- Submissions based on data from the Phase 3 ATHENA trial
evaluating Rubraca monotherapy versus placebo (ATHENA-MONO)
presented at ASCO 2022
- The ATHENA-MONO trial met its primary endpoint, showing Rubraca
monotherapy versus placebo improved progression-free survival (PFS)
by investigator assessment in both populations in the primary
efficacy analyses: HRD-positive and all patients randomized
(ITT)
- Safety of Rubraca observed in ATHENA-MONO was consistent with
both the current US and European labels
- The Company has submitted a supplemental New Drug Application
with the FDA and a Type II variation with the EMA
Clovis Oncology, Inc. (NASDAQ: CLVS) today announced that it has
submitted a supplemental New Drug Application (sNDA) with the US
Food and Drug Administration (FDA) and a Type II variation with the
European Medicines Agency (EMA) for approval of Rubraca®
(rucaparib) as first-line maintenance treatment for women with
advanced ovarian cancer regardless of biomarker status who have
responded to first-line platinum-based chemotherapy.
The Company believes that the encouraging PFS results, the
primary endpoint of the study, are strongly supportive of an
approval and of use in the front-line setting and are grateful for
the support of the clinical community familiar with the
results.
The submissions were based on the positive data from the
monotherapy analysis of the randomized, Phase 3 ATHENA
(GOG-3020/ENGOT-ov45) trial (ATHENA-MONO). These data demonstrated
that Rubraca as first-line maintenance treatment significantly
improved investigator-assessed progression-free survival (PFS)
compared with placebo in women with advanced ovarian cancer
irrespective of biomarker status in each of the populations
studied.
“We believe the compelling PFS results, the primary endpoint of
the ATHENA-MONO trial, are strongly supportive of an approval and
reinforce the potential of Rubraca as an important new first-line
maintenance treatment for ovarian cancer,” said Patrick J. Mahaffy,
President and CEO of Clovis Oncology. “We are grateful to the
patients who participated in the trial and for the support of the
clinical community familiar with these results.”
The ATHENA-MONO study included 538 women with high-grade
ovarian, fallopian tube, or primary peritoneal cancer. The primary
efficacy analysis evaluated two prospectively defined molecular
populations in a step-down manner: 1) homologous recombination
deficiency (HRD)1 positive (inclusive of BRCAm tumors and
BRCAwt/LOH high tumors), and 2) all patients randomized (ITT) in
the trial. The primary endpoint for the trial was PFS by
investigator review.
In the HRD population, median PFS by investigator review for
those treated with Rubraca was 28.7 months compared to 11.3 months
among those who received placebo (p=0.0004). The Rubraca arm
(n=185) showed statistically significant improvement over the
placebo arm (n=49) with a hazard ratio of 0.47 (95% CI: 0.31-0.72)
representing a 53 percent reduction in the risk of disease
progression.
In the ITT population, median PFS by investigator review for
those treated with Rubraca was 20.2 months compared to 9.2 months
for those who received placebo (p<0.0001). The Rubraca arm
(n=427) showed statistically significant improvement over the
placebo arm (n=111) with a hazard ratio of 0.52 (95% CI: 0.40-0.68)
representing a 48 percent reduction in the risk of disease
progression.
The safety profile observed in ATHENA-MONO was consistent with
both the current US and European labels for rucaparib. The most
common (≥2%) treatment-emergent grade ≥3 adverse events (TEAEs)
among all patients treated with rucaparib (n=425) in the
ATHENA-MONO comparison were anemia or decreased hemoglobin (28.7%),
neutropenia or neutrophil count decreased (14.6%), increased
ALT/AST (10.6%), thrombocytopenia or platelet count decreased
(7.1%), asthenia/fatigue (4.9%), and leukopenia/white blood cell
count decreased (3.5%). AST/ALT elevations were not accompanied by
significant changes in bilirubin and there were no reports of drug
induced liver toxicity as defined by Hy’s Law.
The discontinuation rate due to TEAEs was 11.8% for
rucaparib-treated patients and 5.5% for the placebo arm; there were
three deaths (0.7%) due to TEAEs for rucaparib-treated patients and
zero for the placebo arm. Median treatment duration for the
rucaparib arm was 14.7 months versus 9.9 months for the placebo
arm. Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
was reported by two patients in the rucaparib group (one MDS during
treatment; one AML during long-term follow-up) and no patients in
the placebo group.
As previously disclosed, the FDA has recommended that the
Company wait for more mature overall survival data from ATHENA-MONO
to submit the sNDA or, if it chooses to submit the sNDA prior to
receiving more mature overall survival data, then the sNDA may need
to be discussed at an Oncologic Drugs Advisory Committee (ODAC)
meeting. In addition, the FDA will consider overall survival data
from other rucaparib clinical trials when it reviews the
ATHENA-MONO dataset. Not all rucaparib overall survival data has
been submitted to the FDA nor is all data currently public. There
can be no assurances regarding the timing or outcome of the FDA and
EMA reviews of the submissions, nor, if approved, the scope of the
resulting label.
Rubraca is not currently approved in the first-line ovarian
cancer maintenance setting.
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 is an unlicensed medical product outside of the US and
Europe.
Rubraca Ovarian Cancer US FDA Approved Indication
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.
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%).
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.
Please Click here for full Prescribing
Information for Rubraca.
You may also report side effects to Clovis Oncology, Inc. at
1-415-409-7220 (US toll) or 1-844-CLVS-ONC (1-844-258-7662; US
toll-free).
Rubraca (rucaparib) European Union (EU) including Northern
Ireland, and Great Britain (GB) 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 EU SmPC (including for Northern
Ireland). Click here to access the current GB SmPC.
Healthcare professionals should report any suspected adverse
reactions via their national reporting systems.
About the ATHENA Clinical Trial
ATHENA (GOG 3020/ENGOT-ov45) (NCT03522246) is an international,
randomized, double-blind, phase III trial consisting of two
separate and fully independently powered study comparisons
evaluating Rubraca monotherapy (ATHENA-MONO) and Rubraca in
combination with nivolumab (ATHENA-COMBO) as maintenance treatment
for patients with newly diagnosed advanced epithelial ovarian,
fallopian tube, or primary peritoneal cancer. ATHENA enrolled
approximately 1000 patients across 24 countries, all women with
newly diagnosed ovarian cancer who responded to their front-line
chemotherapy. The trial completed accrual in 2020 and was conducted
in association with the Gynecologic Oncology Group (GOG) in the US
and the European Network of Gynaecological Oncological Trial groups
(ENGOT) in Europe. GOG and ENGOT are the two largest cooperative
groups in the US and Europe dedicated to the treatment of
gynecological cancers.
ATHENA-MONO is evaluating the benefit of Rubraca monotherapy
versus placebo in 538 women in this patient population. The primary
efficacy analysis evaluated two prospectively defined molecular
sub-groups in a step-down manner: 1) HRD-positive (inclusive of
BRCA mutant) tumors, and 2) the intent-to-treat population, or all
patients treated in ATHENA-MONO.
The ATHENA-COMBO portion of the trial, anticipated to read out
in Q1 2023, is evaluating the magnitude of benefit of adding Opdivo
(nivolumab) to Rubraca monotherapy in the ovarian cancer front-line
maintenance treatment setting. ATHENA-COMBO is anticipated to be
the first Phase 3 dataset to readout evaluating the combination of
a PARP inhibitor and an immune checkpoint inhibitor as maintenance
treatment following completion and response to front-line
chemotherapy.
About Ovarian Cancer
Ovarian cancer is the eighth leading cause of cancer-related
death among women worldwide. In 2020, GLOBOCAN estimated 314,000
women received a new diagnosis of ovarian cancer and approximately
207,200 women died from ovarian cancer. According to the American
Cancer Society, an estimated more than 19,000 women will be
diagnosed with ovarian cancer in the United States and there will
be an estimated nearly 13,000 deaths from ovarian cancer in 2022.
According to GLOBOCAN, an estimated 66,000 women in Europe are
diagnosed each year with ovarian cancer, and ovarian cancer is
among those cancers with the highest rate of deaths. According to
the NIH National Cancer Institute, more than 75% of women are
diagnosed with ovarian cancer at an advanced stage.
Despite recent advances in the therapeutic landscape of newly
diagnosed ovarian cancer, advanced ovarian cancer is still
considered incurable for the majority of patients, and the optimal
treatment strategy has yet to be determined.i Although most respond
initially to this treatment, 80% of patients with advanced ovarian
cancer will have a recurrence and require subsequent
therapies.ii
About Biomarkers in Ovarian Cancer
In the high-grade epithelial ovarian cancer setting, a patient’s
tumor can be classified based on the genetic biomarker status:
those with homologous recombination deficiencies, or HRD-positive,
include those with a mutation of the BRCA gene (BRCAm), inclusive
of germline and somatic mutations of BRCA, which represent
approximately 25 percent of patientsiii,iv; and those with a range
of genetic abnormalities other than BRCAm, which result in other
homologous recombination deficiencies that represent an additional
estimated 25 percent of patients (HRD-positive, BRCAwt)v; in
addition, those whose test results show no deficiencies in
homologous recombination repair (HRD-negative) represent the
remaining approximate 50 percent of patients.vi
About Clovis Oncology
Clovis Oncology, Inc. is a biopharmaceutical company focused on
acquiring, developing, and commercializing innovative anti-cancer
agents in the US, 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 US 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 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
expectations concerning future regulatory activities, expectations
for submission of regulatory filings and review of those
submissions by regulatory authorities, our plans to present final
or interim data on ongoing clinical trials, our plans to submit
additional data to, or meet with, the FDA with respect to the
status of or plans for ongoing or planned trials, the timing and
pace of commencement of enrollment in and conduct of our clinical
trials, the potential results of such clinical trials and the
potential for marketing authorizations for new indications, our
expectations regarding the suitability of Rubraca, and our plans to
develop or seek approval for Rubraca in additional indications and
tumor types. 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 and the
timing and scope of any approvals. 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.
1 HRD-positive may also be referred to as HR-deficient, HRD+,
HRd, or biomarker positive.
i Monk BJ et al. ATHENA (GOG-3020/ENGOT-ov45): a randomized,
phase III trial to evaluate rucaparib as monotherapy (ATHENA–MONO)
and rucaparib in combination with nivolumab (ATHENA–COMBO) as
maintenance treatment following frontline platinum-based
chemotherapy in ovarian cancer. Int J Gynecol Cancer. 2021;0:1–6.
ii Hanker LC et al. The impact of second to sixth line therapy on
survival of relapsed ovarian cancer after primary
taxane/platinum-based therapy. Ann Oncol. 2012;23(10):2605-2612.
doi:10.1093/annonc/mds203. iii Pal T, Permuth-Wey J, Betts JA, et
al. BRCA1 and BRCA2 mutations account for a large proportion of
ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. iv
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. v
Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD.
Homologous recombination deficiency: exploiting the fundamental
vulnerability of ovarian cancer. Cancer Discov.
2015;5(11):1137-1154. vi Quesada S, Fabbro M, Jerome Solassol.
Toward more comprehensive homologous recombination deficiency
assays in ovarian cancer part 2: medical perspectives, Cancers.
2022; 14, 1098.
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version on businesswire.com: https://www.businesswire.com/news/home/20220913005245/en/
Clovis Investor Contacts: Anna Sussman, 303.625.5022
asussman@clovisoncology.com or Breanna Burkart, 303.625.5023
bburkart@clovisoncology.com
Clovis Media Contacts: US Lisa Guiterman,
301.347.7964 clovismedia@clovisoncology.com
Europe Jake Davis, +44 (0) 20.3946.3538
Jake.Davis@publicisresolute.com
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