- 43.9% confirmed objective response rate (ORR) in 57
RECIST*-evaluable patients with metastatic
castration-resistant prostate cancer (mCRPC) and a BRCA1/2
mutation
- 52.0% confirmed prostate-specific antigen (PSA) response in
98 PSA-evaluable patients with mCRPC and a BRCA1/2
mutation
- The safety profile of Rubraca was consistent with prior
reports from TRITON2 and for those patients with ovarian cancer and
other solid tumors
- Supplemental new drug application (NDA) for Rubraca in
BRCA1/2-mutant advanced prostate cancer on track for Q4
2019
- Clovis Oncology also highlights efficacy and safety of
Rubraca in recurrent ovarian cancer
Clovis Oncology, Inc. (NASDAQ: CLVS) today announced updated
data from the Phase 2 TRITON2 trial at the European Society for
Medical Oncology (ESMO) Congress 2019, reinforcing the potential of
Rubraca® (rucaparib) for the treatment of patients with metastatic
castration-resistant prostate cancer (mCRPC) with a BRCA1/2
mutation. The data show a 43.9% confirmed objective response rate
(ORR) by investigator assessment in 57 RECIST*/PCWG3**
response-evaluable patients with a BRCA1/2 mutation. When assessed
by independent radiological review, the response rate was similar
(40.4%). In addition, a 52.0% confirmed prostate-specific antigen
(PSA) response rate was observed in 98 response-evaluable patients
with a BRCA1/2 mutation. Confirmed radiographic responses were
durable, with 60 percent lasting 24 weeks or longer (15/25).
The TRITON2 data will be used to support the filing of Clovis
Oncology’s planned supplemental NDA to the Food and Drug
Administration (FDA) for Rubraca in BRCA1/2-mutant advanced
prostate cancer.
“The updated data from the TRITON2 trial confirm the potential
role of rucaparib in treating metastatic castration-resistant
prostate cancer,” said Wassim Abida, M.D., Medical Oncologist,
Memorial Sloan Kettering Cancer Center, and principal investigator
for the TRITON2 study. “These data specifically demonstrate the
efficacy of rucaparib in eligible mCRPC patients with a BRCA1/2
mutation and reinforce the known safety profile in this treatment
setting, showing it has the potential to offer clinical benefit to
eligible patients.”
Confirmed investigator-assessed RECIST* and PSA responses were
also observed in patients with alterations in other DDR genes,
including ATM, CDK12, CHEK2, PALB2, BRIP1, FANCA, and RAD51B.
The median duration of follow-up (as of July 2, 2019) for
patients in TRITON2 was 13.1 months (range 4.1–28.5 months) with
the safety profile consistent with prior reports. The most common
any-grade treatment-emergent adverse events (TEAE) >20% in the
TRITON2 trial were asthenia/fatigue (55.3%), nausea (49.5%),
anemia/decreased hemoglobin (37.9%), decreased appetite (27.9%),
transient increased aspartate transaminase/alanine aminotransferase
(ALT/AST) (24.7%), constipation (24.7%), vomiting (22.1%) and
diarrhea (21.1%).
Clovis Oncology is further evaluating the potential of Rubraca
to treat advanced prostate cancer in the TRITON3 clinical trial - a
multicenter, randomized, open-label Phase 3 study of Rubraca versus
physician’s choice of therapy - for patients with mCRPC. TRITON3 is
currently enrolling patients with BRCA1/2-mutant and ATM-mutant
(both inclusive of germline and somatic) tumors with a primary
objective of assessing radiographic progression-free survival (PFS)
in these patients.
Rubraca in Recurrent Ovarian
Cancer
An exploratory data analysis from the pivotal Phase 3 ARIEL3
trial evaluating Rubraca for the maintenance treatment of recurrent
ovarian cancer assessed PFS in the subgroups who had achieved a
partial response (PR) or complete response (CR) on the most recent
platinum regimen. The data show that PFS was longer in patients
receiving Rubraca than placebo regardless of whether patients
achieved a CR or PR on their last platinum-based regimen. Patients
in the intent-to-treat population who received rucaparib treatment
had a significantly greater reduction in risk for progression or
death versus placebo whether they had achieved a CR (hazard ratio
of 0.33 [95% CI, 0.23-0.49]; rucaparib, n=126; placebo, n=64) or a
PR (hazard ratio of 0.38 [95% CI, 0.30-0.49]; rucaparib, n=249;
placebo, n=125) to their last platinum-based therapy. Improvements
in investigator-assessed PFS were also demonstrated in patients
from the BRCA mutant and BRCA mutant or BRCA wild type/high loss of
heterozygosity populations who were treated with Rubraca compared
with placebo. The safety profile in Rubraca-treated patients who
had either a CR or PR to their last platinum-based chemotherapy was
consistent with that of the ITT population reported. Among patients
with residual disease at baseline, confirmed RECIST responses were
seen in a number of patients treated with rucaparib, including
23/104 (22.1%) patients with non-measurable but assessable disease
at baseline.
An integrated analysis of safety data from Study 10, ARIEL2 and
ARIEL3 are consistent with the known safety profile of Rubraca in
patients with platinum-sensitive, recurrent ovarian cancer, in both
the treatment and maintenance settings. The analysis included 937
patients treated with Rubraca in the treatment (Study 10 and
ARIEL2, n=565) and maintenance (ARIEL3, n=372) settings. Overall,
102/937 (10.9%) patients discontinued due to any grade
treatment-related TEAE (treatment setting: 53/565 [9.4%]);
(maintenance setting: 49/372 [13.2%]). The most frequent any grade
adverse events leading to discontinuation were asthenia/fatigue
(23/937 [2.5%]), anemia/ hemoglobin decreased (20/937 [2.1%]) and
thrombocytopenia/platelets decreased (19/937 [2.0%]). The most
frequent grade ≥3 treatment-related TEAE leading to discontinuation
was anemia/hemoglobin decreased (15/937 [1.6%]) and
asthenia/fatigue (7/937 [0.7%]).
“The ARIEL3 data presented at ESMO this year demonstrate that
rucaparib contributes to a significant increase in progression-free
survival over placebo, irrespective of whether a patient had CR or
PR to previous platinum-based therapy and provides strong evidence
for efficacy in women with recurrent ovarian cancer in the
second-line maintenance setting,” said Professor Jonathan
Ledermann, M.D., Professor of Medical Oncology, UCL Cancer
Institute and UCL Hospitals, London, Global Principal Investigator
for non-U.S. sites in the ARIEL3 study. “The current data provide
physicians with a compelling argument to make maintenance therapy
essential for all eligible patients, including women who have had a
complete response.”
Data from the Study 10, ARIEL2 and ARIEL3 trials supported the
approvals of Rubraca for the treatment and maintenance treatment of
recurrent ovarian cancer in the U.S. and EU. The European
Commission authorization of Rubraca, resulted in Rubraca being the
first poly (ADP ribose) polymerase (PARP) inhibitor to be approved
for both treatment and maintenance treatment among eligible women
with ovarian cancer in the EU.
“Rubraca continues to demonstrate meaningful clinical benefit in
the recurrent ovarian cancer treatment and maintenance settings,
and our updated prostate data are highly consistent with the data
presented at ESMO last year,” said Patrick J. Mahaffy, President
and CEO of Clovis Oncology. “We are moving forward with plans to
file an sNDA in advanced mCRPC by the end of 2019, and we believe
that, similar to its ovarian cancer profile, Rubraca may offer an
important treatment option for patients with advanced prostate
cancer, for whom new options are needed. We are committed to
further exploring the potential of Rubraca and look forward to
starting the tumor-agnostic study before year-end and furthering
our combination studies that are now enrolling patients.”
Clovis Oncology’s ESMO Rubraca poster presentations are
available online at clovisoncology.com.
Clovis Analyst/Investor Event at ESMO Webcast Details
In addition, the Company will present greater detail about its
planned sNDA filing and regulatory strategy in mCRPC at its
Investor/Analyst event today at 6:30pm CEST, which will be webcast
live and available via replay from the following link:
https://ir.clovisoncology.com/investors-and-news/events-and-presentations/event-details/2019/Investor-Analyst-Presentation-at-ESMO-2019/default.aspx.
About Rubraca® (rucaparib)
Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and
PARP3 that is being developed in multiple tumor types, including
ovarian and mCRPC, as monotherapy, and in combination with other
anti-cancer agents. Exploratory studies in other tumor types are
also underway.
Rubraca U.S. FDA approved indications
Rubraca is indicated as monotherapy for the maintenance
treatment of adult patients with recurrent epithelial ovarian,
fallopian tube, or primary peritoneal cancer who are in CR or PR to
platinum-based chemotherapy.
Rubraca is indicated as monotherapy for the treatment of adult
patients with deleterious BRCA mutations (germline and/or somatic)
associated epithelial ovarian, fallopian tube, or primary
peritoneal cancer who have been treated with ≥2 chemotherapies and
selected for therapy based on an FDA-approved companion diagnostic
for Rubraca.
Select important safety information
MDS/AML occurs uncommonly in patients treated with Rubraca, and
are potentially fatal adverse reactions. In approximately 1100
treated patients, MDS/AML occurred in 12 patients (1.1%), including
those in long-term follow-up. Of these, five occurred during
treatment or during the 28-day safety follow-up (0.5%). The
duration of Rubraca treatment prior to the diagnosis of MDS/AML
ranged from 1 month to approximately 28 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 (see Dosage and Administration
[2.2] in full Prescribing Information) 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 cytogenetic analysis. 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 laboratory abnormalities in ARIEL3 (≥25%, grade 1–4)
were increase in creatinine (98%), decrease in hemoglobin (88%),
increase in cholesterol (84%), increase in ALT (73%), increase in
AST (61%), decrease in platelets (44%), decrease in leukocytes
(44%), decrease in neutrophils (38%), increase in alkaline
phosphatase (37%) and decrease in lymphocytes (29%).
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%).
Most common laboratory abnormalities in Study 10 and ARIEL2
(≥35%; grade 1–4) were increase in creatinine (92%), increase in
ALT (74%), increase in AST (73%), decrease in hemoglobin (67%),
decrease in lymphocytes (45%), increase in cholesterol (40%),
decrease in platelets (39%) and decrease in absolute neutrophil
count (35%).
Co-administration of Rubraca 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 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. You may report side effects to the FDA
at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side
effects to Clovis Oncology, Inc. at 1-844-258-7662.
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
≥2prior lines of platinum-based chemotherapy, and who are unable to
tolerate further platinum-based chemotherapy.
Efficacy of Rubraca as treatment for relapsed or progressive
EOC, FTC, or 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 for,
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 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.
* Response Evaluation Criteria in Solid Tumors (RECIST) is a
standardized methodology for determining therapeutic response to
anticancer using changes in lesion appearance on imaging studies **
Prostate Cancer Working Group (PCWG3) is an international expert
committee of prostate cancer clinical investigators who have
recommended modifications to RECIST for use in the conduct of
trials in metastatic castration-resistant prostate cancer (mCRPC),
which were adopted in the TRITON2 protocol.
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version on businesswire.com: https://www.businesswire.com/news/home/20190928005026/en/
Clovis Investor Contacts: Anna Sussman, +1 303.625.5022
asussman@clovisoncology.com or Breanna Burkart, +1 303.625.5023
bburkart@clovisoncology.com Clovis Media Contacts:
U.S. Lisa Guiterman, +1 301.217.9353
clovismedia@sambrown.com or Christy Curran, +1 615.414.8668
clovismedia@sambrown.com EU Jake Davis, +44 (0) 20.3946.3538
Jake.Davis@publicisresolute.com
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