LYNPARZA® (olaparib) Receives Additional FDA Approval in the US for Ovarian Cancer

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

WILMINGTON, Del.–(BUSINESS WIRE)–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
    approval
    4) 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 of
disease progression or death
(PFS)

 

Reduction in the risk of
death (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

  1. LYNPARZA (olaparib) Tablets Prescribing Information. AstraZeneca
    Pharmaceuticals LP, Wilmington, DE.
  2. 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.
  3. LYNPARZA (olaparib) Capsules Prescribing Information. AstraZeneca
    Pharmaceuticals LP, Wilmington, DE.
  4. 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.
  5. 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.
  6. US Food and Drug Administration. FDA approves Lynparza to treat
    advanced ovarian cancer. Accessed August 2017.
  7. Data on File, US-11033, AstraZeneca Pharmaceuticals LP.
  8. 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.
  9. O’Connor M. Targeting the DNA damage response in cancer. Mol Cell.
    2015; Accessed August 2017.
  10. 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 Bio
    l. 2005;70:139-148.
  11. 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.
  12. 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.
  13. 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.
  14. National Institutes of Health. Ph II study to evaluate olaparib with
    abiraterone in treating metastatic castration resistant prostate
    cancer. Available
    Online
    . Accessed August 2017.
  15. Centers for Disease Control and Prevention. Ovarian Cancer Statistics. Available
    Online
    . Accessed August 2017.
  16. National Cancer Institute. BRCA1 and BRCA2: cancer risk and genetic
    testing. Available
    Online
    . Accessed August 2017.

US-9482 Last Updated 8/17

Contacts

AstraZeneca
Michele Meixell, +1 302-885-2677
Alexandra Engel,
+1 302-885-2677