- Subgroup analysis from the Phase 3 ATHENA trial evaluating
Rubraca monotherapy versus placebo (ATHENA-MONO) presented in a
Mini Oral session at the ESMO Congress 2022
- Results reinforce potential of Rubraca as a first-line
maintenance treatment option in a broad population of patients with
ovarian cancer irrespective of molecular characteristics, with or
without high risk factors for progression
Clovis Oncology, Inc. (NASDAQ: CLVS), today announced results
from a subgroup analysis of data from the monotherapy comparison of
the randomized, Phase 3 ATHENA (GOG-3020/ENGOT-ov45) trial
(ATHENA-MONO). These data showed that Rubraca as first-line
maintenance treatment improved progression-free survival (PFS)
versus placebo across disease risk subgroups including surgical
outcome, response to first-line chemotherapy, and additional
analyses in other subgroups. The data were presented by Rebecca S.
Kristeleit, MD, PhD, of Guy’s and St. Thomas’ NHS Foundation Trust
in London and lead ENGOT/NCRI National Cancer Research Institute
(https://www.ncri.org.uk/) investigator of the ATHENA trial as a
Mini Oral abstract at the European Society of Medical Oncology
(ESMO) Congress 2022 in Paris.
“These additional results from the ATHENA-MONO analysis of the
Phase 3 ATHENA trial demonstrate that rucaparib should be
considered a new first-line maintenance treatment option for women
with advanced ovarian cancer,” Dr. Kristeleit said. “In this
analysis, rucaparib prolonged progression-free survival for
patients with or without high risk factors for progression,
irrespective of molecular characteristics, adding to our
understanding of the efficacy of rucaparib in the broadest
population of patients assessed in a clinical trial for first-line
PARP inhibitor monotherapy.”
ATHENA is a double-blind, placebo-controlled, Phase 3 trial of
Rubraca in first-line ovarian cancer maintenance treatment. It has
two parts which are statistically independent. The results
presented at ESMO are from the ATHENA-MONO part (Rubraca versus
placebo), with results from the ATHENA-COMBO part (Rubraca plus
nivolumab versus Rubraca) expected in Q1 2023.
“As further demonstrated by the additional data presented at
ESMO, the ATHENO-MONO analysis continues to reinforce the potential
of Rubraca as a first-line maintenance therapy for women with
advanced ovarian cancer,” said Patrick J. Mahaffy, President and
CEO of Clovis Oncology. “We remain grateful to the patients who
participated in the trial and for the support of the clinical
community familiar with these results.”
ATHENA-MONO enrolled 538 women with high-grade ovarian,
fallopian tube, or primary peritoneal cancer. The primary efficacy
analysis evaluated two prospectively defined molecular subgroups in
a step-down manner: 1) homologous recombination deficiency
(HRD)-positive (inclusive of BRCAm tumors and BRCAwt/LOH high
tumors), and 2) all patients randomized (overall intent-to-treat
population [ITT]) in ATHENA-MONO. The following exploratory
subgroup analyses are included in the ESMO presentation:
PFS by Surgical Outcome
Patients who received Rubraca as maintenance therapy showed
benefit regardless of surgical outcome, whether there was complete
resection (R0) during cytoreductive surgery or not.
In HRD-positive patients:
- Patients who had a complete resection following cytoreductive
surgery (R0):
- Rubraca (n=107), median PFS not yet reached (NR); placebo
(n=33), median PFS of 22.1 months
- Hazard ratio of 0.52 (95% [Confidence Interval] CI:
0.30-0.92)
- Patients who did not have a complete resection following
cytoreductive surgery (non-R0):
- Rubraca (n=78), median PFS of 20.3 months; placebo (n=16),
median PFS of 9.1 months
- Hazard ratio of 0.29 (95% CI: 0.15-0.56)
Among the ITT population:
- Patients who had a complete resection following cytoreductive
surgery (R0):
- Rubraca (n=263), median PFS of 25.1 months; placebo (n=73),
median PFS of 12.0 months
- Hazard ratio of 0.60 (95% CI: 0.43-0.84)
- Patients who did not have a complete resection following
cytoreductive surgery (non-R0):
- Rubraca (n=164), median PFS of 13.9 months; placebo (n=38),
median PFS of 6.4 months
- Hazard ratio of 0.41 (95% CI: 0.27-0.62)
PFS by First-Line Chemotherapy Response
Similarly, patients treated with Rubraca as maintenance therapy
showed benefit among all subgroups when evaluated against response
per RECIST v1.1 at any time during first-line chemotherapy.
Among HRD-positive patients:
- Patients who demonstrated a partial response to first-line
chemotherapy:
- Rubraca (n=33), median PFS of 14.8 months; placebo (n=9),
median PFS of 9.1 months
- Hazard ratio of 0.43 (95% CI: 0.18-1.02)
- Patients who demonstrated a complete response to first-line
chemotherapy:
- Rubraca (n=38), median PFS of 25.8 months; placebo (n=4),
median PFS NR
- Hazard ratio of 0.41 (95% CI: 0.10-1.63)
Among the ITT population:
- Patients who demonstrated a partial response to first-line
chemotherapy:
- Rubraca (n=76), median PFS of 12.2 months; placebo (n=22),
median PFS of 6.4 months
- Hazard ratio of 0.37 (95% CI: 0.21-0.65)
- Patients who demonstrated a complete response to first-line
chemotherapy:
- Rubraca (n=73), median PFS of 15.6 months; placebo (n=11),
median PFS of 6.4 months
- Hazard ratio of 0.48 (95% CI: 0.23-1.03)
Additional Analyses in the ITT Population by Subgroup
Additional analyses in other subgroups based on baseline
clinical characteristics, including FIGO stage, timing of surgery,
and CA-125 levels, also demonstrated that patients treated with
Rubraca experienced a progression-free survival benefit compared to
those treated with placebo. Safety was similar between subgroups
analyzed.
Dr. Kristeleit’s presentation, as well as other
company-sponsored Rubraca data presented at ESMO, can be viewed at
the time of presentation at
https://www.clovisoncology.com/pipeline/scientific-presentations/.
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 1,146 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 first-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 readout in
Q1 2023, is evaluating the magnitude of benefit of adding Opdivo
(nivolumab) to Rubraca monotherapy in the ovarian cancer first-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 submission
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.
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/20220911005019/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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