Neoadjuvant Talazoparib Shows Activity in BRCA1/2+ Early HER2-Negative Breast Cancer

Talazoparib (Talzenna) monotherapy elicited pathologic complete response (pCR) rates that were comparable to those observed with combination anthracycline and taxane-based chemotherapy regimens when used in the neoadjuvant treatment of patients with BRCA1/2-positive, early HER2-negative breast cancer, according to Jennifer K. Litton, MD.

Results from the open-label, multicenter, single-arm, phase 2 NEOTALA trial (NCT03499353) demonstrated that single-agent talazoparib elicited a pCR rate of 45.8% (80% CI, 36.42%-55.22%) by independent central review (ICR) in the evaluable population (n = 48), and a rate of 49.2% (80% CI, 40.97%-57.39%) in the intent-to-treat (ITT) analysis population (n = 61).¹

“Talazoparib monotherapy in patients with a germline BRCA [mutation] does have efficacy. In clinic, we see patients with a recurrence, or they have a BRCA mutation, and they already received an anthracycline and taxane 10 years ago, and now they have a second episode of breast cancer,” Litton said. “For these patients, we need to come up with options beyond anthracyclines and taxanes [so that we can] avoid some of the cardiotoxicity [that we see with those agents]. Talazoparib might be [an option for these patients who experience recurrence], one that can be further studied in the future.”

In an interview with OncLive®, Litton, faculty at The University of Texas Graduate School of Biomedical Sciences and vice president of Clinical Research in the Department of Chief Scientific Office at The University of Texas MD Anderson Cancer Center, discusses the rationale for examining neoadjuvant talazoparib in patients with BRCA1/2-positive, early HER2-negative breast cancer, safety and efficacy results from NEOTALA, and next steps for research.

OncLive^®: What was the rationale for examining the use of neoadjuvant talazoparib in patients with germline BRCA1/2-mutant, early HER2-negative breast cancer?

Litton: We've known for some time now that PARP inhibitors, such as talazoparib, are especially efficacious in patients with a germline BRCA1 or BRCA2 mutation. In the metastatic setting, we have 2 trials that have led to the FDA approval of PARP inhibitors for patients with HER2-negative metastatic breast cancer.

[Those trials are] the phase 3 OlympiAD [NCT02000622] and EMBRACA [NCT01945775] trials. Both [efforts] compared a PARP inhibitor vs standard-of-care chemotherapy, and both showed an improvement in progression free survival [PFS] with the [PARP inhibitor]. Neither [of the trials] went on to show [an] overall survival [OS] benefit [with the PARP inhibitor]. It’s important to [note] that OlympiAD wasn't big enough to look at [OS], but EMBRACA was, and it didn't show [an improvement].

We know that [PARP inhibitors are] efficacious in metastatic cancer, but what was really important about those 2 trials was that [they showed] a significant improvement in quality of life [QoL] with these agents compared with chemotherapy. We also know that we have a target that is identifiable on germline genetic testing.

First, we did a smaller pilot study that looked at [giving] just a 2-month window of talazoparib in patients who had a germline BRCA [mutation]; they could have estrogen receptor–positive or hormone receptor–negative [disease], but all [were] HER2 negative. Prior data demonstrated that a 2-month delay in the initiation of systemic therapy did not [result in] a significant difference in outcome, even in [those with] triple-negative breast cancer [TNBC]. In the window study, biopsies were done before and after [therapy]. Eighty-eight percent of the patients experienced significant [tumor] shrinkage after 2 months. I had several patients who were taking a pill once a day instead of chemotherapy [who told me that they] did not want to come off [of talazoparib; they] did not want to [switch] to chemotherapy.

That really led to us changing [the study design]. We accrued 20 patients at MD Anderson and put them on 6 months of single-agent talazoparib; [they then] went to surgery and could receive chemotherapy afterward. Only 1 patient went on to receive chemotherapy before surgery. As such, out of 19 patients, 10 had a pCR; this included those with TNBC. This is [similar to] what we see with a third-generation chemotherapy.

It was the first time that patients with TNBC, to my knowledge, experienced a pCR from a single targeted agent without chemotherapy. Given the excitement about this, [the agent] then moved into [testing in] a multicenter trial, the results of which were presented during the 2021 ASCO Annual Meeting.

What was the design of the phase 2 NEOTALA trial presented during the meeting?

This study was very similar to the one we did at MD Anderson. [We] still [examined] single-agent talazoparib for 6 months followed by surgery and then physician’s choice [of anticancer therapy]. The sponsor determined they wanted to just accrue patients with TNBC and a non-germline BRCA mutation. Patients also had to be suitable for neoadjuvant therapy and have HER2-negative tumors that were [larger than] 1.5 centimeters. Patients were followed very closely [while receiving talazoparib] with an ultrasound [done at week 12], and then they went to surgery.

The primary end point [of the trial] was pCR. Initially, [the trial] planned to [enroll] about 120 patients; however, due to a decision made by the sponsor [that was] not related to either efficacy or toxicity, they stopped the study early at 60 patients.

What were some of the key findings from this research?

[We asked ourselves whether] this multicenter trial would show what we saw in the 20-patient pilot study [that had been done] at MD Anderson. We [found that] it did. By ICR, we saw a 45.8% pCR in the evaluable population and 49.2% in the ITT population. By investigator assessment, [we saw pCR rates of] 45.8% and 47.5% [in these 2 populations, respectively]. As such, we do [see a] pCR [rate that falls] between 45% and 50% [in patients with] TNBC following [treatment with] a single agent.

The toxicities were [comparable to] what we saw [with the agent’s use] in the metastatic setting, with a slightly higher rate of alopecia [reported in this trial vs] what we saw in the EMBRACA trial. [The alopecia] was mostly grade 1, with very few [cases of] grade 2.

Are any ongoing research efforts generating excitement?

A lot of the research is [being done with] PARP inhibitors—not only in the metastatic setting, but also in the preoperative setting. Multiple ongoing trials that are being done across the country are looking at PARP combinations and novel agents that [are very intriguing].

Reference

1. Litton JK, Beck JT, Jones JM, et al. Neoadjuvant talazoparib in patients with germline BRCA1/2 mutation-positive, early HER2-negative breast cancer (BC): results of a phase 2 study. J Clin Oncol. 2021;39(suppl 15):505. doi:10.1200/JCO.2021.39.15suppl.505