On behalf of my co-authors we’d like to thank the programme committee for the opportunity to share the results of OlympiAD which is an international open label randomised phase III trial of the PARP inhibitor olaparib against standard chemotherapy in patients who have metastatic HER2 negative breast cancer and a germline BRCA mutation.
The poly-ADP ribose polymerase family of enzymes, a couple of the members, especially PARP1 and PARP2, are involved in the repair of a specific type of DNA damage, namely breaks to one of the two strands of the DNA. BRCA1 and BRCA2, on the other hand, are involved in repair of another kind of DNA damage, double strand breaks, through a process that’s called homologous recombination repair. It turns out that if you inhibit PARP1 and PARP2 you create damage that requires the homologous recombination pathway to fix it. So cells that are defective in homologous recombination, and those that have BRCA mutations are the best known example of that, are actually sensitive to drugs that inhibit PARP. Visually the way this works is that if you have single strand break damage normally in a cell that has both PARP activity and BRCA activity the PARP takes care of the single strand break. If you give a PARP inhibitor the enzyme gets stuck on the DNA and creates a lesion that has to be repaired by BRCA1 and BRCA2 but in a normal person, somebody who has BRCA1 and BRCA2 function, it gets fixed. The problem is in a cancer from a patient who has an inherited BRCA mutation that doesn’t have BRCA1 and BRCA2 when the PARP gets trapped that lesion can’t get resolved and the cancer cell dies through something that’s called synthetic lethality.
PARP inhibitors have already been improved for the treatment of ovarian cancer in patients with mutations in BRCA1 and BRCA2 and recently in other circumstances. There have been a couple of small studies that have suggested that breast cancer in BRCA mutation carriers could also be responsive to PARP inhibitors. So this was, as I said, a multicentre trial that was designed to specifically assess whether or not PARP inhibitors could improve progression free survival in this group of patients.
You all spend a lot of time looking at study schema and I don’t want to walk through this in detail except to point out that everybody had centrally confirmed deleterious mutations in BRCA1 or BRCA2, that they had received zero to two prior chemotherapy lines for metastatic disease but they all had received anthracycline and taxane therapy and if they were hormone receptor positive they had received at least one endocrine therapy and progressed. Prior platinum was allowed on the study but if they had received it as adjuvant or neoadjuvant it had to have been twelve months and if they had received it in the metastatic setting they could not have progressed.
Patients were randomised two-to-one to receive olaparib tablets at 300mg twice a day; this is different than the FDA approved capsule formulation which is 400mg twice a day. That is eight capsules twice a day and so the two tablet twice a day formulation was developed for patient convenience. The control arm was a pre-declared choice by the physicians of one of three regimens that are standard in this circumstance. Patients were treated until progression and monitored for PFS as the primary endpoint with a number of secondary endpoints as shown there.
This was a pre-planned statistical analysis to be done at 230 events. There were 205 patients in the olaparib arm and 97 patients in the chemotherapy arm. With that we had a 90% power to detect a significant difference and that would have corresponded to approximately a 37% improvement in progression free survival.
The patients were young because they had BRCA mutations. Interestingly and importantly about a third of the patients were non-white, mainly coming from Asia. Roughly split between BRCA1 and BRCA2 mutations and roughly evenly divided between hormone receptor positive and triple negative disease. Most of them had received prior chemotherapy for their metastases and a little bit more than a quarter had received prior platinum therapy.
This is the primary endpoint which was progression free survival by central radiologic review. The olaparib treatment was superior to chemotherapy with a hazard ratio of 0.58, so an approximately 42% improvement in progression free survival. The confidence interval you can see there, it was highly statistically significant.
Generally olaparib was pretty well tolerated. There were fewer grade 3 or greater side effects in the olaparib arm than in the chemotherapy arm. There were fewer treatment discontinuations due to toxicity and there was less neutropenia. The main side effects were nausea, which was usually mild and only about a quarter of the patients required anti-emetics; anaemia, which did result in transfusion in a proportion of patients, and then fatigue.
This is the first phase III study that has shown an advantage of a PARP inhibitor over standard of care chemotherapy in breast cancer patients with a BRCA mutation. It was generally well tolerated with less than 5% of patients discontinuing treatment for toxicity and a lower rate of grade 3 or greater side effects. We did measure global health related quality of life which we will present this afternoon. It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations and metastatic HER2 negative breast cancer, including importantly women with BRCA mutations in triple negative disease. Thank you very much.
