SERENA-2 Phase II trial results presented at
SABCS 2022 show potential of camizestrant as next-generation
SERD in endocrine therapy
Detailed results from the SERENA-2 Phase II trial showed
AstraZeneca’s next-generation oral selective estrogen receptor
degrader (ngSERD) camizestrant demonstrated a statistically
significant and clinically meaningful improvement in
progression-free survival (PFS) at both 75mg and 150mg dose levels
versus FASLODEX® (fulvestrant) 500mg in post-menopausal patients
with estrogen receptor (ER)-positive locally advanced or metastatic
breast cancer, previously treated with endocrine therapy. Results
will be presented today in an oral presentation at the 2022 San
Antonio Breast Cancer Symposium (SABCS).
In the overall population, camizestrant significantly reduced
the risk of disease progression or death by 42% at a 75mg dose
(based on a hazard ratio [HR] of 0.58, 90% confidence interval [CI]
0.41-0.81; p=0.0124; median PFS of 7.2 versus 3.7 months) and 33%
at a 150mg dose (HR 0.67, 90% CI 0.48-0.92; p=0.0161; median PFS of
7.7 versus 3.7 months) compared to FASLODEX, the current SERD
standard of care.
Among the prespecified subgroup of patients with ESR1 mutations
– comprising 36.7% of the trial population – camizestrant showed a
67% reduction in the risk of disease progression or death at a 75mg
dose (HR 0.33, 90% CI 0.18-0.58; median PFS of 6.3 versus 2.2
months) and a 45% reduction at a 150mg dose (HR 0.55, 90% CI
0.33-0.89; median PFS of 9.2 versus 2.2 months) compared to
FASLODEX. Efficacy was also seen in patients without a detectable
ESR1 mutation, with a 22% and 24% reduction in the risk of disease
progression or death (HR 0.78, 90% CI 0.50-1.22 and HR 0.76, 90% CI
0.48-1.20) respectively for the 75mg and 150mg dose levels.
A clinically meaningful PFS benefit was also observed across
other prespecified subgroups, including in patients with previously
treated with prior cyclin-dependent kinase (CDK) 4/6 inhibitors,
those with lung and/or liver metastases and those with ER-driven
disease.
Mafalda Oliveira, MD, PhD, Vall d’Hebron Hospital and Vall
d‘Hebron Institute of Oncology in Barcelona, Spain, and lead
investigator for the SERENA-2 Phase II trial, said: “These data
reflect an important step toward a potential new treatment option
for patients with advanced ER-positive disease. Based on the
SERENA-2 results, camizestrant was well tolerated at both doses and
significantly improved patient outcomes, nearly doubling median
progression-free survival in this setting compared with the current
SERD standard of care.”
Cristian Massacesi, Chief Medical Officer & Oncology Chief
Development Officer, Oncology R&D, AstraZeneca, said: “SERENA-2
showed a meaningful improvement over fulvestrant, demonstrating the
potential of camizestrant, our next-generation SERD, to optimize
outcomes for patients with advanced ER-driven breast cancer,
irrespective of ESR1 mutation status and prior treatment with
CDK4/6 inhibitors. Our focus on bringing new medicines to patients
across the breast cancer spectrum is unwavering and we look forward
to additional findings from our ongoing Phase III development
program for camizestrant including SERENA-4 and SERENA-6.”
Summary of results: SERENA-2
Efficacy measure
Camizestrant (75mg)
Camizestrant (150mg)
FASLODEX (500mg)
Primary endpoint
Overall population (n)
74
73
73
Median PFS (months)
7.2
7.7
3.7
Adjusted HR (90% CI)
0.58 (0.41-0.81)
0.67 (0.48-0.92)
-
P-value
0.0124*
0.0161*
-
Prespecified sub-populations of
interest
ESR1m detected (n)
22
26
35
Median PFS (months)
6.3
9.2
2.2
Adjusted HR (90% CI)
0.33 (0.18-0.58)
0.55 (0.33-0.89)
-
ESR1m not detected (n)
51
46
37
Median PFS (months)
7.2
5.8
7.2
Adjusted HR (90% CI)
0.78 (0.50-1.22)
0.76 (0.48-1.20)
-
Prior treatment with CDK4/6 inhibitors
(n)
38
37
37
Median PFS (months)
5.5
3.8
2.1
Adjusted HR (90% CI)
0.49 (0.31-0.75)
0.68 (0.44-1.04)
-
Presence of lung and/or liver metastasis
(n)
43
43
43
Median PFS (months)
7.2
5.6
2.0
Adjusted HR (90% CI)
0.43 (0.28-0.65)
0.55 (0.37-0.82)
-
Evidence of ER-driven disease (n)
50
53
53
Median PFS (months)
7.4
12.0
3.2
Adjusted HR (90% CI)
0.53 (0.35-0.79)
0.58 (0.39-0.86)
-
*Statistically significant; HR, hazard
ratio (adjusted for stratification factors [prior use of CDK4/6i
and presence of lung and/or liver metastases]); CI, confidence
interval; PFS, progression free survival; ESR1m, ESR1 mutation.
Camizestrant was generally well tolerated, and its safety
profile was consistent with that observed in previous trials with
no new safety signals identified. The most frequent
treatment-emergent adverse events (TEAEs) were photopsia (12.2%,
24.7%, 35.0% and 0%) and bradycardia (5.4%, 26.0%, 40.0% and 0%),
for 75mg, 150mg or 300mg camizestrant or fulvestrant, respectively,
all of which were Grade 1 or 2. TEAEs at Grade 3 or higher occurred
in 1.4%, 2.7%, 5.0% and 1.4% of patients in the 75mg, 150mg and
300mg camizestrant or fulvestrant arms, respectively, with only two
patients in the 75mg camizestrant arm and no patients in the 150mg,
300mg camizestrant or fulvestrant arms discontinuing therapy due to
TEAEs.
AstraZeneca has a broad clinical development program for
camizestrant in advanced breast cancer. The SERENA-6 Phase III
trial is assessing camizestrant in combination with CDK4/6
inhibitors for the 1st-line treatment of patients with HR-positive
metastatic breast cancer who have developed detectable ESR1
mutations during treatment with aromatase inhibitors, and the
SERENA-4 Phase III trial is evaluating camizestrant plus
palbociclib (CDK4/6 inhibitor) for the 1st-line treatment of
patients with HR-positive, locally advanced or metastatic breast
cancer. The indication sought for SERENA-6 has been granted Fast
Track Designation by the US Food and Drug Administration.
Important Safety Information About FASLODEX® (fulvestrant)
injection
Contraindications
- FASLODEX is contraindicated in patients with known
hypersensitivity to the drug or to any of its components.
Hypersensitivity reactions, including urticaria and angioedema,
have been reported in association with FASLODEX
Warnings and Precautions
Risk of Bleeding
- Because FASLODEX is administered intramuscularly, it should be
used with caution in patients with bleeding diatheses,
thrombocytopenia, or anticoagulant use
Hepatic Impairment
- FASLODEX is metabolized primarily in the liver. A 250 mg dose
is recommended in patients with moderate hepatic impairment
(Child-Pugh class B). FASLODEX has not been evaluated in patients
with severe hepatic impairment (Child-Pugh class C)
Injection Site Reaction
- Use caution while administering FASLODEX at the dorsogluteal
injection site due to the proximity of the underlying sciatic
nerve. Injection site-related events, including sciatica,
neuralgia, neuropathic pain, and peripheral neuropathy, have been
reported with FASLODEX injection
Embryo-Fetal Toxicity and Lactation
- Pregnancy testing is recommended for females of reproductive
potential within seven days prior to initiating FASLODEX
- Advise pregnant women of the potential risk to a fetus. Advise
women of reproductive potential to use effective contraception
during FASLODEX treatment and for 1 year after the last dose.
Advise lactating women not to breastfeed during treatment with
FASLODEX and for 1 year after the final dose because of the
potential risk to the infant
Immunoassay Measurement of Serum Estradiol
- Due to structural similarity of fulvestrant and estradiol,
FASLODEX can interfere with estradiol measurement by immunoassay,
resulting in falsely elevated estradiol levels
Adverse Reactions Monotherapy
- The most common adverse reactions occurring in ≥5% of patients
receiving FASLODEX 500 mg were injection site pain, nausea, bone
pain, arthralgia, headache, back pain, fatigue, pain in extremity,
hot flash, myalgia, vomiting, anorexia, diarrhea, asthenia,
musculoskeletal pain, cough, dyspnea, and constipation
- Increased hepatic enzymes (ALT, AST, ALP) occurred in >15%
of FASLODEX patients and were not dose-dependent
Combination Therapy – FASLODEX plus ribociclib
- The most frequently reported (≥5%) Grade 3 or 4 adverse
reactions in patients receiving FASLODEX plus ribociclib in
descending frequency were neutropenia, leukopenia, infections, and
abnormal liver function tests
- The most common adverse reactions (≥20%) of any grade reported
in patients receiving FASLODEX 500 mg plus ribociclib 600 mg/day
were neutropenia, infections, leukopenia, cough, nausea, diarrhea,
vomiting, constipation, pruritus, and rash
- Additional adverse reactions in patients receiving FASLODEX
plus ribociclib included asthenia, dyspepsia, thrombocytopenia, dry
skin, dysgeusia, electrocardiogram QT prolonged, dry mouth,
vertigo, dry eye, lacrimation increased, erythema, hypocalcemia,
blood bilirubin increased, and syncope
Combination Therapy—FASLODEX plus palbociclib
- The most frequently reported Grade ≥3 adverse reactions in
patients receiving FASLODEX plus palbociclib in descending
frequency were neutropenia and leukopenia
- Adverse reactions (≥10%) of any grade reported in patients
receiving FASLODEX 500 mg plus palbociclib 125 mg/day by descending
frequency were neutropenia, leukopenia, infections, fatigue,
nausea, anemia, stomatitis, diarrhea, thrombocytopenia, vomiting,
alopecia, rash, decreased appetite, and pyrexia
- Additional adverse reactions occurring at an overall incidence
of <10% of patients receiving FASLODEX plus palbociclib included
asthenia, aspartate aminotransferase increased, dysgeusia,
epistaxis, lacrimation increased, dry skin, alanine
aminotransferase increased, vision blurred, dry eye, and febrile
neutropenia
Combination Therapy—FASLODEX plus abemaciclib
- The most frequently reported (≥5%) Grade 3 or 4 adverse
reactions in patients receiving FASLODEX plus abemaciclib were
neutropenia, diarrhea, leukopenia, anemia, and infections
- The most common adverse reactions (≥20%) of any grade reported
in patients receiving FASLODEX 500 mg plus abemaciclib 150 mg twice
daily were diarrhea, fatigue, neutropenia, nausea, infections,
abdominal pain, anemia, leukopenia, decreased appetite, vomiting,
and headache
Indications for FASLODEX Monotherapy FASLODEX is an
estrogen receptor antagonist indicated for the treatment of:
- Hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced breast cancer in postmenopausal
women not previously treated with endocrine therapy
- HR-positive advanced breast cancer in postmenopausal women with
disease progression following endocrine therapy
Combination Therapy FASLODEX is indicated for the treatment
of:
- HR-positive, HER2-negative advanced or metastatic breast cancer
in postmenopausal women in combination with ribociclib as initial
endocrine-based therapy or following disease progression on
endocrine therapy
- HR-positive, HER2-negative advanced or metastatic breast cancer
in combination with palbociclib or abemaciclib in women with
disease progression after endocrine therapy
Please see full Prescribing Information for
FASLODEX with Patient Information
Notes
Hormone Receptor (HR)-positive breast cancer Breast
cancer is the most common cancer and is one of the leading causes
of cancer-related deaths worldwide.1 More than two million patients
were diagnosed with breast cancer in 2020, with nearly 685,000
deaths globally.1
HR-positive breast cancer (expressing estrogen or progesterone
receptors, or both) is the most common subtype of breast cancer
with approximately 70% of breast cancer tumors considered
HR-positive and HER2-low or negative.2
The growth of HR-positive breast cancer cells is often driven by
estrogen receptors (ER),3 and endocrine therapies that target
ER-driven disease are widely used as 1st-line treatment in the
advanced setting, and often paired with cyclin-dependent kinase
(CDK) 4/6 inhibitors.4,5 However, resistance to CDK4/6 inhibitors
and current endocrine therapies develops in many patients with
advanced disease.5 Once this occurs, the treatment options are
limited5 – with chemotherapy being the current standard of care6 –
and survival rates are low with 30% of patients anticipated to live
beyond five years after diagnosis.2
Optimizing endocrine therapy and overcoming resistance for
patients with ER-driven disease at all stages of treatment as well
as identifying new therapies for those who no longer have ER-driven
disease are active areas of focus for breast cancer research.
SERENA-2 SERENA-2 is a randomized, open-label, parallel
group, multicenter Phase II trial evaluating camizestrant at
several dose levels compared to FASLODEX in advanced ER-positive,
HER2-negative breast cancer. The primary endpoints are PFS defined
by response evaluation criteria in solid tumors (RECIST) version
1.1 for 75mg camizestrant versus FASLODEX and for 150mg
camizestrant versus FASLODEX. 240 patients were randomized to
receive camizestrant or FASLODEX until disease progression.
Secondary endpoints include safety, objective response rate and
clinical benefit rate at 24 weeks.
Camizestrant Camizestrant is a potent, next-generation
oral SERD and pure ERα antagonist, that has demonstrated
anti-cancer activity across a range of preclinical models,
including those with ER-activating mutations.
AstraZeneca has a broad clinical development program evaluating
the safety and efficacy of camizestrant when used as a monotherapy
or in combination with other agents to address a number of areas of
unmet need in HR-positive breast cancer.
In addition to SERENA-2 and the ongoing SERENA-4 and SERENA-6
trials, the SERENA-1 Phase I trial demonstrated that camizestrant
is well tolerated and has a promising anti-tumor profile when
administered alone or in combination with palbociclib, a CDK4/6
inhibitor. Combinations with other agents are ongoing in
SERENA-1.
AstraZeneca in breast cancer Driven by a growing
understanding of breast cancer biology, AstraZeneca is starting to
challenge, and redefine, the current clinical paradigm for how
breast cancer is classified and treated to deliver even more
effective treatments to patients in need – with the bold ambition
to one day eliminate breast cancer as a cause of death.
AstraZeneca has a comprehensive portfolio of approved and
promising compounds in development that leverage different
mechanisms of action to address the biologically diverse breast
cancer tumor environment.
With fam-trastuzumab deruxtecan-nxki, a HER2-directed ADC,
AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in
previously treated HER2-positive and HER2-low metastatic breast
cancer and are exploring its potential in earlier lines of
treatment and in new breast cancer settings.
In HR-positive breast cancer, AstraZeneca continues to improve
outcomes with foundational medicines FASLODEX and goserelin and
aims to reshape the HR-positive space with ngSERD and potential new
medicine camizestrant as well as a potential first-in-class AKT
kinase inhibitor, capivasertib. AstraZeneca is also collaborating
with Daiichi Sankyo to explore the potential of TROP2-directed ADC,
datopotamab deruxtecan, in this setting.
PARP inhibitor olaparib is a targeted treatment option that has
been studied in early and metastatic breast cancer with an
inherited BRCA mutation. AstraZeneca with Merck & Co., Inc.,
known as MSD outside the US and Canada continue to research
olaparib in these settings and to explore its potential in earlier
disease.
To bring much-needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is evaluating the potential of datopotamab deruxtecan
alone and in combination with immunotherapy durvalumab,
capivasertib in combination with chemotherapy, and durvalumab in
combination with other oncology medicines, including olaparib and
fam-trastuzumab deruxtecan-nxki.
AstraZeneca in oncology AstraZeneca is leading a
revolution in oncology with the ambition to provide cures for
cancer in every form, following the science to understand cancer
and all its complexities to discover, develop and deliver
life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyze changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care and, one day,
eliminate cancer as a cause of death.
About AstraZeneca AstraZeneca is a global, science-led
biopharmaceutical company that focuses on the discovery,
development, and commercialization of prescription medicines in
Oncology, Rare Diseases, and BioPharmaceuticals, including
Cardiovascular, Renal & Metabolism, and Respiratory &
Immunology. Based in Cambridge, UK, AstraZeneca operates in over
100 countries and its innovative medicines are used by millions of
patients worldwide. Please visit astrazeneca-us.com and follow the
Company on Twitter @AstraZenecaUS.
References
- Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN
Estimates of Incidence and Mortality Worldwide for 36 Cancers in
185 Countries. CA Cancer J Clin. 2021; 10.3322/caac.21660.
- National Cancer Institute. Surveillance, Epidemiology and End
Results Cancer Stat Facts: Female Breast Cancer Subtypes. Available
at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed December 2022.
- Scabia V, et al. Estrogen receptor positive breast cancers have
patient specific hormone sensitivities and rely on progesterone
receptor. Nat Commun. 2022; 10.1038/s41467-022-30898-0.
- Lin M, et al. Comparative Overall Survival of CDK4/6 Inhibitors
Plus Endocrine Therapy vs. Endocrine Therapy Alone for Hormone
receptor-positive, HER2-negative metastatic breast cancer. J
Cancer. 2020; 10.7150/jca.48944.
- Lloyd M R, et al. Mechanisms of Resistance to CDK4/6 Blockade
in Advanced Hormone Receptor-positive, HER2-negative Breast Cancer
and Emerging Therapeutic Opportunities. Clin Cancer Res. 2022;
28(5):821-30.
- National Comprehensive Cancer Network. Clinical Practice
Guidelines in Oncology (NCCN Guidelines). Available at:
https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419.
Accessed December 2022.
US-71678 Last Updated 12/22
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