LYNPARZA’s new tablet formulation approved
as maintenance treatment for women with recurrent ovarian cancer
regardless of BRCA-mutation status
LYNPARZA tablets also indicated in
BRCA-mutated ovarian cancer beyond the third-line setting
Newly-approved tablet formulation means
reduced pill count compared to capsules
AstraZeneca and Merck & Co., Inc., (Merck: known as MSD
outside the U.S. and Canada) today announced that the US Food and
Drug Administration (FDA) has granted approval for the PARP
inhibitor, LYNPARZA® (olaparib), as follows:
- New use of LYNPARZA tablets as a
maintenance treatment of adult patients with recurrent, epithelial
ovarian, fallopian tube or primary peritoneal cancer who are in a
complete or partial response to platinum-based chemotherapy,
regardless of BRCA status;1,2
- New use of LYNPARZA tablets (2 tablets
twice daily) as opposed to capsules (8 capsules twice daily);3
- LYNPARZA tablets also now indicated
(conversion from the current accelerated approval4) for the use in
adult patients with deleterious or suspected deleterious germline
BRCA-mutated (gBRCA) advanced ovarian cancer, who have been treated
with three or more prior lines of chemotherapy; patients for this
indication are selected for therapy based on an FDA-approved
companion diagnostic.1
Sean Bohen, Executive Vice President, Global Medicines
Development and Chief Medical Officer, AstraZeneca said:
“Physicians have almost three years of clinical experience with
LYNPARZA on the market and we are now pleased to bring this
important medicine, in a new tablet formulation, to a broader group
of women. Today’s approvals validate more than 10 years of
dedicated research behind LYNPARZA, the world’s first PARP
inhibitor, which now provides oncologists with the greater
flexibility for use in terms of treatment settings. It builds on
our recently-announced collaboration with Merck, which aims to
further increase the number of treatment options available to
patients.”
Richard Penson, MD, Clinical Director of Medical Gynecologic
Oncology at Massachusetts General Hospital Cancer Center, Associate
Professor of Medicine at Harvard Medical School, and the primary
investigator in the SOLO-2 trial, said: “Today’s approval
demonstrates that olaparib is an effective option for maintenance
therapy for certain ovarian cancer patients, regardless of BRCA
status. We welcome this news in the ovarian cancer community as
more options are important to help us ensure that patients can find
a treatment that is right for them.”
Roger M. Perlmutter, President of Merck Research Laboratories,
said: “We congratulate AstraZeneca on the approval of these new
indications and the new dosage form and schedule for LYNPARZA, an
important therapeutic advance for many patients with ovarian
cancer. This is a significant first regulatory event in our
collaboration with AstraZeneca. We look forward to working with
AstraZeneca in our global collaboration to bring this medicine with
its new indications to patients.”
Two randomized trials supported the new approvals and the
conversion of accelerated approval to full approval, which was
originally based on a single-arm trial:1,3,4
- SOLO-2 (n=295) confirmed the benefit of
LYNPARZA in gBRCA-mutated patients, demonstrating a 70% reduced
risk of disease progression or death (HR 0.30 [95% CI, 0.22-0.41],
P<0.0001) and improved median progression-free survival (PFS) to
19.1 vs 5.5 months for placebo by investigator-assessed
analysis.1
- Study 19 (n=265) showed that LYNPARZA
reduced the risk of disease progression or death by 65% and
improved PFS compared with placebo in patients of any BRCA status
(HR 0.35 [95% CI, 0.25-0.49], P<0.0001; median PFS of 8.4 months
with LYNPARZA vs 4.8 months with placebo).1 Additionally, patients
in Study 19, treated with LYNPARZA as a maintenance therapy, had a
median overall survival (OS) of 29.8 months vs 27.8 months for
placebo (HR 0.73 [95% CI, 0.55-0.95]).1
Table 1. Summary of key efficacy
results from randomized trials:1
Analysis
Reduction in the risk ofdisease
progression or death(PFS)
Reduction in the risk ofdeath (OS)
SOLO-2[gBRCAm]
LYNPARZA
70% (HR 0.30 [95% CI, 0.22-0.41],
P<0.0001)
Data not yet mature Placebo
Study 19[PSR OC*]2
LYNPARZA
65% (HR 0.35 [95% CI, 0.25-0.49],
P<0.0001)
27% (HR 0.73 [95% CI,0.55-0.95]
Placebo
*PSR = Platinum-sensitive recurrent
ovarian cancer
The most common adverse reactions (≥20%) in clinical trials were
anemia, nausea, fatigue (including asthenia), vomiting,
nasopharyngitis/upper respiratory tract infection/influenza,
diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, and
decreased appetite, constipation. and stomatitis. Most common
laboratory abnormalities (≥25%) were decrease in hemoglobin,
increase in mean corpuscular volume, decrease in lymphocytes,
decrease in leukocytes, decrease in absolute neutrophil count,
increase in serum creatinine and decrease in platelets.1
The full data from the SOLO-2 trial can be found in the July 25,
2017 publication of The Lancet Oncology.5
LYNPARZA was first approved under the FDA’s Accelerated Approval
program in December 2014, as a capsule formulation, making it the
first poly ADP-ribose polymerase (PARP) inhibitor approved.3,6
Since then, more than 3,000 advanced ovarian cancer patients have
been treated with LYNPARZA capsules.7 LYNPARZA capsules are not
indicated for maintenance therapy.1
IMPORTANT SAFETY INFORMATION
DOSING AND ADMINISTRATION
To avoid substitution errors and overdose, do not substitute
LYNPARZA tablets with LYNPARZA capsules on a
milligram-to-milligram basis due to differences in the dosing and
bioavailability of each formulation. Recommended tablet dose is 300
mg, taken orally twice daily, with or without food. Continue
treatment until disease progression or unacceptable toxicity. For
adverse reactions, consider dose interruption or dose
reduction.
WARNINGS AND PRECAUTIONS
There are no contraindications for LYNPARZA.
Myelodysplastic Syndrome/Acute Myeloid Leukemia
(MDS/AML): Occurred in <1.5% of patients exposed to
LYNPARZA monotherapy, and the majority of events had a fatal
outcome. The duration of therapy in patients who developed
secondary MDS/AML varied from <6 months to >2 years. 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 bone
marrow dysplasia.
Do not start LYNPARZA until patients have recovered from
hematological toxicity caused by previous chemotherapy (≤Grade 1).
Monitor complete blood counts for cytopenia at baseline and monthly
thereafter for clinically significant changes during treatment. 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 4 weeks, refer the patient to a
hematologist for further investigations, including bone marrow
analysis and blood sample for cytogenetics. Discontinue LYNPARZA 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, cough, and
fever, or a radiological abnormality occurs, interrupt treatment
with LYNPARZA and initiate prompt investigation. Discontinue
LYNPARZA if pneumonitis is confirmed and treat patient
appropriately.
Embryo-Fetal Toxicity: Based on its mechanism of
action and findings in animals, LYNPARZA can cause fetal harm. A
pregnancy test is recommended for females of reproductive potential
prior to initiating treatment. Advise females of reproductive
potential of the potential risk to a fetus and to use effective
contraception during treatment and for 6 months after receiving the
final dose.
ADVERSE REACTIONS—Maintenance Setting
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in clinical trials of LYNPARZA in the maintenance
setting for SOLO-2: nausea (76%), fatigue
(including asthenia) (66%), anemia (44%), vomiting (37%),
nasopharyngitis/upper respiratory tract infection (URI)/influenza
(36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%),
headache (26%), decreased appetite (22%), and stomatitis (20%).
Study 19: nausea (71%), fatigue (including asthenia)
(63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory
tract infection (22%), constipation (22%), headache (21%), and
decreased appetite (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA in the maintenance
setting (SOLO-2/Study 19) were: increase in mean corpuscular
volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in
leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease
in absolute neutrophil count (51%/47%), increase in serum
creatinine (44%/45%), and decrease in platelets (42%/36%).
ADVERSE REACTIONS—Advanced gBRCAm ovarian cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in clinical trials of LYNPARZA for advanced gBRCAm ovarian
cancer after 3 or more lines of chemotherapy (pooled from 6
studies) were: fatigue (including asthenia) (66%), nausea (64%),
vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper
respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia
(22%), decreased appetite (22%), and arthralgia/musculoskeletal
pain (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA for advanced gBRCAm
ovarian cancer after 3 or more lines of chemotherapy (pooled
from 6 studies) were: decrease in hemoglobin (90%), increase in
mean corpuscular volume (57%), decrease in lymphocytes (56%),
increase in serum creatinine (30%), decrease in platelets (30%),
and decrease in absolute neutrophil count (25%).
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 or
moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor
must be co-administered, reduce the dose of LYNPARZA. Advise
patients to avoid grapefruit, grapefruit juice, Seville oranges,
and Seville orange juice during LYNPARZA treatment.
CYP3A Inducers: Avoid concomitant use of strong or
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
Pediatric Use: The safety and efficacy of LYNPARZA have
not been established in pediatric patients.
Lactation: No data are available regarding the
presence of olaparib in human milk, the effects on the breastfed
infant, or the effects 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 1 month after receiving the final dose.
Hepatic Impairment: No adjustment to the starting
dose 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 adjustment to the starting dose
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 200 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 SOLO-2
SOLO-2 was a Phase III, randomized, double-blind, multicenter
trial designed to determine the efficacy of LYNPARZA tablets as a
maintenance monotherapy compared with placebo, in patients with
platinum-sensitive, relapsed or recurrent gBRCA-mutated ovarian,
fallopian tube and primary peritoneal cancer.8 The trial, conducted
in collaboration with the European Network for Gynaecological
Oncological Trial Groups (ENGOT) and Groupe d’Investigateurs
National pour l’Etude des Cancers de l’Ovaire et du sein (GINECO),
randomized 295 patients with documented germline BRCA1 or BRCA2
mutations who had received at least two prior lines of
platinum-based chemotherapy and were in complete or partial
response.5,8 Eligible patients were randomized to receive either
LYNPARZA tablets (300mg twice daily) or placebo twice daily.5
About Study 19
Study 19 was a Phase II, randomized, double-blind,
placebo-controlled, multicenter trial, which evaluated the efficacy
and safety of LYNPARZA capsules compared with placebo in relapsed,
high-grade serous ovarian cancer patients, involving 82 sites
across 16 countries. Patients received olaparib maintenance
monotherapy, at a dose of 400mg per day or matching placebo.
Treatment continued until disease progression provided that
toxicities were manageable.2
About LYNPARZA® (olaparib)
LYNPARZA was the first FDA-approved oral poly ADP-ribose
polymerase (PARP) inhibitor that may exploit tumor DNA damage
response (DDR) pathway deficiencies to potentially kill cancer
cells.6,9,10 Specifically, in vitro studies have shown that
olaparib-induced cytotoxicity may involve inhibition of PARP
enzymatic activity and increased formation of PARP-DNA complexes,
resulting in DNA damage and cancer cell death.1
LYNPARZA is the foundation of AstraZeneca’s industry-leading
portfolio of compounds targeting DDR mechanisms in cancer
cells.6,9,10
LYNPARZA tablets are currently being investigated in
combinations in a range of tumor types, including breast, prostate,
and pancreatic cancer.11-14
LYNPARZA capsules (400mg twice daily) will still be available
through a limited specialty pharmacy network, for patients
currently being treated for deleterious or suspected deleterious
germline BRCA-mutated advanced ovarian cancer who have been treated
with three or more prior lines of chemotherapy. LYNPARZA tablets
and capsules are not the same.1
If you have been prescribed LYNPARZA tablets, do not take the
capsules. If you have any questions about LYNPARZA, please talk
with your physician or pharmacist.1
About the AstraZeneca and Merck Strategic Oncology
Collaboration
On July 27, 2017, AstraZeneca and Merck & Co., Inc.,
announced a global strategic oncology collaboration to co-develop
and co-commercialize AstraZeneca’s LYNPARZA, the world’s first and
leading PARP inhibitor, and potential new medicine selumetinib, a
MEK inhibitor, for multiple cancer types. The collaboration is
based on increasing evidence that PARP and MEK inhibitors can be
combined with PDL-1/PD-1 inhibitors for a range of tumor types and
is aimed at maximizing the potential of LYNPARZA to become the
preferred backbone of combination therapies. Working together, the
companies will jointly develop LYNPARZA and selumetinib in
combination with other potential new medicines and as a
monotherapy. Independently, the companies will develop LYNPARZA and
selumetinib in combination with their respective PD-L1 and PD-1
medicines.
About AstraZeneca in Ovarian Cancer
Approximately 20,000 women in the United States are diagnosed
with ovarian cancer each year. Among women in the United States, it
is the ninth most common cancer and the fifth leading cause of
cancer death.15
The risk of developing ovarian cancer is increased in women with
specific inherited genetic abnormalities, including BRCA
mutations.16
AstraZeneca is committed to the continued development of our
R&D portfolio for ovarian cancer, with a focus on improved care
for all patients.
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 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
- LYNPARZA (olaparib) Tablets Prescribing
Information. AstraZeneca Pharmaceuticals LP, Wilmington, DE.
- Ledermann J, Harter P, Gourley M, et
al. Olaparib maintenance therapy in platinum-sensitive relapsed
ovarian cancer. N Engl J Med 2012;366:1382-1392.
- LYNPARZA (olaparib) Capsules
Prescribing Information. AstraZeneca Pharmaceuticals LP,
Wilmington, DE.
- AstraZeneca Press Release. LYNPARZA™
approved by the US Food and Drug Administration for the treatment
of advanced ovarian cancer in patients with germline
BRCA-mutations. Available Online. Accessed August 2017.
- Pujade-Lauraine E., Ledermann J., Selle
F., et al. SOLO2/ENGOT-Ov21: A phase 3, randomised, double-blind,
placebo-controlled trial of olaparib tablets as maintenance therapy
in patients with platinum-sensitive, relapsed ovarian cancer and a
BRCA1/2 mutation. Lancet Oncol 2017. Published online.
http://dx.doi.org/10.1016/ S1470-2045(17)30469-2.
- US Food and Drug Administration. FDA
approves Lynparza to treat advanced ovarian cancer. Accessed August
2017.
- Data on File, US-11033, AstraZeneca
Pharmaceuticals LP.
- National Institutes of Health. Olaparib
treatment in BRCA mutated ovarian cancer patients after complete or
partial response to platinum chemotherapy. Available Online.
Accessed August 2017.
- O’Connor M. Targeting the DNA damage
response in cancer. Mol Cell. 2015; Accessed August 2017.
- Tutt AN, Lord CJ, 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
Biol. 2005;70:139-148.
- 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 August 2017.
- 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 August 2017.
- National Institutes of Health. Olaparib
in gBRCA mutated pancreatic cancer whose disease has not progressed
on first line platinum-based chemotherapy (POLO). Available Online.
Accessed August 2017.
- National Institutes of Health. Ph II
study to evaluate olaparib with abiraterone in treating metastatic
castration resistant prostate cancer. Available Online. Accessed
August 2017.
- Centers for Disease Control and
Prevention. Ovarian Cancer Statistics. Available Online. Accessed
August 2017.
- National Cancer Institute. BRCA1 and
BRCA2: cancer risk and genetic testing. Available Online. Accessed
August 2017.
US-9482 Last Updated 8/17
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