WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca today announced that the US Food and Drug Administration (FDA) has accepted the company’s New Drug Application (NDA) for LYNPARZA™ (olaparib) tablets (300mg twice daily) for use in platinum-sensitive, relapsed ovarian cancer patients in the maintenance setting. The FDA has also granted priority review status with a Prescription Drug User Fee Act (PDUFA) set for third quarter 2017. The NDA submission includes the LYNPARZA Phase III SOLO-2 trial data, which showed a reduced risk of disease progression by 70 percent, compared with placebo in germline BRCA-mutated patients.1 SOLO-2 trial results were presented on March 14th at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.
The FDA grants Priority Review to applications for medicines that treat serious conditions and, if approved, would provide a significant improvement in treatment, safety, or efficacy over existing therapies.2 For applications granted priority review, the FDA takes action within six months of submission, compared with the standard 10-month review timeline.
Andrew Coop, Vice President, US Medical Affairs, Oncology, at AstraZeneca, said: “If approved as a maintenance therapy for patients with advanced ovarian cancer, LYNPARZA tablets would help address the unmet medical need and limited treatment options for women living with this disease, and offer patients a potential reduced pill burden for LYNPARZA. Additionally, the US FDA filing acceptance shows how we are progressing the science behind LYNPARZA – the first PARP inhibitor approved in the US more than two years ago – while also investigating LYNPARZA in other tumor types, including breast, pancreatic and prostate.”
Results from the Phase III SOLO-2 trial demonstrated a significant improvement in progression-free survival (PFS) with LYNPARZA tablets, compared with placebo.1 The trial met its primary endpoint of investigator-assessed PFS (HR 0.30; 95% CI 0.22-0.41; P<0.0001; median 19.1 months vs 5.5 months).
PFS as measured by Blinded Independent Central Review (BICR) evaluation, a pre-specified sensitivity analysis supporting the primary endpoint, demonstrated a median PFS of 30.2 months vs 5.5 months for placebo, representing an improvement of 24.7 months (HR 0.25; 95% CI 0.18-0.35; P<0.0001).1
The safety profile for patients treated with LYNPARZA tablets during the SOLO-2 trial was generally consistent to those observed with the currently approved capsule formulation.1,3 Grade ≥3 adverse events were reported in 36.9% of patients treated with LYNPARZA, and in 18.2% of patients who received placebo.1
LYNPARZA tablets are an investigational formulation and are not FDA-approved for any use at this time.3,4 LYNPARZA capsules (400mg 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.3 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
More than 2,600 ovarian cancer patients have been treated with LYNPARZA capsules since it was approved in the US in December 2014.5
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 300mg 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).
Additionally, AstraZeneca has opened a Multiple Patient Expanded Access Program (MPEAP) for olaparib tablets in the US. 6 This program is available to eligible patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer as a maintenance treatment, following complete or partial response to platinum-based chemotherapy.
Healthcare professionals can learn more about the MPEAP for olaparib tablets by calling Parexel at 978-495-4423 or visiting email@example.com
NOTES TO EDITORS
SOLO-2 was a Phase III, randomized, double-blind, multicenter trial, designed to determine the efficacy of LYNPARZA tablets as a maintenance monotherapy compared with placebo, in patients with platinum-sensitive relapsed or recurrent BRCA-mutated ovarian cancer.4 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), randomized 295 patients with documented germline BRCA1 or BRCA2 mutations, who had received at least two prior lines of platinum-based chemotherapy and were in complete or partial response.4,7 Eligible patients were randomized to receive either LYNPARZA tablets (300mg twice daily) or placebo.4
About AstraZeneca in Ovarian Cancer
In the US, ovarian cancer is the ninth most commonly diagnosed cancer and the fifth most common cause of cancer death in women.8 The risk of developing ovarian cancer is increased in women with specific inherited genetic abnormalities, including BRCA mutations.9 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 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.10-12 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 compounds targeting DDR mechanisms in cancer cells.10-12
LYNPARZA tablets are currently being investigated in monotherapy and in combinations in a range of tumor types including breast, prostate, and pancreatic cancer.13-16 LYNPARZA tablets are an investigational formulation and are not FDA-approved for any use.3
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.
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. Pujade-Lauraine E., Ledermann J., Penson R., et al., Treatment with
olaparib monotherapy in the maintenance setting significantly improves
progression-free survival in patients with platinum-sensitive relapsed
ovarian cancer: Results from the Phase III SOLO2 Study. Presented at the
Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO),
March 12 – 15. National Harbor, Maryland.
2. US Food and Drug Administration. Priority Review. Available Online. Accessed March 2017.
3. LYNPARZA (olaparib) Prescribing Information. AstraZeneca Pharmaceuticals LP, Wilmington, DE.
4. National Institutes of Health. Olaparib Treatment in BRCA Mutated Ovarian Cancer Patients After Complete or Partial Response to Platinum Chemotherapy. Available Online. Accessed March 2017.
5. Data on File, 3314404, AstraZeneca Pharmaceuticals LP.
6. National Institutes of Health. Expanded Access Program for Olaparib Tablets as Maintenance Therapy in Patients With Ovarian, Fallopian Tube or Primary Peritoneal Cancer. Available Online. Accessed March 2017.
7. GINECO. Presentation of GINECO. Association ARCAGY - GINECO - Hotel Dieu Hospital. Available Online. Accessed March 2017.
8. Centers for Disease Control and Prevention. Ovarian Cancer Statistics. Available Online. Last Updated June 21, 2016. Accessed March 2017.
9. National Cancer Institute. BRCA1 and BRCA2: cancer risk and genetic testing. Available Online. Accessed March 2017.
10. Food and Drug Administration. FDA approves Lynparza to treat advanced ovarian cancer. Accessed March 2017.
11. O’Connor M. ‘Targeting The DNA Damage Response In Cancer’ (2015) Mol Cell. Accessed March 2017.
12. 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.
13. 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 March 2017.
14. 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 March 2017.
15. National Institutes of Health. Olaparib in gBRCA Mutated Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum-Based Chemotherapy (POLO). Available Online. Accessed March 2017.
16. National Institutes of Health. Ph II Study to Evaluate Olaparib With Abiraterone in Treating Metastatic Castration Resistant Prostate Cancer. Available Online. Accessed March 2017.
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