LYNPARZA reduced risk of disease progression
by 70% with an investigator-assessed progression-free survival of
19.1 vs 5.5 months with placebo
Blinded independent central review showed
significant progression-free survival of 30.2 months vs 5.5 months
with placebo
LYNPARZA tablets demonstrated a safety
profile generally consistent with previous studies
AstraZeneca today presented results from the Phase III SOLO-2
trial demonstrating a significant improvement in progression-free
survival (PFS) in germline BRCA-mutated (gBRCA),
platinum-sensitive, relapsed ovarian cancer patients treated with
LYNPARZA™ (olaparib) tablets (300mg twice daily), compared with
placebo in the maintenance setting. 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).1
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
Additionally, a statistically-significant benefit in time to
second progression or death (PFS2) was also seen in patients
treated with LYNPARZA (HR 0.50; 95% CI 0.34-0.72; P=0.0002; median
not reached vs 18.4 months), compared with placebo, as well as
improvements in other key secondary endpoints.1
Table 1. Progression-Free Survival
by investigator and BICR assessment:
Analysis
Medianprogression-freesurvival, months
Hazard ratio
Investigator-assessedanalysis
LYNPARZA 19.1 0.30 (95% CI, 0.22-0.41),
P<0.0001 Placebo 5.5
BlindedIndependentCentral Review
LYNPARZA 30.2 0.25 (95% CI, 0.18-0.35), P<0.0001
Placebo 5.5
These results, presented at the Society of Gynecologic Oncology
Annual Meeting on Women’s Cancer in National Harbor, Maryland,
build upon prior data in this setting, demonstrating the potential
of LYNPARZA as a maintenance therapy in relapsed ovarian
cancer.1,2
Richard Penson, MD, Associate Professor of Medicine at Harvard
Medical School and Clinical Director of Medical Gynecologic
Oncology at Massachusetts General Hospital said: “The SOLO-2 data
demonstrated a statistically significant and clinically meaningful
improvement in outcomes for those who took olaparib. The results,
which showed a delay in disease progression in the maintenance
setting, highlight the impact of PARP inhibition at the
forefront of the important advances we are making in targeting
ovarian cancer.”
Sean Bohen, Executive Vice President, Global Medicines
Development and Chief Medical Officer at AstraZeneca, said: “We are
extremely pleased with the results from SOLO-2, which support the
potential benefit of LYNPARZA tablets as a maintenance therapy for
patients with relapsed ovarian cancer. The tablet formulation may
offer patients a reduced pill burden for LYNPARZA and a safety
profile that is generally consistent with previous trials. We will
work with regulatory authorities to make LYNPARZA tablets available
to patients as quickly as possible.”
The safety profile for patients treated with LYNPARZA tablets
during the trial was generally consistent to those observed with
the currently-approved capsule formulation.1 Any adverse events
(AE) Grade ≥3 were reported in 36.9% of patients treated with
LYNPARZA and in 18.2% of patients who received placebo.1 The most
common non-hematological AEs reported at a frequency of ≥20% in the
LYNPARZA arm versus placebo were nausea (75.9% vs 33.3%),
fatigue/asthenia (65.6% vs 39.4%), and vomiting (37.4% vs 19.2%).1
Grade ≥3 non-hematological AEs reported at a frequency of ≥2.5% in
the LYNPARZA arm versus placebo were fatigue/asthenia (4.1% vs
2.0%), vomiting (2.6 % vs 1.0%), abdominal pain (2.6% vs 3.0%),
nausea (2.6% vs 0.0%), diarrhea (1.0% vs 0.0%), and constipation
(0.0% vs 3.0%).1
The most common hematological AEs reported in the LYNPARZA arm
versus placebo were anemia (43.6% vs 8.1%), neutropenia (19.5% vs
6.1%), and thrombocytopenia (13.8% vs 3.0%).1 Grade ≥3
hematological AEs reported in the LYNPARZA arm versus placebo were
anemia (19.5% vs 2.0%), neutropenia (5.1% vs 4.0%), and
thrombocytopenia (1.0% vs 1.0%).1
The 300mg twice-daily tablet dose potentially reduces the pill
burden for patients from 16 capsules to four tablets per day.
LYNPARZA tablets are an investigational formulation and are not
FDA-approved for any use.3,4 LYNPARZA capsules (400mg twice daily)
are currently approved in the U.S. 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 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).
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
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.4,5 Eligible patients were randomized
to receive either LYNPARZA tablets (300mg twice daily) or
placebo.4
About AstraZeneca in Ovarian Cancer
In the U.S., ovarian cancer is the ninth most commonly diagnosed
cancer and the fifth most common cause of cancer death in women.6
The risk of developing ovarian cancer is increased in women with
specific inherited genetic abnormalities, including BRCA
mutations.7 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.8-10 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.8-10
LYNPARZA tablets are currently being investigated in monotherapy
and in combinations in a range of tumor types including breast,
prostate, and pancreatic cancer.11-14 LYNPARZA tablets are an
investigational formulation and are not FDA-approved for any
use.3
About ENGOT
ENGOT (European Network for Gynaecological Oncological Trial
groups) is a research network of the European Society of
Gynaecological Oncology (ESGO) and was founded in 2007. Currently,
ENGOT consists of 19 cooperative groups from 15 European countries.
ENGOT's ultimate goal is to bring the best treatment to
gynecological cancer patients through the best science, and
enabling every patient in every European country to access a
clinical trial. ENGOT coordinates and promotes multinational
clinical trials within Europe on patients with gynecological
cancer. This coordination is particularly relevant for academic
clinical trials, translational research, research on rare diseases,
and for clinical trials sponsored by the industry.15
About GINECO
GINECO (Groupe d’Investigateurs National pour l’Etude des
Cancers de l’Ovaire et du sein) is the French Cooperative Group in
Oncology labeled by INCA (Institut National du Cancer or French
NCI) for developing and conducting gynecological and advanced
breast cancer clinical trials at the national and international
level. The network is nationwide over 500 specialized investigators
belonging to more than 150 public or private oncology units. The
GINECO group was founded in 1993 and is member of international
consortia such as ENGOT and GCIG (Gynecologic Cancer InterGroup).
GINECO was the ENGOT leading group for SOLO-2 trial.4,5
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
- 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 SOLO-2 Study. Presented at the
Society of Gynecologic Oncology Annual Meeting on Women’s Cancer
(SGO), March 12 – 15. National Harbor, Maryland.
- Ledermann J., Harter P., Gourley M., et
al., Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed
Ovarian Cancer. N Engl J Med 2012;366:1382-92.
- LYNPARZA (olaparib) Prescribing
Information. AstraZeneca Pharmaceuticals LP, Wilmington, DE.
- 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.
- GINECO. Presentation of GINECO.
Association ARCAGY - GINECO - Hotel Dieu Hospital. Available
Online. Accessed March 2017.
- Centers for Disease Control and
Prevention. Ovarian Cancer Statistics. Available Online. Last
Updated June 21, 2016. Accessed March 2017.
- National Cancer Institute. BRCA1 and
BRCA2: cancer risk and genetic testing. Available Online. Accessed
March 2017.
- Food and Drug Administration. FDA
approves Lynparza to treat advanced ovarian cancer. Available
Online. Accessed March 2017.
- O’Connor M. ‘Targeting The DNA Damage
Response In Cancer’ (2015) Mol Cell. Accessed March 2017.
- 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.
- 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.
- 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.
- 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.
- National Institutes of Health. Ph II
Study to Evaluate Olaparib With Abiraterone in Treating Metastatic
Castration Resistant Prostate Cancer. Available Online. Accessed
March 2017.
- European Network of Gynaecological
Oncological Trial Groups. Mission Statement and ENGOT Activities.
European Society of Gynaecological Oncology 2016. Available Online.
Accessed March 2017.
©2017 AstraZeneca. All rights reserved.
3323614 Last Updated 3/17
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