Litton Talks Talazoparib in BRCA1/2+ Advanced Breast Cancer

Jennifer Litton, MD

Although talazoparib (Talzenna) did not lead to a statistically significant improvement in overall survival (OS) for patients with BRCA1/2-positive, HER2-negative, advanced breast cancer, it is clear that the agent shows a benefit in progression-free survival (PFS) and quality of life (QOL), according to Jennifer Litton, MD.

Results from the phase 3 EMBRACA trial failed to demonstrate a significant improvement in median OS with the PARP inhibitor versus physician’s choice of chemotherapy, at 19.3 months versus 19.5 months. At a median follow-up of 11.2 months, the median PFS was 8.6 months versus 5.6 months with talazoparib versus chemotherapy, respectively, and the benefit was observed across all predetermined patient subgroups. The agent was also found to significantly delay the time to clinically meaningful deterioration in QOL scores.

“The updated data confirm what we learned from the primary analysis: PARP inhibitors are here to stay for patients who have BRCA-mutant disease” said Litton. “[Talazoparib] improves PFS and quality of life. Overall, the oral option is very intriguing for many patients. PARP inhibitors tend to work just as quickly as chemotherapy and could prevent patients who have a large burden of disease from requiring 2 different forms of chemotherapy. We’re seeing dramatic responses with PARP inhibitors.”

In an interview with OncLive, Litton, a breast medical oncology professor at The University of Texas MD Anderson Cancer Center, discussed findings from the phase 3 EMBRACA trial on talazoparib in patients with advanced BRCA1/2-positive breast cancer.

OncLive: Could you provide some background on the EMBRACA study?

Litton: EMBRACA is the largest trial to date of a single-therapy PARP inhibitor [in this space]; in this case, it was talazoparib. [The agent] was given once daily versus several physician’s choice of chemotherapy. There was a 2 to 1 randomization and this was an international study. We reported and published the results [regarding the] the primary end point, which was PFS. Specifically, we saw an improvement in median PFS, which was a difference of 3 months. At that time, the overall survival (OS) data were immature. At the 2020 AACR Virtual Annual Meeting, we presented the final OS data from the trial.

Could you expand on some of the updated findings that were reported?

In the final results of the trial, we showed that there was no statistically significant difference in OS between talazoparib and physician’s choice of chemotherapy [in patients with BRCA1/2-mutated metastatic HER2-negative breast cancer]. We also provided an update on the toxicities reported [with the agent], and they continued to be what we expected. Cytopenias were the most common [event reported], as well as anemia; [these events] were managed with transfusion dose delay/dose reduction. One patient had a diagnosis of acute myeloid leukemia (AML), which was reported with the initial PFS data. It’s important to note that this patient was treated with capecitabine, not talazoparib. In a following update, we had an additional patient diagnosed with AML and this patent was randomized to the talazoparib. We also saw that patients who were randomized to talazoparib had an improvement in QOL and a decreased time to deterioration compared with physician’s choice of chemotherapy.

We also presented [data regarding] several other aspects of the trial; these were all exploratory, and we weren’t examining them when the trial first launched because we knew that as the trial went on, things would change. In fact, as the EMBRACA trial was being conducted, PARP inhibitors became commercially available. Approximately 40% to 50% of patients received a subsequent platinum therapy on one side of the trial and 30% to 40% [of those who didn’t receive talazoparib], received PARP inhibitors; that might have impacted what we were seeing.

As we see in most trials in metastatic breast cancer, the good news for our patients is that we have more options available and they are living longer; however, it is hard to tease out exactly which part of their therapy is adding to their OS. For metastatic cancer trials, it’s paramount that we continue to look at patient-reported outcomes in trials; this is especially important to have this information when we are counseling our patients [about the choices available].

Where are future research efforts focused?

Looking toward the future, we are examining a few combinations that will help us better understand these therapies and the duration of time patients can benefit from them. We are also looking into how patients beyond those harboring germline BRCA mutations can benefit [from this approach]. At this point in time, germline BRCA carriers are the patients most likely to benefit from PARP inhibitors.

Is there anything else that you would like to add?

I'm always intrigued by PARP inhibitors and immunotherapy. I'm often asked if we should use PARP inhibitors, chemotherapy, or immunotherapy first, and I don't believe there has to be a binary choice. In the PARP inhibitor trials, there’s an idea that the sooner you give it to the patient, the better. When analyzing PARP inhibitors, we are seeing an increase in some of the markers that need to be positive, such as PD-1 [expression], in response to PARP inhibitors. Many current and recent trials are showing that the sequences are equally important to the treatment combinations. In closing, I’m excited about the OlympiA trial, which is the adjuvant PARP inhibitor trial for patients with residual high-risk disease. I believe that these data, along with data in the pre-operative space, will bring PARP inhibitors to patients in earlier stages.

Reference

Litton JK, Hurvitz SA, Mina LA, et al. Talazoparib in germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from randomized phase 3 EMBRACA trial. Presented at: the 2020 AACR Virtual Annual Meeting; April 27-28, 2020. Abstract CT071.