WILMINGTON, Del.–(BUSINESS WIRE)–AstraZeneca today presented positive results from its Phase III OlympiAD trial that showed a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) for patients treated with LYNPARZATM (olaparib) tablets (300 mg twice daily), compared to treatment with physician’s choice of a standard of care chemotherapy. In addition to meeting its primary endpoint of PFS assessed by blinded independent central review (BICR), the trial showed that patients treated with LYNPARZA had a 42% reduction in risk of their disease worsening or death (HR 0.58; 95% CI 0.43-0.80; p= 0.0009; median 7.0 vs 4.2 months) compared to those who received chemotherapy (capecitabine, vinorelbine, eribulin).1
The data were presented at the 2017 ASCO Annual Meeting in Chicago, during today’s Plenary Session from 3:10 – 3:25 pm CDT (Abstract LBA4).1Additionally, the trial was designated for the “Best of ASCO” selection, underscoring the importance of these results for patients and physicians.
Mark E. Robson, Clinic Director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, New York and Principal Investigator of OlympiAD said, “The OlympiAD data presented today demonstrate the benefit of olaparib in delaying the progression of advanced BRCA-mutated breast cancer. With few alternatives available, a targeted non-chemotherapy oral treatment in this setting could be a beneficial new option for patients.”
Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said, “The OlympiAD results shared today mark the first time a targeted therapy shows benefit over the current standard of care for patients with HER2-negative gBRCA-mutated metastatic breast cancer. This also represents an important milestone for LYNPARZA as this is the first positive Phase III trial in which a PARP inhibitor has shown a significant benefit for patients outside of ovarian cancer.”
Patients in the trial had HER2-negative germline BRCA1 or BRCA2-mutated breast cancer and were receiving LYNPARZA as their first, second or third-line medicine for metastatic disease. Before enrollment, patients had prior treatment with an anthracycline (unless contraindicated) and a taxane; hormone receptor-positive patients received at least one endocrine medicine or were not eligible for endocrine medicines.1,2
Secondary endpoints showed an improvement in time until second progression or death (PFS2) in the LYNPARZA arm of the trial, compared to those treated with chemotherapy (HR 0.57; 95% CI: 0.40 – 0.83). In addition, the objective response rate (ORR) was more than doubled, with 59.9% of patients in the LYNPARZA arm showing response to treatment, compared to 28.8% of patients treated with chemotherapy.1
A review of the LYNPARZA safety data from the OlympiAD trial did not identify any new safety signals and the overall safety profile was consistent with previous trials of LYNPARZA. There was a lower incidence of grade ≥3 adverse events in the LYNPARZA arm compared to the chemotherapy arm (36.6% vs 50.5% respectively). A smaller proportion of patients discontinued treatment in the LYNPARZA arm compared to the chemotherapy arm (4.9% vs 7.7% respectively).1
LYNPARZA tablets are an investigational formulation and are not FDA-approved for any use.2,3 LYNPARZA capsules (400 mg 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. 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.
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%).
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 300 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).
NOTES TO EDITORS
OlympiAD is a randomized, open label, multi-center Phase III trial assessing the efficacy and safety of LYNPARZA tablets (300 mg twice daily) compared to ‘physician’s choice’ chemotherapy (capecitabine, vinorelbine, eribulin) in 302 patients with HER2-negative metastatic breast cancer with germline BRCA1 or BRCA2 mutations, which are predicted or suspected to be deleterious. The international trial was conducted in 19 countries from across Europe, Asia, North America and South America.1,2
Within the eligible patient population, there was a 1:1 ratio between triple-negative breast cancer (TNBC) and hormone receptor positive (ER+ and/or PR+) patients.1
The primary endpoint of the trial was progression-free survival (PFS) as measured by a Blinded Independent Central Review (BICR).1,2 Secondary endpoints include overall survival (OS), time to second progression or death (PFS2), objective response rate (ORR), and effect on health-related quality of life (HRQoL).1,2
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.4-6 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 approved and potential new medicines targeting DNA damage response (DDR) mechanisms in cancer cells.4-6
LYNPARZA is currently being tested in another separate adjuvant (non-metastatic) breast cancer Phase III trial called OlympiA. This trial is still open and recruiting patients internationally.7
About Metastatic Breast Cancer
Approximately one in eight women are diagnosed with breast cancer in the US.8 Of these patients, approximately one-third are either diagnosed with or progress to the metastatic stage of the disease.9 Despite treatment options increasing during the past three decades, there is currently no cure for patients diagnosed with metastatic breast cancer.10,11 Thus, the primary aim of treatment is to slow progression of the disease for as long as possible, improving or at least maintaining, a patient’s quality of life.9
About Germline BRCA Mutations
BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role 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. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.12
Specific inherited mutations in BRCA1 and BRCA2 increase the risk of female breast and ovarian cancers, and they have been associated with increased risks of several additional types of cancer. Together, BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10% of all breast cancers. In addition, mutations in BRCA1 and BRCA2 account for around 15% of ovarian cancers overall. Breast and ovarian cancers associated with BRCA1 and BRCA2 mutations tend to develop at younger ages than their nonhereditary counterparts.12
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 five 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 majority 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.
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.
1. Robson M., Im SA., Senkus E., et al, OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm), Presented at the American Society of Clinical Oncology Annual Meeting, Chicago; June 2-6, 2017. Abstract available Online. Accessed June 2017.
2. 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 June 2017.
3. LYNPARZA (olaparib) Prescribing Information. AstraZeneca Pharmaceuticals LP, Wilmington, DE.
4. Food and Drug Administration. FDA approves Lynparza to treat advanced ovarian cancer. Accessed June 2017.
5. O’Connor M. ‘Targeting The DNA Damage Response In Cancer’ (2015) Mol Cell.60.547-560. Accessed June 2017.
6. 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.
7. 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 June 2017.
8. National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer. Available Online. Accessed June 2017.
9. O’Shaughnessy J. Extending Survival with Chemotherapy in Metastatic Breast Cancer. The Oncologist 2005;10(3):20–29.
10. American Cancer Society. Breast Cancer Facts & Figures 2015-2016. Available Online. Accessed June 2017.
11. American Cancer Society. Managing Cancer as a Chronic Illness. Available Online. Accessed June 2017.
12. National Cancer Institute. BRCA1 and BRCA2: Cancer Risk and Genetic Testing. Available Online. Accessed June 2017.