Treating Patients With Germline BRCA-Mutated, Her2-Negative Metastatic Breast Cancer
Jennifer K. Litton, MD
Hospital and Institutional Affiliations
The University of Texas MD Anderson Cancer Center
What are your thoughts about the use of poly([ADP]–ribose) polymerase (PARP) inhibitors in the adjuvant setting in BRCA-mutated, HER2-negative disease?
Right now, PARP inhibitors are not indicated in that setting. There is 1 trial looking at it called the OlympiA trial (ClinicalTrials.gov Identifier: NCT02032823). That trial has finished accrual but hasn’t yet reported. Once that very important trial reports we can assess the data at that time.
How do you think germline mutations in the homologous recombination pathway genes could contribute to PARP inhibitor sensitivity, if at all?
We do have some hint of that from our colleagues in ovarian cancer. Patients with ovarian cancer tend to have a higher rate of somatic mutations in DNA damage repair genes than patients with breast cancer. In fact, a little more than 50% of ovarian cancer patients tend to have mutations in either germline or somatic genes in this pathway. In this area, they have been able to move forward with giving PARP inhibitors as single agents to all-comers in several trials.
We are not seeing the same significant activity in breast cancer yet without a known germline BRCA mutation or mutation in another significant DNA damage repair gene. There have been several trials that if you do identify that there are germline or somatic mutations in specific members of the DNA damage repair pathway, there is activity of single-agent PARP inhibitors.
Recently at ASCO [American Society of Clinical Oncology] 2019, Dr Gruber reported [on] 1 of their cohorts of patients with germline or somatic mutations in those patients.1 The trial only had 20 patients, but what was really telling was that they had some responses in patients who also had germline PALB2 mutations. There are other emerging data suggesting that this group of patients might benefit from using PARP inhibitors.
Not all mutations in DNA damage repair pathways are the same. There are some mutations in other genes such as ATM that in early studies are not showing the same degree of response to PARP inhibitors. There are several ongoing trials looking at that that are accruing and will give more information on that.
The addition of veliparib to carboplatin/paclitaxel in BROCADE3 (ClinicalTrials.gov Identifier: NCT02163694) significantly improved progression-free survival (PFS), but not overall survival (OS). What do you make of these seemingly discordant survival findings?
In general, now that we have so many different therapies for metastatic breast cancer, it is not uncommon to see progression-free survival benefit without overall survival benefit.
The BROCADE3 trial is interesting because it is a bit different from other trials, comparing chemotherapy plus or minus a PARP inhibitor. This was a trial for patients with metastatic breast cancer with germline BRCA1/2 mutations who had less than 2 prior lines of cytotoxic therapy. Like the OlympiAD (olaparib; ClinicalTrials.gov Identifier: NCT02000622) and EMBRACA (talazoparib; ClinicalTrials.gov Identifier: NCT01945775) trials, patients could not have progressed on platinum. Patients were randomized 2:1 to veliparib plus carboplatin-paclitaxel vs placebo plus carboplatin-paclitaxel.
Of note, we have known for a long time that it is hard to give full-dose PARP inhibitors at the same time as chemotherapy — because they have overlapping toxicities of cytopenias, veliparib was given at a smaller dose than when it is given as a single agent. What was very intriguing about this trial is that, at the treating physician’s discretion, patients could stop the chemotherapy prior to progression, if it was due to toxicity. They could then go on to veliparib as a single agent or single-agent placebo only. In this situation, the veliparib dose was then increased when given as a single agent.
When we look at the progression-free survival curve, what is intriguing is that the objective response rate is not really different and the clinical benefit rate is not really different. However, 40% of the patients on the veliparib arm were getting monotherapy at some point and 34% of patients were getting placebo only. I think it is interesting that the curves don’t separate until about a year after the trial.
Although this has an impressive progression-free survival compared with the single-agent PARP trials, it does contend with the toxicity and the fact that they are really looking at, in my opinion, maintenance therapy after chemotherapy given that a third of patients were only on a placebo with metastatic cancer.
Extended follow-up for OlympiAD showed that OS did not differ significantly between the treatment arms studied, but that there was an OS benefit that was “suggested” by the data. What does this really mean for patients?
Again, as we interpret any trial with a therapy for metastatic breast cancer, it is challenging to find an overall survival benefit given the amount of therapies we now have available. With OlympiAD, when they extended follow-up in first line, they did show that those patients who received it in first line seemed to have some potential overall survival benefit. Again though, this is an exploratory analysis. It was not statistically set up to look at overall survival. But it was still intriguing.
What was really intriguing to me about the OlympiAD survival difference was that 8% to 9% of patients were on that single-agent pill for 3 years or longer. When we looking at the OlympiAD, as well as the EMBRACA trial, what really stands out to me as a clinician is that the oral option actually improved patient-reported outcomes and delayed time to deterioration. When we are talking about patients with metastatic cancer, quality of life and patient-reported outcomes are essential in these trials moving forward.
There was a recent warning from the US Food and Drug Administration that cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors could cause interstitial lung disease (ILD) and pneumonitis in select breast cancer patient groups. Would this warning influence your prescribing practices?
Not at this time, unless the patient had severe underlying pulmonary disease limiting their function. This is very rare. So far, in my practice, I have seen it once.
When we are looking at this class of drugs, what is very important to note is that we are having progression-free survival curves of over 2 years, which is something we don’t see in metastatic breast cancer.
It absolutely still remains a standard-of-care option. What it tells me is that new onset of cough or shortness of breath needs to be worked up, and maybe a higher level of suspicion is necessary, and to make sure that we are asking about those symptoms and informing our patients.
A recent study presentation2 found that the use of breast radiotherapy (as therapy and prevention) should be considered safe in the gBRCA population as it relates to secondary malignancies. What factors would likely influence the decision to administer radiotherapy?
I am not a breast radiation oncologist, so I would do this in collaboration with one of my breast radiation colleagues.
Certainly, I think it is important for patients to be fully worked up and staged appropriately before starting any systemic therapy. We would make recommendations on referral based on NCCN [National Comprehensive Cancer Network] or ASCO guidelines as far as who should and should not be considered for radiation therapy. A lot of our patients are now getting preoperative therapy as well, so both the clinical and postoperative stage is really important information to get to our radiation colleagues so they can make their best informed decision about whether the patient should get radiation or not and the extent of it as well.