TALZENNA is the first and only PARP inhibitor
approved in combination with standard of care XTANDI for mCRPC
patients in the Europe Union
Pfizer Inc. (NYSE: PFE) today announced that the European
Commission (EC) has approved TALZENNA® (talazoparib), an oral poly
ADP-ribose polymerase (PARP) inhibitor, in combination with XTANDI®
(enzalutamide), for the treatment of adult patients with metastatic
castration-resistant prostate cancer (mCRPC) in whom chemotherapy
is not clinically indicated. With this approval, TALZENNA is now
the first and only PARP inhibitor licensed in the European Union
for use with XTANDI for patients with mCRPC, with or without gene
mutations.
“New treatment options are needed to increase the proportion of
patients with metastatic castration-resistant prostate cancer who
can benefit from current anticancer medicines that keep the disease
under control for longer,” said Robert Jones, MBChB, PhD, Professor
of Clinical Cancer Research, University of Glasgow. “The European
Commission’s approval of talazoparib in combination with
enzalutamide offers a meaningful advancement for the treatment of
patients with metastatic castration-resistant prostate cancer, the
most advanced and aggressive stage of the disease.”
“After years of fighting prostate cancer, it can be devastating
for a patient to learn that their cancer has stopped responding to
testosterone-lowering treatments. At this stage of the disease, the
prognosis is generally poor,” said Erik Briers, MS, PhD, Vice
Chairman, Europa UOMO, a European advocacy movement for people with
prostate cancer. “Patients urgently need new treatment options and
TALZENNA in combination with XTANDI can bring new hope to these
patients.”
This approval by the European Commission of TALZENNA in
combination with XTANDI for the mCRPC indication is valid in all 27
EU member states plus Iceland, Liechtenstein, and Norway.
The approval is based on data from the Phase 3 TALAPRO-2 trial,
a multicenter, randomized, double-blind, placebo-controlled study,
evaluating two mCRPC patient cohorts: Cohort 1 (all-comers [n=805])
and Cohort 2 (those with HRR gene mutations [HRRm; n=399]). The
results from TALAPRO-2 Cohort 1, which were published in The
Lancet, showed that treatment with TALZENNA plus XTANDI reduced the
risk of disease progression or death by 37% versus placebo plus
XTANDI (Hazard Ratio [HR]: 0.63; 95% Confidence Interval [CI],
0.51–0.78; P< 0.0001), meeting the study’s primary endpoint of
improving radiographic progression-free survival (rPFS). At the
time of the analysis, the median rPFS for those treated with
TALZENNA plus XTANDI had not yet been reached versus 21.9 months
for those treated with placebo plus XTANDI. Median rPFS is defined
as the timepoint in which 50% of patients in each treatment arms
have progressed. A trend in overall survival (OS), a key secondary
endpoint, favoring TALZENNA plus XTANDI was also observed, though
these data are immature. The safety of TALZENNA plus XTANDI in the
TALAPRO-2 trial was generally consistent with the known safety
profile of each medicine.
“Today’s approval of TALZENNA in combination with XTANDI
represents an important advancement for men living with prostate
cancer in Europe,” said Chris Boshoff, M.D., Ph.D., Chief Oncology
Officer, Executive Vice President, Pfizer. “The results from the
pivotal TALAPRO-2 trial showed that this combination offers an
effective treatment that addresses disease progression in patients
with or without any specific gene mutation.”
TALZENNA in combination with XTANDI was approved by the U.S.
Food and Drug Administration (FDA) for the treatment of adult
patients with HRR gene-mutated mCRPC in June 2023. Pfizer has also
shared the TALAPRO-2 data with other regulatory agencies to support
regulatory filings.
About Metastatic Castration-Resistant Prostate Cancer
Metastatic castration-resistant prostate cancer (mCRPC) is a
cancer that has spread beyond the prostate gland and has progressed
despite medical or surgical treatment to lower testosterone. There
were ~1.4 million new cases of prostate cancer reported worldwide
in 2020, of which ~470,000 new cases were in Europe.1 Approximately
10%–20% of prostate cancer patients develop mCRPC within 5−7 years
of diagnosis.2 Between 1.2%–2.1% of all prostate cancer cases
globally are mCRPC.3
About TALAPRO-2
The Phase 3 TALAPRO-2 trial is a two-part, two-cohort,
multicenter, randomized, double-blind, placebo-controlled study
that enrolled 1,106 patients with mCRPC (with no systemic
treatments initiated after documentation of mCRPC) at sites in the
U.S., Canada, Europe, South America, and the Asia-Pacific region.
The study included two patient cohorts: all-comers (n=805) and
those with and without gene mutations (HRRm; n=399). Patients on
androgen deprivation therapy (ADT) or who had bilateral orchiectomy
in the trial were randomized to receive TALZENNA 0.5 mg/day plus
XTANDI 160mg/day, or placebo plus XTANDI 160 mg/day.
The primary endpoint of the trial is radiographic
progression-free survival (rPFS), defined as the time from the date
of randomization to first objective evidence of radiographic
progression by blinded independent review, or death, whichever
occurs first, in both Cohort 1 (all-comers) and Cohort 2 (those
with HRRm). Secondary endpoints include overall survival (OS),
objective response rate, duration of response, and PSA
response.
For more information on the TALAPRO-2 trial (NCT03395197), go to
www.clinicaltrials.gov.
About TALZENNA® (talazoparib)
TALZENNA (talazoparib) is an oral inhibitor of poly ADP-ribose
polymerase (PARP), which plays a role in DNA damage repair.
Preclinical studies have demonstrated that TALZENNA blocks PARP
enzyme activity and traps PARP at the site of DNA damage, leading
to decreased cancer cell growth and cancer cell death.
TALZENNA is approved in over 70 countries, including the U.S and
the EU, as a once-daily monotherapy for the treatment of adult
patients with deleterious or suspected deleterious germline breast
cancer susceptibility gene (BRCA)-mutated (gBRCAm) human epidermal
growth factor receptor 2 (HER2)-negative locally advanced or
metastatic breast cancer. In the U.S., TALZENNA is approved in
combination with XTANDI® (enzalutamide) for the treatment of adult
patients with homologous recombination repair (HRR) gene-mutated
metastatic castration-resistant prostate cancer (mCRPC). In the EU,
TALZENNA is now approved in combination with enzalutamide for the
treatment of adult patients with mCRPC in whom chemotherapy is not
clinically indicated.
TALZENNA® (talazoparib) Indication in the U.S.
TALZENNA is a poly (ADP-ribose) polymerase (PARP) inhibitor
indicated for:
Breast Cancer:
- As a single agent, for the treatment of adult patients with
deleterious or suspected deleterious germline BRCA-mutated (gBRCAm)
HER2-negative locally advanced or metastatic breast cancer. Select
patients for therapy based on an FDA-approved companion diagnostic
for TALZENNA.
HRR Gene-mutated mCRPC:
- In combination with enzalutamide for the treatment of adult
patients with homologous recombination repair (HRR) gene-mutated
metastatic castration-resistant prostate cancer (mCRPC).
TALZENNA® (talazoparib) Important Safety
Information
WARNINGS and PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia
(MDS/AML), including cases with a fatal outcome, has been
reported in patients who received TALZENNA. Overall, MDS/AML has
been reported in 0.4% (3 out of 788) of solid tumor patients
treated with TALZENNA as a single agent in clinical studies. In
TALAPRO-2, MDS/AML occurred in 2 out of 511 (0.4%) patients treated
with TALZENNA and enzalutamide and in 0 out of 517 (0%) patients
treated with placebo and enzalutamide. The durations of TALZENNA
treatment in these five patients prior to developing MDS/AML were
0.3, 1, 2, 3, and 5 years, respectively. Most of these patients had
received previous chemotherapy with platinum agents and/or other
DNA damaging agents including radiotherapy.
Do not start TALZENNA until patients have adequately recovered
from hematological toxicity caused by previous chemotherapy.
Monitor blood counts monthly during treatment with TALZENNA. For
prolonged hematological toxicities, interrupt TALZENNA and monitor
blood counts weekly until recovery. If counts do not recover within
4 weeks, refer the patient to a hematologist for further
investigations including bone marrow analysis and blood sample for
cytogenetics. If MDS/AML is confirmed, discontinue TALZENNA.
Myelosuppression consisting of anemia, neutropenia,
and/or thrombocytopenia have been reported in patients treated with
TALZENNA. In TALAPRO-2, Grade ≥3 anemia, neutropenia, and
thrombocytopenia were reported, respectively, in 45%, 18%, and 8%
of patients receiving TALZENNA and enzalutamide. Overall, 39% of
patients (199/511) required a red blood cell transfusion, including
22% (111/511) who required multiple transfusions. Discontinuation
due to anemia, neutropenia, and thrombocytopenia occurred,
respectively, in 7%, 3%, and 0.4% of patients.
Withhold TALZENNA until patients have adequately recovered from
hematological toxicity caused by previous therapy. Monitor blood
counts monthly during treatment with TALZENNA. If hematological
toxicities do not resolve within 28 days, discontinue TALZENNA and
refer the patient to a hematologist for further investigations
including bone marrow analysis and blood sample for
cytogenetics.
Embryo-Fetal Toxicity TALZENNA can cause fetal harm when
administered to pregnant women. Advise male patients with female
partners of reproductive potential or who are pregnant to use
effective contraception during treatment with TALZENNA and for 4
months after receiving the last dose.
ADVERSE REACTIONS
Serious adverse reactions reported in >2% of patients
included anemia (9%) and fracture (3%). Fatal adverse reactions
occurred in 1.5% of patients, including pneumonia, COVID infection,
and sepsis (1 patient each).
The most common adverse reactions (≥ 10%, all Grades), including
laboratory abnormalities, for patients in the TALAPRO-2 study who
received TALZENNA in combination with enzalutamide vs patients
receiving placebo with enzalutamide were hemoglobin decreased (79%
vs 34%), neutrophils decreased (60% vs 18%), lymphocytes decreased
(58% vs 36%), fatigue (49% vs 40%), platelets decreased (45% vs
8%), calcium decreased (25% vs 11%), nausea (21% vs 17%), decreased
appetite (20% vs 14%), sodium decreased (22% vs 20%), phosphate
decreased (17% vs 13%), fractures (14% vs 10%), magnesium decreased
(14% vs 12%), dizziness (13% vs 9%), bilirubin increased (11% vs
7%), potassium decreased (11% vs 7%), and dysgeusia (10% vs
4.5%).
Clinically relevant adverse reactions in <10% of patients who
received TALZENNA with enzalutamide included abdominal pain (9%),
vomiting (9%), alopecia (7%), dyspepsia (4%), venous
thromboembolism (3%) and stomatitis (2%).
Based on animal studies, TALZENNA may impair fertility in males
of reproductive potential.
DRUG INTERACTIONS
Coadministration with P-gp inhibitors The effect of
coadministration of P-gp inhibitors on talazoparib exposure when
TALZENNA is taken in combination with enzalutamide has not been
studied. Monitor patients for increased adverse reactions and
modify the dosage as recommended for adverse reactions when
TALZENNA is coadministered with a P-gp inhibitor.
Coadministration with BCRP inhibitors Monitor patients
for increased adverse reactions and modify the dosage as
recommended for adverse reactions when TALZENNA is coadministered
with a BCRP inhibitor. Coadministration of TALZENNA with BCRP
inhibitors may increase talazoparib exposure, which may increase
the risk of adverse reactions.
USE IN SPECIFIC POPULATIONS
Renal Impairment The recommended dosage of TALZENNA for
patients with moderate renal impairment (CLcr 30 - 59 mL/min) is
0.35 mg taken orally once daily in combination with enzalutamide.
The recommended dosage of TALZENNA for patients with severe renal
impairment (CLcr 15 - 29 mL/min) is 0.25 mg taken orally once daily
in combination with enzalutamide. No dose adjustment is required
for patients with mild renal impairment. TALZENNA has not been
studied in patients requiring hemodialysis.
Please see full U.S. Prescribing Information and Patient
Information for TALZENNA® (talazoparib) at www.TALZENNA.com.
About XTANDI® (enzalutamide) and Important Safety
Information
XTANDI® (enzalutamide) is an androgen receptor signaling
inhibitor. XTANDI is a standard of care and has received regulatory
approvals in one or more countries around the world for use in men
with metastatic castration-sensitive prostate cancer (mCSPC; also
known as metastatic hormone-sensitive prostate cancer or mHSPC),
metastatic castration-resistant prostate cancer (mCRPC),
non-metastatic castration-resistant prostate cancer (nmCRPC) and
nonmetastatic castration-sensitive prostate cancer (nmCSPC) with
biochemical recurrence at high risk for metastasis (high-risk BCR).
XTANDI is currently approved for one or more of these indications
in more than 90 countries, including in the U.S., EU, and Japan.
Over one million patients have been treated with XTANDI
globally.4
Warnings and Precautions
Seizure occurred in 0.6% of patients receiving XTANDI in
eight randomized clinical trials. In a study of patients with
predisposing factors for seizure, 2.2% of XTANDI-treated patients
experienced a seizure. It is unknown whether anti-epileptic
medications will prevent seizures with XTANDI. Patients in the
study had one or more of the following predisposing factors: use of
medications that may lower the seizure threshold, history of
traumatic brain or head injury, history of cerebrovascular accident
or transient ischemic attack, and Alzheimer’s disease, meningioma,
or leptomeningeal disease from prostate cancer, unexplained loss of
consciousness within the last 12 months, history of seizure,
presence of a space occupying lesion of the brain, history of
arteriovenous malformation, or history of brain infection. Advise
patients of the risk of developing a seizure while taking XTANDI
and of engaging in any activity where sudden loss of consciousness
could cause serious harm to themselves or others. Permanently
discontinue XTANDI in patients who develop a seizure during
treatment.
Posterior Reversible Encephalopathy Syndrome (PRES) There
have been reports of PRES in patients receiving XTANDI. PRES is a
neurological disorder that can present with rapidly evolving
symptoms including seizure, headache, lethargy, confusion,
blindness, and other visual and neurological disturbances, with or
without associated hypertension. A diagnosis of PRES requires
confirmation by brain imaging, preferably MRI. Discontinue XTANDI
in patients who develop PRES.
Hypersensitivity reactions, including edema of the face
(0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI
in eight randomized clinical trials. Pharyngeal edema has been
reported in post-marketing cases. Advise patients who experience
any symptoms of hypersensitivity to temporarily discontinue XTANDI
and promptly seek medical care. Permanently discontinue XTANDI for
serious hypersensitivity reactions.
Ischemic Heart Disease In the combined data of five
randomized, placebo-controlled clinical studies, ischemic heart
disease occurred more commonly in patients on the XTANDI arm
compared to patients on the placebo arm (3.5% vs 2%). Grade 3-4
ischemic events occurred in 1.8% of patients on XTANDI versus 1.1%
on placebo. Ischemic events led to death in 0.4% of patients on
XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms
of ischemic heart disease. Optimize management of cardiovascular
risk factors, such as hypertension, diabetes, or dyslipidemia.
Discontinue XTANDI for Grade 3-4 ischemic heart disease.
Falls and Fractures occurred in patients receiving
XTANDI. Evaluate patients for fracture and fall risk. Monitor and
manage patients at risk for fractures according to established
treatment guidelines and consider use of bone-targeted agents. In
the combined data of five randomized, placebo-controlled clinical
studies, falls occurred in 12% of patients treated with XTANDI
compared to 6% of patients treated with placebo. Fractures occurred
in 13% of patients treated with XTANDI and in 6% of patients
treated with placebo.
Embryo-Fetal Toxicity The safety and efficacy of XTANDI
have not been established in females. XTANDI can cause fetal harm
and loss of pregnancy when administered to a pregnant female.
Advise males with female partners of reproductive potential to use
effective contraception during treatment with XTANDI and for 3
months after the last dose of XTANDI.
Adverse Reactions (ARs)
In the data from the five randomized placebo-controlled trials,
the most common ARs (≥ 10%) that occurred more frequently (≥ 2%
over placebo) in XTANDI-treated patients were musculoskeletal pain,
fatigue, hot flush, constipation, decreased appetite, diarrhea,
hypertension, hemorrhage, fall, fracture, and headache. In the
bicalutamide-controlled study, the most common ARs (≥ 10%) reported
in XTANDI-treated patients were asthenia/fatigue, back pain,
musculoskeletal pain, hot flush, hypertension, nausea,
constipation, diarrhea, upper respiratory tract infection, and
weight loss.
In AFFIRM, the placebo-controlled study of metastatic CRPC
(mCRPC) patients who previously received docetaxel, Grade 3 and
higher ARs were reported among 47% of XTANDI-treated patients.
Discontinuations due to ARs were reported for 16% of XTANDI-treated
patients. In PREVAIL, the placebo-controlled study of
chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in
44% of XTANDI patients and 37% of placebo patients.
Discontinuations due to ARs were reported for 6% of XTANDI-treated
patients. In TERRAIN, the bicalutamide-controlled study of
chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in
39% of XTANDI patients and 38% of bicalutamide patients.
Discontinuations with an AR as the primary reason were reported for
8% of XTANDI patients and 6% of bicalutamide patients.
In PROSPER, the placebo-controlled study of nonmetastatic CRPC
(nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of
XTANDI patients and 23% of placebo patients. Discontinuations with
an AR as the primary reason were reported for 9% of XTANDI patients
and 6% of placebo patients.
In ARCHES, the placebo-controlled study of metastatic CSPC
(mCSPC) patients, Grade 3 or higher ARs were reported in 24% of
XTANDI-treated patients. Permanent discontinuation due to ARs as
the primary reason was reported in 5% of XTANDI patients and 4% of
placebo patients.
In EMBARK, the placebo-controlled study of nonmetastatic CSPC
(nmCSPC) with high-risk biochemical recurrence (BCR) patients,
Grade 3 or higher adverse reactions during the total duration of
treatment were reported in 46% of patients treated with XTANDI plus
leuprolide, 50% of patients receiving XTANDI as a single agent, and
43% of patients receiving placebo plus leuprolide. Permanent
treatment discontinuation due to adverse reactions during the total
duration of treatment as the primary reason was reported in 21% of
patients treated with XTANDI plus leuprolide, 18% of patients
receiving XTANDI as a single agent, and 10% of patients receiving
placebo plus leuprolide.
Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of
patients, and more frequently (> 2%) in the XTANDI arm compared
to placebo in the pooled, randomized, placebo-controlled studies
are hemoglobin decrease, neutrophil count decreased, white blood
cell decreased, hyperglycemia, hypermagnesemia, hyponatremia,
hyperphosphatemia, and hypercalcemia.
Hypertension: In the combined data from five randomized
placebo-controlled clinical trials, hypertension was reported in
14.2% of XTANDI patients and 7.4% of placebo patients. Hypertension
led to study discontinuation in < 1% of patients in each
arm.
Drug Interactions
Effect of Other Drugs on XTANDI Avoid coadministration
with strong CYP2C8 inhibitors. If coadministration cannot be
avoided, reduce the dosage of XTANDI.
Avoid coadministration with strong CYP3A4 inducers. If
coadministration cannot be avoided, increase the dosage of
XTANDI.
Effect of XTANDI on Other Drugs Avoid coadministration
with certain CYP3A4, CYP2C9, and CYP2C19 substrates for which
minimal decrease in concentration may lead to therapeutic failure
of the substrate. If coadministration cannot be avoided, increase
the dosage of these substrates in accordance with their Prescribing
Information. In cases where active metabolites are formed, there
may be increased exposure to the active metabolites.
Please see Full Prescribing Information for additional safety
information.
About Pfizer Oncology
At Pfizer Oncology, we are at the forefront of a new era in
cancer care. Our industry-leading portfolio and extensive pipeline
includes game-changing mechanisms of action to attack cancer from
multiple angles, including antibody-drug conjugates (ADCs), small
molecules, bispecifics and other immunotherapies. We are focused on
delivering transformative therapies in some of the world’s most
common cancers, including breast cancer, genitourinary cancer and
hematologic malignancies, as well as melanoma, gastrointestinal,
gynecological and thoracic cancers, which includes lung cancer.
Driven by science, we are committed to accelerating breakthroughs
to extend and improve patients’ lives.
About the Pfizer/Astellas Collaboration
In October 2009, Medivation, Inc., which is now part of Pfizer
(NYSE: PFE), and Astellas (TSE: 4503) entered into a global
agreement to jointly develop and commercialize XTANDI®
(enzalutamide). The companies jointly commercialize XTANDI in the
United States, and Astellas has responsibility for manufacturing
and all additional regulatory filings globally, as well as
commercializing XTANDI outside the United States.
Disclosure Notice
The information contained in this release is as of January 8,
2024. 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 Pfizer
Oncology, TALZENNA and XTANDI, including their potential benefits,
and an approval by the European Commission for TALZENNA in
combination with XTANDI for the treatment of adult patients with
metastatic castration-resistant prostate cancer in whom
chemotherapy is not clinically indicated, that involves 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, uncertainties
regarding the commercial success of TALZENNA in combination with
XTANDI; 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;
whether TALAPRO-2 trial will meet the secondary endpoint for
overall survival; 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, XTANDI or a combination may be
filed in any jurisdictions for any potential indications; whether
and when any such applications for TALZENNA, XTANDI or a
combination 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, XTANDI or a
combination 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, XTANDI or a combination;
uncertainties regarding the impact of COVID-19 on Pfizer’s
business, operations and financial results; 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, 2022 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.
Category: Prescription Medicines
________________________________ 1 World Health Organization
Global Cancer Observatory. 27-Prostate-fact-sheet.pdf (iarc.fr) 2
Kirby M, et al. Int J Clin Pract. 2011;11:1180-1192. 3 Shore N,
Oliver L, Shui I, Gayle A, Wong OY, Kim J, Payne S, Amin S, Ghate
S. Systematic Literature Review of the Epidemiology of Advanced
Prostate Cancer and Associated Homologous Recombination Repair Gene
Alterations. J Urol. 2021 Apr;205(4):977-986. doi:
10.1097/JU.0000000000001570. Epub 2020 Dec 17. PMID: 33332152. 4
Data on file. Northbrook, IL: Astellas Inc.
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