- TALZENNA® first PARP inhibitor to demonstrate clinical benefit
in combination with XTANDI® in metastatic castration-resistant
prostate cancer (mCRPC)
- Study achieves primary endpoint of radiographic
- Robust, highly consistent efficacy demonstrated in mCRPC both
with or without homologous recombination repair gene mutations
Pfizer Inc. (NYSE: PFE) today announced positive topline results
from the Phase 3 TALAPRO-2 study of TALZENNA® (talazoparib), an
oral poly ADP-ribose polymerase (PARP) inhibitor, in combination
with XTANDI® (enzalutamide) compared to placebo plus XTANDI in men
with metastatic castration-resistant prostate cancer (mCRPC), with
or without homologous recombination repair (HRR) gene mutations.
The study met its primary endpoint with a statistically significant
and clinically meaningful improvement in radiographic
progression-free survival (rPFS) compared with placebo plus XTANDI.
The results of the primary endpoint exceeded the pre-specified
hazard ratio of 0.696.
Results showed a trend toward improved overall survival, a key
secondary endpoint, at the time of the analysis, but these data are
not yet mature. Benefits were also observed in other secondary
endpoints, including investigator assessed rPFS, prostate specific
antigen (PSA) response, time to PSA progression, and overall
response rate. Other secondary endpoints are being analyzed. At the
time of topline analysis, the safety of TALZENNA plus XTANDI were
generally consistent with the known safety profile of each
“XTANDI is a global standard of care, with overall survival
demonstrated in mCRPC, non-metastatic CRPC, and metastatic
castration-sensitive prostate cancer (mCSPC),” said Chris Boshoff,
M.D., Ph.D., Chief Development Officer, Oncology and Rare Disease,
Pfizer Global Product Development. “We are very pleased with the
strong findings from TALAPRO-2, and although no definitive
conclusions can be made across trials, the rPFS appears to be the
longest observed in a randomized trial in this setting. These data
highlight the potential for TALZENNA in combination with XTANDI, if
approved, to become a new standard of care for mCRPC, irrespective
of HRR gene mutation status. We look forward to discussing these
data with global health authorities.”
“These exciting results from TALAPRO-2 underscore our
long-standing commitment to men living with prostate cancer and
delivering the next scientific breakthroughs,” said Suneet Varma,
Global Oncology and U.S. President, Pfizer. “Based on these
compelling combination data with XTANDI, we believe TALZENNA in
prostate cancer may become the next potential blockbuster
opportunity in our leading Pfizer Oncology portfolio, subject to
Detailed results from TALAPRO-2 will be submitted for
presentation at a near-term medical congress. These data will also
be shared with global regulatory authorities to potentially support
a regulatory filing.
TALZENNA or the combination of TALZENNA plus XTANDI have not
been approved by any regulatory agency for the treatment of mCRPC.
In addition to the TALAPRO-2 trial, the combination of TALZENNA
plus XTANDI is being investigated in the TALAPRO-3 trial
(NCT04821622), a global, randomized, double-blind,
placebo-controlled Phase 3 study in men with HRR-deficient
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.
Approximately 10%–20% of prostate cancer patients develop mCRPC
within 5−7 years of diagnosis,1 and in the U.S., in 2020,
approximately 60-90 thousand cases of the three million prostate
cancer cases were mCRPC.2
The Phase 3 TALAPRO-2 trial is a two-part, two-cohort,
multicenter, randomized, double-blind, placebo-controlled study
that enrolled 1,095 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=750) and
those with HRR mutations (HRRm; n=380). 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). The trial is still ongoing for cohort 2. Secondary
endpoints include overall survival, objective response rate,
duration of response and PSA response.
For more information on the TALAPRO-2 trial (NCT03395197) go to
About TALZENNA® (talazoparib)
TALZENNA (talazoparib) is an inhibitor of PARP enzymes, which
play a role in the DNA damage repair response. 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 being evaluated in
several ongoing clinical trials in prostate cancer, as well as
other novel combinations with targeted therapies in various solid
tumors. TALZENNA was approved by the U.S. Food and Drug
Administration in 2018 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
Indication in the U.S.
TALZENNA (talazoparib) is indicated 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. Select patients for therapy based on an
FDA-approved companion diagnostic for TALZENNA.
TALZENNA® (talazoparib) Important Safety
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML)
have been reported in patients who received TALZENNA. Overall,
MDS/AML has been reported in <1% (3 out of 787, 0.4%) of solid
tumor patients treated with TALZENNA in clinical studies. The
duration of TALZENNA treatment in these three patients prior to
developing MDS/AML was 4 months, 24 months, and 60 months
respectively. These patients had received previous chemotherapy
with platinum agents and/or other DNA damaging agents including
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 (≥10%) for TALZENNA vs chemotherapy were anemia (39%
vs 5%), neutropenia (21% vs 35%), and thrombocytopenia (15% vs
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 coadministering 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. For patients
with severe renal impairment, the recommended dose of TALZENNA is
0.5 mg once daily. No dose adjustment is required for patients with
mild renal impairment. TALZENNA has not been studied in patients
Please see full U.S. Prescribing Information and Patient
Information for TALZENNA® (talazoparib) at www.TALZENNA.com.
About XTANDI® (enzalutamide) and Important Safety
XTANDI (enzalutamide) is an androgen receptor inhibitor
indicated in the U.S. for the treatment of patients with
castration-resistant prostate cancer (CRPC) and metastatic
castration-sensitive prostate cancer (mCSPC).
Overall survival benefit has been observed in patients treated
with XTANDI in mCRPC, nmCRPC, and mCSPC.
Warnings and Precautions
Seizure occurred in 0.5% of patients receiving XTANDI in
seven 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
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 seven 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 four
randomized, placebo-controlled clinical studies, ischemic heart
disease occurred more commonly in patients on the XTANDI arm
compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4
ischemic events occurred in 1.4% of patients on XTANDI versus 0.7%
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 four randomized, placebo-controlled clinical
studies, falls occurred in 11% of patients treated with XTANDI
compared to 4% of patients treated with placebo. Fractures occurred
in 10% of patients treated with XTANDI and in 4% 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 four randomized placebo-controlled trials,
the most common ARs (≥ 10%) that occurred more frequently (≥ 2%
over placebo) in XTANDI-treated patients were asthenia/fatigue,
back pain, hot flush, constipation, arthralgia, decreased appetite,
diarrhea, and hypertension. 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 adverse events (AEs) 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 AEs 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 AE as the primary reason were reported for
8% of XTANDI patients and 6% of bicalutamide patients.
In PROSPER, the placebo-controlled study of non-metastatic CRPC
(nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of
XTANDI patients and 23% of placebo patients. Discontinuations with
an AE 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 AEs were reported in 24% of
XTANDI-treated patients. Permanent discontinuation due to AEs as
the primary reason was reported in 5% of XTANDI patients and 4% of
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 neutrophil count decreased, white blood cell decreased,
hyperglycemia, hypermagnesemia, hyponatremia, and
Hypertension: In the combined data from four randomized
placebo-controlled clinical trials, hypertension was reported in
12% of XTANDI patients and 5% of placebo patients. Hypertension led
to study discontinuation in < 1% of patients in each arm.
Effect of Other Drugs on XTANDI Avoid strong CYP2C8
inhibitors, as they can increase the plasma exposure to XTANDI. If
co-administration is necessary, reduce the dose of XTANDI.
Avoid strong CYP3A4 inducers as they can decrease the plasma
exposure to XTANDI. If co-administration is necessary, increase the
dose of XTANDI.
Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and
CYP2C19 substrates with a narrow therapeutic index, as XTANDI may
decrease the plasma exposures of these drugs. If XTANDI is
co-administered with warfarin (CYP2C9 substrate), conduct
additional INR monitoring.
Please see Full Prescribing Information for additional safety
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 people living with cancer. Today, we have an
industry-leading portfolio of 24 approved innovative cancer
medicines and biosimilars across more than 30 indications,
including breast, genitourinary, colorectal, blood and lung
cancers, as well as melanoma.
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 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.
The information contained in this release is as of October 4,
2022. 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,
a potential indication in men with metastatic castration-resistant
prostate cancer, physician and patient uptake and potential
blockbuster opportunity 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, 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
primary endpoint for cohort 2 or 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 the potential indication or for any
other indications; whether and when any such applications for
TALZENNA, XTANDI or a combination 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 our 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, 2021 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 Kirby M, et al. Int J Clin Pract. 2011;11:1180-1192. 2
ScherHI, et al. PLoSOne. 2015;10:e0139440.
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