My first talk relates to the treatment options for patients with germline BRCA mutations who receive neoadjuvant chemotherapy. As you know, the PARP inhibitor olaparib is now approved for the adjuvant therapy of high-risk hormone receptor positive or non-PCR in high-risk triple negative breast cancer patients. Obviously, because of the survival benefit it is now standard of care to use this agent after patients have completed their chemotherapies, if indicated, surgeries. Patients will receive this medication for one year.
However, there are also other agents out there that were not tested in the pure germline BRCA mutated patient population but have shown to be beneficial. For example, pembrolizumab, an immunotherapeutic agent, in the KEYNOTE-522 study, when given in addition to chemotherapy in the neoadjuvant setting and after surgery for six months did show a significant invasive disease-free survival benefit. The overall survival data is not mature yet but this poses the question whether a patient with a germline BRCA mutation after finishing neoadjuvant chemotherapy and surgery and if high risk should receive pembrolizumab for six more months or olaparib or the combination. Now, unfortunately, we do not have any data for this scenario so it really depends on our extrapolation of data. What I would do, and have discussed in my talk, is to continue post-surgery with six more months of pembrolizumab and then initiate one year of olaparib because olaparib, as mentioned, has shown improvement in overall survival in this patient population.
Another question is whether you should add capecitabine for high-risk triple negative breast cancer patients after neoadjuvant therapy. Again, the same argument is relevant to this discussion as well. None of the post-neoadjuvant capecitabine studies reported outcome based on germline BRCA status. Now it will be a third drug that we might have to add. In my personal professional view, I think adding capecitabine after olaparib and pembrolizumab would be too much and, again, there is no data.
The other scenario is for patients with hormonal receptor positive disease. As we all know, the monarchE trial showed an invasive disease-free survival benefit for patients with ER positive, ER and/or PR positive, disease when they received two years of the CDK4/6 inhibitor abemaciclib in addition to their endocrine therapy. As in the pembrolizumab trial, the analysis was not done by germline BRCA mutation status, so we really don’t have any data, but this raises the question again, if we have a germline BRCA positive patient post-neoadjuvant that has hormone receptor positive disease do we follow the OlympiA trial and give one year of olaparib or do we do two years of abemaciclib? Or do we do the combination? Here’s the caveat: some early studies have shown that there might be concerns about cytotoxicity when both agents are combined. I also want to point out that so far we don’t have any survival benefit for abemaciclib but we have survival benefit for olaparib for germline BRCA positive patients. Therefore, my professional opinion would be in those patients to use one year of olaparib in addition to endocrine therapy and maybe consider adding abemaciclib sequentially for two years but, again, this is in the complete absence of any data.