Clovis Oncology Presents Initial Results from the Ongoing Rubraca® (rucaparib) TRITON Program in Metastatic Castration Resistant Prostate Cancer (mCRPC) at ESMO 2018 Congress
October 19, 2018
-
44% confirmed objective response rate (ORR) reported in 25
RECIST-evaluable patients with a BRCA1/2 alteration in initial
data from ongoing TRITON2 Phase 2 study; median duration of response
has not yet been reached -
51% confirmed PSA response rate shown in 45 PSA-evaluable patients
with a BRCA1/2 alteration -
Reductions in target lesion diameters and PSA measurements have
been observed in patients with an ATM alteration -
Preliminary safety data for Rubraca in men with mCRPC are
consistent with those observed in patients with ovarian cancer and
other solid tumors -
TRITON screening poster discussion provides initial genomic
profiling data from TRITON clinical program -
Plasma samples identified alterations in BRCA1 or BRCA2
in approximately 12% of mCRPC patients screened for the TRITON2 study -
Data demonstrate plasma cell-free circulating tumor DNA (cfDNA)
samples highly consistent with tumor tissue in identifying BRCA1
or BRCA2 alterations -
Breakthrough Therapy designation (BTD) granted by FDA to Rubraca
for treatment of patients with BRCA1/2 alterations in mCRPC
based on initial data from ongoing TRITON2 Phase 2 study
BOULDER, Colo.–(BUSINESS WIRE)–Clovis Oncology, Inc. (NASDAQ: CLVS) today announced initial data from
its ongoing Phase
2 TRITON2 clinical trial of Rubraca at the ESMO 2018 Congress
(European Society for Medical Oncology). The data show a 44% confirmed
objective response rate (ORR) by investigator assessment in 25 RECIST*
/PCWG3** response-evaluable patients with a BRCA1/2
alteration. The median duration of response in these patients has not
yet been reached. In addition, a 51% confirmed prostate specific antigen
(PSA) response rate was observed in 45 PSA response-evaluable patients
with a BRCA1/2 alteration.
The TRITON2 results were the basis for Breakthrough Therapy designation
for Rubraca as a monotherapy treatment of adult patients with BRCA1/2
mutated mCRPC who have received at least one prior androgen receptor
(AR)-directed therapy and taxane-based chemotherapy, which was granted
on October 2, 2018 by the U.S. Food and Drug Administration (FDA). These
data will be highlighted in a poster authored by Dr. Wassim Abida,
Medical Oncologist, Memorial Sloan Kettering Cancer Center, and
principal investigator for the TRITON2 study. The data have been
selected for a poster discussion session that will be led by invited
discussant Dr. Joaquin Mateo, of the Prostate
Cancer Translational Research Group, Vall d’Hebron Institute of
Oncology (VHIO) on 21 October at 09:15-9:40 CEST.
“Rubraca has previously demonstrated antitumor activity in its approved
indications for women with advanced ovarian cancer,” said Dr. Abida.
“These new data show that Rubraca may also offer a new approach for the
treatment of mCRPC associated with BRCA1 and BRCA2
alterations, with the potential to achieve a clinical response in
patients with few remaining therapy options.”
Patients enrolled in the TRITON2 study had received prior treatment with
at least one androgen receptor (AR)-directed therapy and taxane-based
chemotherapy and were screened for a deleterious germline or somatic
alteration in BRCA1, BRCA2 or one of 13 other pre-specified
homologous recombination (HR) genes. Study participants were allocated
into three cohorts based on the type of gene alteration and disease
status, which was determined by genomic sequencing and RECIST criteria,
respectively. Each cohort received 600mg Rubraca twice daily and were
grouped based on the following criteria: A) alteration in either BRCA1,
BRCA2 or ATM genes, with tumors that can be measured with
visceral and/or nodal disease; B) alteration in either BRCA1, BRCA2
or ATM genes, with tumors that cannot be measured with visceral
and/or nodal disease, or C) alteration in another HR gene associated
with sensitivity to PARP inhibition, with or without measurable disease.
The primary study endpoints include confirmed ORR per RECIST/PCWG3 in
patients with measurable disease at baseline and PSA response in
patients with no measurable disease at baseline. Secondary endpoints
include overall survival (OS), clinical benefit rate, and safety and
tolerability.1
As of the visit cut-off date of June 29, 2018, 85 patients were treated
with Rubraca; the overall median treatment duration was 3.7 (range,
0.5–12.9) months and median follow up was 5.7 (range, 2.6–16.4) months.
The median treatment duration in patients with a BRCA1/2
alteration was 4.4 months (range, 0.5-12.0 months). Forty-six patients
(54.1%) were evaluable for RECIST/PCWG3 response, including 25 patients
with a BRCA1/2 alteration. By investigator-assessed RECIST/PCWG3,
the confirmed ORR in patients with a BRCA1/2 alteration treated
with Rubraca was 44.0% (11/25). Among the 45 evaluable patients with a BRCA1/2
alteration, 51.1% (23/45) had a confirmed PSA response (95% CI,
35.8–66.3).
Overall, the most common treatment-emergent adverse events (TEAEs) of
any grade (CTCAE Grade 1-4) in all patients regardless of causality
included asthenia/fatigue (44.7%, or 38/85), nausea (42.4%, or 36/85),
anemia/decreased hemoglobin (22.4%, or 19/85) and constipation (28.2%,
or 24/85). Five patients (5.9%) discontinued therapy due to a
non-progression TEAE. One patient died due to disease progression.1
“We are very encouraged by these initial findings from the TRITON2
study, which demonstrate the potential of Rubraca to treat men with
advanced prostate cancer whose disease has progressed after receiving
multiple prior lines of therapy,” said Patrick J. Mahaffy, President and
CEO of Clovis Oncology. “PARP inhibitors are now a validated therapeutic
class in oncology in multiple tumor types, and these new data underscore
the benefit that Rubraca may provide for men with advanced, BRCA-mutant
castration-resistant prostate cancer. Having recently received
Breakthrough Therapy designation based on these data, we are committed
to the rapid development of Rubraca for men with this very
difficult-to-treat disease.”
The poster discussion session also will include the first presentation
of genomic profiling data based on tumor tissue and plasma cfDNA samples
from the TRITON clinical program. The poster, authored by Dr. Simon
Chowdhury, Consultant Medical Oncologist, Guy’s Hospital & Sarah Cannon
Research Institute and co-principal investigator for the TRITON clinical
studies, will be included in the same poster discussion session as the
TRITON2 data, led by invited discussant Dr. Joaquin Mateo, of the Prostate
Cancer Translational Research Group, Vall d’Hebron Institute of
Oncology (VHIO). The poster discussion session takes place on 21 October
at 09:15-9:40 CEST.
The data suggest cfDNA detected from plasma can be used to identify
deleterious HR gene alterations in a manner that is less invasive than
tumor tissue testing. Additionally, due to the invasiveness of tumor
tissue sample collection, archival primary prostate samples are often
used, and data suggest these samples are not representative of the
somatic alterations which emerge in mCRPC.
In the study evaluation, patients’ HR gene alteration status was
determined by screening a total of 1,311 tumor and 638 plasma specimens,
collected from a total of 1,516 patients to determine eligibility for
TRITON2 and TRITON3. There was high concordance (74%) in identifying
patients with deleterious BRCA1/2 mutations by both tissue and
plasma sample. The results demonstrate that detecting genetic
alterations within HR genes using cfDNA sequencing could prove to be a
convenient method to identify patients who might be suitable candidates
for treatment with Rubraca.2 Approximately 12% of men
screened for the TRITON2 study were identified as having a BRCA1/2
alteration by plasma screening.
“Tumor tissue testing relies heavily on archival samples taken when a
patient is newly diagnosed but may not capture all the alterations that
emerge in patients with metastatic disease,” said Dr. Chowdhury. “The
screening data demonstrate that there is a high concordance between
alterations detected in the tissue and plasma assays. Due to the less
invasive nature of obtaining cfDNA through plasma testing, this method
may be more suitable for both physicians and patients and may also
identify more patients eligible for clinical trials of Rubraca.”
Clovis’ Rubraca poster presentations will be available online at clovisoncology.com at
07:30 CEST on Saturday, October 20, 2018.
About the TRITON2 Clinical Study
TRITON2 is an international, multicenter, open-label, Phase 2 study of
Rubraca in men with metastatic castration-resistant prostate cancer with BRCA
gene alterations (inclusive of germline or somatic), which is also
enrolling patients with deleterious alterations of other homologous
recombination (HR) repair genes, including ATM. The study is
currently enrolling across sites worldwide. For more information, please
visit www.tritontrials.com.
About Prostate Cancer
The American Cancer Society estimates that more than 164,000 men in the
United States will be diagnosed with prostate cancer in 2018,3
and the GLOBOCAN Cancer Fact Sheets estimate that approximately 345,000
men in Europe were diagnosed with prostate cancer in 2012.4
Castration-resistant prostate cancer has a high likelihood of developing
metastases. Metastatic castration-resistant prostate cancer, or mCRPC,
is an incurable disease, usually associated with poor prognosis.
According to the American Cancer Society, the five-year survival rate
for mCRPC is approximately 29%.5 Approximately 12% of mCRPC
patients have a deleterious mutation in BRCA1 or BRCA2,
according to an article published in the Journal of Clinical
Oncology Precision Oncology in 2017.6 These
molecular markers may be used to select patients for treatment with a
PARP inhibitor.
About Rubraca
Rubraca is an oral, small molecule inhibitor of PARP1, PARP2
and PARP3 being developed in multiple tumor types, including ovarian,
metastatic castration-resistant prostate, and bladder cancers, as
monotherapy, and in combination with other anti-cancer agents.
Exploratory studies in other tumor types are also underway. Clovis holds
worldwide rights for Rubraca. Rubraca is an unlicensed medical product
outside of the U.S. and Europe.
Rubraca EU Authorized Use
Rubraca is licensed for 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 two or more prior lines of
platinum-based chemotherapy, and who are unable to tolerate further
platinum-based chemotherapy.
Click
here to access the current Summary of Product Characteristics.
Healthcare professionals should report any suspected adverse reactions
via their national reporting systems.
Rubraca U.S. FDA Approved Indications and Important Safety Information
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 a complete or partial response 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 two or more chemotherapies and
selected for therapy based on an FDA-approved companion diagnostic for
Rubraca.
Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur
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 alanine aminotransferase (ALT) (73%),
increase in aspartate aminotransferase (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 alanine
aminotransferase (ALT) (74%), increase in aspartate aminotransferase
(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 (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. 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.
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, 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, and has additional offices in San
Francisco and Oakland, California and Cambridge, UK. Please visit clovisoncology.com for
more information.
Clovis Oncology Forward-looking Statement
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 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 diagnostic tests.
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 date 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, 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.
References
1. Abida W, Bryce AH, Vogelzang NJ et al. Preliminary results
from TRITON2: a phase 2 study of rucaparib in patients with metastatic
castration-resistant prostate cancer (mCRPC) associated with homologous
recombination repair (HRR) gene alterations. Presented at the European
Society of Medical Oncology (ESMO), 19–23 October 2018. Abstract 793PD.
2. Chowdhury S, McDermott R, Piulats JM et al. Genomic profiling
of circulating tumour DNA (cfDNA) and tumour tissue for the evaluation
of rucaparib in metastatic castration-resistant prostate cancer (mCRPC).
Presented at the European Society of Medical Oncology (ESMO), 19–23
October 2018. Abstract 795PD.
3. Key Statistics for Prostate Cancer | Prostate Cancer Facts Available
at: https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html
(accessed October 8, 2018).
4. Fact Sheets by Cancer. Available at http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
5. Survival Rates for Prostate Cancer. Available at https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/survival-rates.html
(accessed October 8, 2018)
6. Abida W, Armenia J, Gopalan A et al. Prospective genomic
profiling of prostate cancer across disease states reveals germline and
somatic alterations that may affect clinical decision making. Journal
of Clinical Oncology Precision Oncology. 2017:1;1–16. Available at: http://ascopubs.org/doi/full/10.1200/PO.17.00029
(accessed October 8, 2018)
* Response Evaluation Criteria in Solid Tumors (RECIST) is a
standardized methodology for determining therapeutic response to
anticancer therapy 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.
Contacts
Clovis Investor Contacts:
Anna Sussman
303.625.5022
asussman@clovisoncology.com
or
Breanna
Burkart
303.625.5023
bburkart@clovisoncology.com
Clovis
Media Contacts:
EU
Ann Hughes
+44(0)7956 700
790
Ann.Hughes@publicisresolute.com
or
US
Lisa
Guiterman
301.217.9353
clovismedia@sambrown.com
or
Christy
Curran
615.414.8668
clovismedia@sambrown.com