- The ARIEL4 study met its primary endpoint, showing a
statistically significant improvement in progression-free survival
for Rubraca versus chemotherapy
- The safety of Rubraca observed in the ARIEL4 study was highly
consistent with both the U.S. and EU labels
- An expanded description of the ARIEL4 study results will be
submitted for presentation at an upcoming medical meeting
Clovis Oncology, Inc. (NASDAQ: CLVS), today announced topline
data from the randomized Phase 3 ARIEL4 study of Rubraca, which met
its primary endpoint of improved investigator-assessed
progression-free survival (InvPFS) compared to chemotherapy in
relapsed ovarian cancer patients with a tumor mutation of BRCA who
have received two or more prior lines of chemotherapy.
“We are pleased with these topline results from the ARIEL4
trial, which confirm the clinical benefit of Rubraca versus
chemotherapy, including platinum-based chemotherapy, as a treatment
for women with BRCA mutation-positive advanced ovarian cancer,
including patients who are platinum-resistant,” said Patrick J.
Mahaffy, President and CEO of Clovis Oncology. “We look forward to
sharing comprehensive results at an upcoming medical meeting.”
The ARIEL4 study (NCT02855944) is a Phase 3 multicenter,
randomized study evaluating Rubraca versus chemotherapy in
platinum-sensitive, partially platinum-sensitive and
platinum-resistant patients with relapsed ovarian cancer and a BRCA
mutation (inclusive of germline and/or somatic) who have received
two or more prior lines of chemotherapy. The primary endpoint of
the study is InvPFS, with a step down analysis from the efficacy
population (if significant) to the ITT population. The efficacy
population comprised the group of patients with a deleterious tumor
BRCA mutation and excluded those with a BRCA reversion mutation as
determined by a blood test developed by Guardant Health.
Development of reversion mutations that restore BRCA protein
function are associated with resistance to platinum-based
chemotherapies and PARP inhibitors in BRCA-mutant cancers, and
these occur more frequently in platinum-resistant vs
platinum-sensitive patients (13% and 2% respectively in the ARIEL2
study).i
Completion of ARIEL4 is a post-marketing commitment in the U.S.
and EU.
349 women were enrolled in North and South America, Europe and
Israel. The efficacy population (n=325) comprised the group of
patients with a deleterious tumor BRCA mutation and excluded those
with a BRCA reversion mutation. The rucaparib arm (n=220)
successfully achieved statistical significance over the
chemotherapy arm (n=105) for the primary endpoint of InvPFS with a
hazard ratio of 0.639 (p=0.0010). The median PFS for the patients
in the efficacy population treated with rucaparib was 7.4 months
vs. 5.7 months among those who received chemotherapy.
In addition, in the ITT population (n=349), the rucaparib arm
(n=233) successfully achieved statistical significance over the
chemotherapy arm (n=116) for the primary endpoint of InvPFS with a
hazard ratio of 0.665 (p=0.0017). The median PFS for the patients
in the ITT population treated with rucaparib was 7.4 months vs. 5.7
months among those who received chemotherapy.
Patients with a BRCA reversion mutation represented 7 percent of
patients enrolled in the study and as anticipated, InvPFS results
for those patients showed limited benefit from Rubraca therapy.
An interim analysis of overall survival, a secondary endpoint in
the study in which 51 percent of events have occurred in the ITT
population, showed a trend toward an overall survival (OS)
advantage in the chemotherapy arm, but was confounded by the high
rate (64%) of per-protocol crossover to Rubraca following
progression on chemotherapy. Importantly, an analysis of the ITT
population of patients showed a trend toward an OS advantage for
those patients who received Rubraca at any point in the trial
versus those who did not.
Adverse events were consistent with the known safety profiles of
Rubraca and chemotherapy.
The most common (>5%) treatment-emergent grade 3/4 adverse
events (TEAEs) among all patients treated with rucaparib (n=232) in
the ARIEL4 study were anemia/decreased hemoglobin (22%),
neutropenia/decreased absolute neutrophil count (10%),
asthenia/fatigue (8%), thrombocytopenia/decreased platelets (8%),
and increased ALT/AST (8%).
“The ARIEL4 study verified that women with relapsed, BRCA
mutation-positive advanced ovarian cancer, including those who are
platinum-sensitive or -resistant, received benefit with rucaparib
treatment when compared to chemotherapy,” said Dr. Amit Oza, Head
of the Division of Medical Oncology & Hematology, Medical
Director of the Cancer Clinical Research Unit at Princess Margaret
(PM) Cancer Centre, co-Director of the Drug Development Program at
PM Cancer Centre, Senior Scientist at the Princess Margaret Cancer
Centre, and Professor of Medicine at University of Toronto. “These
results underscore the importance of rucaparib as a treatment
option for women with BRCA-mutant advanced ovarian cancer.”
Ovarian cancer ranks fifth in cancer deaths among women in the
U.S.ii and EUiii. While there are a growing number of therapies to
treat ovarian cancer, after initial therapy, 70-90% of U.S. womeniv
with advanced disease will recur. In the EU, approximately 70% of
patients experience a relapse within three years following initial
therapy.v
“Ovarian cancer remains a lethal gynecologic cancer and there
are limited treatment options for relapsed disease,” said Dr.
Rebecca Kristeleit, Co-Chief Investigator of ARIEL4 and Consultant
Medical Oncologist, London, UK. “There is a need for therapies that
can extend time to progression. The ARIEL4 data confirm the
clinical relevance of BRCA reversion mutations and advance our
understanding of how best to manage the treatment of women with
advanced ovarian cancer.”
Drs. Rebecca Kristeleit and Amit Oza are coordinating
investigators on the ARIEL4 study. Clovis Oncology plans to provide
an expanded description of the ARIEL4 results at a medical meeting
in 2021.
About Rubraca (rucaparib)
Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2
and PARP3 being developed in multiple tumor types, including
ovarian and metastatic castration-resistant prostate cancers, as
monotherapy, and in combination with other anti-cancer agents.
Exploratory studies in other tumor types are also underway.
Rubraca Ovarian Cancer U.S. FDA Approved Indications
Rubraca is indicated for the maintenance treatment of adult
women with recurrent epithelial ovarian, fallopian tube, or primary
peritoneal cancer who are in a complete or partial response to
platinum-based chemotherapy.
Rubraca is indicated for the treatment of adult women with a
deleterious BRCA mutation (germline and/or somatic)-associated
epithelial ovarian, fallopian tube, or primary peritoneal cancer
who have been treated with two or more chemotherapies. Select
patients for therapy based on an FDA-approved companion diagnostic
for Rubraca.
Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) have
occurred in patients treated with Rubraca, and are potentially
fatal adverse reactions. In 1146 treated patients, MDS/AML occurred
in 20 patients (1.7%), including those in long term follow-up. Of
these, 8 occurred during treatment or during the 28 day safety
follow-up (0.7%). The duration of Rubraca treatment prior to the
diagnosis of MDS/AML ranged from 1 month to approximately 53
months. The cases were typical of secondary MDS/cancer
therapy-related AML; in all cases, patients had received previous
platinum-containing regimens and/or other DNA damaging agents.
Do not start Rubraca until patients have recovered from
hematological toxicity caused by previous chemotherapy (≤ Grade 1).
Monitor complete blood counts for cytopenia at baseline and monthly
thereafter for clinically significant changes during treatment. For
prolonged hematological toxicities (> 4 weeks), interrupt
Rubraca or reduce dose and monitor blood counts weekly until
recovery. If the levels have not recovered to Grade 1 or less after
4 weeks or if MDS/AML is suspected, refer the patient to a
hematologist for further investigations, including bone marrow
analysis and blood sample for cytogenetics. If MDS/AML is
confirmed, discontinue Rubraca.
Based on its mechanism of action and findings from animal
studies, Rubraca can cause fetal harm when administered to a
pregnant woman. Apprise pregnant women of the potential risk to a
fetus. Advise females of reproductive potential to use effective
contraception during treatment and for 6 months following the last
dose of Rubraca.
Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1-4) were
nausea (76%), fatigue/asthenia (73%), abdominal pain/distention
(46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation
(38%), constipation (37%), vomiting (37%), diarrhea (32%),
thrombocytopenia (29%), nasopharyngitis/upper respiratory tract
infection (29%), stomatitis (28%), decreased appetite (23%), and
neutropenia (20%).
Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%;
Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting
(46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased
appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea
(21%), and thrombocytopenia (21%).
Co-administration of rucaparib can increase the systemic
exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may
increase the risk of toxicities of these drugs. Adjust dosage of
CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically
indicated. If co-administration with warfarin (a CYP2C9 substrate)
cannot be avoided, consider increasing frequency of international
normalized ratio (INR) monitoring.
Because of the potential for serious adverse reactions in
breast-fed children from Rubraca, advise lactating women not to
breastfeed during treatment with Rubraca and for 2 weeks after the
last dose.
Click here for full Prescribing Information and additional
Important Safety Information.
Rubraca (rucaparib) European Union (EU) authorized use and
Important Safety Information
Rubraca is indicated as monotherapy for the maintenance
treatment of adult patients with platinum-sensitive relapsed
high-grade epithelial ovarian, fallopian tube, or primary
peritoneal cancer who are in response (complete or partial) to
platinum-based chemotherapy.
Rubraca is indicated as monotherapy treatment of adult patients
with platinum sensitive, relapsed or progressive, BRCA mutated
(germline and/or somatic), high-grade epithelial ovarian, fallopian
tube, or primary peritoneal cancer, who have been treated with ≥2
prior lines of platinum-based chemotherapy, and who are unable to
tolerate further platinum-based chemotherapy.
Efficacy of Rubraca as treatment for relapsed or progressive
epithelial ovarian cancer (EOC), fallopian tube cancer (FTC), or
primary peritoneal cancer (PPC) has not been investigated in
patients who have received prior treatment with a PARP inhibitor.
Therefore, use in this patient population is not recommended.
Summary warnings and precautions:
Hematological toxicity
During treatment with Rubraca, events of myelosuppression
(anemia, neutropenia, thrombocytopenia) may be observed and are
typically first observed after 8–10 weeks of treatment with
Rubraca. These reactions are manageable with routine medical
treatment and/or dose adjustment for more severe cases. Complete
blood count testing prior to starting treatment with Rubraca, and
monthly thereafter, is advised. Patients should not start Rubraca
treatment until they have recovered from hematological toxicities
caused by previous chemotherapy (CTCAE grade ≥1).
Supportive care and institutional guidelines should be
implemented for the management of low blood counts for the
treatment of anemia and neutropenia. Rubraca should be interrupted
or dose reduced according to Table 1 (see Posology and Method of
Administration [4.2] of the Summary of Product Characteristics
[SPC]) and blood counts monitored weekly until recovery. If the
levels have not recovered to CTCAE grade 1 or better after 4 weeks,
the patient should be referred to a hematologist for further
investigations.
MDS/AML
MDS/AML, including cases with fatal outcome, have been reported
in patients who received Rubraca. The duration of therapy with
Rubraca in patients who developed MDS/AML varied from less than 1
month to approximately 28 months.
If MDS/AML is suspected, the patient should be referred to a
hematologist for further investigations, including bone marrow
analysis and blood sampling for cytogenetics. If, following
investigation for prolonged hematological toxicity, MDS/AML is
confirmed, Rubraca should be discontinued.
Photosensitivity
Photosensitivity has been observed in patients treated with
Rubraca. Patients should avoid spending time in direct sunlight
because they may burn more easily during Rubraca treatment; when
outdoors, patients should wear a hat and protective clothing, and
use sunscreen and lip balm with sun protection factor of 50 or
greater.
Gastrointestinal toxicities
Gastrointestinal toxicities (nausea and vomiting) are frequently
reported with Rubraca, and are generally low grade (CTCAE grade 1
or 2), and may be managed with dose reduction (refer to Posology
and Method of Administration [4.2], Table 1 of the SPC) or
interruption. Antiemetics, such as 5-HT3 antagonists,
dexamethasone, aprepitant and fosaprepitant, can be used as
treatment for nausea/vomiting and may also be considered for
prophylactic (i.e. preventative) use prior to starting Rubraca. It
is important to proactively manage these events to avoid prolonged
or more severe events of nausea/vomiting which have the potential
to lead to complications such as dehydration or
hospitalization.
Embryofetal toxicity
Rubraca can cause fetal harm when administered to a pregnant
woman based on its mechanism of action and findings from animal
studies. In an animal reproduction study, administration of Rubraca
to pregnant rats during the period of organogenesis resulted in
embryo-fetal toxicity at exposures below those in patients
receiving the recommended human dose of 600 mg twice daily (see
Preclinical Safety Data [5.3] of the SPC).
Pregnancy/contraception
Pregnant women should be informed of the potential risk to a
fetus. Women of reproductive potential should be advised to use
effective contraception during treatment and for 6 months following
the last dose of Rubraca (see section 4.6 of the SPC). A pregnancy
test before initiating treatment is recommended in women of
reproductive potential.
Click here to access the current SPC. Healthcare professionals
should report any suspected adverse reactions via their national
reporting systems.
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, for
those indications that require them, 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, with additional office locations in the U.S. and
Europe. Please visit www.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. Examples of forward-looking
statements contained in this press release include, among others,
statements regarding our expectations for submission of regulatory
filings, the timing and pace of commencement of and enrollment in
our clinical trials, including those being planned or conducted in
collaboration with partners, the potential results of such clinical
trials, our expectations regarding the suitability of Rubraca, and
our plans to develop Rubraca in additional indications and tumor
types, and our expectations regarding the outcomes of early studies
or trials supporting further development, both non-clinical and
clinical. 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
our clinical development programs for our drug candidates and those
of our partners, whether future study results will be consistent
with study findings to date, the timing of availability of data
from our clinical trials and the initiation, enrollment, timing and
results of our planned clinical trials and the corresponding
development pathways, effectiveness and suitability of diagnostic
tests, the risk that final results of ongoing trials may differ
from initial or interim results as a result of factors such as
final results from a larger patient population may be different
from initial or interim results from a smaller patient population,
the risk that additional pre-clinical or clinical studies may not
support further development in certain additional indications or
tumor types, and actions by the FDA, the EMA or other regulatory
authorities regarding data required to support drug applications
and whether to approve drug applications. 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 Lin et al. BRCA Reversion Mutations in Circulating Tumor DNA
Predict Primary and Acquired Resistance to the PARP Inhibitor
Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discovery. 2019.
https://cancerdiscovery.aacrjournals.org/content/9/2/210. Last
accessed December 2020.
ii American Cancer Society. Cancer Facts & Figures 2018.
Atlanta, GA: American Cancer Society; 2018.
iii World Health Organization. GLOBOCAN: estimated cancer
incidence, mortality and prevalence worldwide in 2018. Available at
http://gco.iarc.fr/. Last accessed December 2020.
iv Ovarian Cancer Research Alliance (OCRA)
https://ocrahope.org/patients/about-ovarian-cancer/recurrence/ Last
accessed December 2020.
v Ledermann J et al. Newly diagnosed and relapsed epithelial
ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis,
treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi24-32.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20201221005205/en/
Clovis Investor Contacts: Anna Sussman, 303.625.5022
asussman@clovisoncology.com or Breanna Burkart, 303.625.5023
bburkart@clovisoncology.com Clovis Media Contacts:
U.S. Lisa Guiterman, 301.217.9353 clovismedia@sambrown.com
Europe Jake Davis, +44 (0) 20.3946.3538
Jake.Davis@publicisresolute.com
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