIEL3 study also successfully
achieved the key secondary endpoint of improved PFS by blinded,
independent central review (BICR) in all three study
populations
- Rucaparib improved objective
response rate vs. placebo among evaluable trial participants in all
three study populations
- Safety data from ARIEL3 demonstrate
consistency with prior rucaparib studies
- ARIEL3 data to be presented by
Professor Jonathan A. Ledermann, MD, during Proffered Paper session
on Gynecological Cancers on Friday, September 8
- Data also will be highlighted in
ESMO press program on Friday, September 8
Clovis Oncology, Inc. (NASDAQ: CLVS) announced the first
presentation of a comprehensive dataset from its Phase 3 ARIEL3
study of rucaparib at the 2017 European Society for Medical
Oncology (ESMO) Congress taking place in Madrid. The ARIEL3 study
successfully achieved its primary endpoint and key secondary
endpoint, demonstrating improved progression-free survival (PFS) by
both investigator review and blinded independent central review
(BICR) in each of the three populations studied. The data will be
presented by Professor Jonathan A. Ledermann, MD, European and ROW
Principal Investigator for the ARIEL3 study, during the Proffered
Paper session on Gynecological Cancers the afternoon of Friday,
September 8.
“The comprehensive ARIEL3 results presented for the first time
today demonstrate the potential of rucaparib to extend the time
during which the disease is controlled for women with
platinum-sensitive, advanced ovarian cancer,” said Patrick J.
Mahaffy, President and CEO of Clovis Oncology. “Very importantly,
this benefit was demonstrated across all three ARIEL3 populations
by both investigator review and blinded independent central
assessment, including among women whose cancer does not exhibit a
BRCA mutation or homologous recombination deficiency. In
particular, ARIEL3 shows 13.7 months – well over a year – of median
PFS in the all-comers population in the trial as determined by
blinded independent review, which we believe could be extremely
important for women battling this difficult disease. We are
grateful to the patients, caregivers and investigators who
participated in this study, and are working closely with European
regulatory authorities to make rucaparib available to women living
with ovarian cancer.”
“These results reinforce rucaparib’s potential to provide an
enduring and significant clinical benefit in women with advanced
ovarian cancer, regardless of their tumor genetics,” said Professor
Jonathan Ledermann, MD, Professor of Medical Oncology, Director,
Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer
Institute, and European and ROW Principal Investigator for the
ARIEL3 study. “It is both impressive and encouraging that rucaparib
demonstrated improvements in key primary, secondary and exploratory
endpoints in all three ARIEL3 patient populations. It is also
clinically significant that rucaparib not only sustained patients’
most recent response to platinum, but in some trial participants
also enhanced that response, including the radiological elimination
of residual tumor.”
In December 2016, Rubraca® became the first PARP inhibitor
approved by the U.S. Food and Drug Administration (FDA) as
monotherapy for treatment of patients with deleterious BRCA
mutation (germline and/or somatic) associated advanced ovarian
cancer who have been treated with two or more prior chemotherapies.
During the fourth quarter of 2016, a Marketing Authorization
Application (MAA) was submitted and accepted in Europe for Rubraca
in the same ovarian cancer-treatment indication. Based on the
ARIEL3 findings, Clovis Oncology plans to submit a supplemental New
Drug Application (sNDA) to the U.S. FDA for a second line or later
maintenance treatment indication in ovarian cancer by the end of
October 2017, and in early 2018, plans to file an MAA in Europe for
the maintenance treatment indication upon receipt of a potential
approval for the treatment indication.
ARIEL3 is a double-blind, placebo-controlled, phase 3 trial of
rucaparib that enrolled 564 women with platinum-sensitive,
high-grade ovarian, fallopian tube, or primary peritoneal cancer.
The primary efficacy analysis evaluated three prospectively defined
molecular sub-groups in a step-down manner: 1) tumor BRCA mutant
(tBRCAmut) patients, inclusive of germline and somatic mutations of
BRCA (n=196); 2) HRD patients, including BRCA-mutant patients and
BRCA wild-type with high loss of heterozygosity, or LOH-high
patients (n=354), and, finally, 3) the intent-to-treat population,
or all patients treated in ARIEL3 (n=564).
Following is a table and summary of the primary efficacy
analyses and selected exploratory PFS endpoints per Response
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by each of
investigator review, which was the primary analysis of ARIEL3, and
BICR, a key secondary endpoint of the study. Each of these
analyses, and their related Kaplan-Meier curves, will be included
in today’s presentation by Professor Ledermann.
ARIEL3 Analysis Population PFS by
Investigator Review
(Primary Endpoint)
PFS by Blinded Independent Central Review
(Key Secondary Endpoint)
Primary Analyses Hazard Ratio
Median PFS (months)
Rucaparib vs. Placebo
Hazard Ratio Median PFS (months)
Rucaparib vs. Placebo
tBRCAmut
(n=196)
0.23; p<0.0001 16.6 vs. 5.4 0.20;
p<0.0001 26.8 vs. 5.4 HRD
(n=354)
0.32; p<0.0001 13.6 vs. 5.4 0.34;
p<0.0001 22.9 vs. 5.5 Intent-to-Treat
(n=564)
0.36; p<0.0001 10.8 vs. 5.4 0.35;
p<0.0001 13.7 vs. 5.4
Exploratory Analyses BRCAwt
/ LOH high
(n=158)
0.44; p<0.0001 9.7 vs. 5.4 0.55; p=0.0135
11.1 vs. 5.6
BRCAwt / LOH low(n=161)
0.58; p=0.0049 6.7 vs. 5.4 0.47; p=0.0003
8.2 vs. 5.3
PFS: progression-free survival; tBRCAmut: tumor BRCA mutant;
HRD: homologous recombination deficiency; BRCAwt: BRCA wild type;
LOH: loss of heterozygosity
Significant Improvement in PFS in the tBRCAmut Patient
Population
The most robust clinical outcomes were observed among ARIEL3
patients with a germline or somatic BRCA mutation (n=196). By
investigator review, the rucaparib arm successfully achieved
statistical significance over the placebo arm for the primary
endpoint of PFS with a hazard ratio of 0.23 (95% CI, 0.16-0.34;
p<0.0001). The median PFS for the tBRCAmut patients treated with
rucaparib was 16.6 months (95% CI, 13.4-22.9) vs. 5.4 months (95%
CI, 3.4-6.7) among those who received placebo.
By BICR, the rucaparib arm improved PFS over the placebo arm
with a hazard ratio of 0.20 (95% CI, 0.13-0.32; p<0.0001). The
median PFS for the tBRCAmut patients treated with rucaparib was
26.8 months (95% CI, 19.2-NR) vs. 5.4 months (95% CI, 4.9-8.1)
among those who received placebo.
Results were consistent for the germline BRCA (n=130) and
somatic BRCA (n=56) populations.
Significant Improvement in PFS in the HRD Patient
Population
This population included patients with a germline or somatic
mutation of BRCA, as well as those whose tumors were BRCA wild type
(BRCAwt) but determined to be HRD as defined by a Foundation
Medicine assay (n=354). By investigator review, the rucaparib arm
successfully achieved statistical significance over the placebo arm
for the primary endpoint of PFS with a hazard ratio of 0.32 (95%
CI, 0.24-0.42; p<0.0001). The median PFS for the HRD patients
treated with rucaparib was 13.6 months (95% CI, 10.9-16.2) vs. 5.4
months (95% CI, 5.1-5.6) among those who received placebo.
By BICR, the rucaparib arm improved PFS over the placebo arm
with a hazard ratio of 0.34 (95% CI, 0.24-0.47; p<0.0001). The
median PFS for the HRD patients treated with rucaparib was 22.9
months (95% CI, 16.2-NR) vs. 5.5 months (95% CI, 5.1-7.4) among
those who received placebo.
Significant Improvement in PFS in All Patients
Studied
Rucaparib also showed statistical significance in all 564
patients enrolled in the study. By investigator review, the
rucaparib arm successfully achieved statistical significance over
the placebo arm for the primary endpoint of PFS with a hazard ratio
of 0.36 (95% CI, 0.30-0.45; p<0.0001). The median PFS for all
patients treated with rucaparib was 10.8 months (95% CI, 8.3-11.4)
vs. 5.4 months (95% CI, 5.3-5.5) for those who received
placebo.
By BICR, the rucaparib arm improved PFS over the placebo arm
with a hazard ratio of 0.35 (95% CI, 0.28-0.45; p<0.0001). The
median PFS for all patients enrolled in ARIEL3 and treated with
rucaparib was 13.7 months (95% CI, 11.0-19.1) vs. 5.4 months (95%
CI, 5.1-5.5) for those who received placebo.
Exploratory PFS Endpoint Achieved in BRCAwt/LOH High
Subgroup
The exploratory PFS endpoint was achieved in the 158 patients
identified as BRCAwt LOH high. By investigator review, the
rucaparib arm successfully achieved its endpoint over the placebo
arm for the primary endpoint of PFS with a hazard ratio of 0.44
(95% CI, 0.29-0.66; p<0.0001). The median PFS for these patients
treated with rucaparib was 9.7 months (95% CI, 7.9-13.1) vs. 5.4
months (95% CI, 4.1-5.7) for those who received placebo.
By BICR, the rucaparib arm improved PFS over the placebo arm
with a hazard ratio of 0.55 (95% CI, 0.35-0.89; p=0.0135). The
median PFS for these patients treated with rucaparib was 11.1
months (95% CI, 8.2-NR) vs. 5.6 months (95% CI, 2.9-8.2) for those
who received placebo.
Exploratory PFS Endpoint Achieved in BRCAwt/LOH Low
Subgroup
The exploratory PFS endpoint was achieved in the 161 patients
identified as BRCAwt and LOH low. By investigator review, the
rucaparib arm successfully achieved its endpoint over the placebo
arm for the primary endpoint of PFS with a hazard ratio of 0.58
(95% CI, 0.40-0.85; p=0.0049). The median PFS for these patients
treated with rucaparib was 6.7 months (95% CI, 5.4-9.1) vs. 5.4
months (95% CI, 5.3-7.4) for those who received placebo.
By BICR, the rucaparib arm improved PFS over the placebo arm
with a hazard ratio of 0.47 (95% CI, 0.31-0.71; p=0.0003). The
median PFS for these patients treated with rucaparib was 8.2 months
(95% CI, 5.6-10.1) vs. 5.3 months (95% CI, 2.8-5.5) for those who
received placebo.
Exploratory Endpoint of Response Rate
Enrollment in ARIEL3 included one-third of patients who had
achieved a complete response to their prior platinum-based therapy,
and two-thirds of patients who had achieved a partial response to
their prior platinum-based therapy. Of those with a partial
response, 37% had measurable disease at the time of enrollment and
were therefore evaluable for response. By investigator-assessed
RECISTv1.1, the confirmed objective response rate (ORR) in the
tBRCAmut group treated with rucaparib was 38% (15/40), of these,
18% (7/40) were complete responses. This compared with 9% (2/23)
ORR in the placebo group (p=0.0055) and 0% complete responses. The
confirmed ORR in the HRD group treated with rucaparib was 27%
(23/85), of these, 12% (10/85) were complete responses. This
compared with 7% (3/41) ORR in the placebo group (p=0.05) and 0%
complete responses. Finally, among the intent-to-treat population,
the confirmed ORR in patients treated with rucaparib was 18%
(26/141), of these 7% (10/141) were complete responses. This
compared with 8% (5/66) ORR in the placebo group (p=0.05) and 2%
(1/66) complete responses.
RECIST responses were not assessed by independent blinded
review.
Summary of ARIEL3 Safety
The most common treatment-emergent adverse events (TEAEs) of
grade ≥3 reported in patients treated with rucaparib in the ARIEL3
study were anemia/decreased hemoglobin (19%), increase in ALT/AST
(10%), neutropenia (7%), asthenia/fatigue (7%), thrombocytopenia
(5%), vomiting (4%) and nausea (4%). The discontinuation rate for
TEAEs (excluding disease progression) was 13.4% for
rucaparib-treated patients and 1.6% for the placebo arm. The rate
of treatment-emergent myelodysplastic syndrome (MDS)/acute myeloid
leukemia (AML) in the rucaparib arm was <1% (3/372), and no
patients on the placebo arm experienced treatment-emergent
MDS/AML.
About the ARIEL3 Clinical Trial
The ARIEL3 pivotal study of rucaparib is a confirmatory
randomized, double-blind study comparing the effects of rucaparib
against placebo to evaluate whether rucaparib given as a
maintenance treatment to platinum-sensitive ovarian cancer patients
can extend the period of time for which the disease is controlled
after a complete or partial response to platinum-based
chemotherapy. The study enrolled 564 patients with high-grade
epithelial ovarian, fallopian tube or primary peritoneal cancer. To
be eligible for the study, participants had to have received at
least two prior platinum-based treatment regimens, been sensitive
to the penultimate platinum regimen, and achieved a complete or
partial response to their most recent platinum-based regimen. There
were no genomic selection criteria for this study. Trial
participants were randomized 2:1 to receive 600 milligrams of
rucaparib twice daily (BID) or placebo.
About Rucaparib
Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2
and PARP3 being developed in ovarian cancer as well as several
additional solid tumor indications. In December 2016, rucaparib
became the first PARP inhibitor approved by the U.S. Food and Drug
Administration (FDA) as monotherapy for treatment of patients with
deleterious BRCA mutation (germline and/or somatic) associated
advanced ovarian cancer who have been treated with two or more
prior chemotherapies. During the fourth quarter of 2016, the
Marketing Authorization Application (MAA) submission in Europe for
rucaparib in the same ovarian cancer treatment indication was
submitted and accepted for review. By the end of October 2017,
Clovis Oncology plans to submit a supplemental New Drug Application
(sNDA) in the U.S. for a second line or later maintenance treatment
indication in ovarian cancer based on the ARIEL3 data, and in early
2018, plans to file an MAA in Europe for the maintenance treatment
indication upon receipt of a potential approval for the treatment
indication. Studies open for enrollment or under consideration
include ovarian, prostate, breast, pancreatic, gastroesophageal,
bladder, lung and urothelial cancers. Clovis is also developing
rucaparib in patients with mutant BRCA tumors and other DNA repair
deficiencies beyond BRCA – commonly referred to as homologous
recombination deficiencies, or HRD. Clovis holds worldwide rights
for rucaparib.
About Ovarian Cancer
Ovarian cancer is the sixth deadliest cancer amongst women in
Europe,i where more than 65,000 women are diagnosed annually.ii
Ovarian cancer is challenging to treat, and most women will relapse
after surgery and chemotherapy. The 80 to 85 percent of women
diagnosed in the later stages of the disease (III and IV) have
particularly poor outcomes.iii Approximately one in four women with
ovarian cancer have a germline or somatic BRCA mutation,iv and new
treatment options are needed to treat unique patient
populations.
About Clovis Oncology
Clovis Oncology, Inc. is a biopharmaceutical company
focused on acquiring, developing and commercializing innovative
anti-cancer agents in the U.S., Europe and additional
international markets. Clovis Oncology targets
development programs at specific subsets of cancer populations, and
simultaneously develops, with partners, diagnostic tools intended
to direct a compound in development to the population that is most
likely to benefit from its use. Clovis Oncology is
headquartered in Boulder, Colorado, and has additional offices
in San Francisco, California and Cambridge, UK.
Please visit clovisoncology.com for more information.
To the extent that statements contained in this press release
are not descriptions of historical facts regarding Clovis Oncology,
they are forward-looking statements reflecting the current beliefs
and expectations of management made pursuant to the safe harbor
provisions of the Private Securities Litigation Reform Act of 1995.
Examples of forward-looking statements contained in this press
release include, among others, statements regarding our expectation
of timing for submission of the sNDA for rucaparib, European
approval of rucaparib for the treatment indication and the filing
of an MAA for a second line or later maintenance indication for
rucaparib. Such forward-looking statements involve substantial
risks and uncertainties that could cause our future results,
performance or achievements to differ significantly from that
expressed or implied by the forward-looking statements. Such risks
and uncertainties include, among others, the uncertainties inherent
in the clinical development programs for our drug candidates,
including the result of clinical trials, whether future study
results will be consistent with study findings to-date, the
corresponding development pathways of our companion diagnostics,
the timing of availability of data from our clinical trials and the
results of our clinical trials, the initiation, enrollment and
timing of our planned clinical trials, actions by the FDA, the
EMA or other regulatory authorities regarding whether to approve
drug applications that may be filed, as well as their decisions
that may affect drug labeling, pricing and reimbursement, and other
matters that could affect the availability or commercial potential
of our drug candidates or companion diagnostics. Clovis
Oncology does not undertake to update or revise any forward-looking
statements. A further description of risks and uncertainties can be
found in Clovis Oncology’s filings with the Securities and Exchange
Commission, including its Annual Report on Form 10-K and its
reports on Form 10-Q and Form 8-K.
i World Health Organization. Globocan 2012: estimated cancer
incidence, mortality and prevalence worldwide in 2012.
http://globocan.iarc.fr/Pages/fact_sheets_population.aspxii Ferlay
J, et al. Eur J Cancer 2013;49:1374–1403iii American
Cancer Society. Survival rates for ovarian cancer, by stage.
https://www.cancer.org/cancer/ovarian-cancer/detection-diagnosis-staging/survival-rates.htmliv
Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic
mutations in homologous recombination genes predict platinum
response and survival in ovarian, fallopian tube, and peritoneal
carcinomas. Clin Cancer Res. 2014;20(3):764-775.
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Clovis Investor Contacts:Anna Sussman,
303.625.5022asussman@clovisoncology.comorBreanna Burkart,
303.625.5023bburkart@clovisoncology.comorClovis Media
Contacts:USLisa Guiterman,
301.217.9353clovismedia@sambrown.comorChristy Curran,
615.414.8668clovismedia@sambrown.comorEUAnn Hughes, +44 (0)
7944 168 187Ann.Hughes@publicisresolute.com
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