Only once-daily PARP inhibitor approved in
Europe for hereditary breast cancer
Pfizer Inc. (NYSE:PFE) today announced that the European
Commission approved TALZENNA® (talazoparib), an oral poly
(ADP-ribose) polymerase (PARP) inhibitor, as monotherapy for the
treatment of adult patients with germline breast cancer
susceptibility gene (gBRCA)1/2-mutations, who have human epidermal
growth factor receptor 2-negative (HER2-) locally advanced (LA) or
metastatic breast cancer (MBC). Patients should have been
previously treated with an anthracycline and/or a taxane in the
(neo)adjuvant, locally advanced or metastatic setting unless
patients were not suitable for these treatments. Patients with
hormone receptor-positive (HR+) breast cancer should have been
treated with a prior endocrine-based therapy, or be considered
unsuitable for endocrine-based therapy.1 This approval follows the
medicine’s approval by the U.S. Food and Drug Administration (FDA)
in October 2018.
“Today’s approval of TALZENNA for certain patients with
advanced-stage breast cancer and an inherited BRCA mutation is the
latest example of our successful precision medicine approach to
drug development,” said Andreas Penk, M.D., Regional President,
Oncology International Developed Markets at Pfizer. “This important
milestone builds on Pfizer’s decades-long legacy of developing
therapies that improve outcomes for patients with breast cancer. We
are thrilled that we can now offer these patients in Europe, who
are often diagnosed at a younger age and have limited treatment
options, an effective, once-daily, alternative treatment to
chemotherapy.”
The European Commission’s approval of TALZENNA, which was
acquired as part of Pfizer’s acquisition of Medivation, is based on
results from the EMBRACA trial - the largest Phase 3 study of a
PARP inhibitor in gBRCA-mutated, HER2- LA or MBC. The global trial
evaluated once-daily TALZENNA compared to physician’s choice
standard chemotherapy (capecitabine, eribulin, gemcitabine or
vinorelbine) in patients with an inherited BRCA1/2 mutation in
triple-negative or HR+/HER2- LA or MBC who may have received up to
three prior cytotoxic chemotherapy regimens for their advanced
disease. The primary endpoint was progression-free survival (PFS),
as assessed by blinded independent central review (BICR).1,2
“In the EMBRACA trial, TALZENNA reduced the risk of disease
progression by 46 percent and more than doubled the overall
response rate compared to chemotherapy,” said Johannes Ettl, M.D.,
Department of Obstetrics and Gynecology, Klinikum rechts der Isar,
Technical University of Munich in Germany and an investigator in
the EMBRACA trial. “This improvement in outcomes for patients
treated with TALZENNA reinforces the increasingly key role of
genetic testing in treatment decision-making for patients with
locally advanced or metastatic breast cancer.”
In the EMBRACA trial, TALZENNA significantly outperformed
chemotherapy, extending median PFS to 8.6 months compared to 5.6
months for those treated with standard chemotherapy [95% CI:
7.2-9.3 vs. 4.2-6.7, respectively]. The superior PFS benefit with
TALZENNA was observed across prespecified patient populations,
including patients with triple-negative breast cancer, HR+/HER2-
disease, with or without a history of CNS metastasis, and those who
received prior cytotoxic chemotherapy regimens. Secondary endpoints
from the EMBRACA trial included objective response rate (ORR),
overall survival (OS) and safety. TALZENNA demonstrated an ORR of
62.6% (95% CI: 55.8-69.0), more than double that in the standard
chemotherapy arm (27.2%) (95% CI: 19.3-36.3). OS is an event-driven
endpoint and the data are not yet mature.1
Based on pooled data from patients who received 1 mg TALZENNA in
clinical studies for solid tumors, the most common adverse
reactions (≥ 25%) of patients receiving TALZENNA were fatigue
(57.1%), anemia (49.6%), nausea (44.3%), neutropenia (30.2%),
thrombocytopenia (29.6%) and headache (26.5%). Grade 3 or higher
adverse reactions (≥ 10%) in patients treated with TALZENNA were
anemia (35.2%), neutropenia (17.4%) and thrombocytopenia
(16.8%).1
About EMBRACA
The pivotal, Phase 3, open-label, 2:1 randomized EMBRACA trial
is the largest Phase 3 trial of a PARP inhibitor in gBRCA-mutated,
HER2- LA or MBC. The trial evaluated TALZENNA (1 mg once daily)
compared to physician’s choice chemotherapy (capecitabine,
eribulin, gemcitabine or vinorelbine) in 431 patients with an
inherited BRCA1/2 mutation and locally advanced or metastatic
triple-negative or HR+/HER2- breast cancer who may have received up
to three prior cytotoxic chemotherapy regimens. Of the patients
enrolled, 190 were from European countries, such as Belgium,
France, Germany, Ireland, Italy, Poland, Spain and the United
Kingdom. The primary endpoint was PFS, as assessed by BICR. Safety,
ORR and OS were key secondary endpoints.1,2
Primary results from the EMBRACA trial were published in the New
England Journal of Medicine, simultaneous to the online publication
of patient-reported outcomes data in Annals of Oncology in August
2018.2,3
For more information on the EMBRACA trial, go to
www.clinicaltrials.gov.
About Germline (Inherited) BRCA-Mutated Breast Cancer
BRCA1 and BRCA2 are human genes that produce proteins involved
in DNA repair. When either of these genes is altered or mutated,
DNA repair may not progress correctly. This can lead to the
development of certain types of cancer such as breast cancer.4 BRCA
mutations can be hereditary (germline) or occur spontaneously
(somatic).5 Together, germline BRCA1 and BRCA2 mutations account
for about 25 to 30% of hereditary breast cancers and approximately
3 to 6% of all breast cancers.5,6,7,8,9
Epidemiologic studies indicate that individuals with
gBRCA-mutated breast cancer are diagnosed in their 30s-40s, which
is approximately 20 years younger than the overall breast cancer
population.10,11
BRCA-mutated breast cancer is metastatic if the disease has
spread beyond the breast or to other parts of the body, including
the bones, liver, lung or brain.12 There is currently no cure for
MBC, the most advanced stage (stage IV) of the disease. The goal of
treatment is to delay or slow disease progression while maintaining
quality of life.13,14
Current European and U.S. clinical guidelines recommend gBRCA
testing to inform therapeutic considerations for HER2- LA or MBC
patients.15,16
About talazoparib
Talazoparib is an inhibitor of PARP enzymes, which play a role
in DNA repair. Preclinical studies suggest that talazoparib may
work by blocking PARP enzyme activity and trapping PARP at the site
of DNA damage, leading to decreased cancer cell growth and cancer
cell death. Talazoparib anti-tumor activity also was observed in
human patient-derived xenograft breast cancer tumor models that
expressed mutated or wild-type BRCA1/2.1
In addition to gBRCA-mutated LA or MBC, talazoparib is being
evaluated in several ongoing clinical trials in breast and other
cancers, including early triple-negative breast cancer and prostate
cancer, as well as other novel combinations with targeted therapies
and studies with immunotherapy in various solid tumors.
Indication in the U.S.
TALZENNA® (talazoparib) is approved in the U.S. for the
treatment of adult patients with deleterious or suspected
deleterious germline breast cancer susceptibility gene
(gBRCA)‑mutated (gBRCAm) human epidermal growth factor receptor
2‑negative (HER2-), locally advanced or metastatic breast cancer.
Select patients for therapy based on an FDA-approved companion
diagnostic for TALZENNA.17
TALZENNA® (talazoparib) Important Safety Information from the
U.S. Prescribing Information
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML)
have been reported in patients who received TALZENNA. Overall,
MDS/AML have been reported in 2 out of 584 (0.3%) solid tumor
patients treated with TALZENNA in clinical studies. The duration of
TALZENNA treatment in these two patients prior to developing
MDS/AML was 4 months and 24 months, respectively. Both patients had
received previous chemotherapy with platinum agents and/or other
DNA damaging agents including radiotherapy.
Myelosuppression consisting of anemia,
leukopenia/neutropenia, and/or thrombocytopenia have been reported
in patients treated with TALZENNA. Grade ≥3 anemia, neutropenia,
and thrombocytopenia were reported, respectively, in 39%, 21%, and
15% of patients receiving TALZENNA. Discontinuation due to anemia,
neutropenia, and thrombocytopenia occurred, respectively, in 0.7%,
0.3%, and 0.3% of patients.
Monitor complete blood counts for cytopenia at baseline
and monthly thereafter. Do not start TALZENNA until patients have
adequately recovered from hematological toxicity caused by previous
therapy. If hematological toxicity occurs, dose modifications
(dosing interruption with or without dose reduction) are
recommended. With respect to MDS/AML, for prolonged
hematological toxicities, interrupt TALZENNA and monitor blood
counts weekly until recovery. If the levels have not recovered
after 4 weeks, refer the patient to a hematologist for further
investigations. If MDS/AML is confirmed, discontinue TALZENNA.
TALZENNA can cause fetal harm when administered to
pregnant women. Advise women of reproductive potential to use
effective contraception during treatment and for at least 7 months
following the last dose. A pregnancy test is recommended for
females of reproductive potential prior to initiating TALZENNA
treatment. Advise male patients with female partners of
reproductive potential or who are pregnant to use effective
contraception during treatment with TALZENNA and for at least 4
months after receiving the last dose. Based on animal studies,
TALZENNA may impair fertility in males of reproductive potential.
Advise women not to breastfeed while taking TALZENNA and for at
least 1 month after receiving the last dose because of the
potential for serious adverse reactions in nursing infants.
The most common adverse reactions (≥20%) of any grade for
TALZENNA vs chemotherapy were fatigue (62% vs 50%), anemia (53% vs
18%), nausea (49% vs 47%), neutropenia (35% vs 43%), headache (33%
vs 22%), thrombocytopenia (27% vs 7%), vomiting (25% vs 23%),
alopecia (25% vs 28%), diarrhea (22% vs 26%), and decreased
appetite (21% vs 22%).
The most frequently reported Grade ≥3 adverse
reactions (≥5%) for TALZENNA vs chemotherapy were anemia (39%
vs 5%), neutropenia (21% vs 36%), and thrombocytopenia (15% vs
2%).
The most common lab abnormalities (≥25%) for TALZENNA vs
chemotherapy were decreases in hemoglobin (90% vs 77%), leukocytes
(84% vs 73%), lymphocytes (76% vs 53%), neutrophils (68% vs 70%),
platelets (55% vs 29%), and calcium (28% vs 16%) and increases in
glucose (54% vs 51%), aspartate aminotransferase (37% vs 48%),
alkaline phosphatase (36% vs 34%), and alanine aminotransferase
(33% vs 37%).
Coadministration with P-gp inhibitors or BCRP
inhibitors may increase TALZENNA exposure. If coadministering
with the P-gp inhibitors amiodarone, carvedilol, clarithromycin,
itraconazole, or verapamil is unavoidable, reduce the TALZENNA dose
to 0.75 mg once daily. When the P-gp inhibitor is discontinued,
increase the TALZENNA dose (after 3–5 half-lives of the P-gp
inhibitor) to the dose used prior to the initiation of the P-gp
inhibitor. When co-administering TALZENNA with other known P-gp
inhibitors or BCRP inhibitors, monitor patients for potential
increased adverse reactions.
For patients with moderate renal impairment, the
recommended dose of TALZENNA is 0.75 mg once daily. No dose
adjustment is required for patients with mild renal impairment.
TALZENNA has not been studied in patients with severe renal
impairment or in patients requiring hemodialysis.
TALZENNA has not been studied in patients with moderate or
severe hepatic impairment. No dose adjustment is required
for patients with mild hepatic impairment.
Please see full U.S. Prescribing Information and Patient
Information for TALZENNA® (talazoparib) at www.TALZENNA.com.
About Pfizer Oncology
At Pfizer Oncology, we are committed to advancing medicines
wherever we believe we can make a meaningful difference in the
lives of patients. Today, Pfizer Oncology has an industry-leading
portfolio of 18 approved innovative cancer medicines and
biosimilars across more than 20 indications, including breast,
prostate, kidney, lung and hematology. Pfizer Oncology is striving
to change the trajectory of cancer.
Pfizer Inc: Working together for a healthier world®
At Pfizer, we apply science and our global resources to bring
therapies to people that extend and significantly improve their
lives. We strive to set the standard for quality, safety and value
in the discovery, development and manufacture of health care
products. Our global portfolio includes medicines and vaccines as
well as many of the world's best-known consumer health care
products. Every day, Pfizer colleagues work across developed and
emerging markets to advance wellness, prevention, treatments and
cures that challenge the most feared diseases of our time.
Consistent with our responsibility as one of the world's premier
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For more than 150 years, we have worked to make a difference for
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DISCLOSURE NOTICE: The information contained in this release is
as of June 21, 2019. Pfizer assumes no obligation to update
forward-looking statements contained in this release as the result
of new information or future events or developments.
This release contains forward-looking information about
TALZENNA® (talazoparib) and an approval by the European Commission,
including its potential benefits, that involve substantial risks
and uncertainties that could cause actual results to differ
materially from those expressed or implied by such statements.
Risks and uncertainties include, among other things, the
uncertainties inherent in research and development, including the
ability to meet anticipated clinical endpoints, commencement and/or
completion dates for our clinical trials, regulatory submission
dates, regulatory approval dates and/or launch dates, as well as
the possibility of unfavorable new clinical data and further
analyses of existing clinical data; the risk that clinical trial
data are subject to differing interpretations and assessments by
regulatory authorities; whether regulatory authorities will be
satisfied with the design of and results from our clinical studies;
whether and when applications for TALZENNA may be filed in other
jurisdictions or for any other indications; whether and when any
such other applications for TALZENNA that may be pending or filed
may be approved by regulatory authorities, which will depend on
myriad factors, including making a determination as to whether the
product’s benefits outweigh its known risks and determination of
the product’s efficacy and, if approved, whether TALZENNA will be
commercially successful; decisions by regulatory authorities
impacting labeling, manufacturing processes, safety and/or other
matters that could affect the availability or commercial potential
of TALZENNA; and competitive developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended
December 31, 2018 and in its subsequent reports on Form 10-Q,
including in the sections thereof captioned “Risk Factors” and
“Forward-Looking Information and Factors That May Affect Future
Results”, as well as in its subsequent reports on Form 8-K, all of
which are filed with the U.S. Securities and Exchange Commission
and available at www.sec.gov and www.pfizer.com.
1 TALZENNA® (talazoparib). Summary of Product Characteristics. 2
Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with
advanced breast cancer and a germline BRCA mutation. N Engl J Med.
2018;379(8):753-763. 3 Ettl J, Quek R G W, Lee K-H, et al. Quality
of life with talazoparib versus physician’s choice of chemotherapy
in patients with advanced breast cancer and germline BRCA1/2
mutation: patient-reported outcomes from the EMBRACA phase III
trial. Ann Oncol. 2018: mdy257. doi:10.1093/annonc/mdy257. 4
National Cancer Institute. BRCA mutations: Cancer risk and genetic
testing.
https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet.
Accessed September 10, 2018. 5 Kleibl Z, Kristensen VN. Women at
high risk of breast cancer: molecular characteristics, clinical
presentation and management. The Breast. 2016;28:136-144. 6 Tung N,
Lin NU, Kidd J, et al. Frequency of germline mutations in 25 cancer
susceptibility genes in a sequential series of patients with breast
cancer. J Clin Oncol. 2016;34(13):1460-1468. 7 Nelson HD, Fu R,
Goddard K et al. Risk Assessment, Genetic Counseling, and Genetic
Testing for BRCA-Related Cancer: Systematic Review to Update the
U.S. Preventive Services Task Force Recommendation [Internet].
Rockville (MD): Agency for Healthcare Research and Quality (US);
2013 Dec. Report No.: 12-05164-EF-1. 8 Meynard G, Villanueva C,
Thiery-Vuillemin A, et al. Real-life study of BRCA genetic
screening in metastatic breast cancer. Annals of Oncology. 2017;
Volume 28, Issue suppl_5, mdx365.047. 9 Fasching PA, Hu C, Hart SN,
et al. Cancer predisposition genes in metastatic breast cancer -
association with metastatic pattern, prognosis, patient and tumor
characteristics. Paper presented at: San Antonio Breast Cancer
Symposium; December 5-9, 2017; San Antonio, TX. 10 Kuchenbaecker
KB, Hopper JL, Barnes DR, et al. Risks of Breast, Ovarian, and
Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers.
JAMA. 2017;317(23):2402–2416. doi:10.1001/jama.2017.7112. 11
Mavaddat N, Barrowdale D, Andrulis IL et al. Pathology of breast
and ovarian cancers among BRCA1 and BRCA2 mutation carriers:
results from the Consortium of Investigators of Modifiers of
BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 2012;21(1):134.
12 American Cancer Society. Treatment of invasive breast cancer, by
stage.
http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-treating-by-stage.
Accessed September 20, 2018. 13 O’Shaughnessy J. Extending Survival
with Chemotherapy in Metastatic Breast Cancer. The Oncologist.
2005;10:20-29. 14 Smith I. Goals of treatment for patients with
metastatic breast cancer. Semin Oncol. 2006 Feb; 33(1 Suppl 2):
S2-5. 15 Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO
International Consensus Guidelines for Advanced Breast Cancer (ABC
4). Ann Oncol. 2018;29(8):1634-1657. doi:10.1093/annonc/mdy192. 16
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
for Breast Cancer V.1.2019. © National Comprehensive Cancer
Network, Inc. 2019. All rights reserved. Accessed May 8, 2019. To
view the most recent and complete version of the guideline, go
online to NCCN.org. NCCN makes no warranties of any kind whatsoever
regarding their content, use or application and disclaims any
responsibility for their application or use in any way. 17
TALZENNA® (talazoparib) Prescribing Information. New York. NY:
Pfizer Inc: 2018.
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