We’ve conducted an adjuvant therapy study in BRCA1 and BRCA2 germline mutation carriers who have HER2 negative breast cancer and have some high risk features. They have had adjuvant or neoadjuvant chemotherapy and all the usual breast cancer treatments for those higher risk forms of breast cancer before entering this randomised placebo controlled study.
The background to this study is that germline BRCA1 and BRCA2 mutation carriers develop breast cancer and they often develop breast cancer that needs intensive treatment including adjuvant systemic therapy with chemotherapy. What our study has asked is whether adding to that standard of care treatments of surgery, radiotherapy if needed and at least six cycles of adjuvant or neoadjuvant chemotherapy, if we were to add a year of the targeted therapy, the PARP inhibitor olaparib, and compared that with placebo would we improve the primary endpoint of invasive disease free survival at an estimated three year time point? So this was a double-blind, placebo controlled adjuvant therapy context study of the PARP inhibitor olaparib in patients with germline mutations in BRCA1 and BRCA2.
This was an adjuvant therapy trial randomised with double-blind placebo control. It was targeting a hazard ratio for the primary endpoint of invasive disease free survival of 0.7 and had a planned interim analysis to be conducted when 165 events had taken place in the mature cohort of patients, the first 900 patients recruited to the study. The study recruited 1,800 patients in total and that interim analysis was set to have very stringent criteria for calling superiority, a superiority boundary, at that hazard ratio of 0.7 but with a required statistical significance with a p-value of less than 0.005 to call the study and for that level of effect on the hazard ratio to be seen in a mature population within the study, the first half, the first 900 patients recruited. So that superiority boundary was crossed and the IDMC recommended the full primary analysis which we have then gone on and conducted and report in our plenary presentation and the associated paper in The New England Journal.
The key findings of OlympiA are that the primary endpoint was met. So the effect of one year of olaparib on invasive disease free survival showed a hazard ratio of 0.58. There was a difference in the rate of IDFS events at three years of 8.8% and this was very highly statistically significant with a p-value of less than 0.001. The secondary endpoints of distant disease free survival were also improved by olaparib for one year with a hazard ratio of 0.57 and an absolute difference in the three year rate of distant disease free survival of 7.1% and that, again, was very highly statistically significant at less than 0.001.
So those are the main findings. The overall survival analysis shows that there are fewer deaths in the olaparib arm than in the placebo arm but that very stringent criteria at interim analysis and the multiple testing procedure and conservation of alpha for future longer term analyses are required. To call significance the p-value would need to be less than 0.001 for overall survival and a hazard ratio of 0.68 actually had a p-value of 0.02 and therefore this is not a statistically significant result at this time but alpha is conserved for a more appropriate longer term follow-up of overall survival as, at present, the median follow-up in the study for the ITT population is only 2.5 years. So we’re reporting early as the result of a significant effect stimulated by an interim; we need the longer follow-up for overall survival and alpha is conserved to enable that future analysis.
So we’re very encouraged by this result and the fact the study met its primary endpoint. We’re also very encouraged that the safety and tolerability profile of olaparib in this new adjuvant therapy setting indicates that the treatment has limited and manageable toxicities and we did not find that there were significant problems with the global assessment of quality of life. A deeper analysis of individual quality of life domains is ongoing and will be reported subsequently. But our interpretation would be that olaparib for a year has met the criteria to be considered by the regulatory agencies as a potential new therapy strategy in germline mutation carriers with BRCA1 and BRCA2 HER2 negative breast cancer and with high risk features which lead them to normally be treated with adjuvant or neoadjuvant chemotherapy. This would be a follow-on treatment from those standards of care. We believe it’s appropriate for this to be assessed in that regard by regulators.
Another important finding from OlympiA is the importance of testing for germline mutations in these genes, BRCA1 and BRCA2 beyond informing women of their risk of developing a breast cancer and the risks to others in their family of developing hereditary cancers. Here, now, as a biomarker that can help define what a treatment plan for their cancer might be. So we believe this result stimulates the need to consider broader testing in the blood, germline, for BRCA1 and BRCA2 mutations in women with breast cancer. Perhaps not all women with breast cancer, perhaps some women at greater age and with absolutely no family history and with certain histological types don’t need to consider it but we probably need to consider testing many women, most women, with breast cancer who might have met the eligibility for OlympiA for these mutations as a way of determining what their adjuvant therapy should be.