Market Overview

US FDA Accepts Regulatory Submission for LYNPARZA® (olaparib) in Metastatic Breast Cancer and Grants Priority Review

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LYNPARZA has the potential to offer a new treatment option for
patients with germline BRCA-mutated, HER2-negative metastatic breast
cancer

Regulatory submission acceptance is first for a PARP inhibitor
beyond ovarian cancer

AstraZeneca and Merck & Co., Inc., (Merck: known as MSD outside the US
and Canada) today announced that the US Food and Drug Administration
(FDA) has accepted and granted priority review for a supplemental New
Drug Application (sNDA) for the use of LYNPARZA® (olaparib)
tablets in patients with germline BRCA-mutated (gBRCAm),
HER2-negative metastatic breast cancer who have been previously treated
with chemotherapy in the neoadjuvant, adjuvant, or metastatic settings.
A Prescription Drug User Fee Act (PDUFA) date is set for the first
quarter of 2018.

This is the first submission for a poly ADP-ribose polymerase (PARP)
inhibitor outside ovarian cancer and the third indication submission for
LYNPARZA in the US. The sNDA is based on the positive results
from the Phase
III OlympiAD trial
published in the New England Journal of
Medicine
.1

LYNPARZA was first approved in December 2014 as a capsule
formulation, making it the first ever PARP inhibitor to be approved.2
Since then, LYNPARZA has been used to treat more than 3,000 advanced
ovarian cancer patients.3 LYNPARZA tablets are
currently being tested in a range of tumor types, including breast,
prostate, and pancreatic cancers.4,5,6

LYNPARZA tablets are currently approved in the US as a maintenance
treatment for 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.7,8
The medicine is also indicated for use in adult patients with
deleterious or suspected deleterious gBRCA-mutated 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.7

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 OlympiAD

OlympiAD is a randomized, open-label, multicenter Phase III trial
assessing the efficacy and safety of LYNPARZA tablets (300mg 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 across Europe, Asia, North America
and South America.1,9

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.2,10,11
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.7

LYNPARZA is the foundation of AstraZeneca's industry-leading portfolio
of compounds targeting DDR mechanisms in cancer cells.2,10,11

About Metastatic Breast Cancer

Approximately one in eight women are diagnosed with breast cancer in the
US.12 Of these patients, approximately one-third are either
diagnosed with or progress to the metastatic stage of the disease.13
Despite treatment options increasing during the past three decades,
there is currently no cure for patients diagnosed with metastatic breast
cancer.14,15 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.13

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.16

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 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

 
1.     Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast
cancer in patients with a germline BRCA mutation. N Engl J Med.
2017; DOI: 10.1056/NEJMoa1706450
2. US Food and Drug Administration. FDA approves Lynparza to treat
advanced ovarian cancer. Accessed October 2017.
3. Data on File, US-11033, AstraZeneca Pharmaceuticals LP.
4.

US 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 October 2017.

5.

US National Institutes of Health. Study of Olaparib (Lynparza™)
Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic
Castration-Resistant Prostate Cancer (PROfound Study). Available
Online
. Accessed October 2017.

6.

US 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 October 2017.

7. LYNPARZA (olaparib) Tablets Prescribing Information. AstraZeneca
Pharmaceuticals LP, Wilmington, DE.
8. 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.
9.

US 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 October 2017.

10. O'Connor M. Targeting the DNA damage response in cancer. Mol Cell.
2015;60:547-560. Accessed October 2017.
11. Tutt ANJ, 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.
12.

National Cancer Institute. SEER Cancer Stat Facts: Female Breast
Cancer. Available
Online
. Accessed October 2017.

13. O'Shaughnessy J. Extending survival with chemotherapy in metastatic
breast cancer. The Oncologist. 2005;10(3):20–29.
14.

American Cancer Society. Breast Cancer Facts & Figures 2015-2016. Available
Online
. Accessed October 2017.

15.

American Cancer Society. Managing Cancer as a Chronic Illness. Available
Online
. Accessed October 2017.

16.

National Cancer Institute. BRCA1 and BRCA2: Cancer Risk and
Genetic Testing. Available
Online
. Accessed October 2017.

 

US-14682 Last Updated 10/17

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