Olaparib Approved In Japan: Breast Cancer
Olaparib’s Study Design For BRCA1 or BRC2 Variants in Early Breast Cancer
OlympiA was a global double-blind placebo-controlled randomized phase 3 trial that evaluated the efficacy and safety of one year of adjuvant Olaparib versus placebo in adult patients with germline pathogenic, BRCA1 or BRC2 breast cancer variants who had completed standard chemotherapy administered either as adjuvant or neoadjuvant therapy and had surgery and radiation therapy if needed for what needed to be a, at least a high risk early breast cancer or two negative stages of early breast cancer.
What About BRAC Genes Codes For Proteins in Eligible Patients?
Since the BRCA genes code for proteins critical for homologous recombination repair of DNA, patients with pathologic variants in these proteins genes develop (breast) cancers with substantial deficiencies in the function of this critical pathway, which is essential for cell survival.
As a result, these (breast) cancers become very dependent on an alternative pathway of DNA repair in which Poly (ADP-ribose) polymerases or PARP has a central function since inhibition of PARP is selectively lethal for (breast) cancer cells with its vulnerability OlympiA hypothesizes that the administration of the PARP inhibitor Olaparib would improve outcomes in patients with pathologic, germline, BRCA variants and high-risk early breast cancer patients.
What is the Efficacy of the Olaparib OlympiA in Locally Advanced Early Breast Cancer Patients?
With an acceptable toxicity profile, the study design is to detect at least a 30% reduction in the primary endpoint of invasive disease, free survival events, distant disease-free survival, overall survival, safety, and quality of life assessments secondary endpoints on review of the planned event.
A data-driven interim analysis with a median follow-up of 2 and a half years, the study IDMC recommended complete analysis and reporting of the results presented by Dr. Tut yesterday. They demonstrated a statistically significant and clinically meaningful improvement in IDFs; 77.1% of patients in the placebo cohort were alive and free of cancer recurrence and new other cancers at three years, compared with 85.9% of patients in the Olaparib cohort.
An absolute 8.8%, which corresponds to a 43% reduction in the risk of IDFs events, clearly remains for high-risk early breast cancer patients following receipt of standard multimodality therapies. Importantly, this benefit was consistent across all key subgroups, such as the type of VRCA mutation hormone receptor status, whether they had received platinum as part of their chemotherapy, and some other factors.
Additionally, 3-year distant disease pre-survival clinically meaningful improvement in breast cancer patients was also statistically significant, with just the median of 2 and a half years of follow-up. We saw that. 80.4% of the patient cohort receiving placebo were alive and free of distant metastases at three years. So, 20% have already developed distant metastases, which generally result in death within a short time.
There was an clinically meaningful improvement to 87.5% in the Olaparib group, indicating a substantial impact on this essential secondary endpoint. At the time of the analysis, 86 deaths were reported in the placebo cohort, compared to only 59 in the Olaparib cohort. While indeed encouraging, these results must be considered preliminary as a difference did not meet protocol-specified criteria for the significance of this initial analysis.
Our safety data was consistent with the experience with Olaparib in metastatic breast cancer patients and other advanced cancers. 25% of patients on Olaparib required dose reductions, and 26% discontinued the medication early. The most common grade 3 toxicity was anemia, seen in 8.7%; 5.8% of patients required blood transfusion support.
Statistically significant adjuvant treatment, global health quality did not decline with Olaparib or placebo during the year of therapy. New primary cancers have been reported in 32 patients receiving placebo in 19 receiving Olaparib. To date, there is certainly no evidence that Olaparib may be causing increased second cancers, though we will need to follow patients long-term to define that vital endpoint fully.
What Is The Next Stage For The OlympiA Trial?
Our immediate next steps for the trial are to complete and report the ongoing total quality of life analyses that were included in the trial’s design for the longer term. Since all patients have completed adjuvant treatment, we have maintained the study blind so we can adequately evaluate overall survival and long-term safety, which will improve the strength of our exploratory and translational studies.
When we have more follow-up data from the trial, we are pleased that OlympiA was published in the New England Journal of Medicine. Concurrently, in a sense, with the presentation at ASCO.
Furthermore, I would encourage interested clinicians to look carefully at the manuscript and a detailed supplemental appendix that provides much information that can help physicians make assessments on their own, from data in this cancer research.
The potential utility of the drug would be helpful. At the same time, we await the input and opinions of our guideline groups, as well as FDA and EMA around the world, who will present the information for consideration for full regulatory approval.
Charles Edward Geyer, Jr., MD, FACP – About The Author, Credentials, and Affiliations
He specializes in breast medical oncology and is qualified by the American Board of Internal Medicine in both medical oncology and internal medicine. He works at UPMC Magee Womens Hospital.
He earned his medical degree from Texas Tech University Health Science Center, then went on to finish a residency at Baylor College of Medicine, a chief residency at Baylor College of Medicine, and a medical oncology fellowship at Baylor College of Medicine.
Dr. Geyer received his medical degree from Texas Tech University School of Medicine and worked at the Baylor College of Medicine Affiliated Hospitals in Houston for his internship, residency, chief residency, and medical oncology fellowship.
He holds board certifications in both internal medicine and medical oncology. From 2004 to 2011, he was the director of medical affairs at the NSABP in Pittsburgh.
He has also worked on various hospital committees and held multiple senior positions at major cancer hospitals in Virginia and Texas.
Dr. Geyer has co-authored over 100 peer-reviewed publications and participated on steering committees for game-changing multinational phase 3 trials such as the KATHERINE and OlympiA trials.
The AstraZeneca and MSD Strategic Oncology Collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize Lynparza (selumetinib), the world’s first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor.
Olaparib approved in Japan (global clinical development), through the combined efforts, can be an effective and targeted treatment in patients with breast cancer, is statistically significant.
The businesses will collaborate to develop Lynparza and Koselugo as monotherapies and in conjunction with other potential new medications. Lynparza and Koselugo will be developed independently by the firms in conjunction with their respective PD-L1 and PD-1 medications, including Olaparib approved in Japan for global clinical development.
With olaparib approved in Japan for breast cancer, which is statistically significant in BRCA-mutated HER2-negative early high-risk early breast cancer.
Reference
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UMPC – Providers Page Charles E. Geyer. UPMC, 2022
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AstraZeneca – Lynparza approved in Japan as adjuvant treatment for patients with BRCA-mutated HER2-negative early high-risk early breast cancer. AstraZeneca Press Release, August 25, 2022