LYNPARZA® (olaparib) 1st-line maintenance therapy nearly doubled the time without disease progression or death in Phase III POLO trial for patients with germline BRCA-mutated metastatic pancreatic cancer

22% of patients receiving LYNPARZA remained progression-free after two years vs. 10% on placebo following platinum-based chemotherapy

AstraZeneca and Merck’s LYNPARZA is the only PARP inhibitor to demonstrate benefit in this setting in a Phase III trial

AstraZeneca and Merck & Co., Inc., (Merck: known as MSD outside the U.S. and Canada) today announced detailed results from the Phase III POLO trial evaluating LYNPARZA®  (olaparib) 300 mg tablets twice daily versus placebo as a 1st-line maintenance monotherapy for patients with germline BRCA-mutated (gBRCAm) metastatic adenocarcinoma of the pancreas (pancreatic cancer) whose disease had not progressed following platinum-based chemotherapy. The results of the trial will be presented as a late-breaker oral during the plenary session (Abstract #LBA4) at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The results were published online today in the New England Journal of Medicine (NEJM).

Results from the trial showed a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) for LYNPARZA versus placebo, improving the time without disease progression by a median of 7.4 months for patients treated with LYNPARZA compared to 3.8 months on placebo (HR 0.53 [95% CI 0.35-0.82], p=0.004). More than twice as many patients showed no disease progression both at one year (34% on LYNPARZA vs. 15% on placebo) and two years (22% vs. 10%) respectively.

José Baselga, Executive Vice President, Oncology R&D, said: “These unprecedented results raise new hope for patients that have seen little progress over a long period of time. From as early as six months after initiation, more than twice as many patients taking LYNPARZA lived without progression of their disease compared to those on placebo and we are now working with regulatory authorities to bring LYNPARZA to patients as quickly as possible.”

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories, said: “We are encouraged by the results of the POLO trial which showed a considerable reduction in risk of disease progression or death with LYNPARZA for germline BRCA-mutated metastatic pancreatic cancer patients who did not progress on chemotherapy. Currently less than 3% of metastatic pancreatic cancer patients survive more than five years after diagnosis. The results of this trial reinforce Merck and AstraZeneca’s commitment to develop innovative treatments for cancers with few options.”

Hedy L. Kindler, MD, Co-Principal Investigator of the POLO trial and Professor of Medicine, University of Chicago Medicine, said: “Despite efforts to identify therapies, targeted or combination treatments to improve patient outcomes, pancreatic cancer remains an area of high unmet need. The results of the POLO trial may open the door to a new era of personalized, biomarker-led care in metastatic pancreatic cancer and reinforces the importance of knowing BRCA status at diagnosis.”

Kaplan-Meier estimates of PFS by Blinded Independent Central Review (BICR)

From the New England Journal of Medicine, Golan T, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer, Jun 2 [Epub ahead of print] Copyright © 2019 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

The safety and tolerability profile of LYNPARZA in the POLO trial was in line with that observed in prior clinical trials. The most common adverse events (AEs) ≥20% were fatigue/asthenia (60%), nausea (45%), abdominal pain (29%), diarrhea (29%), anemia (28%), decreased appetite (25%) and constipation (23%). The most common ≥ grade 3 AEs were anemia (11%), fatigue/asthenia (6%), decreased appetite (3%), abdominal pain (2%), vomiting (20%) and arthralgia (1%). AEs led to dose interruption in 35% of patients on LYNPARZA while 6% of patients discontinued treatment.

LYNPARZA is a first-in-class poly ADP-ribose polymerase (PARP) inhibitor approved in the US since 2014. LYNPARZA has a broad clinical-development program and AstraZeneca and Merck are working together to deliver LYNPARZA as quickly as possible to more patients across multiple cancer types.

LYNPARZA is not currently FDA-approved for gBRCAm pancreatic cancer treatment in the first-line maintenance setting. LYNPARZA is currently approved for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status. It is approved as first-line maintenance treatment in BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy. For first-line maintenance in advanced ovarian cancer and the metastatic breast cancer setting, physicians should select patients for therapy based on an FDA-approved companion diagnostic.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

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 also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count 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 LYNPARZA treatment 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.

Females
Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONS— Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2 were: 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%), decreased appetite (21%) and dyspepsia (20%).

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/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 (pooled from 6 studies) were: decrease in hemoglobin (90%), mean corpuscular volume elevation (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, there is a potential for decreased efficacy of LYNPARZA.

USE IN SPECIFIC POPULATIONS

Lactation: No data are available regarding the presence of olaparib in human milk, its 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 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min) but patients should be monitored closely for toxicity. 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 POLO
POLO is a Phase III randomized, double-blinded, placebo controlled, multi-center trial of LYNPARZA tablets (300 mg twice daily) as maintenance monotherapy versus placebo. The trial randomized 154 patients with gBRCAm metastatic pancreatic cancer whose disease had not progressed on 1st-line platinum-based chemotherapy. Patients were randomized (3:2) to receive LYNPARZA or placebo until disease progression. The primary endpoint was PFS, and key secondary endpoints include overall survival, time to second disease progression, overall response rate, disease control rate and health-related quality of life.

About LYNPARZA
LYNPARZA® (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells.  Inhibition of PARP with LYNPARZA leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. LYNPARZA is being tested in a range of tumor types with defects and dependencies in the DDR.

LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad and advanced clinical trial development program, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types. LYNPARZA is being tested in a range of DDR-deficient tumor types and is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DDR mechanisms in cancer cells.

About Pancreatic Cancer
Pancreatic cancer is the 12th most common cancer worldwide. Germline BRCA-mutated pancreatic cancer accounts for five to nine percent of all cases globally. In the US this year, approximately 56,770 people will be diagnosed and more than 45,000 will die from pancreatic cancer, which accounts for about 7% of all US cancer deaths. Early diagnosis of pancreatic cancer is difficult, as often there are no symptoms until the disease has advanced. The five-year survival rate for all stages is just 9%, and for the 52% of people who are diagnosed after the cancer has spread to a distant part of the body, the five-year survival rate is just 3%.

About BRCA Mutations
BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role in 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, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About the AstraZeneca and Merck strategic oncology collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as Merck outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize LYNPARZA, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop LYNPARZA and selumetinib in combination with other potential new medicines and as monotherapies. 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 Oncology as a key growth driver for AstraZeneca 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 therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. 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.

 

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US-29584 Last Updated 6/19