Talazoparib Improves QOL, But Not OS in Advanced BRCA1/2+ Breast Cancer

Jennifer Litton, MD

Treatment with talazoparib (Talzenna) did not demonstrate a statistically significant overall survival (OS) benefit in patients with BRCA1/2-mutated metastatic HER2-negative breast cancer, according to updated findings from the phase 3 EMBRACA trial (NCT01945775).¹ However, lead author Jennifer Litton, MD, said that there is still reason to believe treatment with the PARP inhibitor can improve OS.

“In patients with germline BRCA1/2-mutated advanced breast cancer, talazoparib did not [show a] statistically significant improvement in OS compared with chemotherapy,” said Litton, professor of breast medical oncology at The University of Texas MD Anderson Cancer Center, who presented the results during the 2020 AACR Virtual Annual Meeting. “It is important to note that most patients in the study went on to receive subsequent therapies, which may have confounded the survival analysis.”

The FDA approved talazoparib in 2018 for adults with germline BRCA1/2-mutant, HER2-negative locally advanced or metastatic breast cancer based on previously published results from the EMBRACA trial, which showed that the drug was associated with a 3.0-month improvement in median progression-free survival (PFS).²

At a median follow-up of 11.2 months, the median PFS was 8.6 months with talazoparib versus 5.6 months (95% CI, 4.2-6.7) with chemotherapy (HR, 0.54; 95% CI, 0.41-0.71; P <.0001). The PFS benefit with talazoparib was seen across all predetermined patient subgroups.

In EMBRACA, patients were assigned to 1 mg daily of oral talazoparib (n = 287) or physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles (n = 144). Eligible patients had received no more than 3 previous cytotoxic regimens for advanced breast cancer, and they had received previous treatment with a taxane, an anthracycline, or both, unless this treatment was contraindicated.

Investigators observed no statistically significant difference in median OS between the talazoparib and chemotherapy arms (19.3 vs 19.5 months, respectively; HR, 0.848; 95% CI, 0.670-1.073; P = .17). The effect of talazoparib was similar regardless of BRCA status.

Investigators performed the final OS analysis using the intent-to-treat population after observing 324 deaths. After a median follow-up of 44.9 months for talazoparib and 36.8 months for chemotherapy, 216 patients in the talazoparib group and 108 patients in the chemotherapy group had died.

Overall, 48.4% of patients in the experimental arm and 59.7% of patients in the control arm went on to receive subsequent treatment with a PARP inhibitor or platinum-based chemotherapy. Of those who received subsequent treatment, 46.3% in the talazoparib group and 41.7% in the chemotherapy group received platinum therapy.

Litton said that adjusting for post-study treatment reduced the hazard ratio and lowered the upper bound of the confidence interval. However, the difference in median OS still did not reach statistical significance compared with chemotherapy in patients who received subsequent PARP inhibitor and/or platinum therapy (19.3 vs 17.4 months, respectively; HR, 0.756; 95% bootstrap CI, 0.503-1.029) or PARP inhibition alone (19.3 vs 19.1 months, respectively; HR, 0.820; 95% bootstrap CI, 0.617-1.047).

“The hazard ratio and 95% confidence intervals obtained for OS after dose adjustment for subsequent platinum and/or PARP inhibition suggest that the primary OS analysis underestimated the treatment benefit of talazoparib,” Litton said.

Talazoparib Improves QoL

Investigators observed a statistically significant improvement in the estimated change in baseline global health status/QoL in patients treated with talazoparib (2.1; 95% CI, 0.1-4.1) compared with chemotherapy (—5.7; 95% CI, –10.0 to –1.4).

“Compared with chemotherapy, treatment with talazoparib was associated with a significant delay in the time to definitive clinically meaningful deterioration in the quality of life scores,” Litton said.

Furthermore, talazoparib was well tolerated. Approximately 35% of patients in the experimental arm experienced serious adverse events (AEs) compared with 31.0% in the chemotherapy arm. Patients in the 2 arms experienced similar rates of serious and drug-related AEs and grade 3/4 serious AEs. Investigators found that those assigned to talazoparib were less likely to experience AEs resulting in permanent drug discontinuation versus those assigned to chemotherapy (7.7% vs 9.5%, respectively).

In the talazoparib arm, 56.3% of patients experienced grade 3/4 hematological AEs compared with 38.1% of patients assigned to chemotherapy. Most grade 3/4 hematological AEs reported in the talazoparib group were successfully managed with supportive care and dose modifications.

References

1. 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 of the American Association for Cancer Research; April 27-28, 2020. Abstract CT071.
2. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-763. doi:10.1056/NEJMoa1802905

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