AstraZeneca PLC Release: LYNPARZA (Olaparib) Phase III SOLO-2 Data Demonstrated Progression-Free Survival Benefit In BRCA-Mutated Ovarian Cancer As Maintenance Therapy

LYNPARZA reduced risk of disease progression by 70% with an investigator-assessed progression-free survival of 19.1 vs 5.5 months with placebo

Blinded independent central review showed significant progression-free survival of 30.2 months vs 5.5 months with placebo

LYNPARZA tablets demonstrated a safety profile generally consistent with previous studies 

AstraZeneca today presented results from the Phase III SOLO-2 trial demonstrating a significant improvement in progression-free survival (PFS) in germline BRCA-mutated (gBRCA), platinum-sensitive, relapsed ovarian cancer patients treated with LYNPARZA™ (olaparib) tablets (300mg twice daily), compared with placebo in the maintenance setting. 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).¹

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  

Additionally, a statistically-significant benefit in time to second progression or death (PFS2) was also seen in patients treated with LYNPARZA (HR 0.50; 95% CI 0.34-0.72; P=0.0002; median not reached vs 18.4 months), compared with placebo, as well as improvements in other key secondary endpoints.¹ 

Table 1. Progression-Free Survival by investigator and BICR assessment:

Analysis		Median progression-free survival, months	Hazard ratio
Investigator-assessed analysis	LYNPARZA	19.1	0.30 (95% CI, 0.22-0.41), P<0.0001
	Placebo	5.5
Blinded Independent Central Review	LYNPARZA	30.2	0.25 (95% CI, 0.18-0.35), P<0.0001
	Placebo	5.5

These results, presented at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer in National Harbor, Maryland, build upon prior data in this setting, demonstrating the potential of LYNPARZA as a maintenance therapy in relapsed ovarian cancer.^1,2

Richard Penson, MD, Associate Professor of Medicine at Harvard Medical School and Clinical Director of Medical Gynecologic Oncology at Massachusetts General Hospital said:

“The SOLO-2 data demonstrated a statistically significant and clinically meaningful improvement in outcomes for those who took olaparib. The results, which showed a delay in disease progression in the maintenance setting, highlight the impact of PARP inhibition at the forefront of the important advances we are making in targeting ovarian cancer.”

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “We are extremely pleased with the results from SOLO-2, which support the potential benefit of LYNPARZA tablets as a maintenance therapy for patients with relapsed ovarian cancer. The tablet formulation may offer patients a reduced pill burden for LYNPARZA and a safety profile that is generally consistent with previous trials. We will work with regulatory authorities to make LYNPARZA tablets available to patients as quickly as possible.” 

The safety profile for patients treated with LYNPARZA tablets during the trial was generally consistent to those observed with the currently-approved capsule formulation.¹ Any adverse events (AE) Grade =3 were reported in 36.9% of patients treated with LYNPARZA and in 18.2% of patients who received placebo.¹  The most common non-hematological AEs reported at a frequency of =20% in the LYNPARZA arm versus placebo were nausea (75.9% vs 33.3%), fatigue/asthenia (65.6% vs 39.4%), and vomiting (37.4% vs 19.2%).¹ Grade =3 non-hematological AEs reported at a frequency of =2.5% in the LYNPARZA arm versus placebo were fatigue/asthenia (4.1% vs 2.0%), vomiting (2.6 % vs 1.0%), abdominal pain (2.6% vs 3.0%), nausea (2.6% vs 0.0%), diarrhea (1.0% vs 0.0%), and constipation (0.0% vs 3.0%).¹

The most common hematological AEs reported in the LYNPARZA arm versus placebo were anemia (43.6% vs 8.1%), neutropenia (19.5% vs 6.1%), and thrombocytopenia (13.8% vs 3.0%).¹ Grade =3 hematological AEs reported in the LYNPARZA arm versus placebo were anemia (19.5% vs 2.0%), neutropenia (5.1% vs 4.0%), and thrombocytopenia (1.0% vs 1.0%).¹

The 300mg twice-daily tablet dose potentially reduces the pill burden for patients from 16 capsules to four tablets per day.

LYNPARZA tablets are an investigational formulation and are not FDA-approved for any use.^3,4  LYNPARZA capsules (400mg twice daily) are currently approved in the U.S. 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.

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 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%).

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

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).

NOTES TO EDITORS

About SOLO-2
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 gBRCA-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.^4,5 Eligible patients were randomized to receive either LYNPARZA tablets (300mg twice daily) or placebo.⁴

About AstraZeneca in Ovarian Cancer
In the U.S., ovarian cancer is the ninth most commonly diagnosed cancer and the fifth 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.⁷ 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 LYNPARZA^TM (olaparib)
LYNPARZA^TM (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.^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.³ 

LYNPARZA is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DDR mechanisms in cancer cells.^8-10

LYNPARZA tablets are currently being investigated in monotherapy and in combinations in a range of tumor types including breast, prostate, and pancreatic cancer.^11-14 LYNPARZA tablets are an investigational formulation and are not FDA-approved for any use.³

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.¹⁵

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.^4,5

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.

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References

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. Ledermann J., Harter P., Gourley M., et al., Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. N Engl J Med 2012;366:1382-92.
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. GINECO. Presentation of GINECO. Association ARCAGY - GINECO - Hotel Dieu Hospital. Available Online. Accessed March 2017.
6. Centers for Disease Control and Prevention. Ovarian Cancer Statistics. Available Online. Last Updated June 21, 2016. Accessed March 2017.
7. National Cancer Institute. BRCA1 and BRCA2: cancer risk and genetic testing. Available Online. Accessed March 2017.
8. Food and Drug Administration. FDA approves Lynparza to treat advanced ovarian cancer. Available Online. Accessed March 2017.
9. O’Connor M. ‘Targeting The DNA Damage Response In Cancer’ (2015) Mol Cell. Accessed March 2017.
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. 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.
12. 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.
13. 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.
14. National Institutes of Health. Ph II Study to Evaluate Olaparib With Abiraterone in Treating Metastatic Castration Resistant Prostate Cancer. Available Online. Accessed March 2017.
15. European Network of Gynaecological Oncological Trial Groups. Mission Statement and ENGOT Activities. European Society of Gynaecological Oncology 2016. Available Online. Accessed March 2017.