LYNPARZATM (olaparib) Phase III SOLO-2 Trial Shows Significant Progression-Free Survival Benefit

AstraZeneca today announced positive results from the Phase III SOLO-2 trial designed to determine the efficacy of LYNPARZATM (olaparib) tablets (300mg twice daily) as a monotherapy for the maintenance treatment of platinum-sensitive relapsed, BRCA-mutated ovarian cancer.1 Results from the trial demonstrate a clinically-meaningful and statistically-significant improvement of progression-free survival (PFS) among patients treated with LYNPARZA compared to placebo and provide additional evidence to support the potential use of LYNPARZA in this patient population.

Importantly, the median PFS in the LYNPARZA arm of SOLO-2 substantially exceeded that observed in the Phase II maintenance study in patients with platinum-sensitive relapsed ovarian cancer (Study 19).2

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “We are pleased with the robust improvement in progression-free survival demonstrated by LYNPARZA in the SOLO-2 trial. We will work with regulatory authorities to make LYNPARZA tablets available as quickly as possible to patients with ovarian cancer. We remain committed to investigating the full potential of LYNPARZA, both as monotherapy and in combinations, and to identifying all patients who may benefit from this important medicine.”

Initial findings demonstrate that safety profile with LYNPARZA tablets was consistent with previous studies.2 Full results of SOLO-2 will be presented at a forthcoming medical meeting.

Today’s positive results follow the Fast Track Designation for LYNPARZA by the US FDA earlier this year, in patients with a BRCA mutation who have platinum-sensitive, relapsed ovarian cancer.3

LYNPARZA is the first PARP inhibitor approved in the US. LYNPARZA capsules (400mg twice daily) are FDA-approved as 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. LYNPARZA 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.4 LYNPARZA tablets are an investigational formulation and are not FDA-approved for any use.1

Important Safety Information About LYNPARZA™ (olaparib)

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 (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE 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 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. Advise females of reproductive potential of the potential risk to a fetus and to avoid pregnancy by using effective contraception during treatment and for at least one month after receiving the last dose of LYNPARZA.

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 anemia (90%), neutropenia (32%), thrombocytopenia (30%), lymphopenia (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

Nursing Mothers: Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from LYNPARZA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Renal Impairment: No dosage adjustment is necessary for 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 (CLcr <50 mL/min) or end-stage renal disease (CLcr ≤30 mL/min).

Hepatic Impairment: There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 times upper limit of normal).

Please see complete Prescribing Information, including Patient Information (Medication Guide).

NOTES TO EDITORS

About SOLO-2

SOLO-2 was a Phase III, multicenter trial designed to determine the efficacy of LYNPARZA tablets as a maintenance monotherapy compared with placebo, in patients with platinum-sensitive relapsed BRCA-mutated ovarian cancer.1 Patients were randomized to receive either LYNPARZA tablets (300mg twice daily) or placebo until disease progression.1

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), enrolled 295 patients with documented germline BRCA1 or BRCA2 mutations who had received at least two prior lines of platinum-based chemotherapy.1,5

About AstraZeneca in Ovarian Cancer

In the US, ovarian cancer is the 9th most commonly diagnosed cancer and the 5th 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.7AstraZeneca is committed to the continued development of our R&D portfolio for ovarian cancer, with a focus on improved care for all patients, including the development of targeted therapies for patients with specific gene mutations such as BRCA.

About LYNPARZATM (olaparib)

LYNPARZATM (olaparib) is an innovative, first-in-class 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.4

LYNPARZA is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DNA damage response (DDR) mechanisms in cancer cells. 8-10

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.11

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.1,5

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

1. National Institutes of Health. Olaparib Treatment in BRCA Mutated Ovarian Cancer Patients After Complete or Partial Response to Platinum Chemotherapy. Available at: http://clinicaltrials.gov/show/NCT01874353. Last accessed October 2016.
2. Ledermann J, Harter P, Gourley C, et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol. 2016; S1470-2045(16)3037 1-12
3. FDA Approval Letter. U.S. Food and Drug Administration, Silver Spring, MD. Available Online. Accessed July, 2016.
4. LYNPARZA (olaparib) Prescribing Information. AstraZeneca Pharmaceuticals LP, Wilmington, DE.
5. GINECO. Presentation of GINECO. Association ARCAGY - GINECO - Hotel Dieu Hospital. Available Online. Accessed October 2016.
6. Centers for Disease Control and Prevention. Ovarian Cancer Statistics. Available Online. Last Updated June 21, 2016. Accessed October 2016.
7. National Cancer Institute. BRCA1 and BRCA2: cancer risk and genetic testing. Available Online. Accessed October 2016.
8. Food and Drug Administration. FDA approves Lynparza to treat advanced ovarian cancer. Available Online. Accessed October 2016.
9. O’Connor M. ‘Targeting The DNA Damage Response In Cancer’ (2015) Mol Cell. Available Online. Accessed October 2016.
10. 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.
11. European Network of Gynaecological Oncological Trial Groups. Mission Statement and ENGOT Activities. European Society of Gynaecological Oncology 2016. Available Online. Accessed October 2016.

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