Novel Agents in the Adjuvant Setting: PARP Inhibitors

Dr. Charles Geyer: I would be happy to overview OlympiA real quick. Just a reminder, this is really a big, phase three, double blind, placebo-controlled trial that was designed to assess the benefits of a year adjuvant Olaparib following standard, multimodality therapy, both for patients with TNBC and for those with high-risk ER positive, HER2 negative when they have a pathogenic variant in BRCA1 or BRCA2. So, this was taking PARP inhibitors into early breast cancer. The study was originally designed, focused on triple negative, and it actually opened that way, so the eligibility criteria for triple negative breast cancer are straight forward, non-PCR or positive nodes, or if negative nodes, tumor greater than two centimeters. Very straight forward, easy to identify, triple negative patients of high risk meeting the criteria. As the study was being launched, though, there was the obvious concern that this was probably the only opportunity we would have to do a big, global study looking at PARP inhibitors for BCRA associated breast cancers and we know that particularly with BRCA2 cancers, a number of them are ER positive and so we were able to - after getting safety data on combining Olaparib with the endocrine therapies - we were able to add a cohort. But they had to be they - it was the regulators wanted us to be sure that their degree of risk in the short term matched our triple negative population. So, it's a very high-risk ER-positive group for more positive nodes or they had locally advanced disease that didn't really respond well to neoadjuvant chemotherapy. We used a CPS+EG score from MD Anderson to define that, but that's basically what it was. So, the majority of patients - 80% of the patients in the trial - had triple negative breast cancer, but we were very pleased we were able to include patients who are ER positive. When we looked at the interim analysis that was of course pre-specified with about two and a half years of median follow-up, we saw that three-year invasive disease-free survival, our primary endpoint was improved from 77 to 86%, hazard rate of 0.58, distant disease-free survival also improved to a similar degree 80% to 88% meeting the pre-specified boundary for efficacy. There was no difference across the stratification groups that we used in the study of neoadjuvant versus adjuvant chemo, prior platinum, yes no hormone receptor status, pathogenic variants. The toxicity was as expected from the metastatic studies. And the PROQOL studies really showed minimal differences between Olaparib and placebo while patients were on the treatment. At the initial analysis, we had 86 deaths reported on the placebo arm and 59 on the Olaparib arm. So there was a hazard of 0.68, similar to the other end points, but it didn't cross the pre-specified boundary because it was so early. The study plan for conducting a second interim analysis of overall survival when we reached the initial plan number for definitive events, this basically worked out to be an additional year of follow-up so with a median follow-up of 3.5 years versus 2.5 years. Andrew Tutt presented the survival data and an ESMO Virtual Plenary Program, which was a little unusual because we were wanting to get it out before the FDA basically reported the results in the label that we knew were coming. So that was reported in that format in March and we published it in Annals of Oncology this month. So it is available for review. Basically, with the additional year of follow-up, the number of deaths on the placebo arm increased to 109, that was Olaparib increased to 75, so the hazard ratio was maintained at 0.68 but because of the increased number of events the P value was.009 which crosses significance boundary. Our four-year assessment of IDFS and DDFS show the difference held up and very importantly our cases of AML, MDS remain low at 0.2% with Olaparib and 0.3% with placebo. So our view of it is, is that the efficacy data that supported now by the document improvement in overall survival with the safety of QL data certainly justifies Olaparib as adjuvant therapy in patients meeting the TNBC eligibility criteria.