Robson Highlights Olaparib Efficacy and Genetic Testing Updates in Breast Cancer

Mark Robson, MD

Mark Robson, MD

In results of an exploratory analysis from the phase III OlympiAD trial presented at the 2018 Miami Breast Cancer Conference, improvements in progression-free survival (PFS) with olaparib (Lynparza) over treatment of physician's choice (TPC) remained consistent regardless of baseline tumor burden for patients with HER2-negative breast cancer with a germline BRCA1/2 mutation (gBRCA1/2m).

These results suggest that treating patients with chemotherapy based on the extent of metastatic sites is not a logical strategy, according to Mark Robson, MD, who presented the results at the meeting.

Based on results of the OlympiAD trial, olaparib was approved in January for the treatment of patients with germline BRCA-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy. Resultsshowed olaparib reduced the risk of disease progression or death by 42% and improved PFS by 2.8 months versus standard chemotherapy in previously treated patients withBRCA-positive, HER2-negative breast cancer.

“The opportunity to have a highly effective oral agent with limited toxicity, even if for a relatively small subset of patients, is an important advance. The future is to extend that, both to extend its efficacy in the patients withBRCAmutations and also, of course, to see if we can find ways to make that same vulnerability manifest in other settings,” Robson says.

In an interview withTargeted Oncology, Robson discussed the current and future role of olaparib, as well as the role of genetic testing in the treatment of breast cancer.

TARGETED ONCOLOGY:Can you give an overview of the OlympiAD trial and the analysis you presented?

Robson:OlympiAD was a randomized phase III trial of olaparib compared to conventional chemotherapy in patients who had inherited mutations in BRCA1andBRCA2and had failed prior anthracycline and taxane therapy. All patients were HER2-negative, they could have been HR-positive or triple-negative. What that showed was that there was a statistically significant improvement in progression-free survival with no improvement in overall survival, as of yet, at least in the preliminary analysis with preservation of quality of life across the subsets.

One of the questions that came up is whether people will do better if they have more disease versus less disease. The analysis that we presented here looked at the benefit in patients who had 1 metastatic site versus more than 1 metastatic site. It appeared there were similar degrees of benefit in each. This is relevant because we think if I have somebody with a little bit of disease, I want to give them a PARP inhibitor, and if I have somebody with a lot of disease, I want to give them chemotherapy. This doesn’t suggest that this is a logical strategy. Even people who had significant disease burden benefitted from the PARP inhibitor.

TARGETED ONCOLOGY:What were the safety findings with olaparib in this study?

Robson:There was relatively little grade 3 toxicity — with one exception that I'll come back to – but there was a fair amount of nausea. A fair number had nausea while a few were vomiting, but most of it was low-grade. Much of it improved over the timeline treatment and was manageable with standard oral antiemetics, so it didn't lead to dose reduction or discontinuation very often. There were certainly some cytopenias , mild suppression, although no febrile neutropenia. The most significant toxicity was the rate of anemia, which was a 16% rate of grade 3 anemia and 18% of the patients ended up getting a transfusion. The transfusion rate may be a little overestimated, because people did have to have certain hemoglobin parameters in order to continue on trial without dose reduction. It may well be, this is speculative, that more people got transfused on trial than would get in the clinic. But nonetheless, it's very clearly a relevant toxicity.

TARGETED ONCOLOGY:What does this trial say about the role of olaparib and how do you see this changing?

Robson:It certainly tells us this is another option for people to receive as opposed to non-specific chemotherapy agents. Again, if you think about the setting in which these drugs have been used, which is people who have gotten prior anthracyclines and taxanes, especially with that triple-negative disease, the therapeutic options were limited in that setting. The opportunity to have a highly-effective oral agent with limited toxicity, even if for a relatively small subset of patients, is an important advance. The future is to extend that, both to extend its efficacy in the patients withBRCAmutations and also, of course, to see if we can find ways to make that same vulnerability manifest in other settings.

TARGETED ONCOLOGY:Can you speak to the NCCN guidelines updates?

Robson:The NCCN guidelines have been updated to allow metastatic breast cancer to be an indication for genetic testing. This is going to be a complicated and evolving area. I think whether or not the payers are caught up with that yet remains to be seen. How that is going to merge with the continued benefit from genetic counseling, particularly for family members, is going to be an interesting paradigm shift in the genetic counseling community as well.

TARGETED ONCOLOGY:Regarding genetic testing, do we know exactly who in practice is most responsible for making sure genetic testing is done?

Robson:I think it's a team effort. Everybody is responsible. The American Society for Breast Surgery just managed to get one of the major payers to agree that breast surgeons could do genetic testing, even though before they had been very resistant to allowing that. Certainly, many breast surgeons do genetic testing because of the implications for primary management. I think oncologists in the metastatic setting certainly need to be thinking about this, and it might make sense to be a little bit more aggressive about recognizing those who could be tested even before then so that you have that information in place.

I think we are moving towards a world where, for cancer patients in general, not just breast cancer, having a comprehensive assessment of the genome of both their tumor and their normal DNA is just going to be a part of the staging essentially. We're not there yet, it's going to be a while. But we will be there.

TARGETED ONCOLOGY:Can you discuss the importance of germline versus tumor results?

Robson:This is a place where there is still some separation between what's going on in breast and what's going on in ovary. In ovarian cancer, you don't have to have a germline mutation. Actually, in ovarian cancer, you don't have to have any kind of mutation, but it clearly does benefit people more if they have mutations in these pathway genes. Those indications from the very beginning were both germline and somatic. In breast cancer, the studies were only directed toward germline alterations. Somatic alterations are a little less common, but there is really very little reason to suspect that it wouldn't work in the appropriate background. We just don't have those studies yet.