Case 4: OlympiAD Trial for BRCA+ Metastatic TNBC

Hope Rugo, MD, FASCO: I think testing is an interesting question but then, of course, the biggest issue is how we take the data we have from clinical trials and apply that to our patients. Adam, can you tell us a little bit about some of the studies?

Adam Brufsky, MD, PhD: The NCCN [National Comprehensive Cancer Network] guidelines generally recommend germline sequencing for any breast cancer subtype that is a potential family history or any breast cancer subject who has a BRCA1 or BRCA2 mutation. Although, there is some question about somatic sequencing. They recommend either olaparib or talazoparib.

Just to kind of refresh everybody’s memory, the idea is to inhibit DNA repair. That DNA could be damaged when there’s a legion, a methylation of one of the base pairs of DNAs. There’s basic excision repair, and what you’re trying to do is inhibit PARP [poly ADP ribose polymerase] so you don’t have that repair. When you don’t have that repair, you have a double-stranded DNA break that needs to be repaired by specific DNA repair complexes in the cell that involve BRCA1 and BRCA2 for homologous recombination. But if you lack 1 of those 2 genes, you can’t get the repair. Therefore, the DNA gets scrambled and the cell dies.

There are a lot of platinum trials in advanced triple-negative breast cancers, and all of them have varying response rates. The trial that a lot of us are interested in is the TNT trial of 29 metastatic triple-negative breast cancer patients who were treated with docetaxel versus carboplatin. The response rate in both arms was about 35%, but I thought the response was about 60% in the BRCA-positive, triple-negative population.

So at least in my mind, this is why I would use platinum. I think we’re going to talk about BROCADE 3 in a minute. The TNT trial was carboplatin versus docetaxel. Again, there was a prior subgroup analysis based on whether they were BRCA-positive or not. The primary endpoints are shown here. Overall, it was about a 30%, 35% response rate. But in the patient with the germline BRCA mutation, the response rate to carboplatin was about 68%.

Interestingly enough, there was a randomized phase 2 study that was supposed to be turned into a phase 3 trial, but for some reason they decided not to pursue it. But the bottom line here, interestingly enough, is that this is a trial of nab-paclitaxel and carboplatin and nab-paclitaxel and gemcitabine versus gemcitabine and carboplatin. The addition of paclitaxel plus carboplatin actually was the winner of this trial, believe it or not. And interestingly enough, there appeared to be a survival benefit, although it was not statistically significant in this phase 2 experience.

But on the other hand, if you’re thinking of using a combination regimen in this disease, it’s something to consider, even though these are phase 2 data.

Here are the PARP inhibitor trials. This is the OlympiAD study, which took women with less than 2 prior chemotherapies in the metastatic setting. You had to have progressed on at least 1 endocrine therapy if you had chemotherapy. These patients were given a physician’s choice of chemotherapies—the typical ones that would be used—versus olaparib. Fifty-seven percent of the patients had a BRCA1 mutation, half were hormone receptor–positive, and about a third had prior platinum therapy.

These are the results that I think we’re all very familiar with: Overall, olaparib was superior, with a 7-month PFS [progression-free survival] versus 4.2 months with a hazard ratio of 0.6. Just about every subgroup benefited. I think this is the one that we’re all excited about.

The patients who were triple-negative really seemed to have a better hazard ratio than the other patients. Again, within the realm of statistical error, I’m not sure that this is really different. But on the other hand, all the patients with triple-negative disease appeared to do better with a PARP inhibitor.

Again, in overall follow-up, the survival was 19.3 months versus 17 months, which is not statistically significant. However, for the women who had no prior chemotherapy—and I think this is really important—we have newer data that I’m not sure a lot of us are aware of. If you had not had prior chemotherapy and had a PARP first, versus the prior chemotherapy up front, you can see that the OS [overall survival] is better in the ones who received olaparib. I think this is really important data. If you’re thinking of chemotherapy versus a PARP up front, it may be not a bad idea to do the PARP first.

The major adverse effects are a bit different. Both regimens have nausea. The big one with PARP inhibitors is anemia. I had a patient come in as a consult who actually was getting transfused every 2 or 3 weeks by her oncologist. I recommended cutting the dose of the olaparib. That’s the big one. I think there was a little more neutropenia with the chemotherapy.

Transcript edited for clarity.