ASCO2016: AstraZeneca PLC LYNPARZA (Olaparib): Latest Data Suggest Potential Overall Survival Advantage In Patients With Platinum Sensitive Ovarian Cancer

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca today presented results from a third interim analysis of Study 19 that suggest an improvement in overall survival (OS) for patients with ovarian cancer treated with olaparib maintenance therapy following platinum-based chemotherapy. This was a secondary endpoint of the trial. These results support the previously reported benefits of olaparib in progression-free survival (PFS) compared to placebo, the primary endpoint of the trial.

“These results are a testament to the value of olaparib’s mode of action and the potential significance of targeting the DNA damage response (DDR) pathway, reinforcing our commitment to explore the full potential of DDR targeted treatments across a range of cancers.”

A 27% reduction in risk of death compared to placebo was seen in the overall trial population (HR 0·73 95% CI 0·55–0·96, nominal p=0.02483; median OS 29·8 vs 27·8 months), with the greatest reduction in the risk of death of 38% compared to placebo observed in patients with BRCA1/2 mutations (BRCAm) (HR 0·62, 95% CI 0·41–0·94, nominal p=0.02480; 34·9 vs 30·2 months). As this was the third analysis of survival, the nominal p-values did not meet the criterion for statistical significance and therefore the treatment effect observed for OS can only be considered descriptive. A number of patients continue to benefit from olaparib maintenance therapy, with 15% of BRCAm patients receiving olaparib for over five years.¹

Jonathan Ledermann, Director of the Cancer Research UK & UCL Cancer Trials Centre and lead author of Study 19, “These results are extremely encouraging. The data show that some ovarian cancer patients receive benefits from this treatment for over 5 years, which is significant for patients with limited treatment options.”

The update from Study 19, presented today at the American Society of Clinical Oncology (ASCO) congress in Chicago, is based on a 77% data maturity conducted after more than five years total follow-up, with an additional three years of follow-up since the previous analysis. Two interim analyses of OS from Study 19 have previously been conducted, at 38% data maturity (HR 0·94, 95% CI 0·63–1·39, p=0·75) and 58% data maturity (HR 0·88, 95% CI 0·64–1·21, p=0·44) in the overall trial population.^2,3

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “These results are a testament to the value of olaparib’s mode of action and the potential significance of targeting the DNA damage response (DDR) pathway, reinforcing our commitment to explore the full potential of DDR targeted treatments across a range of cancers.”

This update supports previously presented results on the primary endpoint of the trial of progression-free survival (PFS) which showed a statistically significant difference compared to placebo (HR 0·35, 95% CI 0·25–0·49, p<0.0001), with the greatest effect seen in the BRCAm subgroup (HR 0·18, 95% CI 0·10–0·31, p<0.0001).² A significant improvement in time to first subsequent therapy or death (TFST) (HR 0·32, 95% CI 0·22-0·48, p<0.00001) and time to second subsequent therapy or death (TSST) (HR 0·41, 95% CI 0·28-0·62, p<0.00001) was also observed with maintenance olaparib compared with placebo, consistent with previously reported data on TFTS and TSST.²

There was no change to the overall safety profile and no new safety signals were reported for the patients remaining on treatment since the previous safety analysis. Serious adverse events were reported in 25 (18%) of 136 patients in the olaparib group and 11 (9%) of 128 patients in the placebo group. The most common serious adverse event was small intestinal obstruction (two [1%] patients in the olaparib group and three [2%] in the placebo group).The most common adverse events in patients who were treated for two years or more were nausea (olaparib: 24 patients [75%] vs placebo: 2 patients [40%]), fatigue (18 [56%] vs 2 [40%]), constipation (12 [38%] vs 1 [20%]) and vomiting (12 [38%] vs 0). These long-term safety findings are consistent with previous data from Study 19 and other clinical olaparib monotherapy studies.

Olaparib is the foundation of AstraZeneca’s industry-leading line of potential medicines in development targeting DNA damage response (DDR) mechanisms in cancer cells. DDR is a term describing the network of cellular pathways that minimize the daily impact of DNA damage. Currently, many cancers⁴ are known to have defects in DDR pathways, which makes them dependent on and therefore, highly sensitive to inhibition of the remaining DDR pathways. Targeting DDR deficiencies to preferentially kill cancer cells, while minimizing the impact on normal cells, has the potential for selective, tolerated therapies than chemotherapy that might improve survival in multiple cancers. AstraZeneca is developing a comprehensive pipeline of compounds that target molecular pathways across the DDR system. An extensive Phase III clinical trial program investigating olaparib in BRCAm ovarian cancer patients (SOLO) is currently ongoing. Phase II and III studies in breast cancer, pancreatic cancer, and prostate cancer are also currently underway.^5,6,7,8

Important Safety Information About LYNPARZA™ (olaparib)

There are no contraindications for LYNPARZA.

LYNPARZA may cause serious side effects that can lead to death including bone marrow problems and lung problems. Some people who have ovarian cancer or who have received previous treatment with chemotherapy or certain other medicines for their cancer have developed bone marrow problems called Myelodysplastic syndrome (MDS) or Acute Myeloid Leukemia (AML) during treatment with LYNPARZA. If you develop MDS or AML, your healthcare provider will stop treatment with LYNPARZA.

Symptoms of low blood cell counts are common during treatment with LYNPARZA, but can be a sign of serious bone marrow problems, including MDS or AML. Symptoms to discuss with your healthcare provider include weakness, weight loss, fever, frequent infections, blood in your urine/stool, shortness of breath, feeling very tired, and bruising or bleeding more easily.

You will undergo blood tests before, and every month during, treatment with LYNPARZA to monitor your blood cell counts. Weekly blood tests will be performed if you have low blood cell counts that last a long time. Your healthcare provider may stop treatment with LYNPARZA until your blood cell counts improve.

Tell your healthcare provider if you have any new or worsening symptoms of lung problems, including shortness of breath, fever, cough, or wheezing. Your healthcare provider may do a chest x-ray if you have any of these symptoms. Your healthcare provider may temporarily or completely stop treatment if you develop pneumonitis.

Before you take LYNPARZA, tell your healthcare provider if you:

• have lung or breathing problems
• have liver problems
• have kidney problems
• are pregnant or plan to become pregnant. LYNPARZA can harm your unborn baby and may cause loss of pregnancy (miscarriage). You should not become pregnant during treatment with LYNPARZA. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
  • Females who are able to become pregnant should use effective birth control (contraception) during treatment with LYNPARZA and for at least 1 month after receiving the last dose of LYNPARZA.
  • Talk to your healthcare provider about birth control methods that may be right for you.
  • Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with LYNPARZA.
• are breastfeeding or plan to breastfeed. It is not known if LYNPARZA passes into your breast milk. You and your healthcare provider should decide if you will take LYNPARZA or breastfeed. You should not do both.

Avoid grapefruit, grapefruit juice and Seville oranges during treatment as they may increase the levels of LYNPARZA in your blood.

The most common side effects are anemia, nausea or vomiting, tiredness or weakness, diarrhea, indigestion or heartburn, headache, loss of appetite, changes in how food tastes, changes in kidney function blood tests, sore throat or runny nose, upper respiratory infection, cough, pain in the joints, muscles, and back, rash, and pain or discomfort in the stomach area.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of LYNPARZA. For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

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

NOTES TO EDITORS

About Study 19

Study 19 was a Phase II, randomized, double-blind, placebo-controlled, multicentre trial, which evaluated the efficacy and safety of olaparib against placebo in relapsed, high grade serous ovarian cancer patients, involving 82 sites across 16 countries. Patients received oral olaparib maintenance monotherapy, at a dose of 400mg bid (capsules, manufactured by AstraZeneca) or matching placebo. Treatment continued until disease progression, provided that toxicities were manageable. The primary endpoint was progression-free survival. Overall survival, safety, tolerability, TFST and TSST were also assessed.

About LYNPARZA (olaparib)

LYNPARZA (olaparib) is an innovative, first-in-class oral poly ADP-ribose polymerase (PARP) inhibitor that may exploit tumor DDR pathway deficiencies. Olaparib-induced cytotoxicity is thought to involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.

LYNPARZA is indicated 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. 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.

LYNPARZA is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DNA damage response (DDR) mechanisms in cancer cells. LYNPARZA is the first PARP inhibitor to be approved by regulatory authorities in the EU and US for the treatment of women with BRCA-mutated (BRCAm) ovarian cancer.

About AstraZeneca in Ovarian Cancer

Worldwide, ovarian cancer is the 7th most commonly diagnosed cancer and the 8th most common cause of cancer death in women. The risk of developing ovarian cancer is increased in women with specific inherited genetic abnormalities, including BRCA mutations. AstraZeneca 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 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 6 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, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three main therapy areas - respiratory, inflammation, autoimmune disease (RIA), cardiovascular and metabolic disease (CVMD) and oncology – as well as in infection and neuroscience. 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.

CONTACTS

References

¹ Ledermann J et al. Presented at the American Society of Clinical Oncology Annual Meeting, Chicago; 3-7 June 2016. Abstract available at: [insert link] Accessed May 2016.

² Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014;15:852-861.

³ Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012;366:1382-1392.

⁴ O’Connor M, 'Targeting The DNA Damage Response In Cancer' (2015) 60 Molecular Cell

⁵ 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 at: https://clinicaltrials.gov/ct2/show/NCT02000622 Last accessed May 2016.

⁶ National Institutes of Health. Olaparib as Adjuvant Treatment in Patients With Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer (OlympiA) Available at: https://clinicaltrials.gov/ct2/show/NCT02032823 Last accessed May 2016.

⁷ Mateo J et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015;373:1697-1708.

⁸ National Institutes of Health. Efficacy and Safety Study of Olaparib in Combination With Paclitaxel to Treat Advanced Gastric Cancer. Available at: http://clinicaltrials.gov/ct2/show/NCT01924533 Last accessed May 2016.