OlympiAD was the first positive Phase III
trial to evaluate the efficacy and safety of a PARP inhibitor
beyond ovarian cancer
LYNPARZA tablets reduced risk of disease
worsening or death by 42%
The overall safety profile was consistent
with previous trials of LYNPARZA
AstraZeneca today presented positive results from its Phase III
OlympiAD trial that showed a statistically-significant and
clinically-meaningful improvement in progression-free survival
(PFS) for patients treated with LYNPARZATM (olaparib) tablets (300
mg twice daily), compared to treatment with physician’s choice of a
standard of care chemotherapy. In addition to meeting its primary
endpoint of PFS assessed by blinded independent central review
(BICR), the trial showed that patients treated with LYNPARZA had a
42% reduction in risk of their disease worsening or death (HR 0.58;
95% CI 0.43-0.80; p= 0.0009; median 7.0 vs 4.2 months) compared to
those who received chemotherapy (capecitabine, vinorelbine,
eribulin).1
The data were presented at the 2017 ASCO Annual Meeting in
Chicago, during today’s Plenary Session from 3:10 – 3:25 pm CDT
(Abstract LBA4).1 Additionally, the trial was designated for the
“Best of ASCO” selection, underscoring the importance of these
results for patients and physicians.
Mark E. Robson, Clinic Director of the Clinical Genetics Service
at Memorial Sloan Kettering Cancer Center, New York and Principal
Investigator of OlympiAD said, “The OlympiAD data presented today
demonstrate the benefit of olaparib in delaying the progression of
advanced BRCA-mutated breast cancer. With few alternatives
available, a targeted non-chemotherapy oral treatment in this
setting could be a beneficial new option for patients.”
Sean Bohen, Executive Vice President, Global Medicines
Development and Chief Medical Officer at AstraZeneca, said, “The
OlympiAD results shared today mark the first time a targeted
therapy shows benefit over the current standard of care for
patients with HER2-negative gBRCA-mutated metastatic breast cancer.
This also represents an important milestone for LYNPARZA as this is
the first positive Phase III trial in which a PARP inhibitor has
shown a significant benefit for patients outside of ovarian
cancer.”
Patients in the trial had HER2-negative germline BRCA1 or
BRCA2-mutated breast cancer and were receiving LYNPARZA as their
first, second or third-line medicine for metastatic disease. Before
enrollment, patients had prior treatment with an anthracycline
(unless contraindicated) and a taxane; hormone receptor-positive
patients received at least one endocrine medicine or were not
eligible for endocrine medicines.1,2
Secondary endpoints showed an improvement in time until second
progression or death (PFS2) in the LYNPARZA arm of the trial,
compared to those treated with chemotherapy (HR 0.57; 95% CI: 0.40
- 0.83). In addition, the objective response rate (ORR) was more
than doubled, with 59.9% of patients in the LYNPARZA arm showing
response to treatment, compared to 28.8% of patients treated with
chemotherapy.1
A review of the LYNPARZA safety data from the OlympiAD trial did
not identify any new safety signals and the overall safety profile
was consistent with previous trials of LYNPARZA. There was a lower
incidence of grade ≥3 adverse events in the LYNPARZA arm compared
to the chemotherapy arm (36.6% vs 50.5% respectively). A smaller
proportion of patients discontinued treatment in the LYNPARZA arm
compared to the chemotherapy arm (4.9% vs 7.7% respectively).1
LYNPARZA tablets are an investigational formulation and are not
FDA-approved for any use.2,3 LYNPARZA capsules (400 mg twice daily)
are currently approved in the US as a monotherapy in patients with
deleterious or suspected deleterious germline BRCA-mutated (as
detected by an FDA-approved test) advanced ovarian cancer who have
been treated with three or more prior lines of chemotherapy. The
indication is approved under accelerated approval based on
objective response rate and duration of response. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in confirmatory trials.3
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
There are no contraindications for LYNPARZA.
Myelodysplastic Syndrome/Acute Myeloid Leukemia
(MDS/AML): Occurred in <1% of patients treated with
LYNPARZA, and the majority of those reports were fatal. The
duration of therapy in patients who developed secondary MDS/AML
varied from <6 months to >2 years. In a randomized
placebo-controlled trial, MDS/AML occurred in 2% of patients
treated with LYNPARZA. All of these patients had previous
chemotherapy with platinum agents and/or other DNA damaging agents,
including radiotherapy, and some of these patients also had a
history of previous cancer or of bone marrow dysplasia.
Monitor patients for hematological toxicity at baseline and
monthly thereafter. Do not start LYNPARZA until patients have
recovered from hematological toxicity caused by previous
chemotherapy (≤Grade 1). For prolonged hematological toxicities,
interrupt LYNPARZA and monitor blood counts weekly until recovery.
If the levels have not recovered to Grade 1 or less after four
weeks, refer the patient to a hematologist for further
investigations, including bone marrow analysis and blood sample for
cytogenetics. Discontinue if MDS/AML is confirmed.
Pneumonitis: Occurred in <1% of patients exposed to
LYNPARZA, and some cases were fatal. If patients present with new
or worsening respiratory symptoms such as dyspnea, fever, cough,
wheezing, or a radiological abnormality occurs, interrupt treatment
with LYNPARZA and initiate prompt investigation. Discontinue if
pneumonitis is confirmed.
Embryo-Fetal Toxicity: LYNPARZA can cause fetal harm. A
pregnancy test should be performed on all pre-menopausal women
prior to treatment. Advise females of reproductive potential of the
potential risk to a fetus and to use effective contraception during
treatment and for six months after receiving the final dose.
ADVERSE REACTIONS
In clinical studies, the most common adverse reactions (Grades
1-4) in ≥20% of patients included anemia (34%), nausea (75%),
fatigue (including asthenia) (68%), vomiting (43%), diarrhea (31%),
dysgeusia (21%), dyspepsia (25%), headache (25%), decreased
appetite (25%), nasopharyngitis/pharyngitis/URI (43%), cough (21%),
arthralgia/musculoskeletal pain (32%), myalgia (25%), back pain
(25%), dermatitis/rash (25%), and abdominal pain/discomfort
(47%).
Common lab abnormalities (Grades 1-4) included decrease in
hemoglobin (90%), decrease in absolute neutrophil count (32%),
decrease in platelets (30%), decrease in lymphocytes (56%), mean
corpuscular volume elevation (85%), and increase in creatinine
(30%).
DRUG INTERACTIONS
Anticancer Agents: Clinical studies of LYNPARZA in
combination with other myelosuppressive anticancer agents,
including DNA damaging agents, indicate a potentiation and
prolongation of myelosuppressive toxicity.
CYP3A Inhibitors: Avoid concomitant use of strong and
moderate CYP3A inhibitors. If the strong or moderate CYP3A
inhibitor must be co-administered, reduce the dose of LYNPARZA.
Advise patients to avoid grapefruit and Seville oranges during
LYNPARZA treatment.
CYP3A Inducers: Avoid concomitant use of strong and
moderate CYP3A inducers when using LYNPARZA. If a moderate inducer
cannot be avoided, be aware of a potential for decreased efficacy
of LYNPARZA.
USE IN SPECIFIC POPULATIONS
Lactation: No data are available regarding the presence
of olaparib in human milk, the effects on the breastfed infant or
on milk production. Because of the potential for serious adverse
reactions in the breastfed infant, advise a lactating woman not to
breastfeed during treatment with LYNPARZA and for one month after
receiving the final dose.
Hepatic Impairment: No dose adjustment is required in
patients with mild hepatic impairment (Child-Pugh classification
A). There are no data in patients with moderate or severe hepatic
impairment.
Renal Impairment: No dosage adjustment is necessary in
patients with mild renal impairment (CLcr 51-80 mL/min). In
patients with moderate renal impairment (CLcr 31-50 mL/min), reduce
the dose to 300 mg twice daily. There are no data in patients with
severe renal impairment or end-stage renal disease (CLcr ≤30
mL/min).
Please see complete Prescribing Information, including
Patient Information (Medication Guide).
NOTES TO EDITORS
About OlympiAD
OlympiAD is a randomized, open label, multi-center Phase III
trial assessing the efficacy and safety of LYNPARZA tablets (300 mg
twice daily) compared to ‘physician’s choice’ chemotherapy
(capecitabine, vinorelbine, eribulin) in 302 patients with
HER2-negative metastatic breast cancer with germline BRCA1 or BRCA2
mutations, which are predicted or suspected to be deleterious. The
international trial was conducted in 19 countries from across
Europe, Asia, North America and South America.1,2
Within the eligible patient population, there was a 1:1 ratio
between triple-negative breast cancer (TNBC) and hormone receptor
positive (ER+ and/or PR+) patients.1
The primary endpoint of the trial was progression-free survival
(PFS) as measured by a Blinded Independent Central Review
(BICR).1,2 Secondary endpoints include overall survival (OS), time
to second progression or death (PFS2), objective response rate
(ORR), and effect on health-related quality of life (HRQoL).1,2
About LYNPARZATM (olaparib)
LYNPARZATM (olaparib) was the first FDA-approved oral poly
ADP-ribose polymerase (PARP) inhibitor that may exploit tumor DNA
damage response (DDR) pathway deficiencies to preferentially kill
cancer cells.4-6 Specifically, in vitro studies have shown that
olaparib-induced cytotoxicity may involve inhibition of PARP
enzymatic activity and increased formation of PARP-DNA complex,
resulting in disruption of cellular homeostasis and cell
death.3
LYNPARZA is the foundation of AstraZeneca’s industry-leading
portfolio of approved and potential new medicines targeting DNA
damage response (DDR) mechanisms in cancer cells.4-6
LYNPARZA is currently being tested in another separate adjuvant
(non-metastatic) breast cancer Phase III trial called OlympiA. This
trial is still open and recruiting patients internationally.7
About Metastatic Breast Cancer
Approximately one in eight women are diagnosed with breast
cancer in the US.8 Of these patients, approximately one-third are
either diagnosed with or progress to the metastatic stage of the
disease.9 Despite treatment options increasing during the past
three decades, there is currently no cure for patients diagnosed
with metastatic breast cancer.10,11 Thus, the primary aim of
treatment is to slow progression of the disease for as long as
possible, improving or at least maintaining, a patient’s quality of
life.9
About Germline BRCA Mutations
BRCA1 and BRCA2 are human genes that produce proteins
responsible for repairing damaged DNA and play an important role
maintaining the genetic stability of cells. When either of these
genes is mutated, or altered, such that its protein product either
is not made or does not function correctly, DNA damage may not be
repaired properly. As a result, cells are more likely to develop
additional genetic alterations that can lead to cancer.12
Specific inherited mutations in BRCA1 and BRCA2 increase the
risk of female breast and ovarian cancers, and they have been
associated with increased risks of several additional types of
cancer. Together, BRCA1 and BRCA2 mutations account for about 20 to
25 percent of hereditary breast cancers and about 5 to 10% of all
breast cancers. In addition, mutations in BRCA1 and BRCA2 account
for around 15% of ovarian cancers overall. Breast and ovarian
cancers associated with BRCA1 and BRCA2 mutations tend to develop
at younger ages than their nonhereditary counterparts.12
About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a
quickly growing portfolio of new medicines that has the potential
to transform patients’ lives and the Company’s future. With at
least six new medicines to be launched between 2014 and 2020 and a
broad pipeline of small molecules and biologics in development, we
are committed to advance New Oncology as one of AstraZeneca’s five
Growth Platforms focused on lung, ovarian, breast and blood
cancers. In addition to our core capabilities, we actively pursue
innovative partnerships and investments that accelerate the
delivery of our strategy as illustrated by our majority investment
in Acerta Pharma in hematology.
By harnessing the power of four scientific platforms –
Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response
and Antibody Drug Conjugates – and by championing the development
of personalized combinations, AstraZeneca has the vision to
redefine cancer treatment 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, primarily for the treatment of diseases in
three main therapy areas - Oncology, Cardiovascular & Metabolic
Diseases and Respiratory. The Company also is selectively active in
the areas of autoimmunity, neuroscience and infection. AstraZeneca
operates in over 100 countries and its innovative medicines are
used by millions of patients worldwide. For more information,
please visit www.astrazeneca-us.com and follow us on Twitter
@AstraZenecaUS.
References
1. Robson M., Im SA., Senkus E., et al, OlympiAD: Phase III
trial of olaparib monotherapy versus chemotherapy for patients
(pts) with HER2-negative metastatic breast cancer (mBC) and a
germline BRCA mutation (gBRCAm), Presented at the American Society
of Clinical Oncology Annual Meeting, Chicago; June 2-6, 2017.
Abstract available Online. Accessed June 2017.
2. National Institutes of Health. Assessment of the Efficacy and
Safety of Olaparib Monotherapy Versus Physicians Choice
Chemotherapy in the Treatment of Metastatic Breast Cancer Patients
With Germline BRCA1/2 Mutations (OlympiAD). Available Online.
Accessed June 2017.
3. LYNPARZA (olaparib) Prescribing Information. AstraZeneca
Pharmaceuticals LP, Wilmington, DE.
4. Food and Drug Administration. FDA approves Lynparza to treat
advanced ovarian cancer. Accessed June 2017.
5. O’Connor M. ‘Targeting The DNA Damage Response In Cancer’
(2015) Mol Cell.60.547-560. Accessed June 2017.
6. Tutt A N J, Lord C J, McCabe N. Exploiting the DNA Repair
Defect in BRCA Mutant Cells in the Design of New Therapeutic
Strategies for Cancer. Cold Spring Harb Symp Quant
Niol. 2005;70:139-48.
7. National Institutes of Health. Olaparib as Adjuvant Treatment
in Patients With Germline BRCA Mutated High Risk HER2 Negative
Primary Breast Cancer (OlympiA). Available Online. Accessed June
2017.
8. National Cancer Institute. SEER Cancer Stat Facts: Female
Breast Cancer. Available Online. Accessed June 2017.
9. O’Shaughnessy J. Extending Survival with Chemotherapy in
Metastatic Breast Cancer. The Oncologist 2005;10(3):20–29.
10. American Cancer Society. Breast Cancer Facts & Figures
2015-2016. Available Online. Accessed June 2017.
11. American Cancer Society. Managing Cancer as a Chronic
Illness. Available Online. Accessed June 2017.
12. National Cancer Institute. BRCA1 and BRCA2: Cancer Risk and
Genetic Testing. Available Online. Accessed June 2017.
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