FDA Grants Priority Review for Maintenance
Setting in Ovarian Cancer Patients with PDUFA Set for Q3
2017
AstraZeneca today announced that the US Food and Drug
Administration (FDA) has accepted the company’s New Drug
Application (NDA) for LYNPARZA™ (olaparib) tablets (300mg twice
daily) for use in platinum-sensitive, relapsed ovarian cancer
patients in the maintenance setting. The FDA has also granted
priority review status with a Prescription Drug User Fee Act
(PDUFA) set for third quarter 2017. The NDA submission includes the
LYNPARZA Phase III SOLO-2 trial data, which showed a reduced risk
of disease progression by 70 percent, compared with placebo in
germline BRCA-mutated patients.1 SOLO-2 trial results were
presented on March 14th at the Society of Gynecologic Oncology
Annual Meeting on Women’s Cancer.
The FDA grants Priority Review to applications for medicines
that treat serious conditions and, if approved, would provide a
significant improvement in treatment, safety, or efficacy over
existing therapies.2 For applications granted priority review, the
FDA takes action within six months of submission, compared with the
standard 10-month review timeline.
Andrew Coop, Vice President, US Medical Affairs, Oncology, at
AstraZeneca, said: “If approved as a maintenance therapy for
patients with advanced ovarian cancer, LYNPARZA tablets would help
address the unmet medical need and limited treatment options for
women living with this disease, and offer patients a potential
reduced pill burden for LYNPARZA. Additionally, the US FDA filing
acceptance shows how we are progressing the science behind LYNPARZA
– the first PARP inhibitor approved in the US more than two years
ago – while also investigating LYNPARZA in other tumor types,
including breast, pancreatic and prostate.”
Results from the Phase III SOLO-2 trial demonstrated a
significant improvement in progression-free survival (PFS) with
LYNPARZA tablets, compared with placebo.1 The trial met its primary
endpoint of investigator-assessed PFS (HR 0.30; 95% CI 0.22-0.41;
P<0.0001; median 19.1 months vs 5.5 months).
PFS as measured by Blinded Independent Central Review (BICR)
evaluation, a pre-specified sensitivity analysis supporting the
primary endpoint, demonstrated a median PFS of 30.2 months vs 5.5
months for placebo, representing an improvement of 24.7 months (HR
0.25; 95% CI 0.18-0.35; P<0.0001).1
The safety profile for patients treated with LYNPARZA tablets
during the SOLO-2 trial was generally consistent to those observed
with the currently approved capsule formulation.1,3 Grade ≥3
adverse events were reported in 36.9% of patients treated with
LYNPARZA, and in 18.2% of patients who received placebo.1
LYNPARZA tablets are an investigational formulation and are not
FDA-approved for any use at this time.3,4 LYNPARZA capsules (400mg
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.3 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
More than 2,600 ovarian cancer patients have been treated with
LYNPARZA capsules since it was approved in the US in December
2014.5
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 300mg 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).
Additionally, AstraZeneca has opened a Multiple Patient Expanded
Access Program (MPEAP) for olaparib tablets in the US. 6 This
program is available to eligible patients with platinum-sensitive
relapsed high-grade epithelial ovarian, fallopian tube or primary
peritoneal cancer as a maintenance treatment, following complete or
partial response to platinum-based chemotherapy.
Healthcare professionals can learn more about the MPEAP for
olaparib tablets by calling Parexel at 978-495-4423 or visiting
olaparib@parexel.com.6
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 BRCA-mutated ovarian
cancer.4 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.4,7 Eligible patients were randomized
to receive either LYNPARZA tablets (300mg twice daily) or
placebo.4
About AstraZeneca in Ovarian Cancer
In the US, ovarian cancer is the ninth most commonly diagnosed
cancer and the fifth most common cause of cancer death in women.8
The risk of developing ovarian cancer is increased in women with
specific inherited genetic abnormalities, including BRCA
mutations.9 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 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.10-12 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 compounds targeting DDR mechanisms in cancer
cells.10-12
LYNPARZA tablets are currently being investigated in monotherapy
and in combinations in a range of tumor types including breast,
prostate, and pancreatic cancer.13-16 LYNPARZA tablets are an
investigational formulation and are not FDA-approved for any
use.3
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 six
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, the genetic drivers of cancer 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. Pujade-Lauraine E., Ledermann J., Penson R., et al.,
Treatment with olaparib monotherapy in the maintenance setting
significantly improves progression-free survival in patients with
platinum-sensitive relapsed ovarian cancer: Results from the Phase
III SOLO2 Study. Presented at the Society of Gynecologic Oncology
Annual Meeting on Women’s Cancer (SGO), March 12 – 15. National
Harbor, Maryland.2. US Food and Drug Administration. Priority
Review. Available Online. Accessed March 2017.3. LYNPARZA
(olaparib) Prescribing Information. AstraZeneca Pharmaceuticals LP,
Wilmington, DE.4. National Institutes of Health. Olaparib Treatment
in BRCA Mutated Ovarian Cancer Patients After Complete or Partial
Response to Platinum Chemotherapy. Available Online. Accessed March
2017.5. Data on File, 3314404, AstraZeneca Pharmaceuticals LP.6.
National Institutes of Health. Expanded Access Program for Olaparib
Tablets as Maintenance Therapy in Patients With Ovarian, Fallopian
Tube or Primary Peritoneal Cancer. Available Online. Accessed March
2017.7. GINECO. Presentation of GINECO. Association ARCAGY - GINECO
- Hotel Dieu Hospital. Available Online. Accessed March 2017.8.
Centers for Disease Control and Prevention. Ovarian Cancer
Statistics. Available Online. Last Updated June 21, 2016. Accessed
March 2017.9. National Cancer Institute. BRCA1 and BRCA2: cancer
risk and genetic testing. Available Online. Accessed March 2017.10.
Food and Drug Administration. FDA approves Lynparza to treat
advanced ovarian cancer. Accessed March 2017.11. O’Connor M.
‘Targeting The DNA Damage Response In Cancer’ (2015) Mol Cell.
Accessed March 2017.12. 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;70:139-48.13. 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 March 2017.14. 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 March 2017.15.
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
March 2017.16. National Institutes of Health. Ph II Study to
Evaluate Olaparib With Abiraterone in Treating Metastatic
Castration Resistant Prostate Cancer. Available Online. Accessed
March 2017.
3323618 Last Updated 3/17
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