LYNPARZA® (olaparib) achieved a 72% objective response rate in patients with relapsed germline BRCA-mutated advanced ovarian cancer

AstraZeneca and Merck’s LYNPARZA increased the time without disease progression or death by 4.2 months vs. physician’s choice chemotherapy in platinum-sensitive relapsed patients following two or more prior lines of chemotherapy

Based on results in the Phase III SOLO3 trial, LYNPARZA is the first and
only PARP inhibitor to demonstrate efficacy vs. chemotherapy in this setting

AstraZeneca and Merck & Co., Inc., (Merck: known as MSD outside the US and Canada) today presented full results from the open-label Phase III SOLO3 trial which compared LYNPARZA® (olaparib) 300 mg tablets twice daily versus physician’s choice chemotherapy (paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine) in the treatment of patients with germline BRCA1/2-mutated (gBRCAm) advanced ovarian cancer, who received two or more prior lines of chemotherapy. The results were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

Results from the trial showed a statistically-significant and clinically-meaningful improvement in objective response rate (ORR) in the LYNPARZA arm versus the chemotherapy arm (72% vs. 51% [95% CI 1.40-4.58], p=0.002). ORR measures the proportion of patients with reduction in tumor burden of a predefined amount and for a minimum time period. The trial also met the key secondary endpoint of progression-free survival (PFS), demonstrating a statistically-significant and clinically-meaningful improvement in the time patients lived without disease progression for LYNPARZA (median 13.4 months) versus chemotherapy (median 9.2 months [HR 0.62, p=0.013]).

José Baselga, Executive Vice President, Oncology R&D, said: “LYNPARZA has the potential to provide a much-needed improvement and alternative over standard of care chemotherapy for certain patients with relapsed BRCA-mutated advanced ovarian cancer. This is the fourth positive Phase II/III trial in advanced ovarian cancer for LYNPARZA, across multiple lines of therapy. We look forward to working closely with regulatory authorities to include findings from this trial in the prescribing information for LYNPARZA.”

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories, said: “LYNPARZA is the first and only PARP inhibitor to demonstrate efficacy versus chemotherapy in relapsed BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. The positive SOLO3 results reaffirm AstraZeneca and Merck’s ongoing commitment to explore potential treatment options beyond standard of care for BRCA-mutated patients with advanced stage disease.”

Summary of endpoints[i]

 

Lynparza
(300 mg bid)

Chemotherapy

ORR (primary endpoint)

 

Number of patients[i]

151

72

Number of patients with response (%)

109 (72.2%)

37 (51.4%)

Odds ratio (95% CI)

2.53 (1.40, 4.58)

p-value

0.002

PFS (key secondary endpoint)[ii]

 

Number of patients

178

88

Number of patients with event (%)

110 (61.8%)

49 (55.7%)

Hazard ratio (95% CI)

0.62 (0.43, 0.91)

Median in months

13.4

9.2

p-value

0.013

iAssessed by blinded independent central review (BICR)

iiAnalysis was done at 59.8% maturity.

The safety and tolerability profile of LYNPARZA in the SOLO3 trial was consistent with previous trials. The most common adverse events (AEs) ≥ 20% were nausea (65%), fatigue/asthenia (52%), anemia (51%), vomiting (38%), diarrhea (28%), neutropenia (23%) and abdominal pain (21%).The most common ≥ Grade 3 AEs were anemia (21%), neutropenia (10%), fatigue/asthenia (5%) and thrombocytopenia (4%). AEs led to dose interruption in 48% percent of patients on LYNPARZA, while 7% of patients discontinued treatment.

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 SOLO3
SOLO3 is a Phase III randomized, open-label, controlled, multicenter trial to evaluate the efficacy and safety of LYNPARZA tablets (300 mg twice daily) following two or more prior lines of chemotherapy. The trial randomized 266 patients with a deleterious or suspected deleterious BRCA1 or BRCA2 mutation. Eligible patients were randomized (2:1) to receive LYNPARZA 300mg tablets twice daily or physician’s choice single-agent chemotherapy (paclitaxel, topotecan, pegylated liposomal doxorubicin or gemcitabine). The primary endpoint was overall response rate (ORR) by blinded independent central review and key secondary endpoints included progression-free survival (PFS), time to second disease progression or death and overall survival. The SOLO3 trial addresses a post-approval commitment from the December 2014 initial US approval of Lynparza in ovarian cancer.

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 ovarian cancer
Approximately 22,000 women in the United States are diagnosed with ovarian cancer (including ovarian, fallopian tube and primary peritoneal cancers) each year. Among women in the United States, it is the ninth most common cancer and the fifth leading cause of cancer death.

The risk of developing ovarian cancer is increased in women with specific inherited genetic abnormalities, including BRCA mutations.

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 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 MSD 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 one of AstraZeneca’s four 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 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-29585 Last Updated 6/19