- TRITON3 study evaluating Rubraca monotherapy versus
chemotherapy or second-line androgen deprivation therapy in
patients with metastatic castration-resistant prostate cancer
(mCRPC) with mutations in BRCA or ATM achieved the primary endpoint
of improved radiographic progression-free survival (rPFS) by
independent radiology review (IRR)
– Median rPFS of 11.2 months for Rubraca vs
6.4 months for control group in the BRCA subgroup – Median rPFS of
10.2 months for Rubraca vs 6.4 months for control group in the ITT
population (inclusive of all patients with a BRCA or ATM mutation
enrolled in TRITON3)
- Safety profile of Rubraca observed in TRITON3 was consistent
with Rubraca labelling
- TRITON3 is the confirmatory study for Rubraca’s current US
accelerated approval in mCRPC and will also serve as the basis of a
supplemental New Drug Application (sNDA) for US label expansion to
be submitted during Q1 2023
- TRITON3 data have been submitted for presentation at the
Prostate Cancer Foundation Annual Scientific Retreat later this
month and will also be submitted for presentation at a 2023 medical
meeting
Clovis Oncology, Inc. (NASDAQ: CLVS) today announced positive
top-line data from the Phase 3, open-label, multicenter, randomized
TRITON3 trial demonstrating that Rubraca monotherapy treatment
achieved the primary endpoint of significantly improved
radiographic progression-free survival (rPFS) by independent
radiology review (IRR) compared with the control group, which
consisted of physician’s choice of docetaxel, abiraterone acetate,
or enzalutamide. Benefit was observed in both primary efficacy
analyses of patients with chemotherapy-naïve metastatic
castration-resistant prostate cancer (mCRPC): first, those who had
mutations in BRCA, as well as all patients randomized in the trial,
inclusive of mutations in BRCA or ATM (the overall intent-to-treat
population (ITT)). The safety profile of Rubraca observed in the
TRITON3 study was consistent with Rubraca labelling.
During the first quarter of 2023, the Company plans to submit a
supplemental New Drug Application (sNDA) to the FDA for the BRCA
subgroup of patients and intends to discuss with the FDA submitting
for the broader ITT population.
“We believe that the positive results from TRITON3 further
demonstrate the important role that Rubraca can play as a treatment
option for men with metastatic castration-resistant prostate cancer
associated with homologous recombination deficiency, and we look
forward to submitting these data to the regulatory authorities in
the US during Q1 2023. Not only does this provide a potential
treatment option for eligible men with earlier stage disease, but
it is the first and only PARP inhibitor that has demonstrated
superior radiographic PFS compared to chemotherapy, which is today
the standard of care for these patients,” said Patrick J. Mahaffy,
President and CEO of Clovis Oncology. “Most importantly, I would
like to thank the patients, physicians, and our colleagues whose
commitment to this trial made these results possible, which now
offer the potential to make a difference in the lives of many men
with advanced prostate cancer.”
“Men with this type of metastatic prostate cancer want to get
their genetically targeted therapy as early as possible, and this
trial clearly shows the value of rucaparib as a treatment for these
men,” said Alan H. Bryce, MD, chair of the Division of Hematology
and Medical Oncology at the Mayo Clinic and principal investigator
of the TRITON3 trial. “A key point is that rucaparib can replace
chemotherapy in this setting. The current standard of care for
these men is chemotherapy with docetaxel, and rucaparib is the only
PARP inhibitor which has beaten a docetaxel-containing control arm
in a clinical trial.”
“This trial demonstrates the potential for rucaparib to treat
men with early-stage metastatic castration-resistant prostate
cancer,” said Karim Fizazi, MD, PhD, medical oncologist at Gustave
Roussy, and a full professor in Oncology at the University of
Paris-Saclay and principal investigator of the TRITON3 trial. “To
my knowledge, this is the first time in two decades that a
potential new treatment, rucaparib, has shown in a randomized
controlled trial radiographic PFS efficacy over an investigator’s
choice control arm that included docetaxel chemotherapy, a
long-standing standard of care for men with metastatic
castration-resistant prostate cancer, and this is excellent news
for patients.”
TRITON3 is a Phase 3, multicenter, open-label, randomized trial
of Rubraca in patients with chemotherapy-naïve mCRPC. The study
enrolled 405 patients with a mutation in BRCA or ATM who were
randomized to Rubraca or the control group, which consisted of
physician’s choice of docetaxel, abiraterone acetate, or
enzalutamide. Approximately 55% of the patients in the control arm
received docetaxel. The primary endpoint was rPFS by IRR, in
patients with mutations in BRCA1, BRCA2 or ATM. TRITON3 was
designed as a Phase 3 trial to confirm and expand the efficacy data
from TRITON2 in an earlier treatment setting against a relevant
control arm.
Patients were required to have disease progression after
treatment with one prior next-generation AR-targeted therapy
(abiraterone acetate, enzalutamide, apalutamide or investigational
agent), as well as a deleterious mutation in BRCA or ATM. Following
a protocol amendment, patients were permitted to have received a
qualifying AR-targeted therapy in either the hormone-sensitive or
castration-resistant setting, and as a result, approximately 18% of
patients in TRITON3 had received prior AR-targeted therapy in the
metastatic hormone-sensitive setting only.
The primary efficacy analysis evaluated two prospectively
defined molecular sub-groups in a step-down manner: 1) the BRCA
subgroup, and 2) all patients randomized (ITT) in TRITON3,
inclusive of those with BRCA or ATM mutations.
Following is a summary of the primary efficacy analyses of rPFS
by independent radiologic review (IRR), the primary analysis of
TRITON3.
Significant Improvement in rPFS in the BRCA Patient
Population
The Rubraca arm (n=201) achieved statistical significance over
the control arm (n=101) for the primary endpoint of rPFS with a
hazard ratio of 0.50 (95% CI: 0.36-0.69). The median PFS for the
population of patients with BRCA mutations treated with Rubraca was
11.2 months vs 6.4 months among those who received physician’s
choice (p<0.0001).
Significant Improvement in rPFS in the ITT population,
inclusive of those with BRCA or ATM mutations
Rubraca also showed statistical significance in all 405 patients
randomized in TRITON3. The Rubraca arm (n=270) successfully
achieved statistical significance over the control arm (n=135) for
the primary endpoint of rPFS with a hazard ratio of 0.61 (95% CI:
0.47-0.80). The median PFS for all patients enrolled in TRITON3 and
treated with Rubraca was 10.2 months vs 6.4 months among those who
received physician’s choice (p=0.0003).
rPFS in Exploratory ATM Mutation Subgroup
In the exploratory subgroup of men with tumor ATM mutations
(n=103), the hazard ratio for rPFS was 0.97 (95% CI: 0.59-1.52).
Median rPFS in the Rubraca arm (n=69) was 8.1 months vs 6.8 months
in the control arm (n=34) with a nominal p-value (p=0.8421).
Secondary Endpoint of Overall Survival Summary
The hazard ratio for the interim analysis of the secondary
endpoint of overall survival (OS) in the BRCA subgroup and ITT
population, which are not yet mature, favored Rubraca. The hazard
ratio for OS in the exploratory subgroup of ATM, which is mature,
favored the control arm. The 95% confidence intervals for these OS
analyses included less than one for the exploratory endpoint ATM,
signifying no statistical difference in outcomes between Rubraca
and control.
Summary of TRITON3 Safety
The safety profile of Rubraca observed in TRITON3 was consistent
with Rubraca labelling. The most common (≥5%) treatment-emergent
grade 3 or higher adverse events (TEAEs) among all patients treated
with Rubraca in the TRITON3 study were anemia/decreased hemoglobin
(23.7%), neutropenia/decreased neutrophil count (7.4%),
asthenia/fatigue (7.0%), thrombocytopenia/decreased platelet count
(5.9%) and increased ALT/AST (5.2%). The discontinuation rate for
TEAEs was 14.8% for Rubraca-treated patients and 21.5% for the
control arm.
Clovis Oncology will submit an expanded description of the
TRITON3 results for presentation in a scientific session at the
Prostate Cancer Foundation Annual Scientific Retreat later this
month and plans to submit additional data to a medical meeting in
early 2023.
Rubraca is not currently approved in the chemotherapy-naïve
mCRPC setting.
About the TRITON3 Clinical Trial
TRITON3 (NCT02975934) is a Phase 3, multicenter, open-label,
randomized trial of Rubraca in patients with chemotherapy-naïve
mCRPC. Patients with a mutation in BRCA or ATM were randomized to
Rubraca or the control group, which consisted of physician’s choice
of docetaxel, abiraterone acetate, or enzalutamide. The primary
objective was efficacy, as analysed by independent radiology review
(IRR) of radiographic progression-free survival (rPFS) in patients
with mutations in BRCA1, BRCA2 or ATM. TRITON3 was designed as a
Phase 3 trial to confirm and expand the efficacy data from TRITON2
in an earlier treatment setting against a relevant control arm.
About Prostate Cancer
The American Cancer Society estimates that approximately 268,000
men in the US will be diagnosed with prostate cancer in 2022, and
the GLOBOCAN Cancer Fact Sheets estimated that approximately
473,000 men in Europe were diagnosed with prostate cancer in 2020.
Castrate-resistant prostate cancer has a high likelihood of
developing metastases. Metastatic castrate-resistant prostate
cancer (mCRPC) is an incurable disease, usually associated with
poor prognosis.i Approximately 43,000 men in the US were expected
to be diagnosed with mCRPC in 2020.ii According to the National
Cancer Institute, the five-year survival rate for mCRPC is
approximately 30%. BRCA or ATM mutations have been detected in
approximately 19% of patients with mCRPC according to articles
published in JCO Precision Oncology in 2017 and in Clinical Cancer
Research in 2021. These molecular markers may be used to select
patients for treatment with a PARP inhibitor.iii
About Rubraca (rucaparib)
Rubraca 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 US FDA Approved Indications
Ovarian Cancer
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.
Prostate Cancer
Rubraca is indicated for the treatment of adult patients with a
deleterious BRCA mutation (germline and/or somatic)-associated
metastatic castration-resistant prostate cancer (mCRPC) who have
been treated with androgen receptor-directed therapy and a
taxane-based chemotherapy. This indication is approved under
accelerated approval based on objective response rate and duration
of response. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
confirmatory trials.
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. In TRITON2, MDS/AML was not
observed in patients with mCRPC (n=209) regardless of homologous
recombination deficiency (HRD) mutation.
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. For males on Rubraca treatment who have female
partners of reproductive potential or who are pregnant, effective
contraception should be used during treatment and for 3 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 TRITON2 (≥ 20%; Grade 1-4) were
fatigue/asthenia (62%), nausea (52%), anemia (43%), AST/ALT
elevation (33%), decreased appetite (28%), rash (27%), constipation
(27%), thrombocytopenia (25%), vomiting (22%), and diarrhea
(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).
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, 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 potential for
marketing authorizations for new indications, our expectations
regarding the suitability of Rubraca, and our plans to develop
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, including that of secondary endpoints such
as overall survival, and the maturity of such data, 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 Sumanasuriya S. and Bono J., Treatment of Advanced Prostate
Cancer—A Review of Current Therapies and Future Promise, Cold
Spring Harb Perspect Med, 2018, June; 8(6); a030635. ii Scher H. et
al, Prevalence of Prostate Cancer Clinical States and Mortality in
the United States: Estimates Using a Dynamic Progression Model,
PLoS One, 2015; 10(10) iii Congregado B., PARP Inhibitors: A New
Horizon for Patients with Prostate Cancer, Biomedicines, 2022 Jun;
10 (6)
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