April 17, 2018 Source: businesswire 230
AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US (Merck: known as MSD outside the US and Canada) presented data from the Phase III OlympiAD trial, showing the final overall survival (OS) results for LYNPARZA®(olaparib) in metastatic breast cancer at the American Association for Cancer Research (AACR) Annual Meeting in Chicago, April 14-18, 2018.
The trial compared LYNPARZA with chemotherapy (physician’s choice of capecitabine, eribulin or vinorelbine) for patients with germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC) and met its primary endpoint of progression-free survival (PFS).
Results at AACR include updated findings from the secondary endpoint of overall survival (OS). While the trial was not powered to demonstrate a statistically-significant difference, the median OS was 19.3 months in patients treated with LYNPARZA and 17.1 months for patients treated with chemotherapy (HR 0.90; 95% CI 0.66-1.23; p=0.513). At the final OS data cut-off (64% maturity), nearly 13% of patients remained on LYNPARZA and no patients remained on chemotherapy.
Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “OlympiAD is the first Phase III trial to demonstrate disease control with a PARP inhibitor in BRCA-mutated HER2-negative metastatic breast cancer. While the trial was not powered to show overall survival compared to chemotherapy, the results are another encouraging marker in the use of LYNPARZA for this patient population.”
Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories, said: “For patients and physicians, these results are meaningful in that they support the progression-free survival endpoint – which showed that patients treated with LYNPARZA gained seven months chemotherapy-free time – and reinforce the importance of identifying BRCAstatus to optimize metastatic breast cancer management.”
LYNPARZA is indicated in patients with gBRCAm HER2-negative MBC previously treated with chemotherapy. Hormone receptor (HR)-positive breast cancer should have been treated with prior endocrine therapy or be considered inappropriate for endocrine treatment. An FDA-approved companion diagnostic is required for this indication.
When analyzing the predefined subgroups, the results were consistent with the overall analysis, which did not show a statistically-significant difference between arms. The greatest difference was seen in patients who had not received chemotherapy in the metastatic setting with a median difference in OS of 7.9 months with LYNPARZA (HR 0.51; 95% CI 0.29-0.90; nominal p=0.02; median 22.6 vs 14.7 months).
Table 1: Predefined subgroups for OS analysis
|HR||95% CI||Nominal p Value|
|Prior chemotherapy for metastatic breast cancer|
|No (1st line)||22.6||14.7||0.51||0.29-0.90||0.02|
|Yes (2nd line / 3rd line)||18.8||17.2||1.13||0.79-1.64||0.52|
|Prior platinum-based chemotherapy for breast cancer|
|Estrogen receptor positive (ER+) and/or hormone-receptor positive (HR+)||21.8||21.3||0.86||0.55-1.36||0.51|
|Triple-negative breast cancer (TNBC)||17.4||14.9||0.93||0.62-1.43||0.75|
The safety profile of LYNPARZA remained consistent with the primary analysis. Serious adverse events (AEs) (Grade ≥3) were reported in 38% of patients who received LYNPARZA vs 49.5% of patients in the chemotherapy arm. AEs leading to drug discontinuation were 4.9% for LYNPARZA vs 7.7% for chemotherapy. AEs leading to dose reductions were 25.4% for LYNPARZA vs 30.8% for chemotherapy. AEs leading to dose interruptions were 36.1% for LYNPARZA vs 28.6% for chemotherapy. Please see Important Safety Information below.
These results build on previously reported findings, which demonstrated LYNPARZA significantly improved PFS (HR 0.58; 95% CI 0.43-0.80; p=0.0009 median 7.0 vs 4.2 months) and showed data beyond initial disease progression, prolonging time to second progression or death (PFS2) by 3.9 months (HR 0.57; 95% CI 0.40-0.83; p=0.003 median 13.2 months vs 9.3 months). Previously reported findings also showed LYNPARZA doubled objective response rates (52% [95% CI 44-60] vs 23% [95% CI 13-35]). The data from the OlympiAD trial can be found in the August 10, 2017 issue of the New England Journal of Medicine.
In January 2018, LYNPARZA was approved by the US FDA in the treatment of gBRCAm metastatic breast cancer based on the OlympiAD data.
A Phase III trial (n=1800), OlympiA, is evaluating LYNPARZA as an adjuvant treatment in patients with gBRCA HER2-negative breast cancer, with results expected in 2020. The trial is powered to assess potential benefit in OS.
LYNPARZA is approved in the US for advanced ovarian cancer and has treated more than 4,000 patients. 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 settings, including breast, ovarian, prostate and pancreatic cancers.
IMPORTANT SAFETY INFORMATION
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.
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.
Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.
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 (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%).
ADVERSE REACTIONS—gBRCAm, HER2-negative breast cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).
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 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).
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.
LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:
For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.
For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
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