AstraZeneca presented, at ASCO on June 5, 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.
A 27% reduction in risk of death compared to placebo was seen in the overall trial population (HR 073, 95% CI 055–096, nominal p=0.02483; median OS 298 vs 278 months), with greater reduction in the risk of death of 38% compared to placebo observed in patients with BRCA1/2 mutations (BRCAm) (HR 062, 95% CI 041–094, nominal p=0.02480; 349 vs 302 months).[i] 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.2
Elisabeth Åvall Lundqvist, Professor in clinical oncology, Linköpings University comments the results:
Swedish national guidelines recommends treatment with maintenance olaparib for patients with BRCA mutations and late relapse of high grade serous ovarian cancer in accordance with the EU approval. The recommendation is based on the remarkable difference in median PFS of 6,9 months and a HR of 0.18, favoring olaparib. The results presented today showing an OS advantage for olaparib further emphasizes the potential of olaparib in this setting. The results also indicates a potential benefit beyond the BRCA mutated population which brings hope to more patients with this devastating disease. Individual patients may benefit more than 5 years, without additional long-term toxicity,which is an important finding. Nevertheless, we need to understand the mechanism behind divergent responses among BRCA mutated patients and identify predictive markers for long-term, short-term and no responders. In summary, Olaparib lives up to the expectations so far, now we await the results from the randomized phase III study, SOLO-II.
Jonathan Ledermann, Director of the Cancer Research UK & UCL Cancer Trials Centre and lead author of Study 19, said, “These results are extremely encouraging. The data show that some ovarian cancer patients receive benefit 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 094, 95% CI 063–139, p=075) and 58% data maturity (HR 088, 95% CI 064–121, p=044) in the overall trial population.[ii],[iii]
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 035, 95% CI 025–049, p<0.0001), with the greatest effect seen in the BRCAm subgroup (HR 018, 95% CI 010–031, p<0.0001).2A significant improvement in time to first subsequent therapy or death (TFST) (HR 032, 95% CI 022-048, p<0.00001) and time to second subsequent therapy or death (TSST) (HR 041, 95% CI 028-062, 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).2The 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.
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NOTES TO EDITORS
About Study 19
Study 19 was a Phase II, randomised, double-blind, placebo-controlled, multicentre trial, which evaluated the efficacy and safety of olaparibagainst 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.
Olaparib is an innovative, first-in-class oral poly ADP-ribose polymerase (PARP) inhibitor that exploits tumour DDR pathway deficiencies to preferentially kill cancer cells.Olaparib 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[viii] and the 8th most common cause of cancer death in women.[ix] 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 OncologyAstraZeneca 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 haematology.
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 personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.
AstraZeneca är ett globalt, innovativt bioläkemedelsföretag med fokus på forskning, utveckling och marknadsföring av receptbelagda läkemedel, primärt för behandling av sjukdomar inom områdena hjärta/kärl/metabolism, andningsvägar/inflammation/autoimmunitet, cancer, infektion och neurovetenskap. AstraZeneca är verksamt i över 100 länder och våra innovativa läkemedel används av miljontals patienter världen över.
För ytterligare information kontakta:
Petra Eurenius, Kommunikationschef AstraZeneca Nordic-Baltic, telefon: 0709 186562
988.742,011 06,2016 SE
[i] Ledermann J et al. Presented at the American Society of Clinical Oncology Annual Meeting, Chicago; 3-7 June 2016. Abstract available at:http://abstract.asco.org/176/AbstView_176_166142.htmlAccessed June 2016.
[ii] 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.
[iii] 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.
[iv] 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 June 2016.
[v] 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 June 2016.
[vi] Mateo J et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015;373:1697-1708.
[vii] 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 June 2016.
[viii] Cancer Research UK. Ovarian cancer incidence statistics. Available at:http://www.cancerresearchuk.org/cancer-info/cancerstats/types/ovary/incidence/uk-ovarian-cancer-incidence-statistics. Last accessed June 2016.
[ix] Cancer Research UK. Ovarian cancer mortality statistics. Available at:http://www.cancerresearchuk.org/cancer-info/cancerstats/types/ovary/mortality/ Last accessed June 2016.